To study the role of hypotension and associated injuries in increasing the chances of secondary amputation in lower limb with vascular injuries.This study was conducted in the Department of cardiovascular and thoracic surgery( CVTS ), Sher-i- Kashmir Institute of Medical Sciences, ( SKIMS ) Srinagar Kashmir India and comprised all patients sustaining vascular injury due to different causes like road traffic accident, fire arm and blast injuries or falling from height during the last five years. Following admission to our Department, the patients were divided into two groups. The first group with associated injuries was hemodynamically unstable during vascular repair or in post-operative period and the second group had no associated injuries and was hemodynamically stable during vascular repair and in post-operative period.During the past five years, 95 patients were operated for lower limb vascular injury in our department. Of these 25 patients had associated multi-organ injuries and were hemodynamically unstable and needed intensive care monitoring after surgical intervention. Additionally, 10 patients died due to associated multiple organ injuries, 10 needed amputation due to recurrent thrombosis of their anastomosis, and in five patients limb salvage was achieved. Seventy patients who had isolated limb vascular injuries with no associated injuries or hypotension were hemodynamically stable and were kept in low dependency unit after vascular repair. Only Four patients from this group needed amputation for thrombosis of the anastomosis.Patients with shock and related injuries face significant rate of amputation. These patients whether with multi-organ injuries or isolated vascular injuries need judicious treatment for hypovolumic shock during surgical intervention and in post-operative period. Injury to the popliteal vessels has been recognized as one of the most limb-threatening peripheral vascular injuries so far as vascular trauma has been studied. The popliteal artery is a true end artery with a tenuous collateral supply. The popliteal vein provides the bulk of lower limb and foot drainage. This explains why injury to these vessels is so dangerous. Management of these multiply injured patients can be very challenging and restoring perfusion to an ischemic extremity needs to be accomplished within 6–8 hours, if limb is to be salvaged. Clean and sharp cut in the artery closed by primary repair behave differently than an arterial repair with RSV(Reverse saphenous vein graft) graft which needs multiple Fogarty catheterization for retrieval of thrombus. Extensive tissue damage increases chances of compartment syndrome (CS). Post–operative infection and CS are most important causes for amputation. Conventionally there are hard and soft signs of vascular injury. Hard signs which warrant immediate intervention include i) external arterial bleeding, ii) rapidly expanding hematoma, iii) palpable thrill, and audible bruit, iv) signs of acute limb ischemia. Soft signs of vascular injury warrant urgent evaluation in the form color Doppler/angiography. The successful management of vascular injury includes two goals: i) treating the life-threatening problems by fluid resuscitation, control of bleeding and ensuring adequate oxygenation; ii) repairing the injured vessel and save the limb. Arterial repairs include: reverse saphenous vein graft, primary repair, PTFE( polytetrafluroethylene) graft, ligation, and vein patch. CS leads to tissue necrosis, permanent functional impairment, or severe renal failure and death. The general consensus is that intra-compartmental pressures (ICPs) greater than 30mm Hg require intervention. During the first and second world wars, important knowledge had been gained both in diagnosis and treatment of vascular injuries, but vascular reconstructive methods were mainly introduced during the Korean and Vietnam wars with tremendous progress , 2.The studied population included patients with sustained vascular injury due to different causes like road traffic accident, fire arm and blast injuries or falling from height and admitted to our center during the past five years. The patients were divided into two groups of hemodynamically unstable and stable patients during vascular rep air or in post-operative period and notes were taken of their other associated injuries. Severity of injury was assessed by MESS (mangled extremity severity score). All hemodynamically unstable patients during and after surgery, had multiple organ injury and needed intensive care monitoring. However, hemodynamically stable patients were managed in a low dependency unit after vascular repair, and had predominantly isolated lower extremity injury or associated minor injuries. All patients operated for lower limb vascular injury were followed for post-operative outcome with respect to patency of the anastomosis and adequate blood flow for viability of the limb. Distal blood flow was assessed by clinical examination followed by Doppler study to confirm doubtful clinical examination. All patients who needed primary or secondary amputation with MESS score equal to or greater than 7 were excluded from the study. The study included only patients with MESS score of <6 and confirmed to have good vascularity on table by clinical as well as by vascular Doppler examination. Hemodynamic parameters and blood gas analysis were checked during and after operation. Post-operative blood gases and electrolytes were determined four hourly in patients who needed intensive care monitoring. Other associated injuries were taken care of by respective departments including general surgery, plastic surgery, neurosurgery and by critical care specialists.0 double arm prolene. As for associated injuries, the patients referred to other specialties. Hemodynamic parameters, blood gas and electrolytes were checked during the operation.After initial resuscitation and assessment, patients with confirmed arterial injury were operated under general anesthesia immediately following basic work-up. Patients with multi-organ injury were directly shifted to the tertiary care hospital from the spot of injury. Forty patients with isolated limb injury were referred after skeletal fixation by an orthopedist. Exposure was made through an incision in the aspect of knee, approximately central to site of injury. After controlling the affected arterial segment, medial proximal and distal embolectomy was performed, and backflow and inflow were assessed. Arterial repair was done either by primary end-to-end anastomosis or by reverse sephanous vein (RSV) graft. RSV was always taken from contralateral large saphenous vein. Suture material used for anastomosis was always 6During five past years, 95 patients, 87 males and 8 females, aged from 18 to 45 years were operated in our department, for lower limb vascular injury. Younger patients sustained vascular injuries mostly due to motorcycle and fire arm accidents, while older patients received vascular injuries either due to blast injury or fall from height. Following surgical intervention, 25 patients with associated multi-organ injuries needed intensive care monitoring. Of these, 10 patients died due to associated multiple organ injuries, and 10 had amputation due to recurrent thrombosis of their anastomosis, and in five patients limb salvage was achieved, but their functional outcome was not as good as those who never had hypotension during surgical intervention or in post-operative period. After vascular repair, 70 patients with isolated limb vascular damage and no associated injuries were kept in low dependency unit. Patients with isolated limb vascular injury and managed in low dependency unit after surgical intervention never had prolonged hypotension, either during vascular repair or in post-operative period and four patients from this group needed amputation for thrombosis of the anastomosis. One of these patients died due to infectious complications followed by DIC even after amputation. In remaining three, one patient had atherosclerosis, one had hypercoagulabe state for protein C deficiency, and the third patient had no apparent sign of thrombosis of anastomosis.Advances in hemorrhage control, wound care, orthopedic and vascular surgery during Iraq and Afghanistan war have allowed greater attention to shift toward limb salvage efforts. They also suggest that hypotension may result in muscle damage at even lower compartment pressures . PatientPatients with vascular and multi organ injuries ,active hemorrhage and shock have a poor prognosis and demand more urgent management than do patients with isolated limb injuries in which perfusion and blood pressure remains optimal. Shock is associated with a significant rate of amputation. These patients, whether with multi-organ or isolated vascular injuries, need judicious treatment for hypovolumic shock during surgical intervention and post-operative period.


The question whether neural activity follows a rate code or a temporal code is still an unsolved issue in neuroscience. Recent theoretical works have suggested that realistic models of spike-timing-dependent-plasticity (STDP) in recurrent networks could resolve this issue because they observed a seemingly unique relation between the neural code and the resulting pattern of synaptic connections . In partWe have disproved both assumptions. In particular, here we show that already simple STDP models can easily grow bidirectional connections for a temporal code based on spike synchronization unless synchronization is extremely precise (see  for dispThus, both rate coding and temporal coding based on coarse synaptic synchronization can account for the bidirectional connectivity observed, for example, in visual cortex . However


Prostatic stromal hyperplasia with atypia (PSHA) is a rare histologic finding diagnosed incidentally on prostate biopsies, transurethral resection specimens, and radical prostatectomy specimens. PSHA has a bizarre histologic appearance and these lesions often raise concern for sarcoma; however, their clinical course is indolent and does not include extraprostatic progression. We discuss a case of PHSA discovered on prostate biopsy performed for an abnormal digital rectal examination and review the literature on this rare pathologic finding. Prostatic stromal hyperplasia with atypia (PSHA) is a rare histologic finding diagnosed incidentally in specimens from transrectal ultrasound (TRUS-) guided needle biopsy of the prostate, transurethral resection of prostate (TURP), radical prostatectomy, and simple prostatectomy . BecauseA 55-year-old man underwent a 10-core TRUS biopsy for a grossly abnormal digital rectal exam. Histologic examination  revealed PSHA is characterized by one or more ill-defined, uncircumscribed, and hyperplastic stromal nodules infiltrating around benign acini . ImmunohPSHA does not generally present as a symptomatic lesion in and of itself, though symptomatic cases have been reported . In all  This finding has been referred to by a variety of names including: atypical stromal hyperplasia, symplastic leiomyoma, and pseudoneoplastic lesion of the prostate gland. PSHA was previously grouped with low malignant potential findings such as phyllodes tumor and low-grade sarcoma as stromal tumors of unknown malignant potential (STUMP); however, given the univerally benign course of PSHA, this may constitute a misnomer. The current nomenclature emphasizes the expected indolent clinical course with treatment focused on the original disease of interest .


To understand the impact of integrative medicine (IM) therapies on patients receiving care at BraveNet practice-based research network (PBRN) via longitudinal collection of patient-reported outcomes. Previously, the BraveNet PBRN conducted a cross-sectional study including over 4,000 patients receiving clinical care at the 9 IM clinics, which comprise the Bravewell Clinical Network and BraveNet PBRN. This effort provided important information about patients receiving care at these IM clinics as well as the type of medical condition and IM treatments patients were receiving.The current pilot study extends the prior study by collecting patient-reported outcomes every 6 weeks for 6 months from patients receiving various types of IM services . Patients are asked to complete demographics, substance use, exercise habits, Perceived Stress Scale, Arizona Integrated Health Outcomes, and Patient Related Outcomes Measurement Information System-29  measures. Questions examining the patients’ prior IM history, perceived benefits of IM treatments, and satisfaction with IM clinic are also included. Medical records are reviewed to obtain billing and healthcare utilization information. While electronic questionnaires are completed using the REDCap (Research Electronic Data Capture) system, patients may also complete the questionnaires via paper format.The Penny George Institute for Health and Healing  has been successfully piloting this project and 200 participants are enrolled to date. Additional BraveNet PBRN sites are joining the pilot study and expanded results of the entire pilot study will be presented.Practice-based research and patient-reported outcome measures will be key factors in demonstrating the effectiveness of IM interventions in the treatment of many clinical conditions. Multicenter participation provides increased enrollment and allows for generalizability of results from which future randomized controlled trials may be developed.


Gene expression profiling has been widely used to study molecular signatures of many diseases and to develop molecular diagnostics for disease prediction. Gene selection, as an important step for improved diagnostics, screens tens of thousands of genes and identifies a small subset that discriminates between disease types. A two-step gene selection method is proposed to identify informative gene subsets for accurate classification of multiclass phenotypes. In the first step, individually discriminatory genes (IDGs) are identified by using one-dimensional weighted Fisher criterion (wFC). In the second step, jointly discriminatory genes (JDGs) are selected by sequential search methods, based on their joint class separability measured by multidimensional weighted Fisher criterion (wFC). The performance of the selected gene subsets for multiclass prediction is evaluated by artificial neural networks (ANNs) and/or support vector machines (SVMs). By applying the proposed IDG/JDG approach to two microarray studies, that is, small round blue cell tumors (SRBCTs) and muscular dystrophies (MDs), we successfully identified a much smaller yet efficient set of JDGs for diagnosing SRBCTs and MDs with high prediction accuracies . These experimental results demonstrated that the two-step gene selection method is able to identify a subset of highly discriminative genes for improved multiclass prediction.


Pain responses can be suppressed by heterotopic continuous noxious conditioning, e.g. continuous noxious cold stimulation.These diffuse noxious inhibitory controls (DNIC) may be abnormal in migraine . DNIC eWe examined in healthy volunteers blood oxygenation level dependent (BOLD) responses in prefrontal cortex to repeated continuous noxious cold stimulation. The relationships between those responses and degree of inhibition of laser-induced pain during heterotopic cold stimulation were analyzed.Our results show that cold-induced BOLD response in anterior cingulate, orbitofrontal and lateral prefrontal cortices predict cold-induced heterotopic analgesia and attenuation of cerebral BOLD responses to laser stimulation. Prefrontal responses to the onset of cold stimulation were strongly related to the subsequent DNIC effect.We conclude that early responses to noxious conditioning are important for prediction of the analgesic DNIC effect. We hypothesize that this predictive effect of frontal cortices may be abnormal in chronic migraine.


Rapid and efficient selection of emotionally salient or goal-relevant environmental stimuli is crucial for flexible and adaptive behaviors. Emotional events rapidly and automatically capture attention by activating subcortical neural structures Ohman, . BehavioWith regard to the interaction of emotion and attention, there are unsolved and controversial issues. For example, to what extent does emotional stimulus processing depend on attentional resource availability? Previous studies have shown conflicting results, probably due to several factors, including attentional load allocated to competing tasks. Some studies have demonstrated that emotional faces evoke amygdalar responses even when attention is diverted to other stimuli, suggesting that some types of emotional perception occur outside of top-down directed attention  and two ignore-faces conditions (easy and difficult digit/letter-matching tasks). The behavioral data suggested that the experimental design successfully controlled the attentional load and perceptual properties of emotional stimuli  presented foveally or peripherally in the visual field. Their study resulted in two main findings. First, amygdalar activity was strongly suppressed during high attentional loads, which suggests that emotional information processing might be suspended when attention-demanding cognitive tasks are performed simultaneously. Although this finding is not new (Pessoa, Morawetz et al.  directly Pessoa, , this waIn summary, Morawetz et al.  provided


Examining process rates alone may obscure the microbial physiological mechanisms that underlie climate-induced changes in soil C cycling, leading to contradictory patterns among different studies. For instance, in a large-scale survey of soil protease activities from climate manipulations, drier and warmer conditions resulted in lower extracellular enzyme activities (EEA) compared to ambient conditions (Brzostek et al., In this issue, Steinweg et al.  examine These findings challenge our existing knowledge about the mechanisms driving EEA in soils. In the laboratory, EEA increases linearly with temperature over the narrow temperature range observed here (German et al., The work of Steinweg and colleagues is an example of how shifts in gross process rates emerge from multiple interacting microbial mechanisms. However, these physiological feedbacks are often not incorporated into biogeochemical models. For instance, despite ample evidence that soil microbes shift allocation to enzyme production depending upon resource availability, EEA is often modeled simply as a function of the microbial biomass pool size. This approach may be valid in some ecosystems under steady state conditions or during the growing season (Kivlin and Treseder, Shifts in intracellular C allocation may also affect element cycling at the ecosystem scale if the stoichiometric requirements of the microbial biomass are altered. Steinweg and colleagues found that enzyme ratios varied with season, indicating higher microbial C vs. N demand in the winter. They suggest that changes in enzyme stoichiometry may reflect increased microbial maintenance cost during freeze-thaw cycles, which impose a high C cost on the microbial biomass. Shifts in biomass C:N have also been observed in response to altered substrate stoichiometry (Fanin et al., Based on the findings of Steinweg et al.  many of While Steinweg et al.  focus onMultiple processes will have large consequences for soil C storage in future climates, including climate controls on enzyme production and turnover, and tradeoffs in microbial allocation to growth, respiration, and resource acquisition. Yet, because all of these processes interact, the effects of climate change on soil C pools and fluxes can be extremely variable. As Steinweg and colleagues demonstrate, measuring mass-specific microbial responses is the first step toward improving our understanding of microbial physiological responses to altered climate regimes. However, studies that simultaneously examine the links among these mechanisms will be necessary to predict when tradeoffs in microbial C allocation occur and their long-term effects on soil C storage. By viewing ecosystem responses to temperature and precipitation through the lens of microbial physiology, we may arrive at a more mechanistic understanding of soil feedbacks on climate change.


Globally, forests store ~45% of carbon sequestered terrestrially, contribute more to the terrestrial sink per area than any other land cover type, and assimilate an important portion of anthropogenic emissions Bonan, . ForestsThe justification for physiological research on drought-induced tree mortality is often stated as a need to improve the predictive capability of vegetation models through incorporation of mortality mechanisms  must be simulated across the Earth. Dynamic global vegetation models (DGVMs) coupled with general circulation models are a common tool for simulating vegetation response to climate change , derived from tree-ring records and predictable from regional climate, is highly correlated with forest mortality in the southwest USA  improved experimentation to distinguish physiological causes from symptoms, (2) continued model development based on existing knowledge and emerging discovery, (3) improved model validation against both experimental results and regional-scale mortality observations, and (4) high-resolution measurement of forest composition at large scales. While ecologists studying tree mortality have favored investigating physiological mechanism, measuring species composition and mortality at high resolution across regions is crucial for providing baseline observations to constrain model predictions. Without improved input on current forest conditions, even accurate models of forest mortality cannot generate useful predictions of change.


Age-related macular degeneration (AMD) is the most common cause of legal blindness among the elderly in developed countries. The prevalence of advanced forms of AMD is increasing; it is expected to rise by 50% by the year 2020 in the United States. Early identification of AMD susceptibility and implementation of preventive measures are important management strategies. Antibodies against vascular endothelial growth factor (VEGF) have become the treatment of choice in patients with choroidal neovascularization (CNV); however, substantial improvement of vision occurs only in approximately one-third of patients. Early diagnosis and treatment of CNV may increase the success rate of treatment.Standard diagnostic modalities including fundus angiography and optical coherence tomography can detect CNV in clinical stages when vision is affected. In a novel approach, Takeda and coworkers evaluated the role of an eosinophil/mast cell chemokine receptor, CCR3, in CNV. They studied CCR3 expression among patients with AMD and previously untreated surgically excised CNV membranes, donor eyes of age-matched non-AMD controls, atrophic AMD, uveal melanoma, and surgically excised epiretinal membranes. Additionally, in vivo CCR3 bioimaging was performed in transgenic mice with spontaneous CNV using intravenous quantum-dot labeled CCR3 antibody fragments followed by fundus fluorescent imaging which demonstrated hyperfluorescent signals in regions of the fundus that were silent on standard fluorescein angiography. These hyperfluorescent dots were subsequently confirmed to be CNVs using histologic examination. The investigators showed that CCR3 was specifically expressed in the endothelial cells of all human CNV membranes but not in other conditions. Interestingly, they found that CCR3 neutralization was superior to VEGF blockade in suppressing laser-induced CNV in mice. Considering emerging safety concerns about continual blockade of VEGF, which is constitutively expressed in the normal adult human retina and needed for retinal health, a treatment strategy based on more specific targeting of CNV would be desirable.These findings suggest that CCR3 targeting may be a viable strategy for early detection and treatment of CNV, and might be superior to the current standard of care. CCR3 bioimaging would probably be most useful in eyes at high risk for CNV such as multiple large drusen or sound fellow eyes of patients with clinically evident CNV; it can also serve as a useful tool for differentiating lesions mimicking CNV.


Background. Aberrant right hepatic duct (ARHD) draining intocystic duct (CD) is relatively rare but clinically importantbecause of its susceptibility to injuries during cholecystectomy. These injuries are often-times missed or diagnosed late and as aresult can develop serious complications. Methods. Fourconsecutive patients diagnosed with ARHD draining into CD wereidentified for inclusion. Results. The mean age of patients was42.5 years. The diagnosis in one of the patient was incidentalduring a routine endoscopic retrograde cholangiopancreatography(ERCP). Other three patients were diagnosed post-cholecystectomy-one presented with suspected intra-operative biliary injury, onewith persistent bile leak and another with recurrent cholangitis. Inadequate filling of the segment of liver on ERCP with dilationof intrahepatic ducts in the corresponding segment on imaging waspresent in two patients with complete obstruction of ARHD whichwas managed surgically. In another patient, the partiallyobstructed ARHD was managed by endoscopic therapy. Conclusion. ARHD draining into the CD can have varied clinical manifestations. In appropriate clinical settings, it should be suspected inpatients with persistence of bile leak early aftercholecystectomy, segmental dilation of intrahepatic-bile ducts onimaging and paucity of intrahepatic filling in a segment of liveron ERCP. Bile duct injury is an uncommon complication following cholecystectomy. With the increasing use of laparoscopic cholecystectomy (LC), there has been an associated increase in the incidence of bile duct injuries . Early s Therefore, the knowledge of various biliary anomalies and their early identification may further assist in decreasing the rate of biliary tract injuries. Here we present a case-series on various presentations and management of a rare anomaly of biliary tree.A 55-year-old woman presented 3 days postcholecystectomy (LC) with upper abdominal pain. HIDA scan revealed a bile leak. ERCP with minimal contrast injection revealed a leak from cystic stump; therefore a 10 F biliary stent was placed. Six weeks later a repeat ERCP revealed no leak from the cystic duct stump. However, large branch of the right intrahepatic duct was filled through the cystic duct stump . MinimalA 38-year-old Caucasian woman was referred to our hospital for recurrent episodes of gram-negative bacteremia. On presentation she was asymptomatic. Her past surgical history was significant for complicated cholecystectomy requiring conversion from laparoscopic to open technique six years earlier when she was 28 weeks pregnant. The surgical report described normal common and cystic ducts and described bile staining within the hilum where a drain was placed. After a few days drainage stopped and drain was removed. She was found to have minimally abnormal LFT's during a routine blood workup, a year after the surgery. Ultrasound at that time demonstrated dilated biliary tree in a segment of the right lobe of the liver and an ERCP revealed a questionable cystic dilation of distal common bile duct (CBD), for which sphincterotomy was performed. She had recurrent episodes of fever in the subsequent years and blood cultures persistently grew Klebsiella species. Computerized tomography (CT) scan  and MRCPA 27-year-old healthy young woman with history of generalized fatigue presented for further evaluation of abnormal liver biochemistries. Her alkaline phosphatase levels had nearly increased 3 times the upper limits of normal. The most recent LFT revealed elevation of aspartate aminotransferases (AST) (104 U/L) and alanine aminotransferases (ALT) (234 U/L), which were reported as normal two years ago. An abdominal ultrasound showed no focal lesions. MRCP was performed which did not reveal any abnormal findings. Clinical examination was normal. In view of strong clinical suspicion of sclerosing cholangitis, ERCP was performed which revealed diffuse multifocal strictures with beading of intrahepatic ducts bilaterally, suspicious for primary sclerosing cholangitis. An aberrant branch of right hepatic duct draining into CBD with cystic duct originating from the aberrant branch was noted on ERCP .A 50-year-old woman presented with symptomatic cholelithiasis. Elective LC was attempted at an outside facility. Intraoperative cholangiogram (IOC) was interpreted as-right intrahepatic ducts filling without opacification of mid-CBD and CHD. Surgery was aborted in view of suspicion of bile duct injury. Two JP (Jackson-Pratt) drains were placed and she was referred to our center. ERCP performed at our center revealed cystic duct remnant leak and staples were noted close to CBD. There was inadequate filling of intrahepatic ducts in a segment of right hepatic lobe . SphinctAberrant right hepatic duct (ARHD) is branch providing biliary drainage to variable portion of right hepatic lobe and drains directly into the extrahepatic biliary tree. ARHD is a common bile tract anomaly with the incidence of 4.6%–8.4% and it frequently drains into common hepatic duct, CBD or even left hepatic duct . HoweverIOC during LC has been utilized to identify anatomic variants of biliary tract, even though it's routine use is debatable . While sPersistent bile leak may be an initial presentation of injury to the ARHD during cholecystectomy . These pLess frequently, patients with ARHD injury can present in the postoperative period weeks to months later, with cholestatic pattern of abnormality on LFT's, if the aberrant duct is blocked. In addition, these patients can also present with episodes of cholangitis in the obstructed segment of biliary tree as was the case with our second case. A high index of suspicion is required to look for these complications. Segmental dilation of intrahepatic ducts may be revealed on a CT-scan. These patients will require cholangiography (PTC or ERCP) to define the anatomy of biliary tree. Scantiness of intrahepatic filling on ERCP with dilation of intrahepatic branches in the same sector on radiologic imaging should be a useful clue to the diagnosis of obstruction of aberrant branch of bile duct. PTC can be performed when intrahepatic ducts are dilated; sometimes both the procedures may be required to obtain the diagnosis  as was tUsually, the initial management of patients presenting with a bile leak after LC is decompression of biliary tree by placing a stent with or without sphincterotomy or placement of naso-biliary drain or percutaneous drain . If an aThe diagnosis of aberrant right hepatic duct draining into cystic duct can be incidental during ERCP or MRCP if performed before surgery, as in our third patient. In these situations, the knowledge of aberrant anatomy of biliary track would be important for a surgeon to avoid any inadvertent complications if they undergo cholecystectomy or any other biliary surgery. In addition, the safe approach to avoid injury to aberrant bile-ducts during cholecystectomy is adhering to the gallbladder itself, identifying the triangle of Calot and using the “critical view of safety (CVS)”, as described by Strasberg, before dividing the cystic structures. CVS involves 3 steps: (i) clearing triangle of Callot of fat and fibrous tissue, (ii) separation of lowest part of GB from liver bed, (iii) only 2 structures (cystic artery and cystic duct) should be seen entering GB .  In summary, we present a varied clinical presentation and management of a relatively rare but clinically significant anatomic variation of bile duct anatomy. Aberrant bile-duct injury is often missed as subtle signs of injury remain unrecognized both by surgeons as well as by gastroenterologists. Aberrant bile duct injury after cholecystectomy should be strongly suspected in following situations: (i) paucity of intrahepatic filling in a segment of liver on ERCP; (ii) abnormal LFTs with segmental dilation of intrahepatic-bile ducts on abdominal CT-scan or ultrasound.


They provide a broad overview of the important advances that such mechanistic studies in Drosophila have made to our understanding of the age-related decline in muscle mass and strength, immune response, stress resistance, sexual behavior, and cognitive function. Walton and Pizzitelli (Caenorhabditis elegans. The authors dissect molecular and cellular mechanisms through which the spatiotemporal dynamics of unsaturated fatty acids regulates longevity by modulating the Nuclear Hormone Receptor signaling and maintaining the integrity of various organellar membranes. They also explore the mechanistic links between hydrolysis of neutral lipids and several longevity-defining processes, discuss how lipid-derived signaling molecules impact signaling networks central to longevity assurance, and outline the essential roles of mitochondrial membrane lipids in longevity regulation via multiple cellular pathways. Postnikoff and Harkness (Aging of multicellular and unicellular eukaryotic organisms is a highly complex biological phenomenon that affects a plethora of processes within cells. This wide array of longevity-defining cellular processes—which are governed by an evolutionarily conserved signaling network—includes oxidative metabolism and protein synthesis in mitochondria, lipid, and carbohydrate metabolism, NADzzitelli  demonstrzzitelli  explore zzitelli  provide Harkness  offer usHarkness  outline Harkness  provide Harkness  summarizHarkness  provide


Luminescent colloidal quantum dots (QDs) possess numerous advantages as fluorophores in biological applications. However, a principal challenge is how to retain the desirable optical properties of quantum dots in aqueous media while maintaining biocompatibility. Because QD photophysical properties are directly related to surface states, it is critical to control the surface chemistry that renders QDs biocompatible while maintaining electronic passivation. For more than a decade, investigators have used diverse strategies for altering the QD surface. This review summarizes the most successful approaches for preparing biocompatible QDs using various chemical ligands. These applications require an appropriate fluorescent probe having specific chemical and optical properties. Organic and genetically-encoded fluorophores generally have narrow absorption, broad emission, and are vulnerable to continuous irradiation by the excitation source which limits their usefulness in some applications such as multiplexed measurements, long-term imaging, and single molecule imaging, among others ..83].4.2.n-alcanoic acids  (PE-PEG) was the attached to SiO2-OTMS-coated QDs through hydrophobic interactions [2 and PE-PEG showed similar brightness over pH 1–14. They also evaluated the cellular toxicity of these nanoparticles with and without embedded QDs and found that the toxicity is purely due to the exposure of bare nanoparticles, indicating QDs were adequately protected within the silica spheres with no appreciable leaching of heavy metals [Gao’s group  found thractions . As Figuy metals .5.To enable the use of QDs in a wider range of biological applications, all of the preceding methods require a route for attaching biomolecules stably onto the QD surface. A suitable ligand candidate should allow attachment of a diversity of biomolecules including nucleic acids, proteins , polysaccharides, and peptides. Biomolecules are commonly conjugated to the QD surface through the following approaches : (1) cov6.in vivo diagnostics and treatments.Biocompatible QDs are typically generated through either an organic synthetic route requiring subsequent ligand exchange or encapsulation, or a more direct aqueous synthetic route where the nanocrystals are inherently water-soluble. There are nearly countless variations of these methods reported in the literature where each protocol carries its own inherent advantages and disadvantages and must be considered in light of the eventual application. A ligand exchange procedure that uses small charged molecules can maintain minimal hydrodynamic diameters, but they are usually more susceptible to aggregation in biological buffers or solutions of high ionic strength. These compact capping ligands often fail to maintain suitably high luminescence without additional processing. Methods that improve the density of ligands on the QD surface while ensuring a strong binding interaction appear to have the most promise. Polymer and silica coatings are better able to isolate QDs from solution which results in improved colloidal stability, limited non-specific binding, and high QY. However, these characteristics are often achieved at the expense of compact size which can impede cellular mobility  and limi


In trial design, decisions are made about which intervention components/processes to standardise and which remain flexible to maximise utility and/or effectiveness. The intervention-context-system fit for complex interventions impacts on trial recruitment, delivery and outcomes. Survey vignettes and discrete choice experiments are quantitative researcher led approaches which focus on a few measurable attributes. Our aim was to explore the utility of qualitative vignettes as a methodological tool allowing service users/providers to contribute to intervention design.A case series of four acceptability and feasibility studies  with service users and providers. Data were collected at different pre-trial stages: i) vignettes of studies in a systematic review of incentives for breastfeeding and smoking cessation in pregnancy, subsequently modified following emergent qualitative analysis; ii) emergent vignettes in the last of up to 8 serial qualitative interviews investigating infant feeding behaviour, following a systematic review showing poor generalizability of effective interventions in the UK context; iii) intervention vignettes of an effective intervention (groups for weight management) to refine the design for a new population (women treated for breast cancer) and iv) emergent intervention vignettes explored at a second interview with obese older adults.Illustrations of how qualitative vignettes can complement quantitative design tools will be presented.Carefully constructed qualitative vignettes combining known effective and emergent promising intervention aspects can optimise trial design. When talking service users and providers through a potential intervention, different perspectives emerge compared with responses to closed or more abstract questions.


Eating disorders (ED) are chronic, deadly illnesses and especially for adults with anorexia nervosa, existing treatments have limited proven efficacy. Growing knowledge about the neural underpinnings to ED provides an avenue for more targeted, brain directed interventions. Brain stimulation techniques, such as Transcranial Magnetic Stimulation (TMS), transcranial Direct Current Stimulation (tDCS), Vagus Nerve Stimulation (VNS) and Deep Brain Stimulation (DBS) have the ability to directly alter neural activity within the brain. Such methods are being used extensively within both research and clinical settings to treat movement disorders such as Parkinson's and a range of psychiatric illnesses including depression. Findings within such disorders, relevant animal models and more recent research within ED populations have led to a strong rationale for the use of brain stimulation in ED. This paper systematically reviews this literature, identifying deficits in the current knowledge in an attempt to help guide future research and clinical practice within the imminent field of brain directed interventions for ED.Understanding and Treating Eating Pathology stream of the 2013 ANZAED Conference.This abstract was presented in the


Biomedical imaging is a rapidly growing field to provide a state-of-the-art tool for preclinical biomedical research and clinical applications, in view of its ability to noninvasively reveal subtle structural variations of biological tissues and visualize in vivo physiological and pathological processes at the cellular and molecular levels. Mathematical methods are involved with imaging theories, models, and reconstruction algorithms in biomedical imaging. X-ray computed tomography (CT) was a successful application of mathematical method in medical imaging. The CT mathematical model can be reduced to a Radon transform. The inverse transform of Radon transform is invented by Radon in 1917. Magnetic resonance imaging (MRI) is a versatile medical imaging modality. MRI can provide more diagnostic information than any of the existing imaging techniques. It does not involve the use of ionizing radiation, hence free from associated harmful effects. Inverse Fast Fourier Transform (IFFT) is a standard method of image reconstruction in MRI from uniformly sampled K-space data. From nonuniform K-space data, iterative algorithms can improve image quality of image reconstruction for MRI. In the optical molecular imaging, the radiative transport equation (RTE) is the fundamental equation to describe photon propagation in biological tissues. The forward solution predicts photon propagation in the optical molecular imaging. The inverse solution can reconstruct molecular probe distribution in a small animal for providing unique insights into disease pathogenesis, drug development, and responses of therapy. The solutions for RTE usually involve analytical methods, Monte Carlo (MC) method, diffusion approximation (DA) method, simplified spherical harmonics method, and some numerical methods.In this special issue, each paper was reviewed by at least two reviewers and revised according to review comments. This special issue covered most of common biomedical imaging models and various image processing methods, such as registration, segmentation, and so forth, were involved. For Positron Emission Tomography (PET) imaging model, two attenuation correction methods based on X-rays CT (CTAC method) and segmentation of emission images (SE-AC method) were simulated with Monte Carlo method and compared. For synchrotron Micro-CT imaging model, a semiautomatic segmentation algorithm for extracting the complete structure of acini has been proposed. For ultrasound imaging model, a common carotid artery segmentation scheme based on active shape model can get better result and promote the translation of carotid 3D US to clinical care for the monitoring of the atherosclerotic disease progression and regression. For MRI model, a mesh-deformation constraints based image registration algorithm was carefully investigated. Also the development of image segmentation for intracranial aneurysms and rotation covariant image processing method for biomedical applications are summarized. Furthermore, in order to accelerate the parallel imaging, a sparse constrained reconstruction approach with variable splitting methods was proposed and verified: total variation (TV)-minimization interior tomography algorithm, dynamic and robust blind watermarking scheme to resist against common distortions, modified global and modified linear contrast stretching techniques for identification of various stages and species of malaria, a 3D surface-based deformable model as guidance for nonrigid 3D medical image registration and fusion, mathematical or computational modeling for oncogene inactivation, a group factor analysis model for neuroimaging applications by assigning separate factor patterns to control and patient groups yielding more reasonable factor scores and patterns, different MISO Volterra methods to model simulated ultrasound contrast agents signals, an automated process that determines whether an aortic object in a slice is a candidate for aortic dissection or PAU based on contrast enhanced CT data, image-based computational techniques to quantify the severity and directionality of individual scratches and scrapes, combination of genetic algorithm and closed loop to obtain optimal ternary command which maximized the contrast to tissue ratio, and magnetoacoustic tomography with magnetic induction (MAT-MI) for generating electrical conductivity images of biological tissues with high spatial resolution. An acceleration strategy for fluorescence molecular tomography (FMT) with early photons is proposed using graphics processing units (GPUs). The fluorescence molecular tomography (FMT) with early photons can efficiently improve the spatial resolution and fidelity of the reconstructed results. An efficient compressed sensing-based algorithm is proposed for CT image reconstruction from few-view data to suppress the streak artifact. The compressed sensing (CS) algorithm shows the potential to accurately recover images from highly undersampled data. The discriminant analysis techniques are discussed using MRI to identify the correlative pattern of brain changes for differentiating parkinsonian syndromes. A hybrid multiscale and multilevel image fusion algorithm for green fluorescent protein (GFP) image and phase contrast image of Arabidopsis cell is proposed. This algorithm uses different fusion strategies for different detailed subbands, which include neighborhood consistency measurement (NCM) that can adaptively find balance between color background and gray structure. A detrended fluctuation analysis (DFA) method is applied to image analysis to investigate the characteristic of different type of simulated and lymphoma image. A method is presented to estimate the tilt and decentration of intraocular lens (IOL) more accurately. The Bayesian hierarchical model for the analysis of categorical longitudinal data is investigated from sedation measurement for MRI and CT. In vivo MRI of local drug delivery is discussed to visualize and quantify the time resolved distribution of MRI contrast agents.These papers represent an insightful observation into the state of the art, as well as future topics in this biomedical imaging field. We hope that this special issue would attract a wide attention of the peers.Wenxiang CongKumar DurairajPeng Feng


Although the advent of MRI impacted significantly our presurgical investigation, ictal semiology with interictal and ictal EEG has clearly retained its roles in localizing epileptogenesis. MRI-identified lesions considered epileptogenic on semiological and electroencephalographic grounds have increased the likelihood of resective surgery effectiveness whereas a nonlesional MRI would diminish this probability. Ictal propagation and the interplay between its source and destination have emerged as a significant component of seizure evaluation over the past 30 years. Epilepsy and Functional Anatomy of the Human Brain [Ictal semiology and EEG dominated our localization of intractable epileptogenesis prior to the introduction of MRI. Dr. John Girvin and I each attempted to outdo the other in obtaining patient and observer descriptions of the patients' seizures, guided by the most comprehensive observations and perceptions documented by Wilder Penfield and Herbert Jasper in an Brain . SeizureIn addition to Penfield's identification for a semiological pattern as representing temporal lobe epilepsy and subsequent description of mesial temporal ictal semiology , subsequThe works of International League against Epilepsy Commissions on Epileptic Seizure Classification and Terminology have, in sequential fashion, clarified our clinical analyses. The 1981 ILAE Commission classified partial  seizures into simple partial (consciousness preserved) and complex partial (consciousness impaired). This division has encountered clinical and heuristic limitations as it depends upon evaluating an entity—consciousness—that can neither be defined nor assessed. Gloor  discusseCombined with ictal semiology, ictal and interictal EEG were the principal tools before the mid-1980s to localize epileptogenesis in virtually all patients whose intractable focal epilepsies required resective surgery for alleviation. Focal temporal interictal spikes, if predominant over one temporal lobe, lateralised temporal lobe seizure origin in over 90% of patients [For many years, nasopharyngeal or sphenoidal EEG leads supplemented the Ten Twenty EEG electrode system to better record anterior-mesial temporal EEG activity, especially spikes. As illustrated by F. A. Gibbs and E. L. Gibbs , the antOur group at Western/University Hospital was the first to formally study and describe the morphology of scalp-recorded focal seizures-temporal and extratemporal . Recognisubdural electrodes. Inserted as imbedded in silicon strips through burr holes to avoid a craniotomy during the patient's evaluation, these electrodes record directly from the cortical surface. Moreover, they may extend to mesial and inferior cortical surfaces, areas remote from scalp electrodes. For patients with temporal lobe epilepsy, SDE provides more precise and sensitive ictal and interictal recording from the mesial temporal regions. In 1979, Dr. John Girvin and Mr. Dan Jones, EEG technologist, designed Commercially manufactured subdural electrodes were not available in the early 1980s, resulting in some other epilepsy centres purchasing our in-house-manufactured electrodes. Design and manufacture of SDE at UH without any complication continued by Dan Jones and Frank Bihari for over 20 years. Figures However, in 2004 London Health Sciences Centre chose to make use of commercially produced electrodes, though at a significantly greater cost. Our centre was the first to routinely employ subdural electrodes (SDE), and they continue today as a major part of evaluation of about 50% of our patients ultimately operated upon. We studied 27 consecutive patients whose temporal lobe epilepsy clinically implicated both temporal lobes from ictal semiology, scalp EEG, and imaging features. We found that the side of SDE-recorded seizures correlated with that containing most scalp spikes and most scalp-recorded seizures in most but not all patients, confirming the value of both EEG and SDE .Although unable to detect small cortical epileptogenic lesions, plain skull X-rays had disclosed several cranial and intracranial abnormalities of lateralising value. Cranial erosion on skull roentgenography could have resulted from a previous wide fracture or from a subdural or subarachnoid cyst; one or more asymmetrical cranial features may have indicated cerebral hemiatrophy, compatible with accompanying epileptogenesis; intracerebral calcification may have represented tumours or congenital lesions. Pneumoencephalography disclosed displaced or deformed ventricles from tumours, abscesses, hematoma, and other lesions. Cerebral arteriography helped localize expanding lesions but proved less helpful in the study of atrophic lesions . A major advance in evaluating patients for temporal lobe surgery was the advent of MRI. Imaging afforded by MRI discloses focal structural abnormalities underlying intractable epilepsy that may remain undetected by earlier neuroimaging methods . SubsequThree common epileptogenic lesions are particularly well displayed by MRI: mesial temporal sclerosis, cortical dysplasia (CD), and benign tumours such as dysembryoplastic neuroepithelial tumours (DNETs) and gangliogliomas (GGL). Rhythmic epileptiform discharges (REDs) may characterize the scalp EEGs of those with focal CD ; abundanThe presence or absence of mesial temporal sclerosis (MTS) became far better displayed by MRI than any previous imaging modality. This greatly facilitated, with EEG, an assessment as to whether one or both temporal lobes are epileptogenic. In the latter instance, assessment of their relative epileptogenicities may influence a surgical decision. In some patients, MRI and EEG (via REDs) have demonstrated both MTS and CD with comparable epileptogenicity in each, termed “dual pathology” , 19. OriThe appearance of dual pathology in some patients augmented our awareness of seizure propagation and its influence on semiology. Thus, ictal symptoms and signs may signify the site of seizure spread rather than origin. Both normal cerebral connectivity and neuronal pathways developed in the process of epileptogenesis likely participate in seizure spread. For example, occipital seizures may propagate to the mesial temporal region via the “ventral stream,” a multisynaptic pathway that terminates primarily in the amygdala but also in the parahippocampal area . Munari personal communication). However, often a full temporal lobectomy has been performed . Surgical approach and technique have not measurably changed over the years.Three approaches to the mesial temporal region have been described: sylvian fissure, middle temporal gyrus, and inferior temporal pole . Our surThat a substantial left temporal lobectomy will significantly impair verbal memory has become increasingly realized over the past decades creating a distinction between left and right temporal epilepsy in terms of surgical candidature , 25. Con


This study is the first to use quantitative perfusion CMR to evaluate regional differences in myocardial blood flow (MBF) in patients with left bundle branch block (LBBB).LBBB is often associated with underlying CAD but its presence can limit the diagnostic accuracy of non-invasive imaging tests. In particular, there is a high incidence of false-positive results with exercise SPECT due to apparent septal perfusion defects. The use of vasodilator stress has reduced but not eliminated this problem. Several hypotheses have been postulated to explain the cause of such perfusion defects, and these include early activation of the septum, leading to shortened diastole and reduced blood flow; partial volume effects caused by impaired septal thickening; and increased septal intra-myocardial pressure during diastole, resulting in reduced flow reserve. A number of small studies using PET or early quantitative SPECT techniques have evaluated regional differences in MBF in patients with LBBB, but the results have been conflicting and have shown either no regional differences or a relative but not absolute reduction in septal perfusion. This study re-evaluates the unresolved question of septal perfusion in LBBB using quantitative perfusion CMR.9 patients with LBBB and no significant CAD underwent adenosine stress/rest perfusion CMR at 1.5T and X-ray coronary angiography. Absence of CAD was defined as luminal stenosis <40% on quantitative coronary angiography in all major vessels. Mid-ventricular perfusion data were segmented into 3 regions for each patient: septal, adjacent (anterior-inferior) and lateral. MBF and myocardial perfusion reserve (MPR) were then determined for the septal and lateral regions by Fermi function deconvolution.Resting MBF was similar in both septal and lateral regions in all patients  .


Coincident expression of otherwise unrelated inborn errors of metabolism may occur as a result of large deletions of multiple gene, referred to as the contiguous gene deletion syndrome. We describe two male infants who presented with failure to thrive and raised urinary glycerol levels, leading diagnosis of glycerol kinase deficiency, congenital adrenal hypoplasia and myopathy.These clinical diagnoses, suggest Xp21 contiguous gene deletion syndrome.The two male infants currently 48 months and 3 months old, presented with failure to thrive at 10 months and 1 month of age respectively. On evaluation for metabolic causes of poor weight gain, urine organic acids showed high levels of glycerol. Further results revealed pseudo-hypertriglyceridemia which raised the suspicion of glycerol kinase deficiency. Both infants were persistently hyponatremic and hyperkalemic, and the synacthen test showed a suboptimal cortisol peaks. Plasma renin was high with low aldosterone indicating mineralocorticoid defiency.The older male infant who presented at 10 months of age also had significant developmental delay with muscular weakness and markedly raised creatinine kinase.He was confirmed to have Duchene Muscular Dystrophy.Both the infants were started on steroid and salt replacement and monogen feeds containing medium chain triglycerides. Their weight improved with normalization of sodium & potassium levels. The above spectrum of clinical & biochemical features is consistent with a diagnosis of Xp21 contiguous gene deletion syndrome. Although rare, raised urinary glycerol and serum triglycerides leads to suspicion and allows early recognition of this condition, where prompt treatment can prevent life-threatening adrenal crises.


Dilated cardiomyopathy (DCM) occurring due to an unknown etiology or genetic predisposition is termed as idiopathic dilated cardiomyopathy (iDCM), although iDCM may also result from viral exposure. However, the incidence of myocardial inflammation and its relation to left ventricular (LV) function in iDCM remains unknown.Cardiovascular magnetic resonance (CMR) imaging allows for the visualization of myocardial inflammation using early Gadolinium enhancement (EGE). We applied EGE imaging in the setting of clinically suspected iDCM to determine both the incidence and relation of myocardial inflammation to LV function.26 patients  were referred to us for the assessment of iDCM following a clinical suspicion of iDCM, based upon the following criteria: ejection fraction below 45%; invasive exclusion of significant coronary artery disease using a cutoff of 50% stenosis; stable clinical course for at least 3-months prior to the CMR study; exclusion of myocarditis within the past 12 months; as well as exclusion of comorbidities which may otherwise account for patient presentation including valvular heart disease.Standard CMR imaging procedures for the assessment of LV function and EGE were utilized. EGE images were acquired before and early after (over 4 minutes) Gd-DTPA 0.1ml/kgBW contrast injection using T1-weighted images.LV function was assessed by manually tracing endo- and epicardial contours. Myocardial signal intensity was normalized to skeletal muscle, generating a ratio that had to be greater than or equal to 4 to be considered positive for EGE.Eighteen patients (69%) presented with EGE and a significantly increased EGE ratio . The ratio of EGE correlated with LVEDVI  and LVESVI , LVSVI , and LVEF . Patients with elevated EGE had significantly dilated left ventricles and globally reduced ventricular function: LVEDVI  and LVESVI  were increased, while LVSVI  and LVEF  were reduced (Figure Using CMR-based EGE as a surrogate marker of myocardial inflammation, we provide first evidence for a high incidence of inflammation in patients with clinically suspected iDCM. The extent of myocardial enhancement was directly related to reduced ventricular function. CMR-based assessment of myocardial inflammation may be utilized as a biomarker for patient prognosis and guide medical therapy to target those patients in whom there is active myocardial inflammation.


This case report illustrates two unusual cases of parapharyngeal schwannomas mimicking carotid body tumors in terms of characteristic vascular displacement. Carotid body tumors classically cause splaying of internal and external carotid arteries demonstrating the Lyre sign on imaging. Also interestingly, both of these cases were seen in younger ages and include cervical sympathetic chain schwannoma and vagal schwannoma. However, these schwannomas revealed hypovascularity on imaging studies allowing differentiation from hypervascular carotid body tumors. Preoperative distinction between carotid body tumors and schwannomas is very important. Carotid body tumors, cervical sympathetic chain schwannomas, and vagal schwannomas have common location in neck that is the retrostyloid compartment of parapharyngeal space –3. AmongAn 18-year-old female was referred to the otolaryngology department with a swelling on the left side of the neck since 4 months. On examination, nonpulsatile mass near angle of the left mandible was seen. Cranial nerve examination was normal. Doppler ultrasonography revealed hypoechoic mass in the left carotid space showing mild peripheral vascularity . ComputeA 17-year-old female came with history of painless swelling on the left side of the neck and change in voice since 2 months. On examination, there was nontender swelling noted posterior to the angle of the left mandible. USG neck revealed hypoechoic mass on the left parapharyngeal space showing mild vascularity on the Doppler study . On CT sVagal schwannomas, carotid body tumours and cervical sympathetic chain schwannomas are the most common tumours of the retrostyloid parapharyngeal space , 2. CaroSchwannomas or neurilemomas, are derived from schwann cells. They are common in middle age with female preponderance –3. In thPreoperative diagnosis is very important in these retrostyloid parapharyngeal masses as management of carotid body tumors varies from surgery to radiation to observation, while complete surgical excision is the therapy of choice in vagal and cervical sympathetic schwannomas . Also, rBoth of the described tumors displayed splaying of external and internal carotid arteries on CT contrast study, MRI, and DSA which was also confirmed at surgery. However both of these tumors demonstrated mild vascularity on the Doppler USG, CT, and DSA.Although characteristic vascular displacement, that is, splaying of carotid bifurcation helps to distinguish carotid body tumor from other retrostyloid parapharyngeal masses, similar vascular displacement can be seen in vagal and cervical sympathetic chain schwannomas. So, this imaging pitfall should be taken into account while considering differential diagnosis of retrostyloid parapharyngeal tumors.Both of these tumors showed hypovascularity, hence favor schwannomas rather than carotid body tumors. Internal vascularity and enhancement characteristics of the tumor should be given more importance while differentiating schwannomas from carotid body tumors. Hence enhancement pattern is the imaging pearl in differentiating carotid body tumors from schwannomas.


Drug addiction is a serious public health problem that consists of a compulsive drive to take drugs despite repeated severe adverse consequences . FactorsThe accumulated evidence supports the view that a large number of substance users suffer from significant neuropsychological impairments . NeuroimBefore elaborating the idea of drug-induced cognitive changes in patients addicted to illicit drugs, it is important to briefly discuss the influence of potential premorbid deficits on the cognitive performance of some drugs abusers . For exaThe prefrontal cortex (PFC) and the striatum participate in integrated functions that are modulated by glutamate  and dopaPathological changes in the orbitofrontal cortex (OFC) might also be involved in the manifestation of addiction-related behaviors because it is relevant to outcomes related to primary reinforcers . OFC neuImpaired self-control plays a fundamental role in drug-taking behaviors in addictive states . ImpulsiThe available evidence does support the thesis that impulsivity is a vulnerability marker for substance abuse , 12. SevInterestingly, abnormalities have been identified in frontal networks that subsume poor self-regulation and impulse control in cocaine dependency. Specifically, cocaine users were reported to show stronger connectivity within the perigenual anterior cingulate cortex (ACC) social processing/“mentalizing” network . This stAttention represents a number of intimate mechanisms that facilitate the filtering, selection, and processing of information . In subsPoor cognitive performance in areas of risk-taking and decision making may influence the degree to which illicit drug users engage in risky behaviors with consequent negative health consequences. Deficits in tests of decision making have been found in patients who suffer from marijuana , 50, cocIn summary, drug addiction is marked by mild, yet pervasive, cognitive disruptions that may cause the negative progression of the clinical course, threaten sustained abstinence , or incr


The letter by Mullier8C intervals,The inhibition of pre-hepatic/hepatic CYP3A4 metabolism of amiodarone alters both plasma and cardiac substrate:metabolite ratios. It therefore reduces alterations of PR and QTC by inhibiting the rapid component of delayed rectifier K+ current (Ikr), leading to significant QT prolongation in healthy subjects and in patients with dilated or hypertensive cardiomyopathy,The interaction of grapefruit juice with amiodarone is more complicated than previously thought. Naringenin, the naringin (the predominant flavonoid in grapefruit juice) aglycone, has recently been reported to prolong QTEven though cases of QT prolongation and torsades de pointes with amiodarone are rare, a case has been reported of a female patient who presented with marked QT prolongation associated with ventricular arrhythmias including torsades de pointes, requiring electrical cardioversion after amiodarone administration, after she had been drinking large quantities of among others grapefruit juice.


Chronic heart failure (CHF) is the leading cause of hospitalization and death in industrialized countries. CHF is frequently associated with humoral and metabolic disturbances, including reduced bioavailability of the important signalling molecule nitric oxide (NO), which has vasodilating properties. Several studies reported high plasma levels of asymmetrical NG, NG-dimethyl-L-arginine (ADMA), an endogenous inhibitor of NO production, in CHF, contributing to endothelial dysfunction. The Dynamic Vessel Analyzer (DVA) enables dynamic analyses of retinal vessels. NO is a mediator of retinal vasodilator response to flicker light. Reduced response of retinal arterioles to flicker light may be an attractive technique to non-invasively assess endothelial dysfunction. The aim of the study was to test the hypothesis that retinal vessel response to flicker light is reduced in patients with CHF and correlates inversely with serum ADMA levels.16 patients with non-ischemic cardiomyopathy and 22 healthy volunteers were included. Retinal arteriolar flicker response as percent change from baseline and serum ADMA level were measured.Retinal arteriolar flicker response was significantly reduced in CHF patients compared to the healthy control group . ADMA levels tended to be higher in CHF patients . Noteworthy, we observed a highly significant inverse correlation between retinal arteriolar flicker response and ADMA levels .Our findings suggest that analysis of retinal vessels could be an attractive non-invasive method to quantify endothelial dysfunction in CHF.


Candida is the most common human fungal pathogen and the cause of invasive candidiasis, the fourth leading cause of nosocomial bloodstream infection in the United States with an estimated annual cost of ∼US$2 billion and mortality that exceeds 40% despite administration of antifungal therapy in modern intensive care unit facilities Candida yeast cells intravenously and mimics skin-derived bloodstream human candidiasis, has been successfully employed to study fungal and host factors that regulate susceptibility to the infection Candida expresses a variety of virulence factors that contribute to its pathogenesis and could be exploited for development of vaccines and targeted therapeutic strategies. Firstly, Candida albicans filaments' virulence factors, including secreted aspartyl proteases and phospholipases, are thought to be important for Candida invasion in infected organs and, probably, for mediating fungus-induced tissue immunopathology Candida is able to efficiently adhere to and invade epithelial and endothelial cells via induced endocytosis and active penetration; both adhesion and invasion facilitate Candida dissemination Candida to form biofilms on implanted medical devices such as central venous catheters, which are a frequent portal of entry for invasive infection in humans Candida factors that promote its adhesion and invasion, the agglutinin-like sequence (Als) family has attracted significant attention; Als3 in particular, a C. albicans–specific virulence factor, was recently shown to mediate brain-specific Candida endothelial invasion and tissue penetration vps51Δ/Δ C. albicans mutant was shown to be responsible for its increased ability to invade brain endothelial cells in vitro and traffic to the brain in vivo via binding to the gp96 heat shock protein, which is expressed specifically on brain endothelium Candida tissue burden C. albicans virulence factor is its ability to transition between unicellular yeast cells and filamentous growth during infection; in fact, it is the interchange between these morphotypes that is critical for pathogenesis, as strains locked either in the yeast or the filamentous forms have attenuated virulence in vivo albicans Candida species such as Candida glabrata, which is an important cause of invasive candidiasis in humans even though it does not form hyphae. Strikingly, the ability of C. albicans to form filaments in vivo is tissue-specific Candida growth in mice such as the liver and spleen prevent Candida filamentation, whereas hyphal formation is abundant in the kidney, the target organ of murine disseminated candidiasis, where Candida proliferation is inexorable Candida filamentation could lead to the discovery of novel therapeutic interventions.Moreover, a fundamental Candida immune response is fungal recognition by the innate immune system. Over the past decade there has been an explosion in our understanding of how soluble and membrane-bound pattern recognition receptors (PRRs) recognize various pathogen-associated molecular patterns (PAMPs) of Candida yeast and filamentous forms  in modulating downstream anti-Candida immune responses. In addition, more studies are needed to understand how Candida influences its recognition in vivo by employing immune evasion strategies; for example, β-glucan exposure on the Candida surface occurs in infected mouse tissues only late after infection The challenge for future research will be to define how Candida experimental strains impedes on drawing definite conclusions about the in vivo role of certain PRRs, as apparently discrepant results have been reported for some TLRs and CLRs with different fungal strains Candida strains in mammals could potentially be ameliorated by employing non-vertebrate  and/or mini-vertebrate model hosts  that have evolutionarily conserved innate immune pathways , and could allow for facile and inexpensive high-throughput screening of greater numbers of Candida strains C. albicans is the most common agent of human invasive candidiasis, research performed until now has predominantly focused on the recognition of this species, and much less is known about the interaction of other Candida species with the immune system. It is expected that research aiming to gain more insight on the recognition of emerging non-albicans Candida species will represent an important area of research in the coming years.In addition, the notable diversity in PAMP structure among various Candida killing Candida ingestion is followed by assembly of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex at the phagosomal membrane and oxidative burst, which leads to generation of candidacidal reactive oxygen species and K+-influx–induced activation of neutrophil candidacidal granular proteases Candida yeast-to-hyphae conversion, a process dependent on the oxidative burst Candida yeasts and hyphae and appear important for anti-Candida host defense in vivo Neutrophils are indispensable for host defense against invasive candidiasis, and neutropenia is a well-recognized risk factor for development of and adverse outcome after infection in humans Nonetheless, neutrophils have differential effects in invasive candidiasis in vivo depending on the phase of the infection in mice. Specifically, early neutrophil presence after infection is protective, whereas neutrophil presence late after infection is pathogenic Candida phagocytosis and secretion of a variety of pro-inflammatory cytokines and chemokines that orchestrate the antifungal innate immune response Candida compared to neutrophils; the lack of macrophage myeloperoxidase and extracellular trap formation may, at least in part, account for this deficit Candida effects in mice; yet, the importance of Candida-induced nitric oxide formation in human phagocytes is unclear Candida infection. In addition, future studies should aim to shed light on the relative role of recruited versus resident monocytes/macrophages in host defense against invasive candidiasis.Besides neutrophils, monocytes/macrophages are key phagocytic cells for protection against invasive candidiasis, as their depletion in mice leads to increased mortality Candida challenge, monocytes were recently shown to also confer protection following systemic Candida re-infection via functional reprogramming that involves the dectin-1/Raf-1 non-canonical signaling pathway and results in enhanced cytokine production Intriguingly, besides the protective role of monocytes/macrophages in host defense against primary Candida yeast and hyphal forms and respond differentially to the Candida morphotypes by priming the production of distinct cytokines + dendritic cells were recently shown to activate invariant natural killer T cells to mediate innate immune responses against fungi (including Candida) via dectin-1- and MyD88-dependent mechanisms without apparent requirement for fungal lipid antigen presentation Candida effects after systemic infection Candida-specific CD4+ T cells after systemic infection of mice vaccinated with the Als-derived peptide pALS Candida immunity could lead to the design of effective vaccination and immunomodulatory strategies against invasive and mucosal candidiasis in patients.The role of other hematopoietic cells in host defense against invasive candidiasis merits further investigation. For example, dendritic cells are able to phagocytize Candida killing capacity of human myeloperoxidase-deficient phagocytes, invasive candidiasis occurs in patients with myeloperoxidase deficiency, the most common inherited phagocytic disorder In agreement with the requirement of innate immunity for effective host defense in the mouse model of invasive candidiasis, certain innate immune factors have been associated with protection against the infection in humans Candida immunity in humans −/−Card9 and −/−dectin-1 mice are both susceptible to invasive candidiasis Click here for additional data file.


Unfortunately, at present, degenerative retinal diseases such as retinitis pigmentosa remains untreatable. Patients with these conditions suffer progressive visual decline resulting from continuing loss of photoreceptor cells and outer nuclear layers. However, stem cell therapy is a promising approach to restore visual function in eyes with degenerative retinal diseases such as retinitis pigmentosa. Animal studies have established that pluripotent stem cells when placed in the mouse retinitis pigmentosa models have the potential not only to survive, but also to differentiate, organize into and function as photoreceptor cells. Furthermore, there is early evidence that these transplanted cells provide improved visual function. These groundbreaking studies provide proof of concept that stem cell therapy is a viable method of visual rehabilitation among eyes with retinitis pigmentosa. Further studies are required to optimize these techniques in human application. This review focuses on stem cell therapy as a new approach for vision restitution in retinitis pigmentosa. At present, degenerative retinal diseases such as retinitis pigmentosa (RP) and dry type age related macular degeneration (AMD) remain untreatable. Patients with these conditions suffer progressive visual decline resulting from continuing loss of photoreceptor cells and outer nuclear layers. Both disorders are characterized by the progressive dysfunction and death of the light sensing photoreceptors of the retina and other supportive cells. Because of the limited regenerative capacity of the mammalian retina, retinal progenitor cell are being developed to serve as “spare parts” for lost photoreceptor cells. Advances in molecular biology have identified innovative approaches that, for the first time, provide hope for permanent visual rehabilitation. Stem cell therapy can potentially replace lost photoreceptor and retinal pigment epithelial cell and subsequently restore visual function in eyes with degenerative retinal disorders .A potential target disease for stem cell therapy is retinitis pigmentosa (RP). RP is the most commonly inheritable eye disease that causes progressive loss of photoreceptor cells resulting in gradual visual decline. While the onset of RP may occur during infancy, the first symptoms are usually observed in early adulthood, beginning with nyctalopia or night blindness followed by loss of peripheral vision and eventually, as the central photoreceptors in the macula are damaged, loss of fine central vision. Morphologically, these retinas are characterized by centripetal proliferation of bone spicule-like pigmentation, attenuation of retinal blood vessels and optic nerve pallor . At leasTransplantation of progenitor stem cells that can be stimulated to become replacement photoreceptors and supportive outer retina cells can theoretically lead to treatments that restore visual function . RecentlTwo types of stem cells may be utilized to produce retinal progenitor cells. Firstly, Embryonic stem (ESC) and secondly, induced pluripotent stem (IPS) cells. Both types of cells are pluripotent and capable of becoming any cell type. ESC’s are derived from embryos while IPS cells are obtained from a variety of adult tissues such as skin, bone marrow, teeth. IPS cells, if successfully implanted and optimized, can potentially provide an unlimited supply of stem cells for transplantation. Cell replacement is one approach for restoration of vision in RP. Because visual loss usually occurs when the outer retinal photoreceptor layer is lost, therapeutic timing should be at this stage of disease. Singh and colleagues have demonstrated using a murine model of severe human retinitis pigmentosa, that at a stage when no host rod cells are remaining, transplanted rod precursors can reestablish an anatomically distinct and appropriately polarized outer nuclear layer. In their study, restoration of a trilaminar retinal organization was restored to RD1 hosts with only two retinal layers before treatment. The introduced rod precursors continued to develop in the host niche to become mature rods complete with light-sensitive outer segments and connections to host neurons downstream. Visual function was also restored. These findings indicated that stem cell therapy may reinstate a light-sensitive cell layer de novo and restore structurally damaged visual circuits. In this model, total photoreceptor layer reconstruction is one approach to further develop cell-based strategies for retinal repair .ESC’s have been shown to generate functional photoreceptor cells restoring light response of photoreceptor-deficient mice, but there is concern over the risk for tumor formation using ESC. Li and colleagues successfully cultured Nestin(+)Sox2(+)Pax6(+) multipotent retinal stem cells (RSCs) from the adult mouse retina. These ESC’s are capable of producing functional photoreceptor cells that restore light response of photoreceptor-deficient RD1 mutant mice. After several cycles of expansion using growth factors, cultured RSCs still maintained proliferation and differentiation potential .Under optimized differentiation conditions, ESC’s can differentiate into all the major retinal cell types found in the adult retina such as photoreceptor cells under optimized differentiation conditions. Following transplantation into the subretinal space of slowly degenerating RD7 mutant eyes, RSC-derived photoreceptor cells were shown to integrate into the retina, and develop into cells morphologically resembling endogenous photoreceptors and forming synapses with resident retinal neurons. When transplanted into eyes of photoreceptor-deficient RD1 mutant mice, an RP model, RSC-derived photoreceptors can partially restore light response, indicating functionality. In animal studies, no evidence for tumor development was found . Along similar lines, autologous IPS cells are being developed for stem cell transplantation. This lack of immunogenicity confers an important advantage. Because IPS cells are autologous or derived from the same organism, they do not incite immunological reaction nor require use of immunosuppressive medication . Li and colleagues recently transplanted human IPS cell-derived retinal pigment epithelium (RPE) cells into the subretinal spaces of mouse models with the Rpe65rd12 /Rpe65rd12 form of RP. A healthy adult provided skin fibroblasts cultured with lentivirus-delivered genes encoding transcription factors OCT4, SOX2, KLF4, and MYC. Antibody staining of markers  and a teratoma assay demonstrated pluripotency of the hiPS cells. Culturing in differentiation medium guided their fate to RPE. By 12 weeks, from 30% to 50% of the surfaces of 12-well dishes were coated with RPE with characteristic hexagonal shapes, perinuclear melanin granules, and microvilli [The target mice had albinism, which provided a white contrast against which the transplanted pigmented cells would be visible. The mice also had severe combined immune deficiency to prevent graft-vs-host disease. An injection of 1000 hiPS-derived RPE cells was administered into the subretinal space in the right eyes of 34 mice at two days following birth. The mice were sacrificed at six months, shortly before they would have died from severe combined immune deficiency .Successful development into RPE cells was indicated by: 1) microscopic confirmation of pigmented hiPS-derived RPE admixed into the native, albino RPE; 2) quantitative polymerase chain reaction detection of markers of human fetal RPE and IPS-derived RPE; 3) positive staining for rhodopsin indicating that the hiPS-derived RPE cells phagocytosed photoreceptors. Furthermore, in some mice, electroretinogram (ERG) response to measure neuronal function, demonstrated a small but significant improvement of mean β-wave peak difference between treated and control eyes of 13.7 μV P = 0.0246). Furthermore, no tumor growth was observed [. FurtherThe use of retinal progenitor sheet transplantation is another promising approach. Seller and Aramant demonstrated that when freshly dissected sheets of fetal-derived retinal progenitor cells are mixed with RPE and transplanted subretinally, improvements of visual acuity are observed among animals and humans. Visual improvement in this model is attributed to restoration of synaptic connections between transplant and host when transplant processes proliferate into the inner plexiform layer of the host retina and presumably form synapses. One drawback of widespread use of this method is limited supply of fetal donor tissue .Future areas for stem cell development include methods for optimizing stem cell production and delivery. The use of specific extracellular matrix can stimulate the development of human pluripotent stem cells into transient organized neuroepithelum with rapid differentiation into retinal progenitor cells . Garit-HPreviously, RP was considered a devastating and untreatable condition. These pioneering animal studies provide hopeful evidence for the hypothesis that stem cell therapy is a viable means for visual rehabilitation of RP patients. What is now known is that stem cell therapy can potentially replace degenerate photoreceptors and outer retinal cells. When placed in the appropriate tissue niche, these stem cells not only survive but differentiate into critical retinal cells, develop a retina-like organizational structure and exhibit functional characteristics of full-fledged photoreceptors and outer retinal cells. Further studies are needed to optimize techniques and validate these findings before proceeding to human trials. Conflicts of Interest: None declared.


Bone plays metabolic roles through osteocalcin(OC) when it is released into the systemic circulation in uncarboxylated form. Identified novel metabolic roles of OC include increasing insulin secretion and sensitivity, energy expenditure, reduction of fat mass and mitochondrial proliferation and functional enhancement. The onset of puberty can be influenced metabolic factors. This study was aimed to determine serum OC levels in girls with central precocious puberty(CPP) and to investigate the effects of OC on the onset of puberty.Serum OC levels of girls CPP (n=30) and their age-matched controls (n=30) were measured. GnRH stimulation test was performed in CPP group. Bone age was determined in all subjects.Serum OC levels were significantly higher in CPP group compared with control group . Serum OC levels were correlated with peak LH levels during GnRH stimulation test , bone age  and bone age advance , but not related to age, height, weight and BMI.Serum OC seems to be associated with the onset of puberty leaving casual relations unresolved.


To report a case of central serous chorioretinopathy after solar eclipse viewing.A middle-age man developed a sudden-onset unilateral scotoma after viewing a partial solar eclipse in Hong Kong. Fundus examination, fluorescein angiography, and optical coherence tomography showed features compatible with central serous chorioretinopathy. The patient was managed conservatively and reevaluated periodically. Serial optical coherence tomographic evaluations demonstrated an initial increase in the amount of subretinal fluid which spontaneously resolved 10 weeks after the onset of symptoms.This case demonstrates the possibility of development of central serous chorioretinopathy following solar eclipse viewing. Retinopathy following viewing of a solar eclipse without the use of safe eyewear has been well-documented in the literature. The usual lesion consists of mild foveal changes due to photochemical damage to the retina. Patients usually present with reduced visual acuity and a central scotoma. Classical findings on fundus examination include a yellow-white spot in the fovea surrounded by granular changes in the retinal pigment epithelium (RPE). Fundus fluorescein angiography (FA) may reveal a small central foveal window defect. Optical coherence tomography (OCT) may also demonstrate hypo- or hyperreflective lesions in the outer retina and RPE.4Central serous chorioretinopathy (CSCR) is an entity characterized by neurosensory retinal detachment with or without RPE detachment. Previous studies have reported the association of CSCR with various risk factors such as psychological stress, type A personality, pregnancy, untreated hypertension, use of corticosteroids, and psychopharmacologic medications.7Herein, we describe a rare case of CSCR after viewing a solar eclipse. To our knowledge, the association between CSCR and solar eclipse viewing has not been reported in the literature.A 44-year-old Caucasian man with good past health and unremarkable ophthalmic history presented with an acute-onset relative scotoma in his left eye after viewing a partial solar eclipse in Hong Kong on July 22, 2009.The patient was reassessed six weeks later and he still complained of a persistent central scotoma. Nonetheless, visual acuity remained stable. Fundus examination of the left eye showed an increase in subretinal fluid. OCT demonstrated an increase in the serous neurosensory retinal detachment . Ten weeTo the best of our knowledge, this is the first report describing acute CSCR after direct solar eclipse gazing. Unprotected sun-gazing, particularly during an episode of solar eclipse, is a well-known cause of solar retinopathy.Clinical features of CSCR include accumulation of subretinal fluid, neurosensory retinal and RPE detachment, and leakage with angiographic evidence of RPE hyperpermeability.The exact pathogenetic mechanism of CSCR in our case remains unclear. We hypothesize that intense sunlight was preferentially absorbed by melanosomes in the RPE, causing localized RPE damage and thus resulting in CSCR.


In addition, no change in intracerebral incubation period was observed following active rumen digestion of unbound hamster HY TME prions and HY TME prions bound to a silty clay loam soil. These results demonstrate that both unbound and soil-bound prions readily survive rumen digestion without a reduction in infectivity, further supporting the potential for soil-mediated transmission of chronic wasting disease (CWD) and scrapie in the environment.Before prion uptake and infection can occur in the lower gastrointestinal system, ingested prions are subjected to anaerobic digestion in the rumen of cervids and bovids. The susceptibility of soil-bound prions to rumen digestion has not been evaluated previously. In this study, prions from infectious brain homogenates as well as prions bound to a range of soils and soil minerals were subjected to in vitro rumen digestion, and changes in PrP levels were measured via western blot. Binding to clay appeared to protect noninfectious hamster PrP Sc, a misfolded isoform of a normal cellular prion protein (PrPc) found in all susceptible species Sc exhibits resistance to proteolysis and inactivation, increased hydrophobicity, and a propensity for aggregation Sc can seed conversion of PrPc to PrPSc (‘replicate’) and thereby initiate prion propagation and, presumably, disease infection Prion diseases, or transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative diseases that afflict ruminants, including cattle , sheep and goats (scrapie), and deer, elk, and moose (chronic wasting disease or CWD), as well as humans (Creutzfeld-Jakob disease or CJD) Natural transmission of CWD and scrapie occurs primarily or exclusively through ingestion or inhalation of prion-contaminated material shed from infected hosts or present in mortalities Sc survives the digestive processes in the rumen and lower gastrointestinal system. Results from previous in vitro studies of PrPSc fate in rumen digestion have been varied. Scherbel and colleagues observed a near-complete loss of 263 K hamster PrPSc, as detected by western blot, following rumen digestion Sc in scrapie-infected sheep brain homogenates following exposure to rumen and other alimentary fluids Sc was detected post-digestion when precipitation and proteinase-K digestion were used prior to western blotting. An additional limited study found no evidence of scrapie PrPSc digestion in rumen fluids Sc.Prions are orally infectious Sc (both CWD-elk and hamster) has been shown previously Ingestion of prion-contaminated soil has been implicated as a likely mechanism of natural CWD and scrapie transmission Sc levels were measured by western blotting. Intracerebral hamster bioassay was also employed to measure changes in infectious titer. The results demonstrate the strong resistance of both unbound and soil-bound prions to rumen digestion, which further supports the efficacy of soil-bound prion ingestion as a natural route of disease transmission in ruminants.Adsorption of prions to soil may alter prion resistance to host degradation, thus potentially altering their oral infectivity and transmissibility. The objective of this research was to evaluate and compare the ability of rumen digestion to degrade unbound prions as well as prions bound to a range of soils and soil minerals. In vitro anaerobic digestion assays seeded by bovine rumen fluid were conducted, and the resultant PrPAll procedures involved in animal bioassay were approved by the Creighton University Institutional Animal Care and Use Committee and complied with the Guide for the Care and Use of Laboratory Animals. Collection procedures for rumen fluid from cannulated dairy cows was approved by the University of Nebraska-Lincoln Institutional Animal Care and Use Committee.++ or Mg++  using strain-dedicated Tenbroeck tissue grinders .Prion-infected brain tissue was collected without prior buffer profusion from golden Syrian hamsters infected with the hyper (HY) strain of transmissible mink encephalopathy (TME) as previously described Sc/PrPc and uninfected PrPc from brain homogenates were sorbed to a range of soils as described previously 2, Sigma Aldrich, St. Louis, MO) were used and have been described previously HY TME PrP2, 10% H2, and 5% CO2. Rumen fluid was diluted 1∶10 or 1∶5 in McDougall's buffer  with soluble carbohydrates . There was no difference in immunoblot results between 1∶10 and 1∶5 rumen∶buffer dilutions (data not shown).Standard in vitro rumen digestion assay methods were followed Resazurin dye  was used as an indicator of redox state and does not affect in vitro digestion Sc in digested and undigested samples was accomplished using SDS-PAGE/Western blotting as described previously without modification Detection of PrPIntracerebral inoculations of male golden Syrian hamsters  were conducted as described previously Two-tailed student's T-tests assuming unequal variances were performed using Microsoft Excel to determine statistical significance as noted. P values less than 0.05 were considered statistically significant.An in vitro digestion assay was employed to simulate rumen digestion of prion-contaminated material. Standard methods, including standard rumen fluid sampling procedures and substrate and buffer compositions, were used Sc from brain homogenate was not significantly reduced in actively digested samples compared to inactive and buffer controls .Unbound HY TME PrPSc following in vitro rumen digestion, but somewhat inconsistent with Scherbel et al. Sc degradation during active digestion in the absence of detergents. Methodological differences such as rumen fluid seed or western blotting techniques may be responsible for the observed differences. For instance, we collected rumen fluid from a live, cannulated dairy cow while Scherbel et al. collected fluid from a slaughtered beef bull.These results are consistent with the result of Nicholson and colleagues Sc was sorbed to a range of soils and soil minerals and exposed to in vitro rumen digestion. Consistent with the unbound results, HY PrPSc bound to silty clay loam (SCL) soil was not reduced following active rumen digestion (Sc bound to SCL soil demonstrated similar resistance to digestion (data not shown). Increased detection of PrPSc bound to bentonite clay (2)  and not a direct effect on PrPSc.To determine the effect of soil on the susceptibility of prions to rumen digestion, PrPabnormal , the lowSc was not detected on sand samples actively digested .HY TME bound to sandy loam (SL) soil and sand was susceptible to rumen digestion , and PrPdigested , lane 4.c from uninfected hamster brain homogenate  (data not shown). Since there is a well-established relationship between HY TME infectious titer and incubation period Sc levels before and after digestion in unbound and SCL soil-bound PrPSc (Hamsters were inoculated with unbound and SCL-bound HY TME prions subjected to either active or inactive (pre-autoclaved) in vitro rumen digestion. The incubation periods of hamsters inoculated with inactive or active samples were equal . The incnd PrPSc .Sc replication efficiency Also consistent with previous results, the mean incubation time of SCL soil-bound HY TME was significantly longer (13 d) than unbound HY TME  [27]. ThSc resistance to in vitro rumen digestion Sc abundance  To initiate infection via absorption across the lower gastrointestinal epithelium, orally ingested prions must survive passage through the rumen bundance , and conbundance . MoreoveSc resistance to digestion with respect to soil type, where, in contrast to the other soils and minerals, PrPSc levels bound to sand and sandy loam soil were reduced following digestion (2 is not significantly different than unbound prions (data not shown). Based on the established relationship between PMCA replication efficiency and infectious titer We did observe variance in PrPigestion . VariancA number of factors must be considered in extending the present results. First, the results were obtained using in vitro digestion, which is a simulation of in vivo processes with limitations Sc, it may alter PrPSc uptake efficiency, which would not be detected by immunoblot or intracerebral bioassay. Thus, study of soil-bound prions in, for example, the gut-loop system employed by Dagleish and Jeffery Finally, unbound and soil-bound prions surviving rumen passage will be exposed to stomach and intestinal digestion before uptake. These two processes are less complex than rumen digestion, and previous results indicate unbound prions are resistant to both Figure S1Sc without proteinase-K treatment.Rumen digestion of unbound HYTME PrP(DOCX)Click here for additional data file.Table S1PrP Adsorption to Soil and Soil Minerals.(DOCX)Click here for additional data file.


Escherichia coli sepsis in baboons strongly induces procoagulant responses and affects the integrity of the lung. These effects are diminished by the treatment with compstatin, a C3 convertase complement inhibitor [Pulmonary fibrosis is a major and common medical condition, characterized by progressive scaring and decline in lung function. Persistent inflammation and acute lung injury in response to sepsis are potential triggers of the fibrotic response. Recently, we have reported that nhibitor .E. coli sepsis triggered metabolic and signaling pathways related to lung remodeling and fibrosis, and whether complement inhibition could attenuate these pathways.Here we used the baboon model described  in conjuE. coli challenge. Immunochemical and biochemical analysis reveals enhanced collagen synthesis, induction of profibrotic factors and increased cell recruitment and proliferation. Compstatin treatment decreases sepsis-induced expression of extracellular matrix genes, including eight collagen genes. Sirius Red and immunofluorescence staining for procollagens 1 and 3 confirms the collagen deposition in the lung. Ingenuity® pathway analysis of transcriptomics data shows that compstatin treatment reduces sepsis-induced expression of genes involved in fibroblast transformation and connective tissue production, cell chemotaxis, migration and proliferation (see Table Microarray gene expression analysis shows that sepsis augments several fibrotic gene clusters in the lung as early as 24 hours post Our data demonstrate that bacterial sepsis initiates pulmonary collagen deposition, and complement inhibition effectively attenuates the fibrotic response. This suggests that complement inhibitors could be used for prevention of sepsis-induced pulmonary fibrosis.