The Making of a Philosopher: The Contemplative Letters of Charles de Bovelles.
Today the importance of epistolary networks for intellectuals in early modern Europe is well appreciated. Nevertheless, connections reaching outside the canon of celebrated humanists and scientists in the Republic of Letters are little studied. This article examines how Charles de Bovelles (1479-1567) used letters to establish a philosophical persona and publicize his contemplative approach to natural philosophy. Scrutinizing how Bovelles created an epistolary community comprising university alumni and men in religious professions, the article sheds new light on the culture of contemplation in the early sixteenth century.


Smoking and drinking during pregnancy. Their effects on preterm birth.
The effects of cigarette smoking and alcohol consumption on the length of gestation were examined in a prospective study of 30,596 pregnant women in northern California. Preterm births (less than 37 weeks' gestation) were 20% more common in women smoking at least one pack of cigarettes per day. This effect was strongest for births occurring before 33 weeks, where the excess was 60%. This excess was not accounted for by differences in maternal age, education, ethnicity, time prenatal care began, drinking during pregnancy, or eight other potential confounding factors. The results indicate a probable effect of smoking on the time of parturition, which is additional to its well-known effect on intrauterine growth retardation. The effect of alcohol consumption on preterm births was also examined, but no consistent trends were found.


Nutrients and the Pkh1/2 and Pkc1 protein kinases control mRNA decay and P-body assembly in yeast.
Regulated mRNA decay is essential for eukaryotic survival but the mechanisms for regulating global decay and coordinating it with growth, nutrient, and environmental cues are not known. Here we show that a signal transduction pathway containing the Pkh1/Pkh2 protein kinases and one of their effector kinases, Pkc1, is required for and regulates global mRNA decay at the deadenylation step in Saccharomyces cerevisiae. Additionally, many stresses disrupt protein synthesis and release mRNAs from polysomes for incorporation into P-bodies for degradation or storage. We find that the Pkh1/2-Pkc1 pathway is also required for stress-induced P-body assembly. Control of mRNA decay and P-body assembly by the Pkh-Pkc1 pathway only occurs in nutrient-poor medium, suggesting a novel role for these processes in evolution. Our identification of a signaling pathway for regulating global mRNA decay and P-body assembly provides a means to coordinate mRNA decay with other cellular processes essential for growth and long-term survival. Mammals may use similar regulatory mechanisms because components of the decay apparatus and signaling pathways are conserved.


Exportin 1 Inhibition Induces Nerve Growth Factor Receptor Expression to Inhibit the NF-κB Pathway in Preclinical Models of Pediatric High-Grade Glioma.
High-grade glioma (HGG) is the leading cause of cancer-related death among children. Selinexor, an orally bioavailable, reversible inhibitor of the nuclear export protein, exportin 1, is in clinical trials for a range of cancers, including HGG. It inhibits the NF-κB pathway and strongly induces the expression of nerve growth factor receptor (NGFR) in preclinical cancer models. We hypothesized that selinexor inhibits NF-κB via upregulation of NGFR. In HGG cells, sensitivity to selinexor correlated with increased induction of cell surface NGFR expression. Knocking down NGFR in HGG cells increased proliferation, anchorage-independent growth, stemness markers, and levels of transcriptionally available nuclear NF-κB not bound to IκB-α, while decreasing apoptosis and sensitivity to selinexor. Increasing IκB-α levels in NGFR knockdown cells restored sensitivity to selinexor. Overexpression of NGFR using cDNA reduced levels of free nuclear NF-κB, decreased stemness markers, and increased markers of cellular differentiation. In all HGG lines tested, selinexor decreased phosphorylation of NF-κB at serine 536 (a site associated with increased transcription of proliferative and inflammatory genes). Because resistance to selinexor monotherapy occurred in our in vivo model, we screened selinexor with a panel of FDA-approved anticancer agents. Bortezomib, a proteasome inhibitor that inhibits the NF-κB pathway through a different mechanism than selinexor, showed synergy with selinexor against HGG in vitro Our results help elucidate selinexor's mechanism of action and identify NGFR as a potential biomarker of its effect in HGG and in addition suggest a combination therapy strategy for these challenging tumors.


Speckle elimination using shift-averaging in high-rate holographic projection.
Speckle is a major source of noise in holographic projection. Time averaging of multiple holograms may be used to reduce speckle contrast, but multiple holograms must be calculated per each frame, costing in computational power. We show that a single hologram may be used to generate a fully speckle-free reconstruction, by cyclic shifting and time averaging. We demonstrate the concept experimentally, and discuss its application for high-rate holographic projection systems.


Prevalence of internet addiction and anxiety, and factors associated with the high level of anxiety among adolescents in Hanoi, Vietnam during the COVID-19 pandemic.
The COVID-19 pandemic and the resulting isolation measures created an increase in the usage of smart devices and internet among adolescents. This study aims to estimate the prevalence of internet addiction, the prevalence of high level of anxiety as well as to examine factors associated with the high level of anxiety among adolescents in Hanoi, Vietnam during the COVID-19 pandemic. Data was collected using respondent-driven sampling and Google online survey forms from a sample of 5,325 school students aged 11-17 in Hanoi between October and December 2021. A short scale consisting of 5 items was used to measure internet addiction and the GAD-7 was used to measure adolescent anxiety level. The findings revealed that 22.8% and 7.32% of adolescents experienced moderate and severe anxiety. About 32.7% of the study sample exhibited at least three internet addiction indicators. Logistic regression analysis identified significant predictors for high levels of adolescent anxiety. Being female, family experiencing economic difficulties, and exposure to domestic violence were associated with higher risk of anxiety disorder (OR 1.78, 1.45, and 2.89, respectively). Both average daily online time and internet addiction demonstrated gradient association with high level of anxiety. The prevalence of internet addiction and high level of anxiety were high among adolescents in Hanoi, Vietnam during the COVID-19 pandemic. The study highlights the importance of implementing measures at the family and school levels to promote a balanced and healthy approach to smart device use among adolescents.


The diagnostic process in primary care: a comparison of general internists and family physicians.
This investigation examined the formulation of diagnostic hypotheses by general internists and family physicians in response to three patient cases (dyspnea, abdominal pain and syncope). The investigation was conducted in the United States. Physician responses to sequentially presented written clinical information were audiotaped. Each transcribed protocol was scored to enumerate and characterize the hypotheses considered by physicians in each specialty. Results of the analyses of variance of hypothesis measures revealed that internists generated more hypotheses than family physicians and that the internist's hypotheses were more specific and were less likely to be generated by other physicians. In addition, internists tended to consider hypotheses more closely related to the final diagnosis sooner in the case presentation than did family physicians. The findings of increased number, specificity, and uniqueness of hypothesis considered by internists are consistent with previously demonstrated differences in the amount and nature of diagnostic information collected by family physicians and internists.


Similarity in milk microbiota in replicates.
Receiving the same results from repeated analysis of the same sample is a basic principle in science. The inability to reproduce previously published results has led to discussions of a reproducibility crisis within science. For studies of microbial communities, the problem of reproducibility is more pronounced and has, in some fields, led to a discussion on the very existence of a constantly present microbiota. In this study, DNA from 44 bovine milk samples were extracted twice and the V3-V4 region of the 16S rRNA gene was sequenced in two separate runs. The FASTQ files from the two data sets were run through the same bioinformatics pipeline using the same settings and results from the two data sets were compared. Milk samples collected maximally 2 h apart were used as replicates and permitted comparisons to be made within the same run. Results show a significant difference in species richness between the two sequencing runs although Shannon and Simpson's diversity was the same. Multivariate analyses of all samples demonstrate that the sequencing run was a driver for variation. Direct comparison of similarity between samples and sequencing run showed an average similarity of 42%-45% depending on whether binary or abundance-based similarity indices were used. Within-run comparisons of milk samples collected maximally 2 h apart showed an average similarity of 39%-47% depending on the similarity index used and that similarity differed significantly between runs. We conclude that repeated DNA extraction and sequencing significantly can affect the results of a low microbial biomass microbiota study.


Infants' understanding of the causal power of agents and tools.
Tools are objects that are manipulated by agents with the intention to cause an effect in the world. We show that the cognitive capacity to understand tools is present in young infants, even if these tools produce arbitrary, causally opaque effects. In experiments 1-2, we used pupillometry to show that 8-mo-old infants infer an invisible causal contact to account for the-otherwise unexplained-motion of a ball. In experiments 3, we probed 8-mo-old infants' account of a state change event (flickering of a cube) that lies outside of the explanatory power of intuitive physics. Infants repeatedly watched an intentional agent launch a ball behind an occluder. After a short delay, a cube, positioned at the other end of the occluder began flickering. Rare unoccluded events served to probe infants' representation of what happened behind the occluder. Infants exhibited larger pupil dilation, signaling more surprise, when the ball stopped before touching the cube, than when it contacted the cube, suggesting that infants inferred that the cause of the state change was contact between the ball and the cube. This effect was canceled in experiment 4, when an inanimate sphere replaced the intentional agent. Altogether, results suggest that, in the infants' eyes, a ball (an inanimate object) has the power to cause an arbitrary state change, but only if it inherits this power from an intentional agent. Eight-month-olds are thus capable of representing complex event structures, involving an intentional agent causing a change with a tool.


[Antibodies to the hepatitis A virus in the healthy population of Moscow].
Serum specimens collected from 1002 persons in Moscow were tested for the presence of antibodies to hepatitis A virus (anti-HAV antibodies) by solid-phase enzyme immunoassay. The prevalence of these antibodies increased progressively with age from 10% in children aged 5-9 years to over 90% in the age groups of 40-49 years and over, the 50% immunity level being established at the age of 18 years. 79% of infants under 1 year were found to be immune, which was obviously due to the placental transfer of antibodies from mother to child. In a considerable part of seropositive persons over 30 years high or medium antibody titers were detected. These age groups showed a stable proportion of the low, medium and high level of anti-HAV antibodies. The prevalence of such antibodies was not related to sex. The presence of an ample amount of anti-HAV antibodies was determined in all of 18 tested lots of commercial serum immunoglobulin obtained from 3 different manufacturers.


TESTOSTERONE SUPPLEMENTATION AND RETINAL VASCULAR DISEASE.
To determine whether testosterone supplementation is associated with retinal artery occlusion (RAO) or retinal vein occlusion (RVO). Retrospective matched cohort study using data from a large national U.S. insurance database. The testosterone cohort consisted of all male patients who filled a prescription for testosterone from 2000 to 2013. Five controls were matched on age (±3 years), sex, race, and similar time in plan (±3 months) for every exposed patient. Exclusion occurred for <2 years in the plan, <1 eye care visit, medications known to affect androgen levels, and systemic diseases associated with occlusions or increased testosterone. Cox proportional hazard regression assessed the hazard of a new diagnosis of RAO or RVO while controlling for age, race, diabetes mellitus, and hypertension. A total of 35,784 incident testosterone users were compared with 178,860 matched controls. Ninety-three (0.3%) RAOs and 50 (0.1%) RVOs were found in the testosterone cohort and contrasted with 316 (0.2%) RAOs and 232 (0.1%) RVOs in the control group. After multivariate analysis, testosterone supplementation significantly increased the hazard of RAO (hazard ratio: 1.43, 95% confidence interval: 1.12-1.81, P = 0.004), but not of RVO (hazard ratio: 1.03, 95% confidence interval: 0.74-1.42, P = 0.86). Although the incidence of RAO and RVO is low in users of testosterone, supplementation therapy is associated with an increased hazard of RAO, but apparently not of RVO.


No association between use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers prior to hospital admission and clinical course of COVID-19 in the COvid MEdicaTion (COMET) study.
Since the outbreak of SARS-CoV-2, also known as COVID-19, conflicting theories have circulated on the influence of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) on incidence and clinical course of COVID-19, but data are scarce. The COvid MEdicaTion (COMET) study is an observational, multinational study that focused on the clinical course of COVID-19 (i.e. hospital mortality and intensive care unit [ICU] admission), and included COVID-19 patients who were registered at the emergency department or admitted to clinical wards of 63 participating hospitals. Pharmacists, clinical pharmacologists or treating physicians collected data on medication prescribed prior to admission. The association between the medication and composite clinical endpoint, including mortality and ICU admission, was analysed by multivariable logistic regression models to adjust for potential confounders. A total of 4870 patients were enrolled. ACEi were used by 847 (17.4%) patients and ARB by 761 (15.6%) patients. No significant association was seen with ACEi and the composite endpoint (adjusted odds ratio [OR] 0.94; 95% confidence interval [CI] 0.79 to 1.12), mortality (OR 1.03; 95%CI 0.84 to 1.27) or ICU admission (OR 0.96; 95%CI 0.78 to 1.19) after adjustment for covariates. Similarly, no association was observed between ARB and the composite endpoint (OR 1.09; 95%CI 0.90 to 1.30), mortality (OR 1.12; OR 0.90 to 1.39) or ICU admission (OR 1.21; 95%CI 0.98 to 1.49). In conclusion, we found no evidence of a harmful or beneficial effect of ACEi or ARB use prior to hospital admission on ICU admission or hospital mortality.


Auditory brainstem response (ABR) in congenital central alveolar hypoventilation.
Auditory brainstem responses (ABRs) were studied in a child with congenital central alveolar hypoventilation showing marked depression of respiratory drive during sleep. During wakefulness and normoventilation no ABR abnormalities were found, either at the age of 14 months or five years. ABR recordings during sleep at 14 months of age showed marked wave V latency and wave I to wave V interpeak latency prolongation of about 0.4 ms both for periods of hypoventilation and normoxic hypercapnia. ABR findings of this and other studies carried out in sleep apneas are discussed with respect to brainstem dysfunction associated with varied sleep apnea syndromes.


Does warfarin safely prevent clotting of hemodialysis catheters? a review of efficacy and safety.
This article reviews the efficacy and safety of warfarin to prevent tunneled cuffed catheter (TCC) thrombosis in the hemodialysis population. Literature searches of PubMed, EMBASE, the Cochrane Library and Google Scholar were performed until April 1, 2007. Bibliographies of relevant articles were reviewed for additional publications. Minidose (1 mg/day) warfarin is ineffective in preventing TCC malfunction. Warfarin titrated to an international normalized ratio (INR) of 1.5-2.0, 1.8-2.5, and 2.0-3.0 was found to decrease the rate of thrombosis in selected patients. Early initiation of warfarin after catheter placement may be advantageous. Despite evidence of efficacy, safety is of greater concern. There were no major bleeds reported at an INR range of 1.5-2.5 specifically in catheter studies. However, an increase in major bleeding episodes has been reported with INR ranging from 1.4 to 3.0 in patients receiving warfarin for other indications (e.g., graft patency or cardiovascular indications). There is insufficient evidence to recommend the routine use of warfarin to prevent TCC thrombosis in all patients, primarily because of safety concerns. There is an increased risk of bleeding associated with warfarin use in the hemodialysis population. If a decision is made to use warfarin on a case-by-case basis, literature to date suggests that an INR target of 1.5-2.5 should suffice. Bleeding must be monitored carefully in this population, especially in patients using antiplatelet medications for concurrent conditions.


[Some mechanisms of pathogenesis of hypertonic type neurocirculatory dystonia in flying personnel].
Cytochemical analysis was used to compare the activities of hyaloplasmatic and mitochondrial glycerophosphate dehydrogenase, and succinate dehydrogenase in lymphocytes of peripheral blood taken from 14 aviators with the diagnose of hypertonic neurocirculatory dystonia, and 18 healthy aviators. Significantly higher activity of these enzymes in patients is assumed to signify intensification of metabolism and cellular respiration bearing the forced adaptive character. On this evidence, an attempt is made to interpret earlier discovered changes in the immunobiochemical status of these patients and plausible mechanisms of progressive arterial hypertension are hypothesized. Emphasis is laid on the necessity to direct secondary preventive measures at the early phases of hypertension not only on reduction of the vascular tone and correction of the immunobiochemical status but on building-up of cell's functional reserves.


The physical dependence liabilities of oxybutynin and morphine in rats.
The anticholinergic/antispasmodic agent oxybutynin does not induce physical dependence in rats when administered by oral gavage twice daily for 40 days; nor did challenge with naloxone precipitate withdrawal signs in these (oxybutynin-treated) animals. In contrast, morphine treatment resulted in a high degree of physical dependence as evidenced by the withdrawal signs noted after treatment was halted. Challenge with naloxone also induced severe withdrawal signs in morphine-treated rats. Withdrawal signs characterised by squealing, teeth chattering and "wet-dog" shakes were seen in one from five morphine-treated rats challenged with oxybutynin.


The potential impact of periodontal disease on general health: a consensus view.
Evidence for a link between periodontal disease and several systemic diseases is growing rapidly. The infectious and inflammatory burden of chronic periodontitis is thought to have an important systemic impact. Current evidence suggests that periodontitis is associated with an increased likelihood of coronary heart disease and may influence the severity of diabetes. This paper represents a UK and Ireland cross-specialty consensus review, undertaken by a group of physicians and dentists. The consensus group reviewed published evidence (PubMed search for review and original articles), focusing on the past 5 years, on the contributory role of periodontal disease to overall health. In particular, evidence relating to a role for periodontal disease in cardiovascular disease and in diabetes was considered. Initial studies of large epidemiological data sets have sought to find links between periodontitis and systemic disease outcomes, but a causal relationship still needs to be demonstrated between periodontal disease, cardiovascular disease and diabetes through prospective studies. There is a need for prospective studies assessing the association between periodontal disease and patients at particular risk of cardiovascular events which will allow assessment of both cardiovascular disease clinical endpoints and surrogate markers of cardiovascular risk. Of note, periodontal disease is also often more severe in subjects with diabetes mellitus, a group at already increased risk for cardiovascular events. While further research is needed to define the population-attributable risk of periodontal disease to both cardiovascular diseases and to diabetes control and progression, health education to encourage better oral health should be considered as part of current healthy lifestyle messages designed to reduce the increasing health burden of obesity, cardiovascular disease and diabetes.


Generation of a monoclonal antibody reactive to prefusion myocytes.
We established a novel monoclonal antibody, Yaksa that is specific to a subpopulation of myogenic cells. The Yaksa antigen is not expressed on the surface of growing myoblasts but only on a subpopulation of myogenin-positive myocytes. When Yaksa antigen-positive mononucleated cells were freshly prepared from a murine myogenic cell by a cell sorter, they fused with each other and formed multinucleated myotubes shortly after replating while Yaksa antigen-negative cells scarcely generated myotubes. These results suggest that Yaksa could segregate fusion-competent, mononucleated cells from fusion-incompetent cells during muscle differentiation. The Yaksa antigen was also expressed in developing muscle and regenerating muscle in vivo and it was localized at sites of cell-cell contact between mono-nucleated muscle cells and between mono-nucleated muscle cells and myotubes. Thus, Yaksa that marks prefusion myocytes before myotube formation can be a useful tool to elucidate the cellular and molecular mechanisms of myogenic cell fusion.


Serum Albumin Binding and Esterase Activity: Mechanistic Interactions with Organophosphates.
The albumin molecule, in contrast to many other plasma proteins, is not covered with a carbohydrate moiety and can bind and transport various molecules of endogenous and exogenous origin. The enzymatic activity of albumin, the existence of which many scientists perceive skeptically, is much less studied. In toxicology, understanding the mechanistic interactions of organophosphates with albumin is a special problem, and its solution could help in the development of new types of antidotes. In the present work, the history of the issue is briefly examined, then our in silico data on the interaction of human serum albumin with soman, as well as comparative in silico data of human and bovine serum albumin activities in relation to paraoxon, are presented. Information is given on the substrate specificity of albumin and we consider the possibility of its affiliation to certain classes in the nomenclature of enzymes.


Social behaviour in sheep relates to behaviour and neurotransmitter responses to nociceptive stimuli.
Sheep in the field display differences in social behaviour. These differences allow a division into three social groups with distinct behavioural occurrences and frequencies. The behavioural and neurotransmission responses of each of these groups to aversive stimuli were compared. Behavioural responses were seen to both forelimb electric shocks and thermal heating of the nose in all groups. These responses changed with stimulus repetition in a group-dependent manner. Microdialysis probe studies of neurotransmitter release in the somatosensory cortex indicated neurotransmitter responses to stimuli in all animals that varied with both animal group and stimulus repetition. Group 1 animals, aggressive and socially active, showed increases in gamma amino-4-butyric acid (GABA) with initial stimulus presentation; this increased with stimulus repetition. Behavioural responses to the stimuli decreased with repetition and nonstimulus-related behaviours, during the course of the experiment, increased. Both of these appeared dependent upon GABA. Group 2 animals, moderately aggressive and socially active, released opioid-like peptides (OLP) upon initial exposure to stimuli but, with repetition, switched to using GABA. Group 3 animals, nonaggressive and socially inactive, released OLP with initial and repeat stimuli. In groups 2 and 3, both GABA and OLP appear to reduce stimulus-related behaviour, but OLP appeared to also reduce nonstimulus-related behaviour and GABA increased these. Changes were independent of animal liveweight. Glutamate was released in response to stimuli in all 3 groups and, with repetition, fell in groups 1 and 2 but increased in group 3. An animal's social behaviour and status may predict its response to a stimulus.


Candidate Heterotaxy Gene FGFR4 Is Essential for Patterning of the Left-Right Organizer in Xenopus.
Congenital heart disease (CHD) is the most common birth defect, yet its genetic causes continue to be obscure. Fibroblast growth factor receptor 4 (FGFR4) recently emerged in a large patient exome sequencing study as a candidate disease gene for CHD and specifically heterotaxy. In heterotaxy, patterning of the left-right (LR) body axis is compromised, frequently leading to defects in the heart's LR architecture and severe CHD. FGF ligands like FGF8 and FGF4 have been previously implicated in LR development with roles ranging from formation of the laterality organ [LR organizer (LRO)] to the transfer of asymmetry from the embryonic midline to the lateral plate mesoderm (LPM). However, much less is known about which FGF receptors (FGFRs) play a role in laterality. Here, we show that the candidate heterotaxy gene FGFR4 is essential for proper organ situs in Xenopus and that frogs depleted of fgfr4 display inverted cardiac and gut looping. Fgfr4 knockdown causes mispatterning of the LRO even before cilia on its surface initiate symmetry-breaking fluid flow, indicating a role in the earliest stages of LR development. Specifically, fgfr4 acts during gastrulation to pattern the paraxial mesoderm, which gives rise to the lateral pre-somitic portion of the LRO. Upon fgfr4 knockdown, the paraxial mesoderm is mispatterned in the gastrula and LRO, and crucial genes for symmetry breakage, like coco, xnr1, and gdf3 are subsequently absent from the lateral portions of the organizer. In summary, our data indicate that FGF signaling in mesodermal LRO progenitors defines cell fates essential for subsequent LR patterning.


Applied breath analysis: an overview of the challenges and opportunities in developing and testing sensor technology for human health monitoring in aerospace and clinical applications.
The aerospace industry requires the development of a range of chemical sensor technologies for such applications as leak detection, emission monitoring, fuel leak detection, environmental monitoring, and fire detection. A family of chemical sensors are being developed based on micromachining and microfabrication technology to fabricate microsensors with minimal size, weight, and power consumption, and the use of nanomaterials and structures to develop sensors with improved stability combined with higher sensitivity. However, individual sensors are limited in the amount of information that they can provide in environments that contain multiple chemical species. Thus, sensor arrays are being developed to address detection needs in such multi-species environments. These technologies and technical approaches have direct relevance to breath monitoring for clinical applications. This paper gives an overview of developing cutting-edge sensor technology and possible barriers to new technology implementation. This includes lessons learned from previous microsensor development, recent work in development of a breath monitoring system, and future directions in the implementation of cutting edge sensor technology. Clinical applications and the potential impact to the biomedical field of miniaturized smart gas sensor technology are discussed.


Graphene flash memory.
Graphene's single atomic layer of sp(2) carbon has recently garnered much attention for its potential use in electronic applications. Here, we report a memory application for graphene, which we call graphene flash memory (GFM). GFM has the potential to exceed the performance of current flash memory technology by utilizing the intrinsic properties of graphene, such as high density of states, high work function, and low dimensionality. To this end, we have grown large-area graphene sheets by chemical vapor deposition and integrated them into a floating gate structure. GFM displays a wide memory window of ∼6 V at significantly low program/erase voltages of ±7 V. GFM also shows a long retention time of more than 10 years at room temperature. Additionally, simulations suggest that GFM suffers very little from cell-to-cell interference, potentially enabling scaling down far beyond current state-of-the-art flash memory devices.


Treatment Strategies in Acute Post-operative Endophthalmitis after Cataract Surgery at a Tertiary Eye Hospital in Nepal: A 5-year Retrospective Review.
Despite best possible preventive measures, acute postoperative endophthalmitis (POE) is still the most devastating, sight-threatening complication after intraocular surgery and the most feared complication by treating surgeons. It is a retrospective study of 22 eyes diagnosed as acute POE following cataract surgery in the last 5 years (2015-2019), aimed to evaluate the treatment strategies used in its management. Main outcome measures evaluated were rates of repeat intravitreal injection, adjunctive therapeutic regimens, pars plana vitrectomy (PPV) and visual outcome. Twenty one eyes (95.45%) received repeated intravitreal injection. Adjuvant intravitreal steroid was used in 12 eyes (54.54%), oral steroid in 16 eyes (72.72%) and oral antibiotic in 8 eyes (36.36%). PPV was done in 8 eyes (34.78%) and all 8 eyes that underwent PPV had a vision of Hand Movement (HM) close to face. 7 eyes (87.5%) had early PPV within 1 week of diagnosis. The median best corrected visual acuity (BCVA) improved from 1.00 logMar to 0.8 logMar following treatment at 3 months follow up (p= 0.117). Repeat intravitreal injections were commonly employed. Early PPV was performed more commonly regardless of the visual acuity at the time of diagnosis of acute POE.


[The paradox of being physically active but sedentary or sedentary but physically active].
The use of objective methods to measure physical activity and thus assess sedentary lifestyle, may change the definition of individuals as being sedentary or physically active. This situation would also interfere on the benefits of physical activity and the dangerous effects of sedentary lifestyle on health. The aim of this review is to clarify the changes that have recently occurred in this area. These could be included in future health care strategies and recommendations for the population.


Conformational flexibility revealed by the crystal structure of a crenarchaeal RadA.
Homologous recombinational repair is an essential mechanism for repair of double-strand breaks in DNA. Recombinases of the RecA-fold family play a crucial role in this process, forming filaments that utilize ATP to mediate their interactions with single- and double-stranded DNA. The recombinase molecules present in the archaea (RadA) and eukaryota (Rad51) are more closely related to each other than to their bacterial counterpart (RecA) and, as a result, RadA makes a suitable model for the eukaryotic system. The crystal structure of Sulfolobus solfataricus RadA has been solved to a resolution of 3.2 A in the absence of nucleotide analogues or DNA, revealing a narrow filamentous assembly with three molecules per helical turn. As observed in other RecA-family recombinases, each RadA molecule in the filament is linked to its neighbour via interactions of a short beta-strand with the neighbouring ATPase domain. However, despite apparent flexibility between domains, comparison with other structures indicates conservation of a number of key interactions that introduce rigidity to the system, allowing allosteric control of the filament by interaction with ATP. Additional analysis reveals that the interaction specificity of the five human Rad51 paralogues can be predicted using a simple model based on the RadA structure.


Perioperative Bridging With Glycoprotein IIb/IIIa Inhibitors Versus Cangrelor: Balancing Efficacy and Safety.
To review the efficacy and safety of perioperative administration of intravenous (IV) antiplatelet agents as a substitute for oral P2Y12 inhibitors and to provide clinicians guidance on optimal and cost-effective use of these medications. A MEDLINE literature search (1950 to November 2018) was performed using the key search terms abciximab, bridging, cangrelor, cardiac surgery, coronary artery bypass surgery, eptifibatide, intravenous antiplatelet agent, and tirofiban. Additional references were identified from a review of literature citations. In all, 18 original research reports and case reports/series were included in the review. Prevention of postoperative bleeding is critical to decrease morbidity and mortality after cardiac surgery. IV antiplatelet medications have short half-lives and are frequently used to substitute for oral P2Y12 inhibitors to allow platelet function recovery before procedures. Functional recovery of platelets is delayed after abciximab discontinuation and increases postoperative bleeding risk. Eptifibatide and tirofiban have similar pharmacokinetic/pharmacodynamic properties and comparable efficacy and safety in the setting of perioperative bridging. Cangrelor may be considered in patients with renal insufficiency as decreased clearance of eptifibatide or tirofiban may increase the risk of postoperative bleeding. Relevance to Patient Care and Clinical Practice: Comparative studies of IV antiplatelet medications have not been published. Appropriate use of IV antiplatelet medications can prevent perioperative ischemic events and bleeding. Eptifibatide, tirofiban, and cangrelor are preferred over abciximab as a perioperative bridge. The choice of agent should be tailored to clinical characteristics of the patient and institutional acquisition costs.


High incidence of precipitins in sera of heroin addicts.
We analyzed sera of 50 consecutively hospitalized heroin-abuse patients for precipitins against several antigens. Forty-seven addicts had precipitins against extracts from moldy hay, and 34 against extracts from bagasse. Thirty-six showed precipitin bands against extracts from one or more of the following: Aspergillus, Micropolyspora faeni, and Thermoactinomyces vulgaris. These findings were significantly different from those of a control population (P less than .0001 for all antigens tested). The recent culture identification of bacteria and fungi from street heroin suggests that the addicted population may be injecting antigenic material intravenously, with subsequent antibody formation.


Carnitine and choline derivatives containing a trimethylamine group prevent ammonia toxicity in mice and glutamate toxicity in primary cultures of neurons.
Carnitine prevents acute ammonia toxicity in animals. We propose that acute ammonia toxicity is mediated by activation of N-methyl-D-aspartate receptors and have shown that carnitine prevents glutamate neurotoxicity. The aim of this work was to assess whether other compounds containing a trimethylamine group are able to prevent ammonia toxicity in mice and/or glutamate toxicity in primary neuronal cultures. It is shown that betaine, trimethylamine-N-oxide, choline, acetylcholine, carbachol and acetylcarnitine prevent ammonia toxicity in mice. They also prevent glutamate but not N-methyl-D-aspartate neurotoxicity. Choline, acetylcholine and acetylcarnitine afford partial (approximately 50%) protection at nanomolar concentrations and nearly complete protection at micromolar concentrations. Trimethylamine-N-oxide, carbachol and betaine afford nearly complete protection at approximately 0.2 mM. The protective effect against glutamate neurotoxicity is prevented by 2-amino-3-phosphonopropionic acid, an antagonist of metabotropic glutamate receptors. Atropine, an antagonist of muscarinic receptors, prevents the protective effect of most of the above compounds against ammonia toxicity in mice and against glutamate toxicity in cultured neurons. These results support the idea that acute ammonia toxicity is mediated by activation of N-methyl-D-aspartate receptors and that glutamate neurotoxicity could be prevented by activating metabotropic glutamate receptors and/or muscarinic receptors.


Sexual health clinic attendance and non-attendance in Britain: findings from the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3).
In Britain, sexual health clinics (SHCs) are the most common location for STI diagnosis but many people with STI risk behaviours do not attend. We estimate prevalence of SHC attendance and how this varies by sociodemographic and behavioural factors (including unsafe sex) and describe hypothetical service preferences for those reporting unsafe sex. Complex survey analyses of data from Britain's third National Survey of Sexual Attitudes and Lifestyles, a probability survey of 15 162 people aged 16-74 years, undertaken 2010-2012. Overall, recent attendance (past year) was highest among those aged 16-24 years (16.6% men, 22.4% women), decreasing with age (<1.5% among those 45-74 years). Approximately 15% of sexually-active 16-74 year olds (n=1002 men; n=1253 women) reported 'unsafe sex' (condomless first sex with a new partner and/or ≥2 partners and no condom use, past year); >75% of these had not attended a SHC (past year). However, of non-attenders aged 16-44 years, 18.7% of men and 39.0% of women reported chlamydia testing (past year) with testing highest in women aged <25 years. Of those aged 16-44 years reporting unsafe sex, the majority who reported previous SHC attendance would seek STI care there, whereas the majority who had not would use general practice. While most reporting unsafe sex had not attended a SHC, many, particularly younger women, had tested for chlamydia suggesting engagement with sexual health services more broadly. Effective, diverse service provision is needed to engage those at-risk and ensure that they can attend services appropriate to their needs.


First report of a late type III endoleak from fabric tears of a Zenith stent graft.
We report a case of a late type III endoleak from a hole in the fabric of the main body of a Zenith bifurcated endograft 7 years after implantation. Abdominal pain and a rapidly expanding aneurysm were eventually followed by rupture. The defect was detected at open surgery, whereas no evidence of endoleak was found at preoperative computed tomography (CT) or angiogram. The defect was repaired by a relining procedure with an Excluder stent graft. The patient, however, died 3 weeks after admission.


Knowledge, attitudes and practice of nurse regarding adverse drug reaction reporting.
Adverse drug reactions (ADR) are ranked as some of the major causes of patient morbidity and mortality. Spontaneous reporting of ADRs has remained the cornerstone of pharmacovigilance and is important in maintaining patient safety. This study was conducted to assess the nurses' knowledge and attitude towards pharmacovigilance, reasons for not reporting ADRs, and their pharmacovigilance practice. A questionnaire was prepared to investigate knowledge, attitude and practice (KAP) of nurses regarding ADR reporting. In November 2009, the questionnaires were given to 500 nurses of a teaching hospital in Tehran. Knowledge and practice of participants were not satisfying; however, their attitude towards pharmacovigilance was at a high level. About 91% of the nurses had never reported an ADR. Most nurses liked to report the ADRs to the physicians (87.1%) and pharmacists in hospital's ADR center (1.8%) rather than the ADR National Center. The main cause of under-reporting of the suspected ADRs was unawareness about the existence of such a national center. Among nurses who had reported ADR for at least once, the majority preferred using phone (10 out of 50) or Yellow Cards (7 out of 50). Only 1 person out of 50 preferred using internet for submitting the reports. Since the nurses in this study had little knowledge and poor practice regarding the pharmacovigilance and spontaneous reporting system, interventions such as holding pharmacovigilance workshops in the hospitals focusing on the aims of pharmacovigilance, completing the Yellow Card and clarifying the reporting criteria are strongly recommended.


Implications of Caspase 1/ Interleukin-1 Beta (IL-1β) Signaling and Hypoxia-Inducible Factor 1-Alpha (HIF-1α) on Diabetic Retinopathy Pathology.
Diabetic retinopathy (DR) is the leading cause of adult blindness and partial vision loss in modern society for hyperglycemic patients. Accordingly, new treatment options are imperative to the overall reduction of DR prevalence and the ongoing progression of already affected candidates. There are many diseases that are the direct result of specific inflammatory processes. In this literature, DR is looked at as a potential disease that can be alleviated by targeting caspase 1/ interleukin-1 beta (IL-1β), and hypoxia-inducible factor 1-alpha (HIF-1α) signaling pathways and reducing cytokine mobilization within retinal tissues. Caspase-1 is thought to be upregulated during retinal capillary degeneration and other ocular complications. Hypoxia-inducible factor 1-alpha (HIF-1α) is implicated in its role in neovascularization and cell apoptosis within a retinal cell line. Both of these proteins are shown to be significantly elevated in hyperglycemic and galactosemic mice and, when knocked out, seem to have the reverse effect, showing that there is room for potential non-invasive therapy involving these proteins in the future. Vascular endothelial growth factor-alpha (VEGF-A) is also examined as a main signaling protein involved in the manifestation of DR.


Outcomes of acute versus elective primary ventral hernia repair.
The morbidity and mortality associated with acute primary ventral hernia repair have not been well described. We examined the rate of surgical site infection (SSI), hernia recurrence, and mortality in acute versus elective primary ventral hernia repair and identified predictors of morbidity and mortality after primary ventral hernia repair. A retrospective study on all patients undergoing open primary ventral hernia repair at a single institution (2000-2010) was performed. Primary outcomes were mortality at any time, SSI, and recurrence. Survival analysis for the entire, unmatched sample was conducted. We performed a risk-adjusted analysis of outcomes using two methods as follows: (1) case matching and (2) propensity score-adjusted regression model. We identified 497 patients; 57 (11%) underwent acute primary ventral hernia repair. For the entire cohort, survival was worse for patients undergoing acute repair (log rank, 0.03). Following case matching on age, body mass index, American Society of Anesthesiologists score, and hernia size, there was no difference in mortality, SSI, or recurrence. After propensity score adjustment, acute surgery was not a predictor for mortality or SSI; however, incarcerated hernias predicted recurrence. After risk adjustment, acute primary ventral hernia repair was not associated with higher mortality, infection, or recurrence compared with elective repair. Therapeutic study, level IV.


FOLFIRINOX Pharmacodynamic Interactions in 2D and 3D Pancreatic Cancer Cell Cultures.
The multi-drug combination regime, FOLFIRINOX, is a standard of care chemotherapeutic therapy for pancreatic cancer patients. However, systematic evaluation of potential pharmacodynamic interactions among multi-drug therapy has not been reported previously. Here, pharmacodynamic interactions of the FOLFIRINOX agents (5-fluorouracil (5-FU), oxaliplatin (Oxa) and SN-38, the active metabolite of irinotecan) were assessed across a panel of primary and established pancreatic cancer cells. Inhibition of cell proliferation was quantified for each drug, alone and in combination, to obtain quantitative, drug-specific interaction parameters and assess the nature of drug interactions. The experimental data were analysed assuming Bliss independent interactions, and nonlinear regression model fitting was conducted in SAS. Estimates of the drug interaction term, psi (ψ), revealed that the Oxa/SN-38 combination appeared synergistic in PANC-1 (ψ = 0.6, 95% CI = 0.4, 0.9) and modestly synergistic, close to additive, in MIAPaCa-2 (ψ = 0.8, 95% CI = 0.6, 1.0) in 2D assays. The triple combination was strongly synergistic in MIAPaCa-2 (ψ = 0.2, 95% CI = 0.1, 0.3) and modestly synergistic/borderline additive in PANC-1 2D (ψ = 0.8, 95% CI = 0.6, 1.0). The triple combination showed antagonistic interactions in the primary PIN-127 and 3D PANC-1 model (ψ > 1). Quantitative pharmacodynamic interactions have not been described for the FOLFIRINOX regimen; this analysis suggests a complex interplay among the three chemotherapeutic agents. Extension of this pharmacodynamic analysis approach to clinical/translational studies of the FOLFIRINOX combination could reveal additional pharmacodynamic interactions and guide further refinement of this regimen to achieve optimal clinical responses.


Pandemic influenza 1918 H1N1 and 1968 H3N2 DNA vaccines induce cross-reactive immunity in ferrets against infection with viruses drifted for decades.
Alternative influenza vaccines and vaccine production forms are needed as the conventional protein vaccines do not induce broad cross-reactivity against drifted strains. Furthermore, fast vaccine production is especially important in a pandemic situation, and broader vaccine reactivity would diminish the need for frequent change in the vaccine formulations. In this study, we compared the ability of pandemic influenza DNA vaccines to induce immunity against distantly related strains within a subtype with the immunity induced by conventional trivalent protein vaccines against homologous virus challenge. Ferrets were immunised by particle-mediated epidermal delivery (gene gun) with DNA vaccines based on the haemagglutinin (HA) and neuraminidase (NA) and/or the matrix (M) and nucleoprotein genes of the 1918 H1N1 Spanish influenza pandemic virus or the 1968 H3N2 Hong Kong influenza pandemic virus. The animals were challenged with contemporary H1N1 or H3N2 viruses. We demonstrated that DNA vaccines encoding proteins of the original 1918 H1N1 pandemic virus induced protective cross-reactive immune responses in ferrets against infection with a 1947 H1N1 virus and a recent 1999 H1N1 virus. Similarly, a DNA vaccine, based on the HA and NA of the 1968 H3N2 pandemic virus, induced cross-reactive immune responses against a recent 2005 H3N2 virus challenge. DNA vaccines based on pandemic or recent seasonal influenza genes induced cross-reactive immunity against contemporary virus challenge as good as or superior to contemporary conventional trivalent protein vaccines. This suggests a unique ability of influenza DNA to induce cross-protective immunity against both contemporary and long-time drifted viruses.


[Arylsulfatase A--physico-chemical properties and the use of enzyme radioimmunoassay in medical diagnosis].
Arylsulfatase A was isolated from urine and human liver. The enzyme was homogeneous with respect to charge and had high specific activity--64 U/mg and 34 U/mg for arylsulfatase A from urine and liver respectively. The enzyme from urine as well as the liver one contained two nonidentical subunits with molecular weights varying about 5 kDa. Treatment of the enzyme from urine, liver and from placenta with endo-beta-N-acetylglucosaminidase F did not remove all carbohydrate from any subunit even in denaturing conditions. Deglycosylation of the enzyme with this one and other glycosidases under various conditions resulted in a decrease in the apparent molecular weights of subunits only by 1-2 kDa. The difference between molecular weights of subunits did not change upon deglycosylation of arylsulfatase A. The results suggest that the presence of two nonidentical subunits is due to presence of different polypeptides rather than various glycosylation of a single polypeptide chain. Arylsulfatase A from urine was inactivated following reaction with diethyl pyrocarbonate at pH 5.5 or at pH 7.0. This confirmed the presence of histidine essential for its catalytic activity. It was also shown that the enzyme was inactivated with ferrate ion, structural analogue of orthophosphate and strong oxidizing agent. The conditions of inhibition of arylsulfatase A carried out with the use of ferrate as well as catalytic and immunochemical properties of the modified enzyme suggest that ferrate reacted with the active site of arylsulfatase A. The results allow to expect that a reactive histidine is present in enzyme's active site and that this aminoacid is modified with ferrate. A simple, sensitive and specific radioimmunoassay was developed for the determination of arylsulfatase A in human serum and urine. The method allows to measure less than nanogram amounts of the enzyme in human body fluids. The test was used to determine arylsulfatase A in serum specimens of 368 patients with histopathologically confirmed cancer of gastrointestinal tract, breast, lung, central nervous system, kidney and woman genital tract. The highest mean concentration of arylsulfatase A in serum and significantly higher than that in the control group of 96 healthy blood donors was found in the case of groups of lung, kidney and central nervous system cancer. The results indicate that the radioimmunoassay determination of serum level of arylsulfatase A might be helpful in diagnosis of lung and central nervous system cancer. Arylsulfatase A serum level cannot be treated as a valuable indicator in the case of cancer of breast and gastrointestinal tract.(ABSTRACT TRUNCATED AT 400 WORDS)


The low affinity glucose transporter HxtB is also involved in glucose signalling and metabolism in Aspergillus nidulans.
One of the drawbacks during second-generation biofuel production from plant lignocellulosic biomass is the accumulation of glucose, the preferred carbon source of microorganisms, which causes the repression of hydrolytic enzyme secretion by industrially relevant filamentous fungi. Glucose sensing, subsequent transport and cellular signalling pathways have been barely elucidated in these organisms. This study therefore characterized the transcriptional response of the filamentous fungus Aspergillus nidulans to the presence of high and low glucose concentrations under continuous chemostat cultivation with the aim to identify novel factors involved in glucose sensing and signalling. Several transcription factor- and transporter-encoding genes were identified as being differentially regulated, including the previously characterized glucose and xylose transporter HxtB. HxtB was confirmed to be a low affinity glucose transporter, localizing to the plasma membrane under low- and high-glucose conditions. Furthermore, HxtB was shown to be involved in conidiation-related processes and may play a role in downstream glucose signalling. A gene predicted to encode the protein kinase PskA was also identified as being important for glucose metabolism. This study identified several proteins with predicted roles in glucose metabolic processes and provides a foundation for further investigation into the response of biotechnologically important filamentous fungi to glucose.


Peripheral neuropathy in leprosy and its consequences.
Leprosy causes a 'mononeuritis multiplex' of immunological origin that results in autonomic, sensory and motor neuropathy. When detected and treated early, primary impairments may be reversible. However, 11-51% of patients do not recover. In addition, 33-56% of newly registered patients already have clinically detectable impairments, often no longer amenable to drug treatment. Among new patients, 6-27% present with secondary impairments, such as wounds, contractures and shortening of digits. All patients with impairments should be taught methods to prevent further impairment and subsequent disability (POID). As the result of impairments, many people experience limitation of activities of daily living, which can be partially overcome with the help of assistive devices, training, and surgery. As a result of these limitations, because of visible impairments, or simply because of the diagnosis 'leprosy', many people are restricted in their participation in society. Many overcome activity limitations and participation restrictions without assistance, despite residual impairments. However, some require intervention, such as physical or occupational therapy, reconstructive surgery or temporary socioeconomic assistance. Information on these issues is not collected routinely, and the few tools that exist to measure the severity or extent of impairment have not been widely used, nor have they been used to generate cohort-based statistics. There are no agreed indicators for monitoring POID activities or rehabilitation interventions. Work in the general field of rehabilitation has resulted in the ICIDH-2, which provides a conceptual framework for rehabilitation and the entire area of 'consequences of health conditions'. Although experience to date is very limited, the conceptual framework appears appropriate to leprosy. Data on the prevalence and incidence of primary and secondary impairments have been reported from several countries, the link between impairments and activity limitations has been investigated, and a few studies of the magnitude of the need for rehabilitation have been reported. Research priorities include studies of methods to improve detection of autonomic, sensory and motor neuropathy; trials of alternative drugs or regimens for treating neuropathy; studies of the use of various POID-monitoring systems that may be derived from these; studies of the design and use of instruments to assess limitations of activities and restrictions on participation; assessments of needs for rehabilitation and the development of methods to do these; studies of the efficacy of various types of rehabilitation interventions for particular conditions; and studies of the cost-effectiveness of such interventions.


Radiotherapy-associated intra-abdominal angiosarcoma after prostatic adenocarcinoma: Case reports.
Angiosarcoma is a rare soft tissue neoplasm, which accounts for <1% of all soft tissue tumours. It has been previously reported that the incidence rate of angiosarcomas increases following radiotherapy. The present study reports two cases of intra-abdominal angiosarcoma associated with previous radiotherapy treatment. To the best of our knowledge, these associations have not been previously described in English literature. The patients aged 71 and 83 years were admitted to the center for abdominal pain and diarrhea. Each patient had previously had treatment with radiotherapy for prostate adenocarcinoma. During their hospitalization, biopsies were obtained and the diagnosis of angiosarcoma was reached. In each patient the tumors had irregular proliferating vascular channels, lined by atypical endothelial cells, which varied from elongated and spindle-shaped to large and plump. Immunocytochemistry revealed that the tumor cells were positive for the cytoplasmic endothelial markers cluster of differentiation (CD)31 and CD34. The recognition of these associations is important and their occurrence in this rare type of neoplasm should not mislead the pathologist and cause a misdiagnosis of the sarcoma.


Community-based availability of misoprostol: is it safe?
This paper evaluates the safety and acceptability of long-term community-based use of misoprostol for management of postpartum hemorrhage (PPH) in home-births, by comparing deliveries with and without misoprostol use in communities of Kigoma, Tanzania. We administered a standardized survey instrument to women who delivered between August 2004 and May 2007. 940 women completed questionnaires, corresponding to 950 deliveries. Findings showed that the majority of TBAs administered misoprostol at the correct time (76%). Receipt of three or five tablets was most commonly reported (47% and 43% respectively). Misoprostol users were significantly more likely to experience shivering, high temperature, nausea, and vomiting after delivery; adjustment for gynecological history and delivery characteristics revealed no significant differences in experience of symptoms. Misoprostol was highly acceptable to all women surveyed. Misoprostol at the community level is a safe intervention.


Linkage of malignant hyperthermia and hyperkalemic periodic paralysis to the adult skeletal muscle sodium channel (SCN4A) gene in a large pedigree.
Hyperkalemic periodic paralysis (HPP) is caused by mutations of the adult skeletal muscle sodium channel (SCN4A) gene on chromosome 17. Malignant hyperthermia (MH) is a genetically heterogeneous autosomal-dominant disorder occurring in association with various neuromuscular diseases or without other apparent abnormalities. In some families, MH is associated with mutations of a calcium release channel (RYR1) gene on chromosome 19. In other families, linkage of this disorder to the SCN4A gene on chromosome 17 has been suggested. We report on linkage analysis in a family in which both HPP and MH are inherited as autosomal-dominant traits. Two polymorphisms within the SCN4A locus, an RFLP and a (C-A)n repeat, were typed on multiple family members. The findings were consistent with linkage of the polymorphic markers within the SCN4A gene to both HPP (Zmax = 6.79 at theta = 0.0) and MH (Zmax = 1.76 at theta = 0) in this family. Our data provide further evidence that MH is linked to the SCN4A locus in some families.


NetProphet 2.0: mapping transcription factor networks by exploiting scalable data resources.
Cells process information, in part, through transcription factor (TF) networks, which control the rates at which individual genes produce their products. A TF network map is a graph that indicates which TFs bind and directly regulate each gene. Previous work has described network mapping algorithms that rely exclusively on gene expression data and 'integrative' algorithms that exploit a wide range of data sources including chromatin immunoprecipitation sequencing (ChIP-seq) of many TFs, genome-wide chromatin marks, and binding specificities for many TFs determined in vitro. However, such resources are available only for a few major model systems and cannot be easily replicated for new organisms or cell types. We present NetProphet 2.0, a 'data light' algorithm for TF network mapping, and show that it is more accurate at identifying direct targets of TFs than other, similarly data light algorithms. In particular, it improves on the accuracy of NetProphet 1.0, which used only gene expression data, by exploiting three principles. First, combining multiple approaches to network mapping from expression data can improve accuracy relative to the constituent approaches. Second, TFs with similar DNA binding domains bind similar sets of target genes. Third, even a noisy, preliminary network map can be used to infer DNA binding specificities from promoter sequences and these inferred specificities can be used to further improve the accuracy of the network map. Source code and comprehensive documentation are freely available at https://github.com/yiming-kang/NetProphet_2.0. Supplementary data are available at Bioinformatics online.


Gay, lesbian, and bisexual youth risks for emotional, physical, and social problems: results from a community-based survey.
Health problems of gay, lesbian, and bisexual (GLB) youth are reported as differing from those of heterosexual youth. Increased depression, suicide, substance use, homelessness, and school dropout have been reported. Most studies of GLB youth use clinical or convenience samples. The authors conducted a community school-based health survey that included an opportunity to self-identify as GLB. An anonymous self-report health care questionnaire was used during a community-based survey in 2 high schools in an upper middle class district. Significantly increased health risks for self-identified GLB youth were found in mental health, sexual risk-taking, and general health risks compared with self-identified heterosexuals, but not in health domains associated with substance abuse, homelessness, or truancy. Self-identified GLB youth in community settings are at greater risk for mental health, sexual risk-taking, and poorer general health maintenance than their heterosexual peers.


LMN Facial Palsy in Pregnancy: An Opportunity to Predict Preeclampsia-Report and Review.
Facial paralysis is the most frequent unilateral cranial nerve pathology affecting pregnant population 2 to 4 times more often than the nonpregnant population. There exists an association with preeclampsia but this has largely been overlooked. Clinicians often dismiss it for idiopathic palsy as seen in the present case. A 30-year-old woman, Gravida 4, Para 3, presented at 26 weeks pregnancy with complaints of facial weakness, blurring of vision, altered taste sensation, increased noise sensitivity for 1 month, headache since 18 days, and vomiting since 2-3 days. Her pulse was 90/min, BP was 170/120, and RR was 18/min. Uterus was 18 weeks size and proteinuria++ was present. Ultrasonography revealed a 26 weeks fetus, severe bradycardia, and absent liquor. HELLP syndrome was diagnosed after investigations. Six units of fresh frozen plasma were transfused. An informed decision for termination of pregnancy was made. She delivered a 450 gram stillborn. The third stage was complicated with postpartum hemorrhage but it was managed successfully. Women with Bell's palsy during pregnancy should be evaluated critically as in some it may precede preeclampsia which has serious maternal and fetal implications. Therefore, these women should be in regular followup of the obstetrician.


ASBMB and FAOBMB Inc.: present status and future opportunities.
Past and present relationships of three biochemistry and molecular biology organizations: the Australian Society for Biochemistry and Molecular Biology; the Federation of Asian and Oceanian Biochemists and Molecular Biologists (FAOBMB); and the International Union for Biochemistry and Molecular Biology are discussed. The future of these organizations, particularly FAOBMB, is then considered in the light of factors behind their current status and likely future effects of globalization, growth in Asia, changes in disciplinary focus and contribution to global issues.


Comparison of the immunofluorescent-cell counting and plaque methods for the assay of vaccinia virus.
The immunofluorescent-cell counting method was compared with the agarand liquid-overlay plaque techniques for the assay of vaccinia virus. In addition to being as quantitative, reproducible, and simple to use as the two plaque techniques, the immunofluorescent assay method was found to be more sensitive, rapid, and specific.


[A model of the organization of medical care for patients with acute disorders of cerebral blood flow].
Cardio-vascular system holds the first place among the causes of the general population mortality in the Russian Federation. In the Penza region, the Regional Vascular Center works in the frames of the federal program to improve the care of patients with vascular diseases. Since the center started out, new methods to treat the disease treatment (e.g., thrombolytic therapy, the use of surgical and X-ray endovascular interventions for hemorrhagic stroke) were actively introduced. Particular attention is paid to the prevention of cerebral circulation disorders and consultative care.


[Neurobiological inscriptions of psychological trauma during early childhood].
Neurodevelopment is a highly complex process, influenced by a wide range of interacting genetic and environmental factors. Recent developments in fetal, neonatal and infant behavioural genetics and brain imaging methods have allowed for more detailed investigation of the effects of early adverse environment on the developing brain. This review aims to provide background for neurobiological understanding of how the prolonged exposure to stress or trauma during early childhood affects subsequent cognitive, emotional and social development. Initially, a brief overview of brain development is provided - focusing, in particular, on the limbic system structures, which are closely linked to emotional experiences and reactions, learning and memory. Emphasis is placed on the concept of neural plasticity, which is the biological base of memory and learning - the two most important mechanisms through which the environment affects the behavior. Moreover, the concept of sensitive periods, that is to say periods of "vulnerability" or "opportunity" during which particular experiences affect brain growth, functional organization and maturation, is discussed. Brief overview of the neuroendocrine stress response system and the long-term effects of prolonged exposure to stress hormones on early brain development clarify further why children are more vulnerable than adults to the effects of stress. The section dealing with the memory, which is closely linked to the limbic system, attempts to discuss how early exposure to chronic stress or psychological trauma, through neurobiological effects and the process of learning, can lead to dysfunctional behaviors, which in its extreme form can be mental disorders. The two types of memory are discussed: (a) the implicit (nondeclarative), which develops during the prelingual stage of child's development and refers to unconscious memories of previous experiences, and (b) the explicit (declarative) memory, which is closely linked to language development and refers to memories that can be consciously recalled. Given that prenatal or postnatal early experiences can alter the course of brain development, the exposure to maltreatment, whether it takes the form of physical, sexual or emotional abuse, or the kind of extreme neglect and deprivation during the early years of life, is related to alterations in brain structure and function, which in turn contributes to development of chronic post-traumatic disorder (PTSD), anxiety, mood and attachment disorders, memory and learning problems, and other psychopathological conditions. Finally, it is pointed out that a comprehensive and detailed diagnostic assessment of young children who are referred to the child and adolescent mental health services because of presenting with behavioural and emotional disturbances should be an established good clinical practice, given that a wrong diagnosis may have further deleterious effects on the child's psychosocial development. The need for neuropsychological assessment of children who have been exposed to early trauma or stress is thought to have important implications for the recognition and the neurobiological understanding of early trauma, which in turn allows for the development and implementation of appropriate interventions.


Internal dosimetry of plutonium using the late urinary excretion.
An attempt has been made to standardize the methodology of internal dose computation from the late urinary excretion data. The methodology was selected keeping in mind the most recent ICRP publications and the results of internal dosimetry intercomparison studies reported in literature. The key element of this methodology is the PC-based computational software LUDEP 2.05, which implements the new model of the human respiratory tract. Late urinary excretion data of three male subjects involved in accidental intakes of plutonium aerosols more than 25 years ago were interpreted in terms of intakes and internal doses with the aid of the standardized methodology. An important implication of this work is that late urinary excretion data of the occupational workers of any plutonium handling facility could be used to show the compliance with the life-time dose limit.


Soluble CD40 ligand stimulates CD40-dependent activation of the β2 integrin Mac-1 and protein kinase C zeda (PKCζ) in neutrophils: implications for neutrophil-platelet interactions and neutrophil oxidative burst.
Recent work has revealed an essential involvement of soluble CD40L (sCD40L) in inflammation and vascular disease. Activated platelets are the major source of sCD40L, which has been implicated in platelet and leukocyte activation, although its exact functional impact on leukocyte-platelet interactions and the underlying mechanisms remain undefined. We aimed to determine the impact and the mechanisms of sCD40L on neutrophils. We studied neutrophil interactions with activated, surface-adherent platelets as a model for leukocyte recruitment to the sites of injury. Our data show that CD40L contributes to neutrophil firm adhesion to and transmigration across activated surface-adherent platelets, possibly through two potential mechanisms. One involves the direct interaction of ligand-receptor (CD40L-CD40), i.e., platelet surface CD40L interaction with neutrophil CD40; another involves an indirect mechanism, i.e. soluble CD40L stimulates activation of the leukocyte-specific β2 integrin Mac-1 in neutrophils and thereby further promotes neutrophil adhesion and migration. Activation of the integrin Mac-1 is known to be critical for mediating neutrophil adhesion and migration. sCD40L activated Mac-1 in neutrophils and enhanced neutrophil-platelet interactions in wild-type neutrophils, but failed to elicit such responses in CD40-deficient neutrophils. Furthermore, our data show that the protein kinase C zeta (PKCζ) is critically required for sCD40L-induced Mac-1 activation and neutrophil adhesive function. sCD40L strongly stimulated the focal clustering of Mac-1 (CD11b) and the colocalization of Mac-1 with PKCζ in wild-type neutrophils, but had minimal effect in CD40-deficient neutrophils. Blocking PKCζ completely inhibited sCD40L-induced neutrophil firm adhesion. Moreover, sCD40L strongly stimulates neutrophil oxidative burst via CD40-dependent activation of PI3K/NF-KB, but independent of Mac-1 and PKCζ. These findings may contribute to a better understanding of the underlying mechanisms by which sCD40L/CD40 pathway contributes to inflammation and vascular diseases.


Qualitative and quantitative differences between bone graft obtained from the medullary canal (with a Reamer/Irrigator/Aspirator) and the iliac crest of the same patient.
Donor site morbidity and limited volume remain primary drawbacks of using bone graft from the iliac crest and an impetus for finding other sources of autologous bone-graft material. The Synthes Reamer/Irrigator/Aspirator (RIA) has been found to have value as an autologous bone-graft harvesting device. The purpose of this study was to compare the cellular and biochemical characteristics of bone grafts obtained with use of the RIA and from the iliac crest of the same patient. A prospective study was performed on a consecutive series of ten skeletally mature patients presenting for repair of nonunited tibial or femoral fractures. Graft material was harvested from both the iliac crest (in the standard fashion) and the medullary canal of the femur or tibia (with use of the RIA) of each patient. Portions of each autologous graft sample were assessed histologically and by genomewide transcriptional profiling for biochemical markers known to be expressed during fracture-healing. Principal-component analysis comparing the messenger RNA expression profiles in the RIA and iliac crest samples showed that the expression profile at each harvest site was unique and independent of patient, age, sex, or any identified comorbidity. Transcriptional analysis showed that the RIA samples had greater levels of expression of genes associated with vascular, skeletal, and hematopoietic tissues. Additionally, stem cell markers and growth factors that act early in the osteogenic cascade were more abundant in the RIA samples compared with the iliac crest samples. This is the first study to directly compare the histological and molecular profiles of bone grafts from reaming debris and the iliac crest of the same patient. The debris generated during intramedullary reaming, harvested with use of the RIA technique, and the bone graft harvested from the iliac crest possessed a similar transcriptional profile for genes known to act in the early stages of bone repair and formation. This suggests that reaming debris may be a viable alternative to iliac crest bone graft when autologous cancellous graft is needed.


A Filtration-based Method of Preparing High-quality Nuclei from Cross-linked Skeletal Muscle for Chromatin Immunoprecipitation.
Chromatin immunoprecipitation (ChIP) is a powerful method to determine protein binding to chromatin DNA. Fiber-rich skeletal muscle, however, has been a challenge for ChIP due to technical difficulty in isolation of high-quality nuclei with minimal contamination of myofibrils. Previous protocols have attempted to purify nuclei before cross-linking, which incurs the risk of altered DNA-protein interaction during the prolonged nuclei preparation process. In the current protocol, we first cross-linked the skeletal muscle tissue collected from mice, and the tissues were minced and sonicated. Since we found that ultracentrifugation was not able to separate nuclei from myofibrils using cross-linked muscle tissue, we devised a sequential filtration procedure to obtain high-quality nuclei devoid of significant myofibril contamination. We subsequently prepared chromatin by using an ultrasonicator, and ChIP assays with anti-BMAL1 antibody revealed robust circadian binding pattern of BMAL1 to target gene promoters. This filtration protocol constitutes an easily applicable method to isolate high-quality nuclei from cross-linked skeletal muscle tissue, allowing consistent sample processing for circadian and other time-sensitive studies. In combination with next-generation sequencing (NGS), our method can be deployed for various mechanistic and genomic studies focusing on skeletal muscle function.


Tobacco smoking, pregnancy estrogens, and birth weight.
It has been suggested that tobacco smoking during pregnancy reduces birth weight by lowering production rates or levels of total pregnancy estrogens. To evaluate this hypothesis, we examined total estrogen levels by radioimmunoassay in the blood of 141 pregnant women attending the maternity clinic of a major university hospital in Athens during their 26th week of pregnancy. Forty-nine of these women were regular smokers before and during their pregnancy, whereas the remaining 92 had never been regular smokers and did not smoke at all during their pregnancy. Birth weight of offspring was lower among smokers than among nonsmokers by 190.8 g, with a 90% confidence interval of 41.1 to 340.5 g, and higher among women with higher serum estrogen levels (slope b = 1.2 g per 1000 pg/ml with a 90% CI of 0.2 to 2.2 g). There was, however, only a small negative relation between tobacco smoking and serum estrogen levels; in smokers, total estrogen levels were reduced to 91% of the corresponding levels among nonsmokers.


Human immunodeficiency virus type 1 virological synapse formation in T cells requires lipid raft integrity.
Human immunodeficiency virus type 1 (HIV-1) can spread directly between T cells by forming a supramolecular structure termed a virological synapse (VS). HIV-1 envelope glycoproteins (Env) are required for VS assembly, but their mode of recruitment is unclear. We investigated the distribution of GM1-rich lipid rafts in HIV-1-infected (effector) T cells and observed Env colocalization with polarized raft markers GM1 and CD59 but not with the transferrin receptor that is excluded from lipid rafts. In conjugates of effector T cells and target CD4+ T cells, GM1, Env, and Gag relocated to the cell-cell interface. The depletion of cholesterol in the infected cell dispersed Env and GM1 within the plasma membrane, eliminated Gag clustering at the site of cell-cell contact, and abolished assembly of the VS. Raft integrity is therefore critical for Env and Gag co-clustering and VS assembly in T-cell conjugates.


Interferon-gamma is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice.
Congenic MRL-lpr mice homozygous and heterozygous for the IFN-gamma gene disruption were created to assess the role of this pleotropic cytokine on the lymphoaccumulation and lupus-like disease of Fas-defective mice. Early death was prevented, and glomerulonephritis severely reduced in IFN-gamma-/- mice. Hypergammaglobulinemia was maintained with a switch from IgG2a to IgG1 predominance, but the dramatic decrease in levels of the dominant IgG2a anti-dsDNA autoantibodies was not associated with a compensatory increase in TH2-associated IgG subclasses. Remarkably, early death and glomerulonephritis were also prevented in IFN-gamma+/- mice, although autoantibody levels and glomerular immune deposits were equivalent to IFN-gamma+/+ lpr mice, indicating the importance of additional locally-exerted disease-promoting effects of IFN-gamma. IFN-gamma-/- mice exhibited reduced lymphadenopathy concomitant to a decrease in DN B220(+) T cells. In vivo BrdU labeling showed reduced proliferation of DN B220(+) cells in IFN-gamma-/- vs. IFN-gamma+/+ lpr mice, while enhanced proliferation of all other T cell subsets was unaffected. Macrophages of IFN-gamma-/-lpr mice expressed markedly decreased levels of MHC class I and II molecules compared with controls. Moreover, the heightened expression of MHC class II molecules on proximal tubules of IFN-gamma+/+ lpr mice was significantly reduced in both IFN-gamma-/- and IFN-gamma+/- mice. The data indicate that IFN-gamma hyperproduction is required for lupus development, presumably by increasing MHC expression and autoantigen presentation to otherwise quiescent nontolerant anti-self T cells, and also by promoting local immune and inflammatory processes.


Understanding selective oxidations.
Functionalizing organic molecules is an important value-creating step throughout the entire chemical value-chain. Oxyfunctionalization of e.g. C-H or C=C bonds is one of the most important functionalization technologies used industrially. The major challenge in this field is the prevention of side reactions and/or the consecutive over-oxidation of the desired products. Despite its importance, a fundamental understanding of the intrinsic chemistry, and the subsequent design of a tailored engineering environment, is often missing. Industrial oxidation processes are indeed to a large extent based on empirical know-how. In this mini-review, we summarize some of our previous work to help to bridge this knowledge gap and elaborate on our ongoing research.


[Reversible asymmetric septal thickening in the echocardiogram in a case with suspected perimyocarditis (author's transl)].
A 42-year-old male patient, previously in good health, developed signs of pericarditis, pericardial effusion and possible myocarditis 3 weeks after a virus infection of the upper respiratory tract. Because of enlargement of the previously normal cardiac silhouette, an M-mode-echocardiogram was performed. A pericardial effusion and pericardial thickening was diagnosed. Disproportionate septal thickening was noted (septum/posterior wall = 1.4). 3 days after institution of cortisone therapy gradual clinical improvement started. on day 6 a repeat M-mode-echocardiogram showed regression of the pericardial effusion of the septal thickening. Consecutive echocardiograms showed complete disappearing of the pericardial effusion, regression of the pericardial thickening, and complete normalisation of the left ventricular dimensions. Computer-assisted analysis of the first echocardiogram revealed reduced rate of septal and posterior wall thinning and prolongation of the early diastolic period of rapid filling, while peak VCF remained within normal limits. These changes were much less apparent on day 6. On day 26 all relaxation- and contraction parameters were within normal limits. It is concluded that in this case transient disproportionate thickening of the interventricular septum, prolongation of the early diastolic period of rapid left ventricular filling and reduced rate of diastolic septal and posterior wall thinning may have represented edematous and/or inflammatory changes of the myocardium. It is supposed that these findings may represent early changes in acute peri-myocarditis.


PAX5-positive T-cell anaplastic large cell lymphomas associated with extra copies of the PAX5 gene locus.
Cell lineage is the major criterion by which lymphomas are classified. Immunohistochemistry has greatly facilitated lymphoma diagnosis by detecting expression of lineage-associated antigens. However, loss or aberrant expression of these antigens may present diagnostic challenges. Anaplastic large cell lymphoma is a T-cell lymphoma that shows morphologic and phenotypic overlap with classical Hodgkin's lymphoma, which is a tumor of B-cell derivation. Staining for the B-cell transcription factor, paired box 5 (PAX5), has been suggested to be helpful in this differential, as it is positive in most classical Hodgkin's lymphomas, but absent in anaplastic large cell lymphomas. In this study we report four systemic T-cell anaplastic large cell lymphomas that were positive for PAX5 by immunohistochemistry, with weak staining intensity similar to that observed in classical Hodgkin's lymphoma. All diagnoses were confirmed by a combination of morphologic, phenotypic, and molecular criteria. Three cases were anaplastic lymphoma kinase (ALK) negative and one was ALK positive. PAX5 immunohistochemistry was negative in 198 additional peripheral T-cell lymphomas, including 66 anaplastic large cell lymphomas. Unexpectedly, although PAX5 translocations were absent, all evaluable PAX5-positive anaplastic large cell lymphomas showed extra copies of the PAX5 gene locus by fluorescence in situ hybridization (FISH). In contrast, only 4% of PAX5-negative peripheral T-cell lymphomas had extra copies of PAX5. We conclude that aberrant expression of PAX5 occurs rarely in T-cell anaplastic large cell lymphomas, and may be associated with extra copies of the PAX5 gene. PAX5-positive lymphomas with morphologic features overlapping different lymphoma types should be evaluated with an extensive immunohistochemical panel and/or molecular studies to avoid diagnostic errors that could lead to inappropriate treatment. As PAX5 overexpression causes T-cell neoplasms in experimental models, PAX5 may have contributed to lymphomagenesis in our cases.


Preinspiratory calcium rise in putative pre-Botzinger complex astrocytes.
The neural inspiratory activity originates from a ventrolateral medullary region called the pre-Bötzinger complex (preBötC), yet the mechanism underlying respiratory rhythmogenesis is not completely understood. Recently, the role of not only neurons but astrocytes in the central respiratory control has attracted considerable attention. Here we report our discovery that an intracellular calcium rise in a subset of putative astrocytes precedes inspiratory neuronal firing in rhythmically active slices. Functional calcium imaging from hundreds of preBötC cells revealed that a subset of putative astrocytes exhibited rhythmic calcium elevations preceding inspiratory neuronal activity with a time lag of approximately 2 s. These preinspiratory putative astrocytes maintained their rhythmic activities even during the blockade of neuronal activity with tetrodotoxin, whereas the rhythm frequency was lowered and the intercellular phases of these rhythms were decoupled. In addition, optogenetic stimulation of preBötC putative astrocytes induced firing of inspiratory neurons. These findings raise the possibility that astrocytes in the preBötC are actively involved in respiratory rhythm generation in rhythmically active slices.


Hepatocellular carcinoma associated with membranous obstruction of the inferior vena cava: incidence, characteristics, and risk factors and clinical efficacy of TACE.
To analyze the characteristics associated with membranous obstruction of the inferior vena cava (MOVC)-associated hepatocellular carcinoma (HCC) and to evaluate the clinical efficacy of transcatheter arterial chemoembolization (TACE). This retrospective study was approved by an institutional review board, and informed consent was waived. Ninety-eight patients (mean age, 48.5 years +/- 12.9 [standard deviation]) with MOVC were retrospectively evaluated. The diagnosis of Budd-Chiari syndrome was confirmed with results from Doppler ultrasonography, computed tomography, magnetic resonance imaging, and/or inferior venacavography. The cumulative incidences of HCC and the patient survival period were calculated by using the Kaplan-Meier method. Factors associated with the development of HCC were evaluated by using multivariate Cox regression analysis. Among 98 patients with MOVC, liver nodules were detected in 37 patients (38%), 23 of whom had HCC associated with MOVC and 14 of whom had benign nodules. The cumulative incidence of HCC at 1, 5, and 10 years was 7.3%, 13.5%, and 31.8%, respectively. Female sex was the only significant factor associated with the development of HCC (odds ratio, 6.02; P <.001). HCC was of the single nodular type and of peripheral location. Among 23 patients with HCC, 20 patients were treated with only TACE and three with liver transplantation after TACE. After TACE, 14 (61%) of the study patients had a complete response, and survival rates at 1, 2, 3, 4, and 5 years were 90%, 85%, 61%, 61%, and 46%, respectively. The incidence of HCC in patients with MOVC was similar to that found in other studies. TACE resulted in an effective tumor response for HCC and seemed to be effective in prolonging patient survival. Female sex was the only significant factor associated with the development of HCC. A single nodular tumor with a peripheral location appears to have a higher probability of HCC.


Functionalization of mesoporous silica nanoparticles for targeting, biocompatibility, combined cancer therapies and theragnosis.
The advent of Nanotechnology has paved a way for improved disease treatment strategies, the most noteworthy being the mesoporous silica nanoparticles (MSNs) which have gained much recent attention in the field of cancer therapy and its diagnosis. The flaws of the current-day strategies can be overcome by this superior technology through its targeting ability in delivering drugs and image able agents specifically to the tumor sites. MSNs have unique biocompatibility features, its high surface area which contributes in large amount of drug loading and its facility to monitor size and shape of the nanoparticles are few of the positives which makes this technology an enormous asset for the field of Nanotechnology. This review paper is structured in such a way wherein we initially have discussed about the synthesis methods and various functionalization approaches for MSN followed by the different methods used for targeting cancer cells and the latest advances in controlled drug release. Some of the highlights of this review are the biocompatibility of MSNs, in vivo results of MSNs on cancer therapy. This review paper also shortly discuss about combined cancer therapies to overcome the challenges in current-day cancer treatment. Finally, we converge briefly on the recent advancements in the use of hybrid MSNs for obtaining multiple functions.


The association between alcohol use, alcohol use disorders and tuberculosis (TB). A systematic review.
In 2004, tuberculosis (TB) was responsible for 2.5% of global mortality (among men 3.1%; among women 1.8%) and 2.2% of global burden of disease (men 2.7%; women 1.7%). The present work portrays accumulated evidence on the association between alcohol consumption and TB with the aim to clarify the nature of the relationship. A systematic review of existing scientific data on the association between alcohol consumption and TB, and on studies relevant for clarification of causality was undertaken. There is a strong association between heavy alcohol use/alcohol use disorders (AUD) and TB. A meta-analysis on the risk of TB for these factors yielded a pooled relative risk of 2.94 (95% CI: 1.89-4.59). Numerous studies show pathogenic impact of alcohol on the immune system causing susceptibility to TB among heavy drinkers. In addition, there are potential social pathways linking AUD and TB. Heavy alcohol use strongly influences both the incidence and the outcome of the disease and was found to be linked to altered pharmacokinetics of medicines used in treatment of TB, social marginalization and drift, higher rate of re-infection, higher rate of treatment defaults and development of drug-resistant forms of TB. Based on the available data, about 10% of the TB cases globally were estimated to be attributable to alcohol. The epidemiological and other evidence presented indicates that heavy alcohol use/AUD constitute a risk factor for incidence and re-infection of TB. Consequences for prevention and clinical interventions are discussed.


Zinc and reproduction: effects of zinc deficiency on prenatal and early postnatal development.
A large body of evidence supports the concept that human pregnancy outcome is significantly influenced by the nutritional status of the mother. The consumption of "poor diets" has been associated with an increased risk for pregnancy complications, including gross structural birth defects, prematurity, low birth weight, and an increased risk for neurobehavioral and immunological abnormalities after birth. Forty-four years ago, zinc deficiency in mammals was shown to be teratogenic. Maternal zinc deficiency produces effects ranging from infertility and embryo/fetal death, to intrauterine growth retardation and teratogenesis. Postnatal complications of maternal zinc deficiency can also occur, and include behavioral abnormalities, impaired immunocompetence, and an elevated risk for high blood pressure in the offspring. It has been suggested that developmental zinc deficiency in humans can present a significant challenge to the conceptus, increasing the risk for numerous defects. Developmental zinc deficiency can occur through multiple pathways, and the concept that acute phase response-induced changes in maternal zinc metabolism may be a common cause of embryonic and fetal zinc deficiency is presented. Potential mechanisms underlying the teratogenic effects of zinc deficiency are reviewed. The potential value of maternal zinc supplementation in high risk pregnancies is discussed.


Paroxysmal nocturnal haemoglobinuria at Oslo University Hospital 2000-2010.
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare haematological disease characterised by chronic haemolysis, pancytopenia and venous thrombosis. The condition is attributable to a lack of control of complement attack on erythrocytes, thrombocytes and leukocytes, and can be diagnosed by means of flow cytometry. In this quality assurance study, we have reviewed information from the medical records of all patients tested for PNH using flow cytometry at our laboratory over a ten-year period. In the period 2000-2010 a total of 28 patients were tested for PNH using flow cytometry at the Department of Immunology and Transfusion Medicine, Oslo University Hospital. We have reviewed the results of these examinations retrospectively together with information from medical records and transfusion data for the patients concerned. Flow cytometry identified 22 patients with PNH: four with classic disease and 18 with PNH secondary to another bone marrow disease. Five patients had atypical thrombosis. Seventeen patients received antithymocyte globulin or drug treatment; of these, six recovered from their bone marrow disease, while six died and five had a need for long-term transfusion. Five patients with life-threatening bone marrow disease underwent allogeneic stem cell transplantation, three of whom died. Six of 22 patients received eculizumab; the need for transfusion has been reduced or eliminated in three patients treated with eculizumab over a longer period. Flow cytometry identified PNH in a majority of patients from whom we obtained samples. Most patients had a PNH clone secondary to bone marrow failure. Atypical thrombosis should be borne in mind as an indication for the test. Treatment with eculizumab is relevant for selected patients with PNH.


Advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LH(BETA)T(AG) retinal tumors.
The purpose of this study is to analyze the dose response of the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, on tumor burden and hypoxia, and study the treatment effect on vasculature in LH(BETA)T(AG) retinal tumors. This study was approved by the Institutional Animal Care and Use Committee and follows Association for Research in Vision and Ophthalmology guidelines. Eighteen-week-old LH(BETA)T(AG) retinal tumor eyes (n = 30) were evaluated. Mice were divided into five groups and received periocular injections once weekly for two consecutive weeks of: a) 80% DMSO (dimethyl sulfoxide, vehicle control), b) 0.00333 mg/kg, c) 0.167 mg/kg, d) 3.33 mg/kg, and e) 6.67 mg/kg of rapamycin. Tumor sections were analyzed for hypoxia, tumor burden, and vasculature with immunohistochemistry techniques. Reduction in tumor burden and hypoxia was significantly different between rapamycin doses and control (P < 0.002). Eyes treated with rapamycin at 0.167, 3.33, and 6.67 mg/kg showed a significant decrease in tumor burden in comparison with the vehicle control group (P = 0.019, P = 0.001, P = 0.009, respectively) and the 0.00333 mg/kg dose response (P = 0.023, P = 0.001, P = 0.010, respectively). Eyes treated with rapamycin at 3.33 mg/kg showed a significant reduction in the amount of hypoxia in comparison with the lower concentration groups (0.00333 and 0.167 mg/kg) of rapamycin (P = 0.024 and P = 0.052, respectively). The number of mature vessels was significantly lower in the 3.33 mg/kg treated versus vehicle control (P = 0.015; equal variances assumed, t-test for equality of means). The number of neovessels was not significantly different between both groups (P = 0.092). Inhibition of mTOR was shown to reduce tumor burden, hypoxia, and vasculature in the LH(BETA)T(AG) retinoblastoma tumor model. Rapamycin may have a role in combination with chemotherapy or other adjuvant therapies to enhance retinoblastoma tumor control.


Function of beta-carotene and tocopherol in photosystem II.
New and known structural and functional insights in the role of beta-carotene and of alpha-tocopherol in photosytem II are reviewed. A concept is presented connecting the failure of P680 triplet quenching by beta-carotene with the formation of singlet oxygen and its scavenging in the turnover of the D1 protein and by tocopherol in the maintenance of PS II structure and function.


Amide proton transfer magnetic resonance imaging of Alzheimer's disease at 3.0 Tesla: a preliminary study.
Amide proton transfer (APT) imaging has recently emerged as an important contrast mechanism for magnetic resonance imaging (MRI) in the field of molecular and cellular imaging. The aim of this study was to evaluate the feasibility of APT imaging to detect cerebral abnormality in patients with Alzheimer's disease (AD) at 3.0 Tesla. Twenty AD patients (9 men and 11 women; age range, 67-83 years) and 20 age-matched normal controls (11 men and 9 women; age range, 63-82 years) underwent APT and traditional MRI examination on a 3.0 Tesla MRI system. The magnetic resonance ratio asymmetry (MTR asym ) values at 3.5 ppm of bilateral hippocampi (Hc), temporal white matter regions, occipital white matter regions, and cerebral peduncles were measured on oblique axial APT images. MTR asym (3.5 ppm) values of the cerebral structures between AD patients and control subjects were compared with independent samples t-test. Controlling for age, partial correlation analysis was used to investigate the associations between mini-mental state examination (MMSE) and the various MRI measures among AD patients. Compared with normal controls, MTR asym (3.5 ppm) values of bilateral Hc were significantly increased in AD patients (right 1.24% ± 0.21% vs. 0.83% ± 0.19%, left 1.18% ± 0.18% vs. 0.80%± 0.17%, t = 3.039, 3.328, P = 0.004, 0.002, respectively). MTR asym (3.5 ppm) values of bilateral Hc were significantly negatively correlated with MMSE (right r = -0.559, P = 0.013; left r = -0.461, P = 0.047). Increased MTR asym (3.5 ppm) values of bilateral Hc in AD patients and its strong correlations with MMSE suggest that APT imaging could potentially provide imaging biomarkers for the noninvasive molecular diagnosis of AD.