Objective: The report herein presents a case of a 49-year-old woman with left breast cancer who presented seeking immediate autologous reconstruction. Surgical history included an abdominal hysterectomy and an abdominal contouring procedure. This is a first description of a deep inferior epigastric perforator flap after abdominal wall manipulation of this magnitude. Methods: Computed tomographic angiography identified patent medial row perforators. Doppler confirmed the location of the perforators. The flap was designed with the inferior incision at the previous lower abdominal scar. Laser-assisted indocyanine green imaging confirmed adequate flap perfusion on the basis of a single left deep inferior epigastric perforator. Results: The flap was harvested on one perforator and anastomosed to the internal mammary system. The postoperative course was complicated by venous anastomosis kinking, requiring revision, but otherwise unremarkable. Conclusion: Computed tomographic angiography confirmed presence of perforators, communication with the deep inferior epigastric system, and location acceptable for flap design. Laser-assisted indocyanine green angiography facilitated perforator selection and provided intraoperative assessment of flap perfusion. Utilization of these modalities allowed safe completion of an operation considered contraindicated by conventional algorithms and highlights their role in complex perforator flap reconstruction. Deep inferior epigastric perforator (DIEP) flaps have been reported in patients with vertical and short transverse abdominal scars after intra-abdominal surgery.3Clearly, as the body of experience grows, microsurgeons are becoming more aggressive in their surgical efforts. We seek to do so while maintaining patient safety and increasing procedural reliability. The objective of this report was to propose that advanced imaging modalities might permit perforator-based reconstruction in patients previously thought to be ineligible because of prior surgery.A 49-year-old woman with left breast cancer  was seen in consultation seeking immediate autologous breast reconstruction. Review of her surgical history revealed an abdominal contouring procedure performed by another surgeon approximately 6 years prior to presentation. This surgery included resection of skin and fat of the lower abdomen and elevation of an adipocutaneous flap above level of umbilicus. A hysterectomy was performed at the time by a vertical fascial incision. The umbilicus was translocated. Of note, the rectus fascia was not plicated.Physical examination revealed moderate sized breasts with grade 2 ptosis. Abdominal scars included a low transverse incision from hip to hip and a periumbilical scar. Adequate abdominal soft tissue for bilateral reconstruction was present, whereas medial thigh and gluteal donor sites were deemed insufficient .Preoperative evaluation included a computed tomographic angiography. Bilateral deep inferior epigastric artery perforators were identified. These perforators were located approximately 4 cm caudal and lateral to the umbilicus on either side. The right-sided perforator measured 1 mm in diameter, and the left-sided perforator measured 2 mm. Both perforators were traceable to their origin from the deep inferior epigastric artery .The mastectomy specimen weighed 942 g. The flap was centered on the radiographically identified perforators. The lower portion of the abdominal incision incorporated the previous transverse scar, and the flap dissection proceeded cephalad, allowing identification of the perforators on each side. At this point, given the prior surgery and stretching of the upper abdominal wall soft tissue, in addition to standard clinical signs, laser-assisted indocyanine green (ICG) fluorescence imaging was used to assess flap perfusion. The right-sided perforators were temporarily clamped, ICG was injected, and the SPY Elite system  was used to obtain the images.The abdominal flap demonstrated perfusion in zones 1, 2, and 3, based on the single left-sided medial row deep inferior epigastric artery perforator . The flaThe early postoperative course was complicated by venous congestion 2 hours after surgery. Exploration revealed a kink at the coupled venous anastomosis. The venous anastomosis was revised, and the remainder of the patient's course was unremarkable  and 6.,1Cases of DIEP flaps in patients with vertical abdominal scars have been reported in the literature.4In 2010, Jandali et alIn April 2012, Mahajan et alThe use of computed tomographic angiography to guide surgical planning for perforator-based reconstructing has been well described.The introduction of laser-assisted ICG angiographyConventional “abdominoplasty” may have different interpretations and executions by different surgeons, with varying degrees of cephalad undermining and perforator preservation. This variability and resultant perceived flap unreliability has rendered perforator-based reconstructions after extensive abdominal wall procedures “contraindicated.” However, as perforator-sparing techniques are progressively used and engrained across various disciplines of plastic surgery, specifically in abdominal wall procedures, should the need arise, the opportunity to use these perforators in free tissue reconstruction need not be discounted. We suspect that, in this case, the perforators superior to the umbilicus were not injured during the patient's initial procedure despite noted dissection above this level. The case presented illustrates the utility of advanced imaging modalities in delineating surgically altered vascular anatomy and physiology.The combination of preoperative computed tomographic angiography for anatomic assessment and intraoperative laser-assisted ICG angiography for perfusion assessment may allow extension of perforator-based reconstruction in scenarios previously considered contraindicated.


Fragment-based methods are quite popular in 2D QSAR/QSPR studies. In the advanced versions of these approaches for developing highly predictive models, one have to generate a huge set of descriptors that in turn requires well-designed algorithms and high-quality parallelism. To overcome these problems we developed the software for tagged generation of fragmental descriptors.One of the most perspective programming paradigms is functional programming. Programs in pure functional languages are easy to parallelize, tend to be faultless, more clear, easy extensible . DespiteUsing this software we processed several structure-activity/property databases containing hundreds of compounds and generated the sets of more than 500 000 fragmental descriptors in each case. Then for each database 100 most correlated with activity/property descriptors were selected using stagewise MLR. Based on selected descriptors the predictive models were developed using artificial neural networks (ANN) and Random Forest algorithms. Comparison with other fragmental descriptors generation software showed better predictive ability of our models.


Neural stem cells (NSCs) possess the ability to self-renew and to differentiate into the three major cell types found in the central nervous system (CNS). Recent studies have shown that epigenetic gene regulation events such as DNA methylation and histone modification play important roles in regulating NSC fate specification. In this context, we have previously shown that the histone deacetylase inhibitor valproic acid (VPA) enhances neuronal differentiation of NSCs. Perhaps because these patterns of NSC differentiation are exquisitely controlled during normal embryonic development, restoration of damaged neural networks in the injured adult CNS is severely limited. Here, using a mouse model of spinal cord injury(SCI), we examined the effectiveness of NSC transplantation and differentiation control by VPA administration.NSCs were transplanted into the SCI epicenter 7 days after injury. Non-transplanted control and transplanted mice were then intraperitoneally administered VPA or saline daily, for 7 days, whereafter we monitored their hindlimb motor function using the open field locomotor scale for 6 weeks. We next analyzed the migration, morphology, neuronal marker expression and viability of these cells after co-administration with VPA. We examined extensively the roles of the neurons responsible for reconstruction of broken neuronal networks using two neuronal tracers, immunoelectron microscopy, and two cell-ablation methods.We show that transplanting NSCs and administering VPA enhances the functional recovery of their hindlimbs. Neuronal differentiation of transplanted NSCs was promoted in VPA-treated mice. Anterograde corticospinal tract tracing revealed that transplant-derived neurons partially reconstructed the broken neuronal circuits, most likely in a 'relay' manner. Ablation of the transplanted cells abolished the recovery of hindlimb motor function, indicating that transplanted cells contributed directly to the improvement of motor function.These data raise the possibility that epigenetic regulation in transplanted neural stem cells can be exploited to provide treatment for SCI.


The authors discuss this unexpected finding with regard to increased cellular NO utilisation and distal airway mucous barriers to NO diffusion.The well-executed study by Sisson et al.  demonstrOx in CF , 3. ContAn alternative explanation involves NO synthetase (NOS) and arginase activity in airway epithelial cells. Both enzymes compete for L-arginine as substrate and imbalances in activity levels are believed to be important in the pathogenesis of airway inflammation and hyperreactivity . Arginasx after VCPT may be an increase in arginase activity through oscillatory mechanical stimulation of lung epithelial cells. Several studies in animal and cell models have demonstrated that specific patterns of mechanical stimulation can induce vascular endothelial arginase expression and activity. For instance, oscillatory shear stress induced stronger arginase activation than application of unidirectional shear force in porcine [ in vitro study showed that cyclic stretching of vascular smooth muscle cells upregulated arginase mRNA expression and enzyme activity whilst inhibiting NOS [A possible mechanism to explain Sisson et al.'s  surprisi porcine  and ApoE porcine . An in vting NOS . The VCPting NOS  study pr


Peritubular contractile cells within the testis and epididymis surround seminiferous tubules and the epididymal duct. These cells are crucial for the transport of sperm which only acquire motility and fertilizing capacity during transit from the testis to the distal epididymal duct. cGMP contributes to regulate smooth muscle cell function ,2. The rIsolated epididymal duct segments and seminiferous tubules were studied by organ bath and time-lapse video microscopy to assess sperm transport and contractile activity. In all parts of the epididymis, regular contractions which elicited transport of sperm could be observed. Contraction frequency was reduced after the addition of cGMP-elevating agents sildenafil, nitric oxide (NO) or atrial natriuretic peptide (ANP) . In semiWestern blotting, immunohistochemistry and RT-PCR using laser-dissected contractile cells confirmed expression of the corresponding cGMP pathway components. PDE5 activity was assessed using a cGMP-ELISA and sildenafil dose-dependently increased cGMP.In a rat model of chronic sildenafil treatment, PDE5 expression, contractility and sperm transport remained unaltered.Video microscopy allows to visualize contractile activity and sperm transport in seminiferous tubules and the epididymal duct. Distinct patterns of spontaneous contractile activity are observed in both organs. In the epididymis, regular spontaneous and peristaltic contractions elicit movement of sperm and contractile frequency is reduced by increasing cGMP. In contrast, seminiferous tubules, show an irregular contractile activity of smaller amplitude without clear peristalsis. Our results suggest that this irregular activity can be characterized by a spectrum of frequencies generated by Fourier analysis and that increasing cGMP slows down spontaneous contractile activity as indicated by a shift towards lower frequencies.


Fulminant myocarditis (FM) represents a crucial cardiac pathology with extensive hemodynamic compromise occurring in a previously healthy patient. Early death occurs because of acute cardiac decompensation from inflammation, necrosis, and myocytolysis. Nevertheless, in this situation implantation of an extracorporeal circulatory support system may ensure cardiac recovery. We herein report our experience using a biventricular Levitronix CentriMag system for bridge to recovery. Fulminant myocarditis (FM) represents a crucial cardiac pathology characterized by rapid and extensive hemodynamic compromise occurring in a previously healthy patient . In caseA 49-year-old previously healthy woman presented to a local emergency department because of recurrent fatigue, dyspnoea, and chest pain within the last three weeks. She described a “flu-like” upper respiratory infection for the past month that progressively worsened to these specific symptoms. The echocardiographic evaluation showed ejection fraction (EF) about 10% with biventricular failure. Despite pathologic ECG and highly elevated cardiac troponin, urgent cardiac catheterization detected only mild coronary sclerosis. During this procedure she progressed to circulatory collapse with the need for highly inotropic support and mechanical ventilation. For higher level of care the lady was transferred to our institution. Due to rapid aggravation of her condition while admission at our ICU, we initiated intraaortic balloon pump (IABP) implantation via the right femoral artery and venoarterial Extracorporeal Membrane Oxygenation (ECMO) implantation through the right femoral vein and right axillary artery. Despite maximum hemodynamic support, the heart showed no evidence of recovery. Furthermore the lady progressed to multiple organ failure including highly elevated lactate level, acute renal failure, and hepatic insufficiency. Our Heart Team decided on urgent biventricular CentriMag  implantation to decompress and support both ventricles. Through a median sternotomy the right atrium and aorta were cannulated and the patient was transferred from ECMO to cardiopulmonary bypass (CPB). A left ventricular 23 F cannula and a 22 F right atrial p-VAD cannula were placed for biventricular outflow into the CentriMag pumps. The left apex cannulation was chosen for maximum flow and complete left ventricular decompression. For return flow to pulmonary and systemic circulation the pulmonary artery and the ascending aorta were anastomosed with two 18 F sealed inflow cannulas. The patient was then weaned from CPB to BVAD support. The ECMO cannulas were removed and the femoral vessels repaired. With moderate inotropic support the patient was administrated to our ICU . IntraveThe postinterventional course was complicated by renal failure and neurologic morbidity necessitating continuous dialysis and tracheotomy. Left and right ventricular functions were daily assessed by transesophageal echocardiogram (TEE), while contractility and aortic valve opening were studied. Recovery of left ventricular contractility began on postimplantation day seven. We considered BVAD explantation when full recovery of biventricular contractility and aortic valve opening were observed. Weaning started on hospital on day 21, with the patient's condition and cardiac function improving to an ejection fraction (EF) of 50% in sinus rhythm. The CentriMag BVAD was removed nine days later without the need for additional CPB. Transesophageal control echocardiogram showed an EF >60% and sufficient right ventricular function. Ten days later she was discharged to rehabilitation in a stable condition.The patient had signs of FM on histological findings with foci myocyte necrosis and lymphocytic infiltration with interstitial oedema. In spite of serologic studies and viral genome research on myocardial biopsies, including in situ hybridization and polymerase chain reaction, pathogenic agents were not identified.FM is clinically characterized by distinct onset of cardiac symptoms in otherwise healthy patients after nonspecific flu-like symptoms rapidly resulting in severe ventricular dysfunction and cardiogenic shock. Most of these patients with acute fulminant myocarditis are stabilized with heart failure management  and recover within a few weeks . HoweverFor our case percutaneous cannulation and emergency implementation of ECMO was initially the therapy of choice due to her life-threatening condition, maybe as a bridge to decision. With cardiac nonrecovery evident and progressive endorgan dysfunction, support was escalated to biventricular nonpulsatile CentriMag assist device implantation. Arguments in favour of BVAD shortterm support are better unloading of both ventricles, a primary condition for recovery from fulminant myocarditis, and avoidance of significant morbidities associated with prolonged ECMO support . Successful treatment of fulminant myocarditis with severe hemodynamic compromise and end organ failure is possible with early CentriMag biventricular assist device implantation. In most cases it facilitates completely cardiac recovery.


Hundreds of diverse genetic loci have been linked to autism spectrum disorders (ASDs), making large-scale analysis essential for understanding the molecular events underlying the pathogenesis of these disorders. Our laboratory first released the autism database AutDB in 2007 as a bioinformatics tool for systematic curation of all known ASD candidate genes -3. AutDBTo curate the PIN module, our researchers utilize a multi-level annotation model to systematically search, collect and extract information entirely from published, peer-reviewed scientific literature. Although we initially consult public molecular interaction databases (HPRD and BioGRID) and commercial molecular interaction software , every interaction is manually extracted and verified by evaluating the primary reference articles from PubMed. Our manual curation has proved critical for accurate annotation, because these references were the second largest source of references for the initial PIN dataset, providing more interactions than both HPRD and Pathway Studio. Each ASD gene entry within the PIN module is presented as a multi-level display, with interactive graphical and tabular views of its corresponding interactome.The initial PIN dataset includes interactomes for 86 ASD candidate genes, with a total of 1,311 direct protein interactions garnered from 533 unique primary references. These interactomes are composed of 6 interaction types and 13 species, documented by 402 distinct pieces of evidence. Our researchers will expand and maintain the data content of the PIN module with systematic updates.We have created an integrated bioinformatics tool that can be used for the large-scale analysis of the biological relationships among ASD candidate genes. Such network analysis is envisioned to provide a framework for identifying the key molecular pathways underlying ASD pathogenesis, potentially leading to the development of novel drug therapies.


We investigated the occurrence of goal-directed motivational change in the form of apathy in patients with frontotemporal dementia (FTD), particularly those with behavioral variant social and executive deficits (bvFTD). Standardized behavioral inventory was employed to survey and compare apathy ratings from patients and caregivers. In cases of bvFTD, apathy ratings were further related to measures of social cognition, executive function, and atrophy on brain MRI. Results indicated that caregivers rated bvFTD patients as having significantly elevated apathy scores though patient self-ratings were normal. Caregiver and self-ratings of FTD samples with progressive nonfluent aphasia and semantic dementia did not differ from healthy controls and their informants. In the bvFTD sample, caregiver apathy scores were not correlated with general cognitive screening or depression scores, but were significantly correlated with social cognition and executive function measures. Voxel-based morphometry revealed that apathy ratings in bvFTD were related to prominent atrophy in the right caudate , the right temporo-parietal junction, right posterior inferior and middle temporal gyri, and left frontal operculum- anterior insula region. Findings suggest that bvFTD is associated with a significant breakdown in goal-directed motivated behavior involving disruption of cortical-basal ganglia circuits that is also related to social and executive function deficits.


Lesion-symptom mapping studies are based upon the assumption that behavioral impairments are directly related to structural brain damage. Given what is known about the relationship between perfusion deficits and impairment in acute stroke, attributing specific behavioral impairments to localized brain damage leaves much room for speculation, as impairments could also reflect abnormal neurovascular function in brain regions that appear structurally intact on traditional CT and MRI scans. Compared to acute stroke, the understanding of cerebral perfusion in chronic stroke is far less clear. Utilizing arterial spin labeling (ASL) MRI, we examined perfusion in 17 patients with chronic left hemisphere stroke. The results revealed a decrease in left hemisphere perfusion, primarily in peri-infarct tissue. There was also a strong relationship between increased infarct size and decreased perfusion. These findings have implications for lesion-symptom mapping studies as well as research that relies on functional MRI to study chronic stroke.


Chimera states are spatio-temporal patterns of synchrony and disorder observed in homogeneous oscillatory media with nonlocal coupling. They are characterized by coexistence of distinct spatial regions with regular synchronized and irregular incoherent motion. Initially discovered for phase oscillators, chimera states have been also found in systems of nonlocally coupled discrete maps , time-coWe demonstrate the existence of chimera states for neural oscillators . In detaSurprisingly, we find that for increasing coupling strength classical chimera states undergo transitions from one to multiple domains of incoherence. Then patches of synchronized dynamics appear within the incoherent domain giving rise to a multi-chimera state. We find that, depending on the coupling strength and range, different multi-chimeras arise in a transition from classical chimera states. The additional spatial modulation is due to strong coupling interaction and thus cannot be observed in simple phase-oscillator models.


Even if better clinical outcomes have been achieved with the implantation of newer generation continuous-flow left ventricular assist devices (LVADs), infection complications are still a major risk for these patients in long-term follow-up.We present a case of a 56-year-old male with dilated cardiomyopathy who was urgently implanted with left ventricular assist device HeartMate II. During the entire postoperative period, we observed repeated life-threatening septic complications. Clinical signs of infection disappeared after prolonged treatment with broad-spectrum antibiotics and patient was discharged to outpatient monitoring. During the entire duration of circulatory support, no LVAD suction events were detected, pump power consumption remained in the normal range and the patient was listed for heart transplantation. Patient was two month rehospitalized due to worsening of his status. Hemoglobinuria, an increase of inflammatory markers, and alteration in hepatic and renal function were detected. TEE imaging showed no obstructive formation in inflow or outflow cannulas; only velocities were decreased. The LV was severely dilated and the aortic valve was opening at each contraction. Patient was initially considered for systemic thrombolysis, but this urgent status was finally solved with explantation of the LVAD and subsequent heart transplantation. Massive obstruction with thrombus-like formation was found in the outflow cannula. Histopathologic examination and microbiologic culturing of the mass showed extensive fungal growth (Aspergillus species). During the postoperative period, patient was aggressively treated with antifungal therapy. He was discharged 8 weeks after the transplantation.We believe that clinical decision-making in patients with signs of ongoing sepsis and end-organ dysfunction together with any signs of LVAD malfunction should be very straightforward in terms of device exchange or explantation.


Congenital muscular torticollis (CMT), also known as fibromatosis colli, is recognized as unilateral contracture and shortening of the sternocleidomastoid (SCM) muscle due to muscle atrophy and interstitial fibrosis, causing ipsilateral head tilt and turn Do, . Its freThis 31-year-old woman exhibited a fixed left head tilt and turn with minor limitation of cervical range of motion since childhood. Her forceps-assisted birth by vaginal delivery was not associated with perinatal injuries. During childhood, she reported persistent head tilt to the left. She had headaches and back pain presumably from compensatory efforts at straightening her neck posture. There was no sensory trick or abnormal posturing of other body segments. Palpation of her neck musculature revealed a non-tender, taut fiber within the left SCM. She had limitation of right head tilt  into the affected SCM but experienced substantial relief of their torticollis and associated pain following partial myectomy of the anterior belly of the SCM muscle. Biopsy in both cases demonstrated fibrous transformation of skeletal muscle fibers Figures , pathognCMT is a rare cause of pseudodystonia expressed as torticollis, whose recognition is important in order to avoid ineffective and potentially harmful antidystonic treatments. CMT is usually recognized in neonates as a circumscribed palpable mass confined to the SCM, affected unilaterally, which may gradually disappear between 4 and 8 months of age or be associated with other orthopedic abnormalities such as hip dysplasia or lower extremity abnormalities (Morrison and MacEwen, Although isolated successes have been reported with chemodenervation (Bouchard et al., Besides CMT, other causes of pseudodystonic torticollis include focal myopathies, rotational atlantoaxial subluxation, posterior fossa tumors, congenital Klippel–Feil anomaly, syringomyelia, trochlear nerve palsy, and vestibular torticollis.


Objective: The aim of this work was to review de literature about the role of mesenchymal stem cells in bone regenerative procedures in oral implantology, specifically, in the time require to promote bone regeneration.Study Design: A bibliographic search was carried out in PUBMED with a combination of different key words. Animal and human studies that assessed histomorphometrically the influence of mesenchymal stem cells on bone regeneration procedures in oral implantology surgeries were examined.Reults:- Alveolar regeneration: Different controlled histomorphometric animal studies showed that bone regeneration is faster using stem cells seeded in scaffolds than using scaffolds or platelet rich plasma alone. Human studies revealed that stem cells increase bone regeneration.- Maxillary sinus lift: Controlled studies in animals and in humans showed higher bone regeneration applying stem cells compared with controls.- Periimplantary bone regeneration and alveolar distraction: Studies in animals showed higher regeneration when stem cells are used. In humans, no evidence of applying mesenchymal stem cells in these regeneration procedures was found.Conclusion: Stem cells may promote bone regeneration and be useful in bone regenerative procedures in oral implantology, but no firm conclusions can be drawn from the rather limited clinical studies so far performed. Key words:Mesenchymal stem cells, bone regeneration, dental implants, oral surgery, tissue engineering. Embryonic stem cells are derived from blastocysts  and are Surgical bone regeneration procedures such as guided bone regeneration or maxillary sinus augmentation, are well established , but metThe aim of this work was to review de literature about the role on MSC in bone regenerative procedures in oral implantology, specifically, in the time require to promote bone regeneration.A bibliographic search in PUBMED with a combination of different key words: mesenchymal stem cells, bone regeneration, dental implants, tissue engineering, dental pulp stem cells, periodontal ligament stem cells, apical papilla stem cells, deciduous teeth stem cells, oral implantology, oral surgery. Moreover, the references of the articles were also assessed. English articles published until 2011 were evaluated. Animal and human studies that assessed the influence of MSC on bone regeneration procedures in oral implantology surgeries were examined. Studies about alveolar bone regeneration, maxillary sinus lift, periimplantary bone regeneration and alveolar distraction were identified.-Inclusion criteriaDue to the number of studies performed no strict inclusion criteria could be performed. Only studies that used MSC to performed bone regeneration where histologic or histomorfometric analysis was performed were included. The studies should specify the moment where the analysis was carried out.•Clinical Human studies: Clinical trials, case-controls and case series were included. Case reports were excluded.• Animal studies: Controlled studies were included. Non-controlled studies were excluded.When we applied these inclusion criteria, 26 articles were specifically analyzed. Data about study design, bone regeneration surgery performed and time of histologic -histomorfometric study was carefully taken in account. Different MSC sources, scaffolds and growth factors were used in the reviewed articles so no differences between studies could be performed in this sense.Tissue engineering is an emerging interdisciplinary field, which applies principles of life sciences and engineering towards the development of biological substitutes that restore, maintain and improve the function of damaged and/or lost tissues . In tiss-Alveolar bone regeneration•Animal studiesDifferent studies have compared bone regeneration using MSC and PRP. Yamada et al.  in 10 mmMylonas et al.  applied Other studies exposed that MSC can also accelerate bone formation in alveolar shockets ,27, in 1Clinical human studiesMeijer et al.  implante-Maxillary sinus lift •Animal studiesControlled studies in animals using MSC to increase bone regeneration in maxillary sinus lifts have been performed. Pieri et al.  in a spl•Clinical human studiesClinical case series studies using MSC with different biomaterials have been performed. Shayesteh et al.  performeGronshor et al.  in a conVery recently the first controlled clinical trial using engineered bone stem cells in maxillary sinus elevation has been performed. Rickert et al.  executed-Periimplantary bone regeneration•Animal studiesAnimal studies have evaluated MSC combined with PRP in order to enhance periimplantary bone regeneration. Yamada et al.  regeneraDifferent studies have evaluated the regeneration potential of stem cells harvested from different sources. Ito et al.  compared-Alveolar distraction•Animal studiesQi et al.  evaluateControlled animal studies reveal that stem cells combined with PRP accelerate bone regeneration in oral implantology surgeries. This combination has shown higher capacity than PRP alone to promote bone regeneration. Controlled, long-term follow up clinical human studies have not been performed, but so far, no serious complications related to stem cells grafting (like systemic inflammatory response) have been reported. There is only one very recently clinical trial performing maxillary sinus lift using stem cells seeded on a xenograft showing similar morphometric results than autografts with xenograft. The interesting results of this clinical work as well as those of previous animal studies, indicate that stem cells may promote bone regeneration and be useful in human oral implantology. Many different scaffolds are used; for this reason and the heterogeneity between studies, no big conclusions can be performed yet. More clinical controlled studies applying stem cells are necessary to validate in humans, the favorable results observed in animals.


Cu+ is significantly more bactericidal than Cu2+ due to its ability to freely penetrate bacterial membranes and inactivate intracellular iron-sulfur clusters. Copper ions can also catalyze reactive oxygen species (ROS) generation, which may further contribute to their toxicity. Transporters, chaperones, redox proteins, receptors and transcription factors and even siderophores affect copper accumulation and distribution in both pathogenic microbes and their human hosts. This review will briefly cover evidence for copper as a mammalian antibacterial effector, the possible reasons for this toxicity, and pathogenic resistance mechanisms directed against it.Recent findings suggest that both host and pathogen manipulate copper content in infected host niches during infections. In this review, we summarize recent developments that implicate copper resistance as an important determinant of bacterial fitness at the host-pathogen interface. An essential mammalian nutrient, copper cycles between copper (I) (Cu Copper is both an essential mammalian micronutrient and a potent antibacterial agent. The Smith Papyrus, an ancient Egyptian medical text dated at 2400 BC, is the earliest medicinal archive to recommend copper sulfate to sterilize water and treat infections ] Liochev, .−9 s before reacting with organic molecules in vivo ]:Hydroxyl radicals are extremely reactive, cannot be scavenged by enzymatic reaction, and have a diffusion controlled half-life of ~10Hydrogen peroxide can in turn participate in reaction 1 and may further propagate radical formation.Escherichia coli mutant with multiple copper efflux deficiencies to hydrogen peroxide  oxidation by macrophage-like THP-1 cells was found to be ATP7A-dependent, suggesting metal catalyzed oxidation by secreted copper ions .Phagosomal copper may add to, and perhaps synergize with, the diverse cellular microbial killing strategies described since Elie Metchnikoff's pioneering work on phagocytosis Gordon, . These sM. tuberculosis upregulates genes encoding copper efflux-associated P1B-type ATPases during macrophage infection  exhibit higher growth than concomitant rectal isolates in a medium containing an inhibitory concentration of copper  may reduce the outer membrane's copper permeability , copper sequestration (CusF and siderophores), and copper oxidation (mixed copper oxidases and superoxide dismutase mimics). For the sake of brevity, the following sections primarily discuss Cu2+ detection and resistance proteins that have been described in E. coli  transcriptionally activates both plasmid- and chromosomally-encoded copper homeostatic systems in response to intracellular Cu+ sensing through CueR, a MerR-family metalloregulatory transcriptional activator  located at the dimer interface   system confers copper-tolerance under moderate to high copper levels in oxic conditions  proton antiporter family, CusB belongs to the membrane fusion protein family which anchor into the cytoplasmic membrane with a long periplasm-spanning domain, and CusC is an outermembrane protein with homology to the TolC-stress response protein  studies of the closely related E. coli, the periplasmic chaperone CusF binds copper, ultimately delivering it to CusCBA for export  such as methanobactin and phytochelatin  from copper toxicity, suggesting that yersiniabactin's iron uptake function does not contribute to this phenotype. Copper oxidation state selectivity among microbial small molecules is also observed in pyoverdin and pyochelin, two major siderophore types expressed by P. aeruginosa . Cu+ is more toxic than Cu2+ when applied under anoxic conditions, as demonstrated by Macomber and Imlay . CueO is structurally similar to the large, cross-Kingdom family of MCOs [including ascorbate oxidase and the ferroxidases Fet3 and ceruloplasmin  pathway with copper-bound active sites   and (7)]:+ concentrations while increasing oxidized—and less toxic—Cu2+ ion concentrations. Periplasmic Cu,Zn-SOD may similarly protect against copper stress, although there are distinctive pathogenic advantages to deploying a non-protein catalyst such as copper-yersiniabactin in the phagosomal microenvironment  that help resist copper toxicity. SOD activity may promote bacterial survival in several pathologically important host niches and its connection with copper suggests new insights into host defense mechanisms that are critical to infection pathogenesis.Copper-yersiniabactin confined within the phagolysosome may thus greatly diminish concentrations of superoxide (a reductant), while maintaining or increasing production of hydrogen peroxide (an oxidant). This may have the effect of minimizing reduced CuMuch remains to be understood about the mechanisms by which mammalian hosts deploy copper to resist infection, and how pathogenic bacteria respond to these strategies. ATP7A's emerging role in direct antibacterial immunity warrants its detailed study in mammalian cells that encounter bacterial pathogens. Cell type, pathogen, and regulatory activity may result in unforeseen interactions between copper and other innate immune effector molecules. Possible cooperation with mammalian copper absorption and trafficking may suggest routes by which copper-based immunity could be therapeutically supported. Both basic and translational research efforts will be necessary to understand these details.E. coli binds copper during humans infections  (Grass et al., in vivo and in environmental settings will be necessary to optimize antimicrobial uses of copper.Copper's inherent toxicity has renewed interest in its use as an antimicrobial. Three hundred different copper and copper alloy surfaces are registered with the U.S. Environmental Protection Agency as antimicrobials and trials are underway to determine whether copper treated surfaces can significantly reduce nosocomial infections (The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Next generation sequencing platforms and high-throughput genotyping assays have remarkably expedited the pace of development of genomic tools and resources for several crops. Complementing the technological developments, conceptual shifts have also been witnessed in designing experimental populations. Availability of second generation mapping populations encompassing multiple alleles, multiple traits, and extensive recombination events is radically changing the phenomenon of classical QTL mapping. Additionally, the rising molecular breeding approaches like marker assisted recurrent selection (MARS) that are able to harness several QTLs are of particular importance in obtaining a “designed” genotype carrying the most desirable combinations of favourable alleles. Furthermore, rapid generation of genome-wide marker data coupled with easy access to precise and accurate phenotypic screens enable large-scale exploitation of LD not only to discover novel QTLs via whole genome association scans but also to practise genomic estimated breeding value (GEBV)-based selection of genotypes. Given refinements being experienced in analytical methods and software tools, the multiparent populations will be the resource of choice to undertake genome wide association studies (GWAS), multiparent MARS, and genomic selection (GS). With this, it is envisioned that these high-throughput and high-power molecular breeding methods would greatly assist in exploiting the enormous potential underlying breeding by design approach to facilitate accelerated crop improvement. IntUnlike regular breeding programmes, the major objective of phenotyping in GS is to predict GEBVs rather than selection of genotypes , 107. PrBy its nature, GS focuses on genetic improvement of QTs rather than understanding their genetic basis , 115. Inin silico and Peleman and van der Voort [Ideotypes or ideal plant types are known to plant breeder, since 1968 when Donald  defined er Voort  describein silico designing of a superior genotype through combining desirable loci (https://www.integratedbreeding.net/ib-tools/breeding-decision). The concept of breeding by design includes (i) locating genes/QTLs associated with important traits (ii) exploring the allelic variation at these loci and the estimation of phenotypic effects of these allelic variants (iii) choosing desirable recombinants by targeting marker/haplotype-defined genomic fragments , 118. ReAvailability of highly saturated genetic maps and populations like ILs has facilitated fine mapping of various QTLs . FurtherOnce genetic loci influencing the expression of the trait have been mapped precisely, allelic variants at all these loci can be mined along with their relative contribution to complex traits, and highly resolved marker haplotypes could be recovered for several agriculturally important traits . With thMoreover, precise phenotyping or phenomics is one of the major bottlenecks in capitalizing the full potential of breeding by design concept . TherefoRapidly decreasing genotyping and sequencing costs are dramatically changing the scenario of genomics-assisted breeding. For instance, a shift has been seen from biparental to multiparental populations, and, with the help of various NGS-based sequencing platforms, a detailed genetic analysis of these complex mapping resources would likely to be feasible. Moreover, extensive recombination and multiallelic nature of these lines make them an excellent platform for practising multiparent MARS and GS. More importantly, the development of such public resources like MAGIC and NAM would strengthen the community-based research approach . Additionally, by virtue of eliminating need for any prior QTL information, MARS and GS schemes would save time, money, and energy that is required for finding significant gene-trait relationships. Still, realization of immense potential of all these approaches would greatly rely on throughput, precision, and cost effectiveness of phenotyping techniques. Though, precise phenotyping has always been a potent limiting factor in genetic analysis of QTs, efforts are underway to meet the growing demands for accurate and HTP screening against various biotic/abiotic stresses. It is envisaged that parallel developments in the next-generation phenotyping systems would help in making GS a practical reality in case of plant species as well. Therefore, rising molecular breeding methods like MARS or GS would enable harnessing unexplored genetic variation to a greater extent, thereby facilitating speedy development of superior cultivars.


Alcohol use and tobacco smoke exposure are frequently correlated, with many individuals smoking and/or experiencing secondhand smoke (SHS) exposure while drinking . Unfortunately, most medical school curricula do not adequately address the topic of screening and brief intervention (SBI) for tobacco use, SHS exposure, and/or problematic drinking. The aim of this study was to assess the effectiveness of a three-part educational intervention for health-professions schools to address the consequences of SHS exposure and develop SBI skills in medical students. Because information regarding the effects of smoking and SHS can be effectively communicated via self-directed online lectures, we developed an online training module including a videotaped lecture series with accompanying PowerPoint slides. To help students develop diagnostic skills related to SHS and other substance exposure, 10 standardized patient cases were included for instruction and testing. Finally, a clinical-instruction DVD provided examples of how practitioners can implement motivational-interviewing strategies in behavior change counseling related to tobacco use, with or without co-occurring alcohol use. Participants in the educational intervention, compared with controls (no intervention), scored significantly higher on the SHS Competency Exam. In addition, 100% of students who received the intervention reported plans to screen for SHS exposure. This educational intervention may be a valuable addition to medical and health professional school curricula while requiring minimal faculty time and effort.


Literary data suggest apparently ambiguous interaction between menopausal status and obesity-associated breast cancer risk based on the principle of the carcinogenic capacity of estrogen. Before menopause, breast cancer incidence is relatively low and adiposity is erroneously regarded as a protective factor against this tumor conferred by the obesity associated defective estrogen-synthesis. By contrast, in postmenopausal cases, obesity presents a strong risk factor for breast cancer being mistakenly attributed to the presumed excessive estrogen-production of their adipose-tissue mass. Obesity is associated with dysmetabolism and endangers the healthy equilibrium of sexual hormone-production and regular menstrual cycles in women, which are the prerequisites not only for reproductive capacity but also for somatic health. At the same time, literary data support that anovulatory infertility is a very strong risk for breast cancer in young women either with or without obesity. In the majority of premenopausal women, obesity associated insulin resistance is moderate and may be counteracted by their preserved circulatory estrogen level. Consequently, it is not obesity but rather the still sufficient estrogen-level, which may be protective against breast cancer in young adult females. In obese older women, never using hormone replacement therapy (HRT) the breast cancer risk is high, which is associated with their continuous estrogen loss and increasing insulin-resistance. By contrast, obese postmenopausal women using HRT, have a decreased risk for breast cancer as the protective effect of estrogen-substitution may counteract to their obesity associated systemic alterations. The revealed inverse correlation between circulatory estrogen-level and breast cancer risk in obese women should advance our understanding of breast cancer etiology and promotes primary prevention measures. New patents recommend various methods for the prevention and treatment of obesity-related systemic disorders and the associated breast cancer.  Many studies support an apparently Janus-faced ambiguous interaction between obesity and breast cancer risk depending on the menopausal status of patients -3. In yoNevertheless, several authors could find confusing and disturbing associations between obesity and breast cancer risk in postmenopausal women. Obese postmenopausal women, who had never used hormone replacement therapy (HRT) exhibited fairly high breast cancer risk . By contIn premenopausal cases, the results of clinical studies justify that obesity induces mild or moderate decrease in circulating estrogen levels reflected by their inclination to anovulatory infertility and long or irregular menstrual cycles . Based oEven larger studies, which equivocally strengthen the protective effect of obesity for premenopausal breast cancer risk, confess that the responsible mechanisms are completely obscure. Evidences, provided by clinical endocrinological studies regarding correlations between defective hormonal status of obese women and decreased breast cancer incidence, are inconsistent or fairly contradictory . ConsideObesity is a well-known cancer risk factor associated with different grades of insulin resistance and a disturbance of male to female circulating sexual steroid levels , 20. HypThe aim of the present study is to clarify the realistic correlations between breast cancer risk and obesity-associated hormonal alterations during the whole life of women. Moreover, this study tries to reveal the sources of the misleading clinical and epidemiologic results suggesting the breast cancer protective effect of obesity in the young. These associations are examined in an analytical review based on the results of prospective, case-control and meta-analytic studies.1). The main stream of obesity related alterations is a self-generating, progressive insulin resistance in thorough interplay with the dysmetabolism and inflammation of adipose tissue mass and with an imbalance of sexual steroid production in the endocrine organs.Clinical and experimental evidences prove that obesity, particularly visceral fatty tissue deposition leads to insulin resistance, associated with diverse immunologic, metabolic and hormonal alterations mediating breast cancer risk  is a defect of insulin-mediated cellular glucose uptake, which may elicit many disorders in the gene regulation of cellular metabolism, growth, differentiation and mitotic activity. The progression of this disorder predisposes patients to a variety of diseases, such as metabolic syndrome, type-2 diabetes, cardiovascular lesions and malignancies at different sites .in the first, compensated phase of insulin resistance maintains serum glucose level within the normal range by means of an increased secretory capacity of insular β-cells . Insulindevelops in the second, partially uncompensated phase of insulin resistance when the enhanced insulin synthesis of pancreatic islet cells is not enough to maintain euglycemia. This is a quartet of elevated fasting glucose, high serum triglyceride, low HDL cholesterol level and hypertension, being characteristic of viscerally obese patients . Each ofHyperglycemia is advantageous for the unrestrained DNA synthesis of tumor cells. It provokes deliberation of free radicals causing derangements in both DNA and enzymes having important role in repair mechanisms [chanisms , 33. Higchanisms . A prospchanisms .Dyslipidemia is a complex disturbance of the lipid metabolism associated with insulin resistance and hyperinsulinemia [ulinemia . Serum lulinemia , 38. Resulinemia .Hypertension usually shows close positive correlation with obesity, insulin resistance and hyperinsulinemia [ulinemia , 41. Eleulinemia , 42. Theulinemia . In postulinemia .Metabolic syndrome is associated with both increased breast cancer risk and high mortality rates in postmenopausal cases , 46. Timis the uncompensated phase of insulin resistance when the secretory capacity of insular β-cells becomes exhausted and the decreased serum insulin level results in hyperglycemia. The disrupted glucose homeostasis, the excessive formation of free radicals and the protein glycation depress the activities of the antioxidant scavengers and enzymes. These noxious processes cause serious damages in all biological structures even at a molecular level , 48. Thehyperandrogenism and anovulatory infertility through several pathways as insulin is a potent regulator of sexual steroid production in the endocrine organs [ovarian androgen production at the expense of reduced estrogen synthesis [Obesity related insulin resistance and excessive insulin synthesis in women may contribute to e organs . Hyperinynthesis . High inynthesis . Therapeynthesis , 59. A rynthesis .adrenal androgen synthesis as well by means of increased adrenal sensitivity to adrenocorticotropin. At the same time, high insulin level may favor the luteinizing hormone(LH) secretion of pituitary. Increased LH level also stimulates androgen biosynthesis by the activation of adrenal gland and ovarian theca cells [Hyperinsulinemia promotes ca cells , 62. Accca cells . In centca cells , 65.Insulin resistance, hyperinsulinemia and excessive IGF-I activity mediate defective estrogen synthesis by counteraction to aromatase enzyme gene expression at cellular level. The aromatase enzyme complex catalyzes the conversion of androgens to estrogens in a wide variety of tissues. In premenopausal women, the ovaries are the principle sources of estradiol; by contrast, in postmenopausal women when the ovaries cease to produce estrogen, it is synthesized in a number of extragonadal sites . These sIn premenopausal insulin resistant women with type-2 diabetes, the ovaries exhibit decreased capacity to convert androgen to estrogen, probably due to a reduction of ovarian aromatase activity . ConversEstrogens decrease low grade inflammatory reactions and may in parallel reduce the glucocorticoid responses. Low estrogen levels after menopause allow the predominance of glucocorticoids and the manifestation of the metabolic syndrome. These observations suggest that the disturbed equilibrium between sex hormones and glucocorticoids may be a critical element in the manifestation of metabolic syndrome-related pathologies .Visceral adipose tissue has important functions in energy homeostasis, metabolic equilibrium, immune responses and in the regulation of cell proliferation. Secretion of signaling molecules; adipokines regulates the cellular microenvironment both locally and systemically -73.The chronic low grade inflammation associated with obesity is an important player in tumor development and progression. Increased IGF-I level may mediate the inflammation of adipose tissue via its effects on immunologically active cells including macrophages and T cells . IGF-I madipocytokines; such as leptin, adiponectin resistin, ghrelin etc. [Adipokines include unique products of fatty tissue known as lin etc. . Leptin lin etc. . High lelin etc. . Converslin etc. . The ballin etc. .Proinflammatory cytokines  produced in excessive adipose tissue mass increase nitric oxide (NO) production, a substrate for reactive oxygen species (ROS). Accumulation of cytokines and ROS further contribute to insulin resistance resulting in elevated circulating glucose and free fatty acid levels. All signaling molecules of fatty tissue including cytokines, hormones and growth factors are involved in the regulation of the proliferation, invasion and metastatic spread of tumor cells . ProinflOut of several hormones affecting body mass and adipose tissue deposition, estrogens promote, maintain and control the ideal distribution of body fat . These sEstrogen regulates the metabolism, differentiation, growth and cell kinetic mechanisms of adipocytes. In healthy premenopausal women central adipocytes show higher insulin sensitivity and exhibit a higher turnover rate despite similar fat content as compared with male cases . ConversObesity and overweight are important concomitants of insulin resistance and they are strongly associated with disturbed equilibrium of male to female sexual hormone concentrations in women . HealthyHealthy premenopausal women are typically protected from cardiovascular diseases and hypertension as compared with men and this has been hypothesized to be because of the protective effects of estrogens. Conversely, obese, diabetic young women, and postmenopausal cases may lose this protected state as their bioavailable estradiol levels are strongly reduced .Estrogen may have crucial role in the maintenance of normal serum lipid levels. Postmenopausal women have higher total cholesterol, LDL cholesterol and triglyceride levels, whereas lower HDL cholesterol levels as compared with premenopausal cases. These changes may be regarded as a shift toward a more atherogenic lipid profile in estrogen deficient milieu . PostmenEstradiol has cardiovascular protective impact by its anti-hypertensive activity as well. Estrogens can downregulate components of the renin-angiotensin system (RAS) and reduce the expression and activity of angiotensin I-converting enzyme , 95. EstClinical and experimental studies support that estradiol has also antioxidant activities , 99 thatpancreatic islet cells [Estrogens have beneficial effects on the energy metabolism and glucose homeostasis by means of several pathways . Estrogeet cells . Estrogeet cells . EstrogeIn the liver, estrogen regulates insulin sensitivity by the balanced activation of glycogen synthase and glycolytic enzymes to maintain the equilibrium of glycogen synthesis and glycogenolysis. In ER-α knockout mice, hepatic insulin resistance was associated with decreased glucose uptake in skeletal muscles [ muscles .In the peripheral tissues, ERs advantageously modulate the insulin stimulated glucose uptake through regulation of the phosphorylation of insulin receptor protein. In hyperinsulinemia, high concentrations of estradiol can inhibit the excessive insulin signaling in adipocytes [ipocytes , which mERs have crucial roles in cellular glucose uptake by regulation of intracellular glucose transporters (GLUTs) and enhancing both GLUT4 expression and translocation . In humaEstrogens and ER signals have pivotal role in the regulation of growth hormone (GH) activity by means of modulation of its secretion and cellular GH receptor function. Estrogens play a major and positive role in the regulation of GH-IGF-I axis in both genders , which mPostmenopausal hormone replacement therapy (HRT) reduced abdominal obesity, insulin resistance, new-onset diabetes, hyperlipidemia, blood pressure, adhesion molecules and procoagulant factors in women without diabetes and reduced insulin resistance and fasting glucose in women with diabetes .Low grade systemic inflammation may be associated with estrogen deficient states, namely menopause and ovariectomy. At early stages of estrogen deficiency estrogen administration decreased the inflammation associated risk of developing cardiovascular disease . NeverthPhytoestrogens may advantageously influence the level of adipokines in insulin resistant women. In postmenopausal cases, diet, physical exercise and daily oral intake of soy isoflavones had a beneficial lowering effect on serum leptin, and TNF-α levels and showed a significant increase in mean serum levels of adiponectin . EpidemiEstrogen advantageously regulates serum levels of available growth factors. In clinical studies estradiol lowered, whereas testosteron increased total IGF-I level and estradiol specifically suppressed unbound, free IGF-I level . CrosstaThe presumed synergistic contribution of ERs and GFRs to cancer development and progression would be a permanent danger without contraregulatory impact. Inhibition of growth factor signaling in apparently ER-negative breast cancer cells successfully restored ER expression suggesting a dynamic, inverse relationship between the two receptor systems . Moreoveobese premenopausal women, peripheral, subcutaneous adiposity is typical and there is a lower incidence of obesity associated dysmetabolism. By contrast, in obesepostmenopausal cases, circulating levels of estrogen are dramatically decreased and adipose tissue distribution becomes more male-like. Predominance of visceral adiposity and the associated metabolic and hormonal disorders mean high risk for obesity related diseases, included breast cancer [Fat deposition is thoroughly affected by male to female sexual steroid level . Circulat cancer .The most important data characterizing the grade of obesity are body mass index (BMI) and weight in kilogram , 5, 118 Some authors reported on the value of WC, HC and WHC ratio in the prediction of premenopausal breast cancer occurrence , 122. CoMagnetic resonance imaging (MRI) was used to quantify separately the mass of visceral and subcutaneous abdominal fat depositions in obese adolescent girls . Mass ofIn conclusion, neither BMI nor circumference measurement may exactly separate the metabolically indifferent, subcutaneous fat and the dangerous visceral fat, which may partially explain the controversial correlations between obesity grade and breast cancer risk.Circulating female sexual steroid levels and fertility continuously decrease during the life of women. The ability to conceive is at its peak in young women under 30 years of age with a continuous decline from the fourth decade, which suggests decreasing fertility even in the premenopausal phase . Menopau1).In premenopausal women, the good equilibrium of sex steroid synthesis defines health and reproductive capacity, whereas good, symptom-free adaptation to the estrogen deficient environment is a prerequisite of postmenopausal health. Changes in the hormonal equilibrium during women’s lives strongly influence the obesity associated breast cancer risk  the coexistence of anovulatory infertility and insulin resistance represents common risk for the cancers of highly hormone dependent breast, endometrium and ovary , 148. MoHyperprolactinemia is also associated with cycle disorders, reproductive dysfunction and hyperandrogenism in women, however, it may be sharply discerned from PCOS and other disorders related to androgen excess. An increased overall cancer risk was found in hyperprolactinemia patients but further investigations are necessary to confirm these results . Data ofHow can we explain the increased prevalence of breast, endometrial and ovarian cancers in women with fertility disorders, even without obesity? In premenopausal cases, slight or moderate decrease in circulating female sexual steroid levels may be enough to block the delicate mechanism of ovulation. At the same time, a slightly estrogen deficient milieu confers preferential cancer risk for the female organ triad having high estrogen demand , 136.In women, multiparity and risk for malignancies at several sites exhibit an inverse relationship -157. HigNulliparity may be associated with ovulatory disorders in the majority of cases and there are studies, which equivocally exhibited increased prevalence of breast cancer in nulliparous women , 162. Fuin vitro fertilization (IVF) in anovulatory cases [Possible role of fertility medications in the increased risk of breast cancer has been hypothesized. However, large studies were not able to find any associated risk of breast cancer after ovulation provocation and ry cases . Moreovery cases . Recentlry cases . Howeverry cases . These rIn postmenopausal estrogen deficient, obese cases the regional distribution of fat deposition near uniformly affects the visceral region in close correlation with their high breast cancer risk .Obese postmenopausal women never using HRT are obviously insulin resistant. Moreover, ageing after menopause is a further factor increasing the cancer risk as it is associated with a continuous estrogen loss and parallel advancing insulin resistance [sistance . In old obese HRT user postmenopausal women, the incidence of breast cancer is equivocally reduced [In  reduced . The pro reduced . In HRT  reduced  yields f reduced  and by i reduced . All theA great challenge is to explain the beneficial anticancer impact of HRT in obese postmenopausal women based on the misbelief that they have excessive circulatory estrogen level. To solve this contradiction, some authors assumed that mediators other than estrogen, such as insulin and insulin-like growth factors might confer the obesity associated breast cancer risk after menopause . Oral contraceptive (OC) use replaces the natural menstrual cycle with relatively steady levels and fluctuations of artificial sex hormones.Recent epidemiological studies have confirmed that combined oral contraceptives provide substantial protection against endometrial and ovarian cancer in the endangered anovulatory women , 169. EfIn PCOS cases, treated with OCs, the volume of cystic ovaries is reduced, ovarian testosterone secretion is decreased and there are favorable effects on carbohydrate and lipid metabolism as well . A recenUse of HRT has highly controversial associations with breast cancer risk. Till now, the carcinogenic capacity of postmenopausal estrogen therapy was a prevailing concept [ concept . By cont concept , 172. ReIn 2011, the WHI Randomized Controlled Trial strengthened that the estrogen treatment in women with prior hysterectomy resulted in a significantly lower risk for breast cancer than in untreated controls . Breast Today, increasing numbers of evidence from the clinical trials suggest that unopposed estrogen as hormone treatment does not increase the risk of breast cancer, and may even reduce it. The earlier concepts regarding the breast cancer risk of hormone replacement therapy are completely changing -178.HRT decreases the accumulation of central fatty tissue in obese postmenopausal women and provides them long term metabolic and health benefits , 167. HR environmental estrogens (xenoestrogens) occurs through diet, household products and cosmetics, but concentrations of single compounds in breast tissue are generally lower than needed for assayable estrogenic responses [Exposure to esponses . ExposurEndocrine disruptors (EDs) are environmental chemicals that are able to bind hormonal receptors. These compounds may disrupt the endocrine regulation of reproduction and adaptive mechanisms and promote the development of endocrine disorders. Since several EDs have a structure similar to that of endogenous steroid hormones such as estrogens, they have an affinity for steroid hormone receptors and may alter the normal hormone-mediated reactions [eactions . EnvironPoor natural light exposure mediates deleterious metabolic and hormonal alterations by excessive melatonin secretion; such as insulin resistance, deficiencies of estrogen, thyroxin and vitamin D [itamin D . Long teBefore the introduction of antiestrogens, high dose estrogen was successfully administered as endocrine therapy for postmenopausal women with advanced breast cancer. Nowadays, the ambiguous, unreliable therapeutic effects and high toxicity of antiestrogens suggest the necessity of finding new strategies for breast cancer treatment . RecentlPhytoestrogen containing health supplement compositions are recommended by some patents for the prevention or treatment of postmenopausal breast cancer and for the alleviation of menopausal symptoms [symptoms . Soybeansymptoms . A recensymptoms .Obesity-associated hormonal disorders confer breast cancer risk during the whole life of women without any ambiguous interaction between obesity and menopausal status. Erroneous results regarding the breast cancer protective effect of obesity in young women derive mainly from the deceivingly lower tumor incidence among them. Further misleading factor may be that hormonal disorders related to anovulatory infertility are strong cancer risk factors for the breast both in obese and non-obese young women. Low incidence rate of breast cancer in young obese women may be a very important misleading finding. In the majority of premenopausal obese cases a predominantly subcutaneous adipose tissue deposition results in milder insulin resistance being counteracted by their preserved hormonal cycle. Consequently, in obese premenopausal women their circulatory estrogen level confers protective effect against breast cancer rather than obesity.Tumor cell kinetics may also provide an explanation for the low breast cancer incidence rate in obese premenopausal cases. A long term exposition to harmful environmental and systemic factors is necessary for cancer initiation; moreover the tumor growth from the initiation to clinically diagnosable size takes further several years. This double delay of clinical appearance of breast cancers may frequently result in a postmenopausal tumor, though it was initiated in the premenopausal period. Anovulatory infertility and the associated hormonal defects seem to be stronger breast cancer risk factors than adiposity alone and these alterations are not rare even among control cases with normal weight. Studies on obesity-related breast cancer risk disregarded the random occurrence of these hormonal alterations both among obese cases and lean controls. Moreover, oral contraceptive use is fairly widespread among premenopausal women, which may reverse the mild hormonal defects and attenuates their cancer risk either in obese or in lean cases. Strict selection of healthy, lean control women for obesity associated breast cancer studies and taking into account the OC use among obese cases and controls will justify the health advantage of normal body weight over obesity.Recognition of the inverse correlation between circulatory estrogen-level and breast cancer risk in obese women should advance our understanding of breast cancer etiology. Moreover, it would promote primary cancer prevention measures and the introduction of causal cancer therapy.2 and 3). Circulatory endogenous estrogen was blamed to provoke cancer initiation and promotion in the highly hormone responsive female organs, however, this misbelief yielded fairly controversial results in the clinical and experimental fields of medicine. Nowadays, overwhelming literary data suggest that estrogens have advantageous impact on dysmetabolism and hyperandrogenism, which are essential sources of tumor development.Changing concepts concerning breast cancer etiology provide completely new strategies against mammary tumors (Tables Recent patents disclose oral contraceptive and metformin derivative treatment possibilities for breast cancer prevention and therapy. Moreover, a new invention provides special estrogen derivatives being metabolically more advantageous for the treatment of PCOS than oral contraceptives. As anovulatory disorders in young women are strong risk factors for breast cancer, insulin resistance screening of asymptomatic occult cases in the population and their hormone treatment would be effective primary breast cancer prevention.In postmenopausal cases, obesity, metabolic syndrome, type-2 diabetes and hysterectomy are strong risk factors for mammary malignancies. Hormone replacement therapy in these endangered cases would be advantageous preventive measure.The present practices of breast cancer therapy have fairly controversial results. Worldwide administration of antiestrogen compounds for breast cancer treatment yielded thorough disappointment. Antiestrogens are cytostatic agents blocking the most important regulatory mechanisms associated with estrogen receptors. They do not have only toxic effects but also strong carcinogenic capacity. Recently, scientists in some centers confess, that one armed estrogen treatment is rather cancer protective than carcinogenic. Certain patents disclose the beneficial effects of phytoestrogens in breast cancer prevention and therapy. Moreover, publications on the high dose estrogen treatment of advanced breast cancer cases are regularly returning and the results are fairly encouraging. Today, we are on the route to regard estrogens as beneficial anti-cancer drugs rather than carcinogenic agents.


To describe uncommon association between central retinal artery obstruction and dominant macular drusen in two young female patients. First patient, a 22-year-old female was presented with right central artery obstruction associated with bilateral dominant macular drusen. Systemic evaluation disclosed the presence of mitral valve regurge. Second patient, a 34-year-old female with a previous history of right central retinal artery obstruction diagnosed elsewhere. Fundus exam showed bilateral dominant macular drusen and her systemic evaluation revealed severe rheumatic valve stenosis, moderate aortic regurge with moderate to severe tricuspid regurge and she underwent mitral valve replacement. To the best of our knowledge, the association between central retinal artery obstruction and dominant macular drusen was not previously reported. Occlusive disorders of the retinal circulation are among the most dramatic problems encountered by the ophthalmologists because of their rapid onset, their potentially profound effects on vision, and their strong association with life-threatening systemic diseases.The causes of retinal arterial occlusion in young adult patients often differ from those found in older adults.8We report herein, two cases of right central retinal artery occlusion associated with bilateral dominant macular drusen in young adult females with cardiac valve diseases.A 22-year-old female presented with sudden loss of vision in her right eye for 10 hours duration with past ocular history of intermittent visual obscurations in both eyes for the last 3 years. Details of ocular examination can be seen in Diagnosis: right central retinal artery occlusion; Management: immediate paracentesis, ocular massage in conjunctions with Carbogen and Diamox.Investigation: The following were within normal limits:Physical examinations, CBC, ESR, Electrolytes, Hgb electrophoresis, PT, PTT, protein electrophoresis, central plasma viscosity, lipid profile, plasma homocysteine, blood sugar, C proteins, antiphospholipid antibodies, plasma fibrinogen, lipoprotein A, abnormal factor V leiden, antithrombin III deficiency, protein S and C deficiency. revealed a delay in retinal arterial filling with prolong arteriovenous transit time with ground glass appearance in the right eye and sharply demarcated hyper fluorescent spots in the temporal aspect of macular in both eyes.Intravenous fluorescein angiography Cardiac evaluation was performed by a cardiologist and her carotid doppler was within normal and echocardiography showed mild mitral regurge. The patient was treated with Aspirin.A 34-year-old female referred with diagnosis of right retinal arterial occlusion presented with history of decreased vision in her right eye for 1 year after an attack of cerebrovascular accident with left side weakness. Surgical and medical history revealed diagnosis of heart valvular disease and she underwent mitral valve replacement three years ago and using warfarin and digoxin. Details of ocular examination can be seen in Diagnosis: old recanalized right central artery occlusions with bilateral macular drusen.Investigation: Systemic evaluation by her Cardiologist showed rheumatic mitral valve stenosis, moderate aortic regurgitations with moderate to severe tricuspid regurge status post mitral valve replacement. revealed to some extent a delay in arterial filling with prolong arteriovenous transit time in right eye and hyper fluorescent spots macular area of both eyes.Intravenous fluorescein angiography Dominant macular drusen (Doyne honey comb dystrophy) is an autosomal dominant disorder, which mimics drusen seen in age-related macular degeneration. This disorder occurs in younger patients at 20 to 30 years of age and the extent of the drusen is variable, with most cases limited to the posterior pole. Affected patients may later develop choroidal neovascularization. It may be relevant that drusen like deposits can be seen in some renal disorders that involve basement membrane abnormalities, such as Alport's syndrome and membranoproliferative glumerulonephritis Type II.910Further literature review showed no reports of association of dominant macular drusen with other systemic disorders, particularly cardiac valvular disorders. Our cases revealed a trait of young adult females with bilateral dominat macular drusen, each of them presented with right central artery occlusion secondary to cardiac valvular disease. This association is based on observations which could be coincidental findings. And to the best of our knowledge these associations have not been reported previously.


Unexpected drug efficacy or resistance is poorly understood in cancers because of the lack of systematic analyses of drug response profiles in cancer tissues of various genotypic backgrounds. The recent development of high-throughput technologies has allowed massive screening of chemicals and drugs against panels of heterogeneous cancer cell lines. In parallel, multi-level omics datasets, including genome-wide genetic alterations, gene expression and protein regulation, have been generated from diverse sets of cancer cell lines, thus providing a surrogate system, known as cancer cell line modeling, that can represent cancer diversity. Taken together, recent efforts with cancer cell line modeling have enabled a systematic understanding of the causal factors of varied drug responses in cancers. These large-scale association studies could potentially predict and optimize target windows for drug treatment in cancer patients. The present review provides an overview of the major types of cell line-based large datasets and their applications in cancer studies. Moreover, this review discusses recent integrated approaches that use multi-level datasets to discover synergistic drug combination or repositioning for cancer treatment. IntroductionLarge-scale datasets from cell line panelsSystematic analysis of multi-level omics and chemical screening dataPerspectives1.in vivo anticancer drug responses or optimize target treatment windows in clinical trials.Cancer cells exhibit varied responses to anticancer agents . Fast hiin vitro cell line modeling in translational cancer studies.The goals of this review are to survey the major types of cell line-based high-throughput datasets and highlight their applications in the systematic modeling of selective drug responses in cancer samples. This review focuses on several representative types of large datasets, including genotyping, gene and protein regulation, and chemical screening from well-defined cancer cell line panels. The major analytical efforts conducted with these representative datasets will be described, together with systematic approaches to integrate the multi-level omics and drug data. We expect that the present review will provide clear insights into the future impact of 2.Several cancer cell line panels have been organized to perform large-scale chemical screening and multi-level omics data profiling. For example, the National Cancer Institute (NCI) developed a panel of 60 well-characterized cancer cell lines from diverse tumor types for the purpose of chemical screening against heterogeneous cancer subtypes . This paMore recently, the sizes of cell line panels for chemical screening and omics data generation have greatly increased. For example, GlaxoSmithKline (GSK) released various genomic profiling datasets from a panel of >300 cancer cell lines that comprised 24 different cancer lineages  7). In . In 7). Genotypic variation among cancer cells is the major cause of inconsistency in anticancer drug responses. The prospect of targeted cancer therapies relies mainly on extensive information on the genetic variations observed in diverse cancer types. Recent efforts based on high-throughput PCR and sequencing technologies have generated reliable annotations of genome-wide genetic alterations in large cancer cell line and tissue sample collections ,9. For eIn addition to somatic mutations in coding regions, SNPs and copy number alterations in cancer cells have been proven to be of significant importance for understanding of cancer progression and therapies. For example, cancer subtype-specific SNP markers or CNA exhibited powerful predictions regarding drug responses, clinical prognostics and oncogenic factor identification ,12. In 2Gene expression analysis in cancers has provided considerable information on diagnostic or prognostic marker signatures and potential drug targets. DNA microarray experiments have generated substantial transcriptome-wide gene expression profile information in various cancer samples. A DNA microarray dataset of the NCI60 cell lines was initially generated to explore the expression of approximately 8,000 unique genes  18). Th. Th18). Cancer transcriptome expression profiles were also generated for the GSK and CCLE cell lines. The GSK dataset includes gene expression data for >300 cell lines, each in triplicate, thus providing a robust statistical analysis  Table I. This daAlthough large-scale gene expression studies have yielded useful information for cancer biomarker identification and targeted cancer therapy development, high-throughput protein expression and activation level screening are required in order to better understand cellular signaling in the contexts of tumorigenesis and drug response. Reverse-phase protein array (RPPA) technologies, which are based on sample spot arrays for specific antibody reactions, allow fast, quantitative measurements of protein expression or phosphorylation in a large cancer sample panel . More thhttp://dtp.nci.nih.gov/index.html). This is the largest dataset for studies of structure-activity relationships between anticancer agents and diverse cancer subtypes. The COMPARE program is a useful tool with which to search for compounds with similar patterns of cellular sensitivity in the NCI60 panel  is another exciting project that has extended ideas about cell line modeling to human cancer tissue samples. An increasingly large collection of clinical cancer samples are directly used to generate multi-level omics data, thus revealing a comprehensive landscape of genetic alterations and transcriptional regulation in each cancer subtype . A recendatasets . TogetheTogether with systematic cell line modeling using large omics datasets, RNAi screening data were recently generated to identify the target genes associated with changes in cancer phenotypes. For example, a kinome-based shRNA screening study was performed to determine the mechanism of resistance against BRAF inhibitors in colon cancers that harbored an activating mutation in the BRAF oncogene . Feedbac


Detection of a novel Gammaretrovirus, Xenotropic Murine leukaemia virus-Related Virus (XMRV) has been reported in peripheral blood mononuclear cells of patients with chronic fatigue syndrome, and in prostate cancer tissue. As Multiple Sclerosis (MS) is a disease with retroviral association (human endogenous retroviruses (HERVs)), we investigated whether XMRV could be contributing to MS aetiology by testing a well defined cohort of Danish MS patients for the presence of XMRV sequences.We have analysed DNA samples isolated from peripheral blood mononuclear cells (PBMCs) from 50 Danish patients with clinically well-characterized MS for evidence of the presence of XMRV gag or env sequences by PCR, using concomitant amplification of the cellular GAPDH gene as control.In this study, which included relevant positive and negative isolation controls and PCR controls, we failed to detect XMRV sequences in PBMCs from Danish MS patients.There is no apparent association between XMRV infection and MS in Denmark.


Septic shock is one of the major causes of death in children and is characterized by a massive inflammatory response. To present date, no studies have been performed to assess the impact of such an ‘inflammatory hit’ on aortic wall structure and myocardial performance.This study shows that despite adequately preserved systolic biventricular function, frequently reduced aortic elasticity may indicate aortic wall pathology, being associated with biventricular hypertrophy and concomitant delayed biventricular relaxation in pediatric patients after septic shock.Septic shock is one of the major causes of death in children and is characterized by a massive inflammatory response. To present date, no studies have been performed to assess the impact of such an ‘inflammatory hit’ on aortic wall structure and myocardial performance. The objectives of the current study were therefore to prospectively assess aortic elasticity and biventricular systolic and diastolic function in a group of pediatric patients after meningococcal septic shock by using MRI.Eighteen pediatric meningococcal septic shock survivors  treated with at least 2 inotropic and vasoconstrictive agents for 48 hours or longer and 18 for age and gender matched controls were prospectively studied. Routine MRI was used to assess aortic pulse wave velocity (PWV) and systolic and diastolic biventricular function. Independent-samples-t-test and Pearson-correlation-coefficient were used for statistical analysis.Sepsis patients showed reduced aortic elasticity vs. controls . Systolic biventricular function was preserved , whereas biventricular mass was increased . Also, delayed biventricular relaxation was found after sepsis: peak filling rates corrected for end-diastolic-volume (PFREDV) across the mitral and tricuspid valve were significantly reduced . Increased PWV in aortic arch and descending aorta were associated with increased LV mass  and delayed LV relaxation parameters.Despite adequately preserved systolic biventricular function, reduced aortic elasticity in pediatric patients after septic shock may indicate aortic wall pathology, being associated with biventricular hypertrophy and concomitant delayed biventricular relaxation. Long-term prognosis after septic shock may therefore be adversely affected considering the cumulative effects of cardiovascular disease during a lifetime.No disclosures.


While monkeys perform a task alternating between behavioral adaptation --relying on feedback monitoring and memory of previous choices-- and repetition of previous actions, firing rates in dorsal Anterior Cingulate Cortex (dACC) modulate with cognitive control levels . FurtherWe used spike-train metrics  to decodWe found that timing sensitivity could improve behavioral adaptation vs. repetition classification of single unit spike trains. Optimal decoding occurred when accounting for spike times at a resolution <= 200 ms. Furthermore, spike-train metrics decoding of unitary discharges was related to the monkeys' response time. A downstream neural decoder could exploit this temporal information through coincidence detection determined by synaptic and membrane time constants. In addition, when decoding two units jointly, we found that each pair had a specific optimal distinction degree between spikes coming from the two different neurons. In a realistic neural decoder, the tuning of this distinction degree might occur through non-linear dendritic integration.To further investigate the computational properties of temporal decoding in the context of decision-making, we are implementing a recurrent spiking neural network with connectivity leading to attractor dynamics. In this framework, each decision is mapped to a state in which a corresponding neural subpopulation shows elevated activity, as observed experimentally in dlPFC . In addiThe spatiotemporal structure of spike trains appears to be relevant in this cognitive task. This opens the possibility for pattern matching-based decoding of dACC activity, potentially leading to adapted behavioral response.


Tightly controlled extracellular matrix (ECM) homeostasis and remodeling is critical for normal organ homeostasis, wound healing and tissue repair. However, excessive or uncontrolled ECM deposition contributes to aberrant homeostasis of tissue microenvironment in various inflammatory diseases and tumors. Matricellular proteins are a set of structurally unrelated ECM proteins that do not exert a primary role in tissue architecture but have regulatory roles in embryonic development, tissue injury, inflammation and tumor progression. Two recent studies demonstrated that matricellular proteins in the ECM surrounding dormant tumor cells may determine the fate of tumor cells to remain quiescent or undergo metastatic outgrowth. The identification of matricellular proteins in regulating ECM homeostasis and remodeling specific organ niches during tumor dormancy may provide potential novel extracellular targets for the development of therapeutic interventions against tumor dormancy.Many cancer patients who have undergone surgical resection of their primary tumors suffer from metastatic relapse several months, years or even decades later. Current evidence supports the idea that tumor cells can be disseminated at an early stage of tumor progression. The disseminated tumor cells (DTCs) exist in a quiescent state at a hostile site, but may switch from quiescence to proliferative metastatic growth in a permissive and supportive microenvironment. Increasing data suggest that tumor dormancy can be regarded as a protracted asymptomatic stage during which tumor cells either remain in a quiescent state or their proliferation is balanced by cell death due to immunosurveillance or insufficient angiogenesis  and periostin (POSTN), play crucial roles in regulating DTC dormancy. TSP-1 is enriched in the basement membrane of mature microvessel stalks and maintains DTCs in a dormant state; however, TSP-1 levels are markedly decreased at the sprouting neovascular tips of newly forming vessels. Interestingly, they also found an increased distribution of matricellular proteins, such as POSTN, tenascin-C and SPARC, together with fibronectin and TGF-β1, around these growing tips. The authors further provided evidence that high POSTN and active TGF-β1 expression surrounding neovascular tip cells enables DTCs to exit from dormancy and triggers metastatic relapse  proteins, mainly including thrombospondins (TSPs), OPN, tenascins, SPARC, POSTN and CCNs, which do not exert a primary role in tissue architecture but regulate similar biological functions in response to external stimuli during embryonic development, tissue injury, inflammation and tumor progression  to maintain quiescence, whereas the perivascular niche accommodates more activated HSCs. Quiescent HSCs reside preferentially at the endosteal region where bone-lining osteoblasts and their secreted proteins are critical components of HSC niches. Interestingly, bone marrow microenvironment is also a critical reservoir for DTCs. When metastasizing to the bone, DTCs take shelter in HSC niches in bone marrow and adopt similar mechanisms to those used by HSCs for homing to bone marrow. That is to say, DTCs may occupy and remodel preexisting physiological HSC niches to help them survive and subsequently grow and metastasize (Wan et al., How do matricellular proteins maintain dormant tumor cells in a quiescent state or reactivate them to metastatic outgrowth? As a class of structurally unrelated ECM proteins, matricellular proteins serve as links between the ECM and cells to regulate cell-cell and cell-matrix interactions, and their functions are highly dependent upon the cues from local microenvironment. These matricellular proteins are often needed for ECM remodeling during embryonic development and their expressions are highly induced at sites of injury, inflammation or tumors within the adult organism. An excessive or uncontrolled matricellular proteins’ function contributes to aberrant remodeling and homeostasis of tissue microenvironment in various inflammatory diseases and tumors. Matricellular protein knockout mice are often viable, but typically exhibit abnormal responses to mechanical stress, wound healing, inflammation and tumor metastasis. POSTN, for example, can directly interact with collagen I, fibronectin and Notch1 via its EMI domain and interact with tenascin-C and BMP-1 via its FAS1 domains (Norris et al., The work by Ghajar et al. and Boyerinas et al. greatly expanded our understanding of the roles of tissue microenvironmental cues in regulating tumor dormancy and subsequent metastatic growth. The identification of matricellular proteins in regulating ECM homeostasis and remodeling specific organ niches during tumor dormancy provides useful extracellular targets for the development of therapeutic interventions to induce or maintain DTCs in a dormant state, or alternatively to activate and then eradicate dormant DTCs.


The majority of neural encoding models employed today consist of a linear feature-selection stage followed by a static memoryless nonlinearity generating the neuronal rate of response. Although such linear-nonlinear (LN) models have been proven useful in characterizing computation in many neurons (see  and refeHere we investigate nonlinear-nonlinear neuron models that combine both biophysics and dendritic computation. Specifically, we consider models in which the nonlinear dendritic processing of input stimuli is described by a Volterra series  and the


To the Editor: Factor et al. recently reported the results of a population-based, case-control study regarding risk factors for pediatric invasive group A streptococcal (GAS) infection  were unlikely to have received NSAIDs in the 2 weeks before their interview should be surprising. A more informative case-control study would have matched case-patients with similar-aged children who had febrile infections not caused by GAS infection; both groups of children would have been equally likely to have received analgesic and antipyretic medications. Furthermore, population-based data suggest that most patients with invasive GAS infection are hospitalized (Prospective studies have failed to define a causal link between NSAIDs and invasive GAS infections (Although NSAIDs may neither alter the risk of developing an invasive GAS infection nor accelerate an established infection, these drugs can mollify the signs and symptoms of streptococcal infection, possibly delaying appropriate management and treatment (


Sir,A 60-years-old male presented to us with complaint of fever and cough with expectoration for last one month and pus discharging sinus on anterolateral aspect of right side chest wall for last one week. There was no history of hemoptysis, chest pain, dyspnoea or any previous swelling on chest wall at the site of discharging sinus. There was no previous history of tuberculosis or any anti-tubercular drugs (ATT) intake. Also there was no past history of intercostal tube drain (ICD) insertion or any history suggestive of pleural effusion. On respiratory system examination, crepts were present in bilateral lung fields. Examination of cardiovascular system and gastrointestinal system was absolutely normal.In laboratory investigation, ESR was raised while complete blood count (CBC), renal function test, liver function test were within normal limit. Smear and culture of sputum was positive for acid fast bacilli. Pus from discharging sinus failed to reveal any growth of pyogenic or fungal organism on staining as well as culture. CECT of -thorax was performed after injecting dye in the discharging sinus which revealed the presence of bronchopleurocutaneous fistula. Frontal CT scout view demonstrates extensive fibrocavitatory changes in both lungs more on right side with right sided mediastinal shift. It also revealed volume loss of right lung associated with extensive pleural thickening and blunting of CPA. Infant feeding tube was used for injecting dye in fistula. Axial chest CT demonstrates movement of dye injected in subcutaneous fistula along posterior pleural space into cavity in posterior segment of right upper lobe. From the cavity dye entered in draining segmental bronchus, thus confirming the presence of bronchopleurocutaneous fistula . There wPatient was diagnosed as a case of pulmonary tuberculosis with bronchopleurocutaneous fistula. Patient was put on antitubercular drugs. Patient responded well and the fistula healed.Bronchopleurocutaneous fistula is a pathological communication between bronchus, pleural space and skin. It usually develops due to pulmonary operations, perforating chest trauma, empyema, lung abscess, pneumonia or massive pulmonary infarction.–3 Occasi4


Implementation of an evidence-based care bundle in critically ill patients has been shown to improve outcome. Use of care bundles to reduce ventilator-associated pneumonia and other ICU complications has been increasing in critical care practice.We conducted a prospective audit on implementation of a care bundle after audit approval. We collected data for 101 patient days from all patients admitted to Hull Royal Infirmary ICU during the month of November 2011. We collected information regarding stress ulcer prophylaxis, deep vein thrombosis (DVT) prophylaxis, ventilator care bundle, blood glucose control, daily assessment of need for a central line, sedation score assessment and delirium score assessment at least twice a day.All patients received stress ulcer prophylaxis. At least 95% of patients received DVT prophylaxis, adequate blood glucose control and appropriate sedation need assessment. There was further scope for improvement in areas of sedation hold practice and assessing daily need for a central line. Poor clinical practice was identified in delirium score assessment and head elevation to reduce VAP. See Table It is very challenging to implement care bundles despite evidence showing that they improve outcome. A recent study suggests that doing a daily quality rounds checklist (QRC) will improve long-term compliance, thereby reducing potential complications for intensive care patients . We have


Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that carries a high burden of morbidity and mortality. Immune system dysfunction has been undisputedly demonstrated to underlie SSc pathogenesis. In particular, pDCs not only circulate in very high number in SSc patients but also secrete high concentrations of specific chemokines that directly drive various features of SSc, including endothelial dysfunction and fibroblast activation.Plasmacytoid dendritic cells (pDCs) were isolated from whole blood of early diffuse SSc, late diffuse SSc, limited SSc patients or healthy controls. The genome-wide profiling of microRNAs (miRNA) was performed on pDC total RNA by using the Illumina miRNA Profiling Array. Genes targeted by differentially expressed miRNAs were identified thanks to a combination of Miranda, Mirtar and MirPath prediction algorithms.On the quest to decipher why pDCs appear so abundantly in SSc and their activity is deregulated, miRNA profiling was performed. miRNA screening demonstrated that seven miRNAs were significantly over- and two were under-expressed in pDCs from patients with early diffuse SSc compared to late diffuse disease, limited SSc or healthy controls and this profile perfectly correlated with pDC abundance in the different disease stages. According to Miranda, Mirtar and MirPath prediction algorithms, this set of 9 miRNAs is predicted to influence a vast number of target genes, mostly involved in three molecular pathways: 1) leukocyte apoptosis, 2) epidermal growth factor EGFR (ErbB) signaling and 3) WNT signaling. Interestingly, the emergence of the leukocyte apoptosis pathway might provide a preliminary hint on why pDCs are expanded early in SSc. On the other side, ErbB and WNT signaling are ultimately involved in immune response regulation and often linked to the malfunctioning of the immune system in SSc.Altogether these unique observations suggest that SSc-associated miRNAs could strongly impact on cellular pathways involved in SSc pathology, and therefore they would provide an important target for disease prediction and therapeutic approaches.


Local populations of sensory cortical cells exhibit a diverse range of activity patterns. However, classical approaches have neither fully accounted for nor characterized this heterogeneity, especially in response to natural stimuli. First, classical single cell recordings suffered from sampling bias and favored highly responsive cells . Second,We analyzed data sets from two recording sessions in anaesthetized cats viewing natural movies. To quantitatively measure the difference between model predictions and the recording, we used the earth mover's distance  to quant