Transcranial Direct Current Stimulation (tDCS) is a non-invasive neuromodulation technique which uses a weak electric current from electrodes across the scalp to modulate targeted brain areas. It has been suggested that tDCS may be useful in reducing psychotic symptoms such as auditory hallucination. The aim of this study was to find alteration of key neurotransmitters in schizophrenia in temporo-parietal area (TPA) after tDCS intervention, using magnetic resonance spectroscopy (MRS) technique.Ten schizophrenia patients with auditory hallucination were recruited from the outpatient clinic of Seoul National University Hospital (SNUH). The anode was placed over the left dorsolateral prefrontal cortex (DLPFC), and the cathode was placed over the left TPA. Patients underwent MRS scan with the very short echo time phase rotation STEAM sequence before and after the tDCS sessions, respectively.Seven of the participants completed MRS scans before and after the tDCS sessions. Positive and Negative Symptom Scale (PANSS) total and general psychophathology scale showed a significant improvement after tDCS. There was no significant difference between glutamate/creatinine (Cr) level before and after tDCS sessions. However, a significant positive correlation between the pre-tDCS glutamate/Cr value in left TPA and the improvement in auditory hallucination measured by Auditory Hallucination Rating Scale (AHRS) after tDCS was found.The results of this investigation show that the schizophrenia patients whose auditory hallucination benefits the most from tDCS treatment had lower glutamate/Cr level in left TPA. Previous studies regarding the relationship between glutamatergic system and treatment response mostly have only focused on the frontal area and striatum. However, this study suggests a potential role of glutamatergic system in TPA in predicting treatment response of auditory hallucination.


Edema bullae typically forms at the site of skin swelling during acute states of volume overload, most commonly during renal or cardiac failure. Herpes zoster is a reactivation of latent varicella zoster virus that typically presents as painful vesicles in a dermatomal distribution. In immunocompromised individuals, disseminated herpes zoster skin manifestations may occur with several lesions in multiple dermatomes or widespread individual lesions or both, even visceral organs can be involved. Additionally, many conditions are known to mimic the lesions and distribution of herpes zoster. A 53-year-old immunosuppressed male with a history of renal transplant presented with dermatomal and non-dermatomal, disseminated herpes zoster that was confirmed by polymerase chain reaction testing. After one week of intravenous antiviral therapy during which his virus infection-associated lesions were resolved, new blisters developed near the insertion site of a peripheral venous line located on a previously uninvolved yet swollen upper extremity. The varicella zoster virus disease was initially suspected, but lab studies and skin biopsy of a blister excluded progressive or persistent viral infection and established a diagnosis of acute edema bullae. The blisters resolved following removal of the peripheral catheter. Acute edema bullae should be added to the list of mimickers of disseminated varicella zoster virus infection. Edema bullae are the blisters that occur following the swelling at an affected site, most commonly in the lower extremities of the patients with acute exacerbation of fluid overload or chronic leg swelling . Herpes A 53-year-old immunosuppressed male with the history of the kidney transplant presented with two weeks of painful vesicles on his left forearm, left leg, and the abdomen. His past medical history was significant for kidney transplant four years prior and disseminated herpes zoster two years prior. His daily medications included 7.5 milligrams of prednisone, 6 milligrams of Tacrolimus, and 720 milligrams of mycophenolate sodium.The cutaneous examination showed individual and grouped, erythematous-based vesicles located in a dermatomal distribution on the left side of his abdomen, and more than 20 individual lesions in a diffuse, nondermatomal distribution on his body. Initial polymerase chain reaction testing of a lesional swab was positive for varicella zoster virus and negative for herpes simplex virus. He was started on 10 mg/kg of intravenous acyclovir three times per day for disseminated herpes zoster involving multiple dermatomes but without organ or central nervous system involvement.After seven days of intravenous antiviral therapy, his VZV-associated lesions had nearly resolved Figure . HoweverThe polymerase chain reaction testing of the new lesions was negative for varicella zoster virus and herpes simplex virus. Microscopic examination of a biopsy taken from the edge of a blister showed a paucicellular subepidermal vesicle with epithelial necrosis, focal ischemic alteration of the eccrine apparatus, and pronounced dermal edema Figure .Correlation of the laboratory studies and microscopic examination of the skin biopsy of the new, painless, polymerase chain reaction VZV-negative bullae in a patient with resolving disseminated herpes zoster following one week of antiviral therapy established a diagnosis of acute edema blister. These blisters were likely secondary to lymphedema from intravenous catheter-associated pressure or trauma since the new blisters were located in a limb previously uninvolved with VZV but associated with intravenous catheter access. The peripheral intravenous catheter was relocated to the left limb and lesions resolved.Edema bullae are the blisters that occur most commonly in the elderly and immobile during acute increases in interstitial fluid pressure . They prWhen capillary filtration develops too rapidly for compensatory lymphatic drainage, dermal edema may occur, leading to blister formation . This ocThe treatment of acute edema blisters is directed towards reducing fluid overload. The elevation of the dependent extremity may promote lymphatic drainage and lesions typically resolve once the fluid imbalance is corrected ,6. In ouThe herpes zoster classically manifests as grouped, painful vesicles in a dermatomal distribution. However, disseminated herpes zoster may present with skin lesions simultaneously involving multiple dermatomes (on one or both sides of the body) or with a widespread distribution of more than 20 lesions either alone or be accompanying lesions that are located in one or more dermatomes. The diagnosis is typically established clinically, but confirmation with polymerase chain reaction testing for VZV deoxyribonucleic acid (DNA) or direct fluorescent antibody testing can be performed . Ninety The treatment of uncomplicated herpes zoster involves oral antiviral therapy for seven to 10 days, while disseminated disease or visceral involvement warrants intravenous therapy. Immunosuppressed patients with uncomplicated herpes zoster may also be treated orally, although intravenous acyclovir is recommended in the severely immunocompromised in order to prevent disseminated disease . This poResolved areas of prior VZV infection may become “immunocompromised districts”, areas of skin with increased susceptibility to other skin disorders, including malignancy (such as cutaneous metastases), opportunistic infections, and granulomatous disorders (such as granuloma annulare and sarcoidosis) . The preMany dermatological conditions are known to mimic VZV infection, including cellulitis, contact dermatitis, dermatitis herpetiformis, drug eruptions, herpes simplex infection, and tinea infection . Rarely,Edema bullae present as the medium to large-sized vesicles and typically manifest during states of volume overload causing acute swelling in the affected site. Our patient’s lesions occurred in the setting immediately following disseminated herpes zoster infection, and were initially misinterpreted as progressive disease. However, the viral studies were negative for VZV and herpes simplex virus, while a lesion biopsy showed a non-inflammatory subepidermal blister; correlation of these studies and the clinical history of recent intravenous therapy near the involved site established the correct diagnosis of acute edema bullae. In conclusion, the acute edema bullae may result from prolonged pressure or trauma from a peripheral venous line; in addition, acute edema bullae can be added to the list of dermatological conditions that may mimic varicella zoster virus infection.


We evaluated the impact of man-made conflict events and climate change impact in guiding evidence-based community “One Health” epidemiology and emergency response practice against re-/emerging epidemics. Increasing evidence of emerging and re-emerging zoonotic diseases including recent Lassa fever outbreaks in almost 20 states in Nigeria led to 101 deaths and 175 suspected and confirmed cases since August 2015. Of the 75 laboratory confirmed cases, 90 deaths occurred representing 120% laboratory-confirmed case fatality. The outbreak has been imported into neighbouring country such as Benin, where 23 deaths out of 68 cases has also been reported. This study assesses the current trends in re-emerging Lassa fever outbreak in understanding spatio-geographical reservoir(s), risk factors pattern and Lassa virus incidence mapping, inherent gaps and raising challenges in health systems. It is shown that Lassa fever peak endemicity incidence and prevalence overlap the dry season (within January to March) and reduced during the wet season (of May to November) annually in Sierra Leone, Senegal to Eastern Nigeria. We documented a scarcity of consistent data on rodent (reservoirs)-linked Lassa fever outbreak, weak culturally and socio-behavioural effective prevention and control measures integration, weak or limited community knowledge and awareness to inadequate preparedness capacity and access to affordable case management in affected countries. Hence, robust sub/regional leadership commitment and investment in Lassa fever is urgently needed in building integrated and effective community “One Health” surveillance and rapid response approach practice coupled with pest management and phytosanitation measures against Lassa fever epidemic. This offers new opportunities in understanding human-animal interactions in strengthening Lassa fever outbreak early detection and surveillance, warning alerts and rapid response implementation in vulnerable settings. Leveraging on Africa CDC centre, advances in cloud-sourcing and social media tools and solutions is core in developing and integrating evidence-based and timely risk communication, and reporting systems in improving contextual community-based immunization and control decision making policy to effectively defeat Lassa fever outbreak and other emerging pandemics public health emergencies in Africa and worldwide.The online version of this article (10.1186/s40249-018-0421-8) contains supplementary material, which is available to authorized users. Please see Additional file The increasing evidence of climate change and other man-made conflict events impacts on emerging and re-emerging zoonotic or vector-borne diseases such as Lassa fever outbreak direct risk-effect occurrence and burden worldwide and particularly in developing countries. Acute Haemorrhagic Fever Syndrome is a general term broadly attributable to diverse mild to severe group of animal and human illnesses that encompass: Lassa fever (arenaviridae), Rift Valley fever (RVF), Crimean-Congo haemorrhagic fever (CCHF) (bunyaviridae), yellow fever (flaviviridae), Ebola and Marburg viral diseases (filoviridae), dengue (dengue haemorrhagic fever (DHF) and other viral diseases such as rickettsial or bacterial diseases with ability to result in epidemics , 2.Mastomys natalensis is the rodent reservoir of the Arena spp. the virus responsible [Lassa fever a known endemic infectious disease of poverty has emerged as a severe outbreak of public health threat and burden in Nigeria in the recent past . Nigeriaponsible . Followiponsible , 3. Spatponsible , 2.nd week, 9.53% of suspected cases were confirmed by laboratory tests. However, of the 75 laboratory confirmed cases 90 deaths occurred i.e. 120% laboratory case fatality. That means 20% of observed Lassa fever related deaths were not confirmed as cases by laboratory tests hinting to a systems gap in the disease detection and surveillance. However, by 2017, this observed health systems gap in infectious disease and outbreak detection and surveillance was not appropriately addressed [Nigeria is no doubt now endemic for Lassa fever, there was an observed 21.3% seropositive prevalence in a countrywide study . A briefddressed . Of the The paper assesses the current trends in re-emerging Lassa fever geo-spatial distribution, inherent gaps and raising health system challenges towards improving interlinkage of laboratory and epidemiology surveillance to evidence for community towards one health approach and practice.M. natalensis and not M. erythroleucus correlates geographically with observed Lassa fever seropositivity prevalence in humans [Since the Lassa fever virus is transmitted to humans via contact with food or household items contaminated by rodent hosts, sexually or direct/indirect contact with body fluids such as the blood, urine, and saliva of an infected person , 5, an in humans . A studyn humans , similarn humans . Peak inn humans . Howevern humans . The endn humans , 14, 15.Hence, in absence of preventive medication or vaccine against Lassa fever, increasing community awareness and health education to avoid contact with reservoir sources mainly rats, prevention of food infestation rodent’s and food safety practice to appropriate waste management coupled with improved water, sanitation and hygiene (WASH) program implementation is crucial. Since, sexual transmission of Lassa virus has also been reported, improved access to sexual and reproductive preventive measures is also important in line with WHO recommendations as well as shared traveller information support.Importantly, there is an urgent need to linking disease ecology with enhanced surveillance data garnered from 1969 across Sub-Saharan Africa , 16.Strengthening local and regional robust and sustainable integrated disease surveillance and response (ISDR) implementation into routine laboratory diagnostic and epidemiologic surveillance services, and surge resource capabilities is imperative. Scaling up adequate community social mobilization, nationwide enlightenment and health education outreach coverage using various social media and mass media outlets by various stakeholders is needed to prevent and respond promptly to potential epidemic events at each identified community health system level . LeveragLeveraging on digital, cloud-sourcing and social media in developing and integrating timely risk communication and reporting systems can be seen to start from the lowest administrative level at the community up to Central or Federal level while a feedback process flows from the development partners and Federal government back to the communities. Fostering key operational coordination, epidemiology and surveillance capacity building programs should ensure effective and concurrent trans-disciplinary outbreak response actions and Lassa fever clinical case management guidelines. Hence, strengthening community health centres and laboratory capacity, data sharing access and operational logistics for evidence operational research priorities and decision making policies, supply chain and timely risk communication and share livelihoods .st and 22nd of August, 2017, with the whole essence of building and strengthening robust and effective health system to achieve increasing access to universal health coverage (UHC) and sustainable development goals(SDGs). Noteworthy, was the technical support from the WHO Africa Regional Office (AFRO) and the National Lassa fever Steering Committee at the forum. The Nigeria Centre for Disease Control (NCDC) in partnership with the aforementioned as well as other supporting partners  participants from State governments affected by Lassa fever endemicity and epidemics.The Federal Government of Nigeria has embarked on integrated infectious diseases prevention and control; however integration in primary healthcare is still seldom and unstructured at all levels nationwide. Integrating community-based “One Health” surveillance and emergency response practice is crucial in addressing the persistent scourge of poverty-related Lassa fever outbreak and other emerging zoonotic disease pandemic threats amongst vulnerable populations across the region. In reviewing the 2016/2017 Lassa fever year, stakeholders hosted an interdisciplinary action review meeting in Abuja between 21Scaling up contextually diagnostic and care access at the point of need no matter the location and time without any encumbrances is critical to improving vulnerable population quality of life, productivity, reduction financial impoverishment and poverty alleviation , 19. TheContemporary increasing in consumer/provider-generated mhealth technology and application, social media penetration and acceptance, online disease data and information literacy and communication to emergency response or recovery to immunization scale coverage and effectiveness should exploited to optimize health benefits, wellbeing impacts and return of investment as coupled with traditional mass media  in reachIn controlling the scourge of Lassa fever an early warning system and rapid response is important. Once one case of Lassa fever is suspected an alert should be made and once this is confirmed in the laboratory then the situation must be treated as an epidemic , 2. ThisBuilding early warning indicators and rapid response to adequately prevent or respond to Lassa fever medical care needs at the hospitals, scaling up access to medical supplies and vaccines stockpile are needed in preparedness and during potential epidemics. The following are usually supplied to Local Government Areas (LGAs) at risk in Nigeria , 17. MedIt is important to note that in effectively tackling this scourge, test kits and laboratory analysis to confirm suspected cases as soon as possible need to be readily accessible. Lassa virus and other emerging viral diseases detection and confirmation requires Biosafety level 4 (BSL-4) laboratories across the world, but very few exist in Africa . Some AfIt is alarming that the true incidence of Lassa fever is unknown as quoted incidences are extrapolations from 1980s studies. Thus the Lassa fever research field is in dire need of more accurate and recent studies on disease incidence, geographic distribution and virus seroprevalence , 30. RivAccelerating health systems strengthening and rebuilding transformations in affected West Ebola outbreak countries is important through improving ISDR system and scaling up access to routine immunization programs; while leveraging on community-based and vulnerable populations’ empowerment and resilience activities in endemic regions to traveller medical information , 35. LikLassa fever virus outbreak, a poverty-related infectious diseases outbreak remains a public health threat and burden on vulnerable populations in West Africa and Nigeria in particular. Robust and sustainable leadership commitment and investment of all stakeholders and affected communities in Lassa fever outbreaks prevention and containment is crucial and requires strengthening integrated Lassa fever outbreak surveillance quality data gathering to support evidence data sharing, contextual local and regional outbreak early warning alert, preparedness and response systems. Collaborative ‘One Health’ approach operational research is needed in understanding spatio-geographical risk factors patterns, reservoir(s) mapping and phylogenetic in guiding evidence-based, appropriately tailored and timely integrated programs and strategic interventions implementation against the zoonotic disease epidemics and pandemics threats in Nigeria and the sub-Saharan Africa foci terrain. Furthermore, fast-tracking R&D for more sensitive diagnostic tools, safer and effective drugs and vaccine development is imperative in improving contextual community-based immunization decision making policy to effectively outwit Lassa fever outbreak and other emerging pandemics public health emergencies. Moreover, fostering local community to regional re-merging and emerging epidemics and pandemics data sharing and coordinated invasive pathogens epidemiology surveillance and early warning indicators metrics capacity building, monitoring and evaluation is crucial for timely and quality risk communication and operational research. Integrating community “One Health” surveillance and rapid response approach practice against Lassa fever epidemic and other emerging pandemic threats offers new opportunities in understanding human-animal and environment interface and expanding zoonotic diseases public awareness and resilience strategies and mitigation measures in attaining national and global health security.Additional file 1:Multilingual abstracts in the five official working languages of the United Nations. (PDF 423 kb)


This review focuses on the cognitive neuroscience of Attention Deficit Hyperactivity Disorder (ADHD) based on functional magnetic resonance imaging (fMRI) studies and on recent clinically relevant applications such as fMRI-based diagnostic classification or neuromodulation therapies targeting fMRI deficits with neurofeedback (NF) or brain stimulation. Meta-analyses of fMRI studies of executive functions (EFs) show that ADHD patients have cognitive-domain dissociated complex multisystem impairments in several right and left hemispheric dorsal, ventral and medial fronto-cingulo-striato-thalamic and fronto-parieto-cerebellar networks that mediate cognitive control, attention, timing and working memory (WM). There is furthermore emerging evidence for abnormalities in orbital and ventromedial prefrontal and limbic areas that mediate motivation and emotion control. In addition, poor deactivation of the default mode network (DMN) suggests an abnormal interrelationship between hypo-engaged task-positive and poorly “switched off” hyper-engaged task-negative networks, both of which are related to impaired cognition. Translational cognitive neuroscience in ADHD is still in its infancy. Pattern recognition analyses have attempted to provide diagnostic classification of ADHD using fMRI data with respectable classification accuracies of over 80%. Necessary replication studies, however, are still outstanding. Brain stimulation has been tested in heterogeneously designed, small numbered proof of concept studies targeting key frontal functional impairments in ADHD. Transcranial direct current stimulation (tDCS) appears to be promising to improve ADHD symptoms and cognitive functions based on some studies, but larger clinical trials of repeated stimulation with and without cognitive training are needed to test clinical efficacy and potential costs on non-targeted functions. Only three studies have piloted NF of fMRI-based frontal dysfunctions in ADHD using fMRI or near-infrared spectroscopy, with the two larger ones finding some improvements in cognition and symptoms, which, however, were not superior to the active control conditions, suggesting potential placebo effects. Neurotherapeutics seems attractive for ADHD due to their safety and potential longer-term neuroplastic effects, which drugs cannot offer. However, they need to be thoroughly tested for short- and longer-term clinical and cognitive efficacy and their potential for individualized treatment. Attention Deficit Hyperactivity Disorder (ADHD) is characterized by symptoms of age-inappropriate inattention, hyperactivity and impulsivity , that are mediated by late developing fronto-striato-parietal and fronto-cerebellar networks Rubia, . The mosSince the advent of fMRI, several hundreds of fMRI studies have been published in ADHD children and adults over the last two decades, the majority of them targeting cognitive functions. The first fMRI studies conducted in very small numbers of ADHD patients found reduced inferior fronto-striatal activation in ADHD children relative to age-matched healthy controls during motor inhibition /anterior insula, the supplementary motor area (SMA), anterior cingulate cortex (ACC), left striatum and right thalamus . Thus, ADHD patients showed enhanced activation in typical regions of the DMN such as in rostromedial prefrontal cortex during interference inhibition  or orbitofrontal cortex (OFC) and striato-limbic regions during tasks that tap into “hot” EF such as reward-related decision making or temporal discounting tasks. One of the most consistent findings is reduced ventral striatum activation during reward anticipation, as shown in a recent meta-analysis of eight fMRI studies of a monetary reward anticipation task using region of interest analysis in 340 ADHD patients and healthy controls , which are hypothesis-driven and measure changes in interactions across brain activations. In children and adults with ADHD, reduced functional connectivity has been observed between task-relevant regions during cool EF tasks, suggesting dysfunction of entire networks and not just regions.In ADHD children, during motor response inhibition and WM tasks reduced functional connectivity has been reported relative to healthy controls between the right IFC and basal ganglia, parietal lobes and cerebellum, and between cerebellum, parietal and striatal brain regions during sustained attention  and transcranial direct current stimulation (tDCS) have found successful applications in other psychiatric disorders. Pioneering applications of these techniques to ADHD over the past decade targeting IFC or DLPFC have been mixed, but revealed some promising findings of improving cognition and clinical behavior. The following sections will review these clinical applications of neuroimaging in ADHD.Despite the fact that ADHD is a neurodevelopmental disorder with consistent evidence for brain structure and function deficits, currently ADHD is diagnosed solely on the basis of subjective clinical and self-rating measures, which are often unreliable, leading to diagnostic variability between clinicians, cultures and countries  and can make predictions  for individual subjects as opposed to group-level inferences. These methods have been shown to provide sensitive and specific diagnostic indicators for individual patients with other pathologies in particular for neurological disorders such as Alzheimer’s disease but also for autism and depression  diagnosis or prognosis of individual patients and build the path for brain function (or brain structure)-based patient stratification and personalized medicine. Multimodal multivariate approaches including several imaging modalities, including functional and structural imaging data as well as non-imaging data such as cognitive and genetic measures are likely to achieve superior classification accuracy than univariate approaches  rTMS promotes cortical excitability, while low frequency (1 Hz) rTMS inhibits cortical excitability  or sham dTMS (N = 13). dTMS is a modification of standard TMS that enables deeper non-invasive cortical stimulation at an effective depth of approximately 3 cm depending on the coil’s design and the stimulation intensity. Stimulation was applied over bilateral prefrontal cortex in 20 daily sessions over 4 weeks, each session consisting of 55 trains of pulses at 18 Hz . The study found an improvement in ADHD symptoms in both groups suggesting a placebo effect and no cognitive improvements in either group  or decreasing  the excitability of neurons via the generation of subthreshold (stimulation-polarity dependent) alterations of membrane potentials that modify spontaneous discharge rates, thus increasing/decreasing cortical function and synaptic strength  relative to sham stimulation (N = 8); furthermore, all symptom improvements were still significant 2 weeks after stimulation, suggesting longer-term effects —that has been shown to interact with physiological slow oscillatory activity, which is typically abnormal in ADHD—over lateral prefrontal cortex during deep sleep in 12/14 ADHD adolescents compared to sham stimulation in a double-blind within patients design with 1 week break in between conditions. The outcome measures were slow oscillatory power during deep sleep in the non-stimulation periods and cognitive function improvements relative to sham tDCS in the next morning. Slow oscillatory power during deep sleep was increased, indicating an enhancement of endogenous oscillatory activity with the intervention. Cognitive improvements were in declarative memory  had to learn to upregulate the rIFC, while the control group (N = 13) had to upregulate a control region, the left parahippocampal gyrus (lPHG). Both groups were tested before and after treatment in clinical and cognitive measures as well as in an fMRI Stop task and were followed up a mean of 11 months later in the main ADHD clinical outcome measure. Participants were trained to enhance activation of the target/control regions in 11 sessions of 8.5 min of rtfMRI-NF over four scan hours over 2 weeks. They were trained on a computer game where a rocket moved towards the sky, passing through clouds, and ultimately reaching some planets every time they managed to increase the activation of the target/control region. The fMRI data showed significantly enhanced activation as well as enhanced linear activation increase in two regions of the rIFC across all 11 sessions in the active relative to the control group and enhanced linear activation increase in three regions of the lPHG in the control relative to the active group  and electromyography-NF (N = 9). Only NIRS-NF resulted in significant improvements in clinical ADHD symptoms and in cognitive inhibition and attention functions after 11 h sessions over 4 weeks, which was, however, not superior to EEG-NF or electromyography-NF  of the left DLPFC in nine ADHD children, compared to EEG-NF  neurobiological basis of different ADHD subtypes such as inattention without hyperactivity, or ADHD with emotional dysregulation. Furthermore, more understanding is needed on comorbid cases with other disorders such as autism, anxiety and affective disorders as well as on females with ADHD and gender differences. Future studies therefore ideally should be longitudinal, multimodal and tied to epidemiological samples.Clinical translation of neuroimaging is still in its infancy in the field of ADHD. Pattern recognition analyses applied to functional  imaging data to make individual predictions on diagnostic status are promising, but more so for homogenous subtypes that likely share the same “biotype” rather than heterogenous large groups of ADHD patients with different comorbidities or medication status. They will need to show replicability and clinical utility which will be the challenge over the next decades.Several brain stimulation studies with heterogeneous study designs have been conducted in small groups of ADHD children and adults, most of them using tDCS in either single or five sessions targeting mostly DLPFC or IFC based on the fMRI studies conducted in ADHD over the last two decades. The findings show some improvements on clinical symptoms or selective cognitive functions, with, however, also negative findings. Larger sham-controlled studies are needed to further test the efficacy of tDCS and potential costs on non-targeted cognitive or behavioral functions. In addition, far more knowledge is needed on the optimal stimulation protocols for different age and patient subpopulations . It is likely that brain stimulation combined with cognitive training has a larger potential to enhance brain plasticity in ADHD than brain stimulation alone. This will also require the development of good cognitive training tasks that target ADHD-relevant functions to be used in combination with brain stimulation techniques. Given minimal side effects, tDCS is a promising tool for the treatment of childhood onset psychiatric disorders, since it provides the opportunity to positively influence atypical brain development early and persistently , potential costs that may accompany the benefits, and their potential for individualized treatment (which ADHD subtype responds to which neurotherapy and why). It is likely that different subgroups of ADHD patients will benefit from either NF, brain stimulation or medication and establishing this knowledge will be crucial to the benefit of individual patients.The author confirms being the sole contributor of this work and approved it for publication.The author has received grants from Lilly and Shire and speaker’s honoraria from Shire, Lilly and Medice.


Retinal artery occlusion is extremely rare in the pediatric population and most patients have risk factors. We report a case of a healthy child with segmental optic atrophy, complicated by incidental branch retinal artery occlusion (BRAO).A 10-year-old boy who had a history of his mother’s gestational diabetes presented with an inferonasal visual field defect in the left eye. His best-corrected visual acuities were 20/20 in both eyes (OU). Fundoscopic examination revealed segmental pallor of the left optic disc, thinning of the superotemporal rim, a relative superior entrance of the central retinal artery and superior peripapillary scleral halo. Fluorescein angiography showed patchy filling delays in the corresponding disc area without retinal vascular abnormalities. Spectral domain optical coherence tomography (SD OCT) via automated segmentation analysis demonstrated sectoral absence of the ganglion cell layer and retinal nerve fiber layer with thinning of the inner plexiform layer, inner nuclear layer and outer plexiform layer in the corresponding retina. OCT angiography (OCTA) showed focal attenuation of superficial and intermediate/deep capillary plexuses in the corresponding areas. Systemic evaluation was unremarkable. The patient was diagnosed with segmental optic atrophy caused by incidental BRAO.Retinal vascular occlusions are rare in childhood, and may present as segmental optic atrophy mimicking congenital anomalies. OCTA allows the detection of previous microvascular abnormalities in the chronic phase. To the best of our knowledge, this is the first report of a child with segmental optic atrophy presumably caused by BRAO, which was documented by SD OCT and OCTA in detail. When segmental atrophy of the optic disc is found in children, benign conditions such as isolated superior segmental optic hypoplasia (SSOH) are mostly considered, particularly in healthy children of an insulin dependent diabetic mother . Rarely,A visually asymptomatic 10-year-old boy presented with an inferonasal visual field defect in the left eye Fig. . He had Optic nerve atrophy is the secondary pathogenic endpoint of numerous diseases that cause intrinsic or extrinsic insult to the visual pathway. Although, partial optic atrophy with homonymous visual field defect is characteristic for cortical visual impairment, various congenital lesions involving the retina, optic nerve, chiasm, optic tract, or retrogeniculate pathways as well as acquired conditions such as periventricular leukomalacia also show segmental optic nerve changes , 7. HoweRetinal artery occlusion is an extremely rare condition in the pediatric population and most patients have some detectable risk factors . Surpris


There are now several immunotherapy trials for ovarian cancer although the clinical benefits have been limited to a subset of patients . We receBRCA mutation (gBRCAm) associated platinum-sensitive recurrent disease [gBRCAm-associated platinum-sensitive recurrent ovarian cancer (NCT02734004) to examine how clinical benefits by immune checkpoint inhibitors are added to PARPi’s activity in the background of gBRCAm. Interestingly, in our study, none of the women receiving durvalumab+olaparib >= 9 months  had germline or somatic mutations in BRCA or other DNA repair genes [PARP inhibitors (PARPi) are intriguing combination therapy partners with other pathway inhibitors such as immune checkpoint blockade . The com disease . A phasegBRCAm, in which the role of neoantigen expression and changes in immune microenvironment induced by PARPi will be further examined. The optimal selection of patients for treatment with PARPi and immune checkpoint inhibitor in non-BRCA mutated settings and better understanding of the mechanisms of action will require further characterization and analysis.PARPi blocks DNA repair, resulting in DNA breaks . FragmenImmunotherapy manifests differently from traditional chemotherapy, eliciting delayed response kinetics . It has The overexpression of PD-L1 is an important and widely explored biomarker for response to immune checkpoint inhibitors. However, PD-L1 expression by immunohistochemistry fails to accurately select all patients suitable for PD-1/PD-L1 inhibitors . The preThe advent of immunotherapy combination therapy presents us with new approaches in ovarian cancer treatment with promising outcomes, preliminarily. Multiple clinical trials are currently being conducted to better define the role of PARPi and immunotherapy combinations, and further investigation is warranted to develop and identify predictive biomarkers. Assessing how immunotherapies should be incorporated with current standard-of-care treatments, such as PARPi is essential to make progress in the treatment of ovarian cancer.


The development of cardiac complications during or after endoscopic procedures is rare. However, mortality from myocardial ischemia, particularly in the elderly population, is elevated. We illustrate the rare case of a 79-year-old man with multiple cardiovascular risk factors who developed a non-ST elevation myocardial infarction (NSTEMI) after endoscopic removal of a foreign body. This case report summarizes a rare complication of a low-risk procedure and highlights the importance of considering this potential adverse event, particularly in patients with significant cardiovascular risk factors, to promote early diagnosis and proper treatment. Incidence of Acute Coronary Syndromes (ACS) following endoscopic procedures is low <1%), and usually these interventions do not require further preoperative testing [%, and usCardiac complications are 2–5 times more likely to occur during emergency procedures than with elective interventions , which cA 79-year-old man, former smoker and with type 2 diabetes, hypertension, and hyperlipidemia, presented to the hospital after swallowing a piece of denture while eating carrots. On arrival physical exam and laboratory tests were unremarkable. Computed tomography (CT) scan showed esophageal distention compatible with ingested foreign body, as well as aortic and coronary atherosclerosis. A flexible esophagogastroduodenoscopy was done attempting foreign body removal; however it was unsuccessful and during the procedure ST-segment elevation was noted on the cardiac monitor. An emergent rigid esophagoscopy was performed and the foreign object was removed. Electrocardiogram (ECG) showed a left bundle branch block (LBBB) that did not meet Sgarbossa criteria; however there was no prior ECG to compare with ; vital sRepeat ECG  showed sCoronary angiography was attempted once but patient became very agitated during the procedure; the Interventional Cardiology team increased the sedation to try to finish the study but patient remained restless and kept moving all his extremities, so continuing the procedure under these circumstances would have been extremely dangerous.Transthoracic echocardiogram (TTE) revealed anteroseptum, apex, and distal-anterior wall akinesis; left ventricular ejection fraction was 30% . Troponin T peaked at 9.37 ng/mL and then trended down. Before being discharged, the medical team discussed extensively the importance of having a coronary arteriogram done to evaluate the presence of obstructive lesions in the coronary vasculature. Despite the insistence of the team and the broad discussion with the patient regarding different methods of anesthesia, patient refused to undergo this procedure given his prior experience. He remained hemodynamically stable and was discharged in stable condition.This is, to the best of our knowledge, the first case report of NSTEMI associated with esophageal microperforation after endoscopy in the setting of foreign body ingestion. A few reports do exist; however, of myocardial ischemia following gastroscopy , suggestMyocardial ischemia results from imbalance between oxygen demand and supply. During endoscopy, catecholamine-induced tachycardia can trigger it in patients with high atheromatous burden and fixed coronary stenosis or with development of hypoxia during a difficult procedure. In our patient, the ACS could have been induced by stress of aspirated dentures and the intervention triggering any of these mechanisms; however we were unable to exclude other etiologies such as Takotsubo cardiomyopathy.Adverse cardiopulmonary events attributable to endoscopic procedures are rare –9 and raCurrent guidelines for preoperative cardiovascular evaluation do not recommend a preoperative 12-lead ECG or any other form of preprocedural cardiac assessment in asymptomatic patients undergoing low-risk interventions , and endECG is an inexpensive and very useful tool that could benefit some asymptomatic patients with multiple cardiovascular risk factors undergoing low-risk procedures and could be a cost-effective test to promote early diagnosis and treatment of cardiac complications. This case report summarizes an example of these adverse events aiming to increase awareness of this potentially fatal complication and highlight the relevance of prompt intervention and judicious use of preprocedural testing  despite guideline statements to the contrary. This underscores that guidelines are just that and are not rigid, unbreakable rules with proper documented justification.


The Accreditation Council for Graduate Medical Education (ACGME) implemented revisions to resident duty hour requirements (DHRs) in 2011 to improve patient safety and resident well-being. Perceptions of DHRs have been reported to vary by training stage and specialty among internal medicine and general surgery residents. The authors explored perceptions of DHRs among all residents at a large academic medical center.medical and pediatric, surgery, or other.The authors administered an anonymous cross-sectional survey about DHRs to residents enrolled in all ACGME-accredited core residency programs at their institution. Residents were categorized as In total, 736 residents representing 24 core specialty residency programs were surveyed. The authors received responses from 495 residents (67%). A majority reported satisfaction (78%) with DHRs and believed DHRs positively affect their training (73%). Residents in surgical specialties and in advanced stages of training were significantly less likely to view DHRs favorably. Most respondents believed fatigue contributes to errors (89%) and DHRs reduce both fatigue (80%) and performance of clinical duties while fatigued (74%). A minority of respondents (37%) believed that DHRs decrease medical errors. This finding may reflect beliefs that handovers contribute more to errors than fatigue (41%). Negative perceived effects included diminished patient familiarity and continuity of care (62%) and diminished clinical educational experiences for residents (41%).A majority of residents reported satisfaction with the 2011 DHRs, although satisfaction was significantly less among residents in surgical specialties and those in advanced stages of training. TDespite the differences we observed between the surgical versus nonsurgical disciplines and senior versus junior residents, it is worth stating that a majority of these subgroups did ultimately report overall satisfaction with the DHRs. Most respondents also indicated that the DHRs were respected and enforced by their institution. While most indicated that situations do exist where violation of DHRs is justified, few reported more than sporadic violations within the past year.Although a majority of respondents believed the DHRs mitigate resident fatigue, only 37% believed that the requirements decreased medical errors. More than one-half of respondents believed that DHRs did not impact (44%) or increased (19%) medical errors. Our findings are congruent with a study using a grounded-theory analysis of resident comments, that found residents did not associate patient safety with DHR compliance , 25. ThiOnly 26% of residents perceived the DHRs to have a positive impact on their clinical educational experience. Prior studies have demonstrated findings of perceived reductions in bedside teaching, clinical educational experiences , and surStrengths of our study are the large sample size and high resident response rate. In addition, we surveyed residents currently enrolled in all ACGME-accredited core residency programs at a large academic institution, and included residents at all levels of training within those programs. We also endeavored to conduct a thorough evaluation of the survey instrument by piloting our survey among experienced medical educators prior to its implementation.Limitations of our study include a cross-sectional study design, single-institution sampling, and a subjective assessment by the study subject relating to Level 1 outcomes . BecauseIn this cross-sectional survey study of residents enrolled in all ACGME-accredited core residency programs at a large academic medical center, a majority of respondents were satisfied with the current ACGME DHRs and believed they affected their training in an overall positive manner. Residents in surgical specialties and those in advanced stages of training were significantly less likely to view DHRs favorably, although in these subgroups as well, a majority of the respondents did report overall satisfaction with the DHRs.


Epigenetic mechanisms have emerged as key players in cancer development which affect cellular states at multiple stages of the disease. During carcinogenesis, alterations in chromatin and DNA methylation resulting from genetic lesions unleash cellular plasticity and favor oncogenic cellular reprogramming. At later stages, during cancer growth and progression, additional epigenetic changes triggered by interaction with the microenvironment modulate cancer cell phenotypes and properties, and shape tumor architecture. We review here recent advances highlighting the interplay between epigenetics, genetics, and cell-to-cell signaling in cancer, with particular emphasis on mechanisms relevant for cancer stem cell formation (CSC) and function. Epigenetic regulators are one of the most commonly mutated classes of genes in cancer. During cancer initiation, mutated epigenetic regulators lead to oncogenic cellular reprogramming and promote the acquisition of uncontrolled self-renewal. The emergence of CSCs requires elaborate reorganization of the epigenome.During cancer growth, epigenetic mechanisms integrate the effect of cell-intrinsic  and cell-extrinsic  changes and establish intratumoral heterogeneity, either promoting or inhibiting the CSC state.‘Loose’ epigenetic constraints in cancer cells enhance cellular plasticity and allow reversible transitions between different phenotypic states. Enhanced cellular plasticity favors cancer cell adaptability and resistance to therapy.Modulation of epigenetic processes allows targeting of the most downstream determinants of the CSC state. The molecular makeup of a cancer is the result of multiple changes occurring progressively during its lifetime. Early in the disease, alterations in key genes disrupt normal cell function and endow cells with the ability to initiate a tumor or a hematological malignancy. Subsequently, as a cancer grows, additional changes superimpose onto the initiating events and affect the biological properties of cells, either enhancing or inhibiting their malignant properties. As a result of this constant modulation of cell function, tumors comprise a remarkable collection of distinct cellular phenotypes which differentially contribute to disease progression.Intratumoral functional heterogeneity  and cell-extrinsic  mechanisms modulate the epigenome of cancer cells, and their combined effect determines which cells preserve the self-renewal capacity acquired during tumorigenesis. These cells, referred to as cancer stem cells (CSCs) or leukemic stem cells (LSCs), are those responsible for driving long-term cancer growth and disease progression cellular plasticity at various stages of the disease.Similarly, The recent identification of driver mutations affecting a wide range of epigenetic regulators in hierarchically organized cancers provides direct evidence for the importance of epigenetic dysregulation in the formation of CSCs. These mutations are typically clonal and promote the acquisition of uncontrolled self-renewal.KMT2A/MLL gene. KMT2A/MLL encodes a histone methyltransferase that orchestrates several essential cellular processes through modification of chromatin, mainly regulating accessibility to enhancer regions de novo self-renewal capacity Leukemias represent a paradigm of hierarchical cancers maintained by LSCs. Numerous studies have identified mutated epigenetic regulators that favor the acquisition of uncontrolled self-renewal ability and initiate the disease. A prominent example is offered by mixed lineage leukemia (MLL)-associated leukemia, which is characterized by chromosomal rearrangements involving the H3F3A, and a K27M substitution is the most common alteration Probably the most compelling evidence supporting a key role of chromatin in the acquisition of uncontrolled self-renewal comes from studies in glioblastoma (GBM), a highly aggressive form of brain cancer characterized by an undifferentiated phenotype and a high frequency of CSCs. Recent sequencing efforts have identified gain-of-function mutations in genes encoding histone H3 in about one third of pediatric GBMs. The gene mainly affected is Proteins involved in the establishment and maintenance of DNA methylation have also been identified as drivers of CSC formation. The methylation status of CpG dinucleotides depends on the action of DNA methyltransferases , which apply the methyl-group to cytosines, and methylcytosine dioxygenases (TET1 and TET2), which convert 5-methylcytosine to 5-hydroxymethylcytosine and initiate a demethylation process. DNMT3A is the DNMT most commonly affected by DNA lesions, being mutated in ∼25% of AML patients de novo self-renewal capacity. In both cases, epigenetic constraints imposed during development to keep cellular plasticity under control are disrupted, and cells transform, losing their normal cellular identity  in many cancers has been the basic observation supporting the hierarchical model of cancer development over the past two decades. Recent single-cell transcriptomic studies have extended our understanding of the gene expression programs that shape tumor architecture and have confirmed that aberrant differentiation programs establish cellular hierarchies within individual cancers. In a pioneering study, colon cancers were shown to contain multiple cell types with transcriptional profiles resembling those of the cellular lineages making up the normal epithelium. Importantly, single cancer cells could recapitulate the lineage diversity of the primary tumors in transplantation assays, demonstrating that multilineage differentiation represents a key source of intratumoral transcriptional heterogeneity The observation that IDH-induced oligodendrogliomas contain differentiated, non-self-renewing cells underscores the diverse, and at times antithetic, role of epigenetic mechanisms in cancer development. During tumorigenesis, mutations in IDH proteins drive CSC emergence partly through alteration of DNA methylation profiles and epigenetic reprogramming of committed oligodendrocytes. However, during tumor growth, additional epigenetic changes occur and establish developmental hierarchies that restrict the proliferative potential of some cells, counteracting the effect of the initiating mutations .Figure 2in vitroWhat are the mechanisms that generate distinct epigenetic states within tumors and confer distinct functional properties to CSCs and differentiated cells? Epigenetic regulators belonging to two distinct groups have so far been identified: those that inhibit cancer cell self-renewal and establish differentiation hierarchies, and those that are hijacked by CSCs to avoid differentiation and sustain their phenotype . Within Although many cancer cells succumb to differentiation during tumor growth, CSCs evade this process and preserve their self-renewal capacity acquired during transformation. Not surprisingly, considering the importance of epigenetic regulators in normal stem cell maintenance, many chromatin-related proteins and DNA-methylating enzymes are essential to maintaining the CSC state. Remarkably, most of the proteins implicated in CSC maintenance are typically not mutated but are co-opted in their wild-type state by CSCs to avoid differentiation and sustain their malignant properties. Prominent examples of hijacked proteins are Polycomb complex proteins. The PRC2 catalytic subunit EZH2 has a tumor-promoting role in many malignancies, and inhibition of its activity or genetically induced loss of the protein strongly impairs tumor growth A key feature of epigenetic mechanisms is their inherent reversibility. Thus, the dependence of CSCs on epigenetic regulators offers an opportunity to target their self-renewal capacity. The chromatin ‘reader’ BRD4 best illustrates this concept As with any therapeutic strategy, epigenetic modulation of CSCs faces challenges. Early concerns regarding targeting wild-type proteins that exert pleiotropic functions in normal cells have been mitigated by the observation that many tested inhibitors are not associated with major toxicity, suggesting that cancer cells exhibit a specific epigenetic vulnerability HOX oncogenes methylated in their promoter regions in particular AML cells and not in others A key question related to epigenetic regulation of the CSC state is: what determines epigenetic heterogeneity within tumors? For example, why do some cells express high levels of histone H1.0 and consequently differentiate, and others instead maintain low H1.0 levels and thus self-renewal capacity Variations in oxygen and nutrient concentrations are a likely source of phenotypic variation within tumors, and histone modifiers have been reported to act as sensors of hypoxia lo cells to CD44hi CSCs. Importantly, this cellular plasticity appears to be dependent on the chromatin status of the ZEB1 promoter because a poised, bivalent configuration allows reversion to CD44hi CSCs upon stimulation, while the presence of repressive marks renders CD44lo cells insensitive to TGF-β et al. identified a subpopulation of cells that is required for continuous tumor growth and is marked by the expression of the histone demethylase JARID1B. However, instead of being a stable subpopulation, JARID1B+ cells are a dynamic subset whose composition changes over time as cells gain and lose JARID1B expression, and transiently acquire stemness properties depending on the tumor context A major difference between normal cellular hierarchies and cancer is that, although cell fate decisions triggered by environmental cues are generally stable and heritable in normal cells, cancer cells maintain an intrinsic plasticity that allows them to easily change their phenotype in response to new signals and possibly switch between cellular states. Evidence exists in some cancers that differentiated cells can reacquire self-renewal ability and revert to a CSC state . This ocet al. who reported the existence of a reversible drug-tolerant state in non-small cell lung cancer (NSCLC)-derived cell lines, and which can survive exposure to lethal concentrations of EGFR tyrosine kinase inhibitors. This drug-tolerant state does not involve drug efflux and is instead associated with an altered chromatin state and requires the histone demethylase KDM5A/JARID1A and IGF-1R signaling NOTCH1-driven T cell ALL, clinical trials using γ-secretase inhibitors (GSI) have shown limited efficacy owing to the presence of a reversible subpopulation of GSI-tolerant cells characterized by BRD4-dependent transcriptional programs. Notably, combined treatment of patient-derived xenografts with NOTCH and BRD4 inhibitors showed greater efficacy than individual treatments Despite significant progress in the development of effective therapies against numerous cancer types, therapeutic resistance is still relatively common. CSCs are the likely source of resistant cells responsible for disease relapse because cells deprived of self-renewing potential are unable to reconstitute the cancer even if they survive treatment. While drug resistance primarily has a genetic basis, chromatin-related mechanisms have emerged as additional players in this context that are exploited by cancer cells to enhance their plasticity and adaptability . A paradEpigenetic alterations affecting chromatin and DNA methylation patterns are universal features of cancer. Historically, it has been difficult to distinguish whether these changes play a functional role in the disease or are a bystander phenomenon that merely reflects alterations in cell behavior. However, studies over the past 5–10 years have crystallized the importance of epigenetic mechanisms at various stages of cancer development and have uncovered unprecedented therapeutic opportunities . The reain vivo. The presence of cellular hierarchies in cancer clearly indicates that mechanisms inhibiting cell self-renewal ability exist, and can efficiently deprive cells of their malignant properties. Differentiation therapies that ‘exaggerate’ such mechanisms and restrict cellular plasticity may prove useful to exhaust CSCs and thus halt tumor maintenance, and also to impair cancer cell adaptability  cells is established? Can cancer cell plasticity be modulated to reduce resistance to treatment? How prevalent are epigenetic mechanisms in the development of therapeutic resistance?Why do cancer cells, including CSCs, show specific sensitivity to epigenetic drugs that target wild-type proteins expressed in normal cells as well? Could epigenetic drugs be generally useful as agents to be administered in combination therapies?Considering the diverse role of epigenetics in cancer, and the possible interference with normal homeostasis, epigenetic modulation of CSCs clearly still faces many challenges, but at the same time offers unprecedented opportunities to hit the beating heart of the disease.


A 79-year-old female with no relevant past medical history was admitted in our emergencydepartment for dyspnea on minimal exertion and chest discomfort over 2 weeks. Blood gasanalysis showed severe hypoxemia and hypocapnia. Troponin was slightly positive. Despitea negative D-dimer assay, contrast-enhanced chest CT was performed to exclude pulmonaryembolism. It showed a large filling defect centered in the pulmonary valve plane (PanelsA and B). Bedside transthoracic echocardiogram showed a large echodense mass, apparentlymobile, extending across the right ventricle outflow tract, pulmonary valve, and themain pulmonary artery, with dilatation of the right sided chambers and transtricuspidpeak gradient of 70 mmHg (Panels C and D). Lower-limb venous compression ultrasound wasnegative for deep vein thrombosis. The patient remained stable, but required high oxygeninspiration fraction to maintain saturation above 90%. As pulmonary embolism was deemedunlikely given the clinical findings, the patient underwent cardiac surgery. Surgeryrevealed a pearly mass in the main pulmonary artery obliterating almost the entire lumenand with upstream extension to the pulmonary valve and right ventricle outflow tract(Panel E). The tumor was excised as much as possible and the pulmonary valve wasreplaced by a homograft. Pathological examination was compatible with angiosarcoma.Pulmonary artery angiosarcoma is exceedingly rare and carries a very poor prognosis. Itcan be clinical and radiologically indistinguishable from acute or chronic pulmonaryartery thromboembolism. Our clinical suspicion was heightened by a negative D-dimerassay and venous ultrasound and the apparent infiltration of pulmonary arterial walls onCT.


Analyses of covariance employed to partial out the influences of language and perceptual impairments, which frequently co-occur in these patients, provided evidence of different underlying cognitive mechanisms. These analyses revealed that language impairments explained the original poor scores obtained by the SD patients on the Ekman 60 and Emotion Selection tasks, which involve verbal labels. Perceptual deficits contributed to Emotion Matching performance in the bvFTD and AD patients. Importantly, all groups remained impaired on one task or more following these analyses, denoting a primary emotion processing disturbance in these dementia syndromes. These findings highlight the multifactorial nature of emotion processing deficits in patients with dementia. Patients with frontotemporal dementia  as well as those with Alzheimer's disease (AD) show deficits on tests of face emotion processing, yet the mechanisms underlying these deficits have rarely been explored. We compared groups of patients with bvFTD (


Fetal or prenatal programming, i.e. the process in which environmental events during pregnancy are shaping and determining the development of the embryo, can be embedded by epigenetic changes including DNA methylation. Apart from environment, also the genome plays an important role and a variety of studies which identified meQTLs  have been published.Focusing on variably methylated regions (VMRs), we investigated if genotype (G), prenatal environment (E) or the combination of both  best explain cordblood DNA methylation in sample of 817 Finnish neonates. Furthermore, we used an epigenetic clock predictor to evaluate if accelerated or decelerated epigenetic age was associated with prenatal environment or with childhood psychiatric problems at age 3.We found that SNP genotype alone best explained methylation status in 44%, SNP x environment in 32% and SNP and prenatal environment in 24% of all VMRs. While functionally relevant meQTLs were located in close proximity to the specific CpG-site, functionally relevant SNPs involved in interaction models showed much broader peaks.Concerning the epigenetic clock, lower gestational age was associated with maternal depression diagnosis and greater depressive symptoms throughout pregnancy. Epigenetic age deceleration was associated with pre-eclampsia. Furthermore, lower epigenetic gestational age was significantly associated with greater total and internalizing problems in boys.Not only environment but also genotype should be considered in epigenetic studies. Furthermore, our results suggest that long-distance effects are present in GxE interactions. The epigenetic clock which mirrors prenatal environment is partially predictive for future development of the child. Lower epigenetic gestational age seems to be developmentally disadvantageous for boys, who in early childhood show greater psychiatric problems.


A case of a renal artery stenosis and ipsilateral renal cell carcinoma with long term results is reported. A 65-year-old man with renovascular hypertension, renal insufficiency, and nephrotic range proteinuria presented with an incidental renal cell carcinoma. Concomitant in situ left partial nephrectomy and splenorenal arterial bypass was achieved. The patient is doing well without evidence of malignancy, stable renal function, markedly improved proteinuria and stable blood pressure more than three years later. The techniques of this procedure are detailed and underscore the possibility of successful removal of a renal cell carcinoma with preservation of renal function despite renal artery stenosis.


Based on the responses of 5,557 Chinese secondary students in Hong Kong, the relationships between perceived family functioning (systemic correlate), parent-adolescent communication (dyadic correlate), and suicidal ideation were examined in this study. Results showed that suicidal ideation was negatively related to global family functioning and parent-adolescent communication. Regression analyses indicated that the dyadic and systemic factors had similar importance in predicting suicidal ideation. Theoretical and practical implications of the findings are discussed.


Social cognition impairments are found in schizophrenia patients and hamper their ability to form social relationships. The biological underpinnings of this social cognition impairment are poorly investigated. We hypothesize that structural disconnectivity, which is replicated in schizophrenia, might has a relevant role in social cognition.The study we present here is under development. We have assessed social cognition using the Mayer, Salovey and Caruso emotional intelligence test (MSCEIT) in 30 patients with schizophrenia and 20 healthy controls. Structural connectivity is assessed with anatomical and Diffusion weighted (DWI) images acquired in a 3 Tesla MRI system. Anatomical and DWI images are processed to obtain fractional anisotropy (FA) values in the tracts connecting prefrontal cortex with anterior cingulate, superior temporal gyrus, insula and superior parietal cortex. The following statistics are assessed i) the differences in MSCEIT scores between patients and controls, ii) the differences in FA values between groups, iii) the relation between MSCEIT punctuation and FA values.In our preliminary analyses, patients show significantly lower MSCEIT scores. Furthermore, MSCEIT scores are directly related to FA values in the tracts connecting prefrontal cortex to anterior cingulate and superior temporal gyrus in the patients.Social cognition impairments seem to be associated with altered structural connectivity in the patients.


Arabidopsis have revealed the involvement of genes and proteins in the glycolytic and other metabolic pathways, particularly processes involved in dehydration tolerance, osmoprotection, and membrane transport. Furthermore, successful recovery appears to be dependent upon the presence of antioxidant protection from reactive oxygen species. Characterization of specific genes and proteins will lead to significant advances in plant cryobiology research.Plant cryobiology has primarily emerged from the classical fields of cryobiology and plant stress physiology. Cryopreservation tools are now available to geneticists for germplasm preservation and the field itself is advancing significantly through the use of molecular techniques. Long-term preservation of vegetatively propagated tissues can minimize the risks of long-term maintenance under tissue culture or field conditions. Cells can be successfully cryopreserved when the adverse affects of ice crystal formation are mitigated by the removal of water or procedures to limit ice formation and crystal growth. The addition of cryoprotectant solutions to hydrated cells may improve the survival of microdissected shoot tips or embryonic axes. Recent discoveries in the genetic pathways leading to cold acclimation and freezing tolerance suggest the involvement of key cold-regulated genes in the acquisition of cold tolerance in plant tissues. Model systems of banana and  The field of plant cryobiology seeks to understand the physiological and molecular processes that allow plants to survive low temperatures. The focus of cryobiology is predominantly cryopreservation: the process and methods that permit long term survival of organisms at liquid nitrogen temperatures.Once cryopreserved, materials remain safe and available for a low annual cost. Novel, mutant, or transformed cell lines that can no longer be maintained in laboratory settings can be cryopreserved to prevent their loss . Clonal Successful cryogenic storage is dependent upon having a reliable source of coolant as well as a good documentation system. Once achieved, propagules often have extended storage longevity compared to conventional storage regimes (refrigerator or freezer conditions). Genetic drift and mutations are minimized compared to when materials are maintained in an actively growing state for extended intervals .Long term storage reduces the frequency of regenerations of accessions in genebanks and facilitates the use of specific individuals in breeding programs. Availability and transportability of cryopreserved pollen allows breeders to have access to materials that might otherwise be unavailable. Cryopreservation of embryo cultures lets breeding programs prolong the availability of juvenile materials while waiting for characterization of mature tree selections . CryothePlant cryobiology is a research discipline that is beginning to enter into the genomics arena. Traditionally, the discipline has been considered an extension of the cold hardiness and drought tolerance fields, centered primarily on long term preservation of seeds, shoot tips, dormant buds, pollen, embryos, cell lines, and other propagule types. A greater application of genomics techniques can increase our understanding of plant cryobiology. By combining physiological and genomic approaches, an array of methods are available to understand how cells are protected from freezing stress.One of the key issues in plant cryobiology is understanding why some genotypes are less tolerant of preservation stresses than other genotypes. Widescale adoption of cryopreservation technologies will likely depend on identifying universal cryoprotection protocols for each propagule type. A characterization of the genetic response to diverse cryoprotectants will determine if methods that rely on rapid cellular desiccation, permeable cryoprotectants, freeze desiccation, or air desiccation all result in similar cellular responses. Do cells sense and respond to the stresses differentially? Alternatively, do cells ultimately respond to either desiccation and/or temperature extremes? Careful analyses of gene expression responses will reveal which stress is perceived by cellular machinery and the pathways that are activated.Seeds and dormant buds can acquire an endogenous tolerance to desiccation and cryogenic temperature stresses. Dormant buds from temperate species collected mid-winter are more amenable to cryopreservation than those collected prior to acquiring cold tolerance or those which lose their cold-hardiness in the springtime . This acThe process of propagule recovery is poorly understood. Do cells acquire adequate protection from undesirable chemical effects  that are generated during recovery? Is it possible to minimize production of free radicals while promoting cellular repair? Comparison of gene expression patterns will provide key information as to the timing and nature of the recovery pathways in systems that survive or fail to survive cryopreservation.Molecular marker technologies have already been applied to cryopreserved plant materials to ascertain if recovered explants are true-to-type. Generally, there is consensus that plant genotypes remain stable after cryopreservation when a single genotype is the conservation target -13. Key Both dehydration and low temperature affect water relations within the cell. Lethal ice forms when hydrated cells are cooled below their freezing point. Thus, for successful cryopreservation, cells must be desiccated to prevent ice propagation. Cells must also have intact membranes and stable proteins to tolerate the desiccation and cold stresses. The rich literatures of cold and desiccation tolerance have revealed that extraordinarily similar response pathways are triggered by these different stresses.It is not surprising that the regulatory mechanisms for desiccation and cold tolerance partially overlap. These stresses invoke second messengers such as calcium, reactive oxygen species, and inositol phosphates within minutes of stress signal perception . The casArabidopsis [Microarray chip methods have identified 299 drought inducible, 54 cold inducible, and 245 abscisic acid (ABA) inducible genes in bidopsis , 20. Of bidopsis . In thisCold treatments cause abrupt changes in the structure of cellular lipids and cytoplasm. Ice forms in hydrated cells and the plasma membrane undergoes an undesirable phase change that is induced by low temperatures. Formation of extracellular ice removes freezable cellular water, but also invokes a desiccation stress.Cold acclimation treatments can increase the levels of unsaturated fatty acids, alter lipid and protein composition, change the lipid/protein ratio, and increase the proportion of phospholipids to stabilize membranes and prevent phase changes , 23. LipoC [Genomic evaluations of cold acclimated and exposed plants have revealed complex response pathways. The DREB1 proteins are transcriptional activators of over 300 genes in the CBF cold response pathway . TranscroC . The coloC . The CBFoC .Desiccation tolerant seeds and pollen undergo extreme dehydration as part of the developmental maturation process. Orthodox seeds can lose most of their moisture during maturation, resulting in moisture contents of around 8%. At low moisture content, the cytoplasm enters a glassy state where molecular movement is minimal . GlassesVegetative cells can also tolerate desiccation. Tonoplast and plasma membrane specific aquaporins, water channels across membranes, may play critical roles in water movement during both desiccation and rehydration. Desiccation stresses may cause the plasma membrane to lose surface area. Sugars and other polyhydric solutes are believed to protect protein and membrane structures during desiccation, though the mode of action remains poorly understood , 32.LEA proteins accumulate in seeds when desiccation tolerance is acquired during seed maturation. LEA proteins are hydrophilic and remain soluble at boiling temperatures (e.g. ). They mA.The genetic response to drought or desiccation has been identified in several model systems. ABA independent pathways ultimately affect the pathways that regulate osmotic equilibrium and detoxification . The DRE/CRT cis-acting element associates with the desiccation-specific DREB2 transcription factor, found in the ABA independent pathway response to drought stress , 38. ERDB.Arabidopsis, several hundred genes were induced by exogenous ABA treatment [Exogenous ABA induces genes that are also activated by dehydration. In reatment . An exogreatment -46. Endogenous ABA is essential for some drought stress-responses , includiMAP kinases also play a role in the regulation of stress responses by affecting protein phosphorylation and dephosphorylation states . MAP kinAn alternative ABA dependent pathway involves the MYC and MYB transcription factors that bind to MYB and MYC recognition sequences and activate the drought inducible RD22 gene .Survival after desiccation is dependent upon cellular protection from the stress of water loss as well as the availability of functional repair mechanisms after rehydration. Desiccation tolerant seeds and pollen generally survive rehydration; whereas it is much more challenging to successfully regenerate less tolerant propagule types. Recovery is dependent upon having enough cells survive for successful propagule regeneration. In shoot tip systems, many of the larger cells in regions surrounding the meristem become extremely plasmolyzed and do not survive cryopreservation .Ribes accessions exhibited higher hydroxyl radical activity, antioxidant status, phenolic accumulation and anthocyanin pigments than Ribes accessions that were cryo-sensitive [The presence of reactive oxygen species within cells after stress can damage cells and generate lipid peroxides, aldehydic products and protein carbonyls , 51. Higensitive . The reaensitive . Reactivensitive . The cytensitive .Arabidopsis T87 suspension cells to facilitate conservation of transgenic lines. Arabidopsis can also be a good model to identify the gene expression responses to cryogenic stress [Arabidopsis shoot tips are easy to produce and readily survive diverse cryo-exposure protocols [et al. published methods for the cryopreservation of Arabidopsis shoot tips using three of the more common shoot tip cryoprotection protocols. Cryoprotectants serve to both dehydrate and promote the glassy state within cells [Arabidopsis methods employed the cryoprotectants Plant Vitrification Solution 2  or in solution-filled cryovials. In contrast, PGD-treated shoot tips are slowly cooled within cryovials to -30 or -35oC prior to LN exposure.Many plant cryobiologists have focused on finding methods to conserve horticultural species that are vegetatively propagated since seed storage does not maintain the genotype of interest. Recently, a cryopreservation protocol has been published for c stress . Arabidorotocols . In 2006in cells . Publishsucrose; ), Plant sucrose; ) and PGDArabidopsis system. Comparisons of gene expression patterns during cryoprotectant treatment, liquid nitrogen exposure, and recovery of Arabidopsis shoot tips using cDNA microarrays have revealed suites of genes up- and down-regulated in shoot tips that survive cryopreservation .Cryoprotectants vary in their toxicity as well as their protective mechanisms , 61, thuMusa shoot tips from multiple species are amenable to vitrification methods [Musa, proteomics approaches have proved advantageous [Musa proteomics efforts (http://www.pdata.ua.ac.be/musa/ modules/listview/?table=spot). These high sucrose treatments serve to decrease Musa meristem water content and increase the intracellular sucrose concentration [             methods , 64. Sinntageous -67. Merintageous . A websintration .Progress in genomic research in other kingdoms may reveal fundamental stress responses of cells to extreme conditions. Insects and microbes have adapted to polar environments . ReptileCryoptopygus antarcticus) from Antarctic regions upregulate structural and cuticle proteins. Furthermore, expression of genes involved in moulting supports a role of moulting in cold tolerance [Onychiurus arcticus) have also served as model to study desiccation and cold tolerance in insects [O. arcticus in various states of desiccation identified clones representing genes that fall into classes of aquaporins, dehydrins, heat shock proteins and those relating to antioxidant production  that were upregulated [Desiccation and cold response pathways are interrelated in insects. Cold acclimated microarthopods (olerance . Arctic  insects . As in p insects . Sequencegulated . Subtracegulated .The Storey laboratory at Carleton University has made remarkable progress identifying genomic responses in cold-tolerant vertebrates. Frogs and reptiles overwinter in a frozen state and use ice nucleators to initiate the freezing process extracellularly and use antifreeze proteins to inhibit recrystallization during freezing. High osmolyte contents limit cell volume reduction, membrane stabilizers such as trehalose and proline prevent lipid biolayer compression, and physiological adaptations regulate the cessation and reactivation of breathing and the heart . Novel gSuccessful cryoprotection in both animals and plants is dependent upon minimizing freezeable water within cells and the maintenance of sufficient cell volumes , 77. ColIt is clear that similar mechanisms have evolved in diverse kingdoms that enable organisms to tolerate extreme temperatures and desiccation. Cells have reduced biochemical reaction rates, increased cellular viscosities, alterations in membrane lipids and changes in protein conformation in response to extremely cold conditions . By miniPrevention of cellular ice formation and maintenance of intact membranes are critical for successful plant cryopreservation. Identification of the genomic responses to cold and desiccation stresses during the cryopreservation process will reveal how propagules respond to diverse cryoprotectants, extreme temperatures, and recover. Understanding plant acclimation is key to determining endogenous responses and more information about the recovery process is needed. Comparing the genetic responses to tolerance and longevity within and among plant species and propagules will guide conservation scientists in their quest to design improved preservation strategies.


Investigations were carried out on two lines of human melanomas  xenografted in nude mice. The tumours were characterised by a similar vascular supply but showed a pronounced difference in the rate of volume growth and in the radiobiologically hypoxic fraction. The distribution of ATP, glucose and lactate in the tumours was investigated using quantitative bioluminescence and single photon imaging. Concentrations of the metabolites were obtained as global values for the entire tumour mass, in regions with densely packed, structurally intact tumour cells ('viable zones'), in areas with necrosis, stromal cells and fibrous material ('necrotic zones') and in adjacent normal tissue. In all melanomas investigated glucose concentrations were significantly lower and lactate concentrations were significantly higher than in normal tissue. In contrast, no significant differences for ATP were detected. ATP and glucose concentrations were significantly less in necrotic than in viable tumour zones, whereas lactate concentrations were nearly equal in these tumour parts. Corresponding results were obtained in central versus peripheral tumour zones. There was no dependency of global or regional metabolite concentrations on tumour size within the volume range 110-1470 mm3. Based on this lack of dependency, metabolic concentrations were averaged over the whole tumour size range. Metabolite concentrations were not significantly different either globally or regionally between the two tumour entities investigated, a finding which held true for all three metabolites registered. Thus, metabolite distributions apparently mirror the similarity in vascularity of MF and EE melanomas rather than reflecting intrinsic properties with regard to tumour growth rates or susceptibility to radiation.


Septic shock is a life-threatening clinical syndrome that, despite its rare occurrence in obstetrics,remains a leading cause of maternal mortality. Its pathophysiology is explained by a profoundsystemic response to a complex variety of host cellular and humoral mediators elaborated afterexposure to microbial toxins. Early recognition, prompt diagnostic workup, and immediate initiationof therapy improve outcomes. Therefore, recent publications have popularized the concept of the“sepsis syndrome,” a preshock list of clinical criteria associated with progressive sepsis. Neededdiagnostic studies should never be withheld because of “pregnancy concerns.” With critically illpatients, the risk-to-benefit ratio supports the use of these diagnostic studies in almost all circumstances.Standard therapy is directed principally at restoring tissue perfusion by intravascularvolume expansion and in some instances vasoactive pharmacological intervention. Simultaneously,identification of the source of infection and commencement of appropriate empiric antibiotic treatmentare critical. In some cases, surgical abscess drainage or debridement of infected necrotic tissuewill need to be considered. Novel approaches to treatment that attempt to reduce the systemicresponse to microbial toxins are promising and under active investigation. Pregnancy-specific considerationsinclude the following: 1) initial signs or symptoms of septic shock may be masked bynormal physiologic alterations of pregnancy; 2) a mixed polymicrobial group of organisms, consistentwith lower genital tract flora, should be anticipated; and 3) initial therapy should be directedat maternal concerns since adverse fetal effects are most likely the result of maternal decompensation.


The prognosis of colorectal cancer has not significantly changed during the last 30 years. While evaluation of tumour cell proliferation may provide prognostic information, results obtained so far have been contradictory Heterogeneity in tumour cell proliferation may explain these contradictions. With in vivo injection of iododeoxyuridine (IdUrd), estimation of labelling index (LI), S-phase transit time (Ts) and potential doubling time (Tpot) may be performed from a single sample. A total of 109 colorectal cancers were studied after in vivo injection of IdUrd before surgical removal. From each cancer, four to eight samples were processed for both flow cytometrical (FCM) and immunohistochemical (IHC) visualization of IdUrd incorporation. LI/IHC was morphometrically quantified at both the luminal border and the invasive margin of these tumours. LI was significantly higher at the luminal border compared with the invasive margin, although they were correlated with each other. Using combined IHC and FCM methods, rapidly growing colorectal cancers (high LI and/or low Tpot) showed an increased survival  in the entire unselected material and for radically removed Dukes' B tumours. FCM data alone did not discriminate for survival, with the exception of Ts in diploid and radically removed Dukes' B tumours.


The question of whether initial prognostic factors in small-cell lung cancer patients have a predictive value for patients' quality of life (QL) during chemotherapy is addressed in the context of a randomised clinical trial comparing early and late alternating chemotherapy (SAKK protocol 15/84). The relative impact of initial tumour stage and performance status, previous weight loss, sex and age on patient-rated QL was analysed over six chemotherapy cycles in 124-130 patients (according to available QL data) with more than 400 questionnaires. Fatigue/malaise, personal functioning, emotional and general well-being were prospectively selected as QL indicators. Predefined summary measures  were analysed separately by scale in various patient groups. General linear models adjusted for treatment arm and response were used to confirm the univariate findings. Within the overall sample, the average QL scores over six cycles were predicted by initial prognostic factors. Patients with poor prognostic factors reported worse QL. Within a limited sample (with baseline QL), patients with poor prognostic factors reported worse QL at baseline and greater improvement under treatment. Graphical comparison of QL patterns over cycles showed permanent discrimination by levels of prognostic factors. The impact of initial prognostic factors was consistently confirmed in the three analyses. Levels of performance status and weight loss best discriminated QL. Initial tumour stage, performance status and previous weight loss can predict QL in small-cell lung cancer during chemotherapy, even after controlling for response to treatment. Our results may contribute to clinical decision-making with regard to the intensity of chemotherapy and QL outcome, especially in patients with extensive disease.


Among these chemicals is bisphenol A (BPA), a pervasive endocrine-disrupting compound used to make polycarbonate plastic and epoxy resins. Now researchers report evidence that exposure to environmentally relevant doses of BPA during pregnancy may alter insulin sensitivity and glucose homeostasis in mice, with potential disease-related consequences for both the mother and her male offspring The study evaluated the effects of two different doses of BPA (10 or 100 μg/kg/d) administered to pregnant mice during days 9–16 of gestation. Glucose metabolism experiments were performed on the mice during pregnancy and subsequently on their offspring.BPA exposure aggravated the insulin resistance that occurs during pregnancy, and four months postpartum, BPA-treated mice weighed more and had more severe insulin resistance than untreated females. The BPA-treated mice also showed elevated plasma levels of insulin, leptin, triglycerides, and glycerol (a breakdown product of triglycerides), as well as molecular changes indicating reduced insulin sensitivity in skeletal muscle and liver.Given that levels of the hormone leptin are normally increased during pregnancy, the authors propose that future research should seek to determine whether BPA directly regulates leptin release from fatty tissue or whether the observed hyperleptinemia is a consequence of the altered metabolic state of these animals.in utero had reduced glucose tolerance, increased insulin resistance, and altered blood parameters compared with offspring of untreated mothers. Moreover, studies of the male offspring’s pancreases showed altered calcium signaling and insulin secretion.Previously the same research team had shown a relationship between BPA exposure and glucose intolerance and insulin resistance in adult male mice. In the present study, they further observed that, at 6 months of age, male offspring exposed to BPA The authors conclude that BPA exposure during pregnancy can alter the mother’s glucose metabolism during pregnancy and later in life, and may contribute to metabolic disorders relevant to glucose homeostasis in the male offspring. The findings also suggest that BPA exposure should be further examined as a risk factor for diabetes.


Intrahepatic stones are difficult to manage, especially when they are associated with bile duct stricture,cholangitis and destruction of liver parenchyma. Suggested modes of treatment include surgical bile ductexploration, endoscopic procedures, transhepatic cholangiolithotomy and liver resection. This paper reports2 patients in whom liver resection was performed because of intrahepatic ductal stones, bile duct stricturesand repeated episodes of cholangitis. Liver resection was uncomplicated and long-term results were satisfactory.Our results support the view that liver resection is indicated in rare instances of intrahepatic bile ductstones associated with bile duct strictures.


The mechanism by which phagocytosed mast cell granules (MCGs) inhibit macrophage superoxide production has not been defined. In this study, rat peritoneal macrophages were co-incubated with either isolated intact MCGs or MCG-sonicate, and their respiratory burst capacity and morphology were studied. Co-incubation of macrophages with either intact MCGs or MCG-sonicate resulted in a dose-dependent inhibition of superoxide- mediated cytochrome c reduction. This inhibitory effect was evident within 5 min of incubation and with MCG-sonicate was completely reversed when macrophages were washed prior to activation with PMA. In the case of intact MCGs, the inhibitory effect was only partially reversed by washing after a prolonged co-incubation time. Electron microscopic analyses revealed that MCGs were rapidly phagocytosed by macrophages and were subsequently disintegrated within the phagolysosomes. Assay of MCGs for superoxide dismutase (SOD) revealed the presence of significant activity of this enzyme. A comparison of normal macrophages and those containing phagocytosed MCGs did not reveal a significant difference in total SOD activity. It is speculated that, although there was no significant increase in total SOD activity in macrophages containing phagocytosed MCGs, the phagocytosed MCGs might cause a transient increase in SOD activity within the phagolysosomes. This transient rise in SOD results in scavenging of the newly generated superoxide. Alternatively, MCG inhibition of NADPH oxidase would explain the reported observations.


A 26-year-old woman born with Tetralogy of Fallot initially underwent a left Blalock-Taussig shunt followed by a complete repair with a transannular patch at 2 years of age. She complained of non-sustained short episodes of palpitations. Her Holter monitor showed episodes of six beat run of non-sustained ventricular tachycardia. She was scheduled to undergo surgical pulmonary valve replacement. In view of her symptoms and Holter results she underwent an electrophysiology study to map any substrate of ventricular tachycardia for intra-operative ablation. Her baseline electrocardiogram demonstrated complete right bundle branch block pattern (RBBB) with QRS duration of 174 msec secondary to surgical interruption of the right bundle branch. During the electrophysiology study she was noted to have intermittent narrow QRS complexes .The QRS On initial assessment of the intracardiac tracings as well as the 12 lead electrocardiogram, there is evidence of baseline RBBB  with intermittent appearance of normally conducted sinus activations with normal AH and slightly shortened HV. However on further analysis there seems to be a premature ventricular complex from the right ventricular apex that occurs immediately after the His deflection causing the apparent narrowing of the QRS complexes.Intermittent transition from wide to narrow QRS complex has been described with multiple mechanisms. These include change in heart rate, 'peel-back' refractoriness, rate dependent progressive shortening of bundle branch refractoriness, gap phenomena, supernormality, loss of pre-excitation, premature ventricular complex (PVC) ipsilateral to the bundle branch block and equal conduction delay in both the bundle branches . PresencThis physiological mechanism may have potential clinical applications for optimizing the timing of pacing intervals to obtain narrow QRS complexes as well to obtain interventricular synchrony.


Experiments conducted in vitro are described which indicate that a family of specifically substituted phosphoramides may share the carcinogenic properties displayed by the structurally novel carcinogen, hexamethylphosphoramide (HMPA). Most of the analogues tested only gave a positive response in vitro when using a substantially modified liver homogenate activation system (S-9 mix). The analogy drawn in our earlier paper between this new class of potential carcinogens and the nitrosamine carcinogens, has been strengthened. The following compounds gave a positive response in the cell transformation assay of Styles: hexamethylphosphoramide (HMPA), hexamethylphosphorous triamide, hexamethylphosphorothioic triamide, tripiperidinophosphine oxide, phosphorothioic trimorpholide and diethoxymorpholinophosphine oxide (DEMPA).


Luminol-enhanced chemiluminescence was measured in fresh whole human blood, or human neutrophils isolated from heparinized blood, human alveolar macrophages and rat alveolar macrophages stimulated with bacterial endotoxin (LPS). Tetraacetate esters of rooperol, a dicatechol showing anticytokine activity, added to cells simultaneously with LPS inhibited the respiratory burst. The effective concentrations of rooperol were in the range of 1-10 μM depending on cell type and corresponded well with inhibition of nitric oxide production by rat alveolar macrophages. Thus rooperol may reduce some effects of excessive phagocytic activity and inflammatory reaction but by quenching free radicals production may also diminish the resistance to bacterial infections.


Endolaryngeal microscopic laryngosurgery (microlaryngosurgery) using a direct laryngoscopeis the preferred surgical method for treating laryngeal lesions under general anesthesia.However, this method does not provide a wide-angle view of the larynx and does not allowdetailed observations of the ventricle and subglottis of the laryngeal cavity, resulting in blindareas. Video-assisted endoscopic laryngosurgery using a direct laryngoscope and a longtransurethral rigid endoscope was therefore utilized to allow clear observations and completeresection of laryngeal lesions in these blind areas. This endoscopic surgical technique isintroduced, and clinical cases are presented.