The Right Liver Lobe Size/Albumin Concentration Ratio in Identifying Esophageal Varices among Patients with Liver Cirrhosis.
BACKGROUND It is necessity to work more on non-invasive markers like right liver lobe size/albumin concentration ratio for predicting esophageal varices. We aimed to see the right liver lobe/albumin ratio in identifying esophageal varices among patients with cirrhosis caused by hepatitis B and C. METHODS A cross-sectional study was conducted among all indoor patients admitted to the Department of Internal Medicine, Pakistan Atomic Energy Commission, General Hospital, Sector H-11/4 Islamabad, Pakistan, during May-December 2016. A non-probability purposive sampling technique was used for data collection. Diagnosed cases of cirrhosis caused by hepatitis B and C virus infection aged 25 years or more were included. A pre-designed questionnaire was used for data collection. Statistical analysis was done using SPSS software version 20. RESULTS A total number of 160 patients were included. Mean ± SD age was 56.04 ± 10.22 years, while 96 (60%) were men. Child-Turcotte-Pugh grades showed 41.88% of the patients with grade A, followed by grade B (38.12%), and grade C (20%). Esophageal varices were observed in 76.25% of the patients. The sensitivity was 86.89%, while specificity was 78.95%. The positive predictive value was 92.98% (95% confidence interval [CI] = 86.64% - 96.91%) and negative predictive value was 65.22% (CI = 49.75% - 78.64%) with a diagnostic accuracy of 85%. CONCLUSION The use of the studied non-invasive markers of portal hypertension particularly the right liver lobe size/albumin concentration ratio, can help physicians to restrict the use of endoscopic screening only to patients presenting a high probability of esophageal varices.


Fibroblast-specific deletion of interleukin-1 receptor-1 reduces adverse cardiac remodeling following myocardial infarction.
It has been hypothesized that interleukin-1alpha (IL-1α) is released from damaged cardiomyocytes following myocardial infarction (MI) and activates cardiac fibroblasts via its receptor (IL-1R1) to drive the early stages of cardiac remodeling. This study aimed to definitively test this hypothesis using cell type-specific IL-1α and IL-1R1 knockout (KO) mouse models. A floxed Il1α mouse was created and used to generate a cardiomyocyte-specific IL-1α KO mouse line (MIL1AKO). A tamoxifen-inducible fibroblast-specific IL-1R1 hemizygous KO mouse line (FIL1R1KO) was also generated. Mice underwent experimental MI (permanent left anterior descending coronary artery ligation) and cardiac function was determined 4 weeks later by conductance pressure-volume catheter analysis. Molecular markers of remodeling were evaluated at various time points by real-time RT-PCR and histology. MIL1AKO mice showed no difference in cardiac function or molecular markers of remodeling post-MI compared with littermate controls. In contrast, FIL1R1KO mice showed improved cardiac function and reduced remodeling markers post-MI compared with littermate controls. In conclusion, these data highlight a key role for the IL-1R1/cardiac fibroblast signaling axis in regulating post-MI remodeling and provide support for the continued development of anti-IL-1 therapies for improving cardiac function after MI. Cardiomyocyte-derived IL-1α was not an important contributor to post-MI remodeling in this model.


Neurocutaneous melanosis in association with dandy-walker complex with extensive intracerebral and spinal cord involvement.
Neurocutaneous melanosis (NCM) is a rare congenital syndrome consisting of benign or malignant melanotic tumors of the central nervous system with large or numerous cutaneous melanocytic nevi. The Dandy-Walker complex (DWC) is characterized by an enlarged posterior fossa with high insertion of the tentorium, hypoplasia or aplasia of the cerebellar vermis, and cystic dilatation of the fourth ventricle. These each two conditions are rare, but NCM associated with DWC is even more rare. Most patients of NCM with DWC present neurological symptoms early in life such as intracranial hemorrhage, hydrocephalus, and malignant transformation of the melanocytes. We report a 14-year-old male patient who was finally diagnosed as NCM in association with DWC with extensive intracerebral and spinal cord involvement.


Neuromuscular training and injury prevention in sports.
Exercises that help develop neuromuscular control and increase functional joint stability are critical in conditioning and rehabilitation programs designed for injury prevention in sports. Information regarding joint movement and joint position provided by mechanoreceptors in the skin, muscles, tendons, ligaments, and joints combine with input from the vestibular and visual systems to maintain balance. Insufficient neurologic input or improperly processing that input at the spinal, brain stem, or cognitive centers can lead to an inadequate response by the motor system resulting in an injury. Therefore, it is important to include drills that enhance neuromuscular control into traditional training, conditioning, and rehabilitation programs for sports.


Relationships Between Brain Intrinsic Connectivity Networks and Measures of Cognition and Emotion: A Study of the Human Connectome Project Data.
Growing evidence suggests that variations in cognitive and emotional behavior are associated with variations in brain function. To achieve a more comprehensive assessment, data-driven techniques, specifically independent component analysis (ICA), can be employed to generate outcome variables that describe unique but complementary aspects of functional connectivity within and between networks. In this study, resting-state fMRI and behavioral data were collected from 50 healthy participants in the Human Connectome Project. The neuropsychological battery evaluated performance in various domains, including episodic memory, fluid intelligence, attention, working memory, executive function, cognitive flexibility, inhibition, and processing speed. Emotional measures were also included to assess emotion recognition and negative affects (sadness, fear, and anger). A multivariate approach was adopted to evaluate the association between cognitive abilities and emotional correlates on spatiotemporal features of intrinsic connectivity networks (ICNs). The results were explored at a false discovery rate-corrected threshold of p < 0.05. There was a significant positive association between within-network connectivity of the left central executive network (CEN) and inhibitory control and attention, and a significant negative association between within-network connectivity of the right CEN and episodic memory. Furthermore, increased within-network connectivity of the default-mode network (DMN) was linked to higher fluid intelligence, while within-network connectivity in the salience network (SN) and dorsal attention network (DAN) was associated with cognitive flexibility. Anger was found to be significantly related to increased functional network connectivity between SN and CEN. Sadness and fear were associated with increased within-network connectivity of the right CEN. Additionally, fear was associated with low-frequency spectral power in SN and DMN. These findings offer new insights into the intricate relation between ICN features and cognitive and emotional functions.


Ventricular assist device implantation in patients with a failing systemic right ventricle: a call to expand current practice.
Ventricular assist device (VAD) implantation is an established treatment modality for patients with end-stage heart failure, and improves symptoms and survival. In the Netherlands, it is not yet routinely considered in patients with congenital heart disease and failing systemic right ventricle (SRV). Recently, a VAD was implanted in 2 SRV patients, one who underwent a Mustard procedure during infancy for transposition of the great arteries (male, 47 years old) and one with a congenitally corrected transposition of the great arteries (male, 54 years old). The first patient is doing well >1 year after implantation; the second patient will be discharged home soon. These examples and other reports demonstrate the feasibility of adopting VAD implantation into routine care for SRV failure. In conclusion, patients with SRV failure may be suitable candidates for VAD implantation: they are relatively young, usually have a preserved subpulmonary left ventricular function, and their specific anatomical and physiological characteristics often make them unsuitable for cardiac transplantation. Therefore it is important to recognise the possibility of VAD implantation early in the process of SRV failure, and to timely refer these patients to a heart failure clinic with experience in VAD implantation in this group of patients for optimisation, screening, and implantation.


Isolation of a hybrid between rat ribosomal RNA and DNA.
A procedure for the isolation and purification of a specific hybrid between rat 28S and 18S ribosomal RNA's and nucleolar DNA is described. The method employed includes the following steps: 1) isolation of the nucleolar DNA, 2) hybridization of [14C]rRNA with the nucleolar DNA, and 3) isolation and purification of the rRNA-DNA hybrid complex by chromatography on hydroxylapatite and centrifugation in a CsCl density gradient. In the isolated hybrid complex the RNA:DNA ratio is close to 1:1, and the degree of enrichment of the DNA by the rRNA cistrons is about 1500 times. The hybrid obtained has a sedimentation constant on the order of 20S, is resistant to the action of pancreatic RNase and RNase T1 and sheep brain DNase, and is characterized by high thermostability. Acording to the physicochemical tests used, the rRNA-DNA hybrid complex is a double-stranded poly-nucleotide with an ordered secondary structure.


Immunotherapy for Alzheimer's disease: rational basis in ongoing clinical trials.
Amyloid-β (Aβ) immunotherapy has recently begun to gain considerable attention as a potentially promising therapeutic approach to reducing the levels of Aβ in the Central Nervous System (CNS) of patients with Alzheimer's Disease (AD). Despite extensive preclinical evidence showing that immunization with Aβ(1-42) peptide can prevent or reverse the development of the neuropathological hallmarks of AD, in 2002, the clinical trial of AN-1792, the first trial involving an AD vaccine, was discontinued at Phase II when a subset of patients immunized with Aβ(1-42) developed meningoencephalitis, thereby making it necessary to take a more refined and strategic approach towards developing novel Aβ immunotherapy strategies by first constructing a safe and effective vaccine. This review describes the rational basis in modern clinical trials that have been designed to overcome the many challenges and known hurdles inherent to the search for effective AD immunotherapies. The precise delimitation of the most appropriate targets for AD vaccination remains a major point of discussion and emphasizes the need to target antigens in proteins involved in the early steps of the amyloid cascade. Other obstacles that have been clearly defined include the need to avoid unwanted anti-Aβ/APP Th1 immune responses, the need to achieve adequate responses to vaccination in the elderly and the need for precise monitoring. Novel strategies have been implemented to overcome these problems including the use of N-terminal peptides as antigens, the development of DNA based epitope vaccines and vaccines based on passive immunotherapy, recruitment of patients at earlier stages with support of novel biomarkers, the use of new adjuvants, the use of foreign T cell epitopes and viral-like particles and adopting new efficacy endpoints. These strategies are currently being tested in over 10,000 patients enrolled in one of the more than 40 ongoing clinical trials, most of which are expected to report final results within two years.


Trends in long-term opioid prescribing in primary care patients with musculoskeletal conditions: an observational database study.
Long-term opioids may benefit patients with chronic pain but have also been linked to harmful outcomes. In the United Kingdom, the predominant source of opioids is primary care prescription. The objective was to examine changes in the incidence, length, and opioid potency of long-term prescribing episodes for musculoskeletal conditions in UK primary care (2002-2013). This was an observational database study (Clinical Practice Research Datalink, 190 practices). Participants (≥18 years) were prescribed an opioid for a musculoskeletal condition (no opioid prescribed in previous 6 months), and issued ≥2 opioid prescriptions within 90 days (long-term episode). Opioids were divided into short- and long-acting noncontrolled and controlled drugs. Annual incidence of long-term opioid episodes was determined, and for those still in a long-term episode, the percentage of patients prescribed each type 1 to 2 years, and >2 years after initiation. Annual denominator population varied from 1.25 to 1.38 m. A total of 76,416 patients started 1 long-term episode. Annual long-term episode incidence increased (2002-2009) by 38% (42.4-58.3 per 10,000 person-years), remaining stable to 2011, then decreasing slightly to 55.8/10,000 (2013). Patients prescribed long-acting controlled opioids within the first 90 days of long-term use increased from 2002 to 2013 (2.3%-9.9%). In those still in a long-term opioid episode (>2 years), long-acting controlled opioid prescribing increased from 3.5% to 22.6%. This study has uniquely shown an increase in prescribing long-term opioids to 2009, gradually decreasing from 2011 in the United Kingdom. The trend was towards increased prescribing of controlled long-acting opioids and earlier use. Further research into the risks and benefits of opioids is required.


Junctophilin-1 is a modifier gene of GDAP1-related Charcot-Marie-Tooth disease.
Mutations in the GDAP1 gene cause different forms of Charcot-Marie-Tooth (CMT) disease, and the primary clinical expression of this disease is markedly variable in the dominant inheritance form (CMT type 2K; CMT2K), in which carriers of the GDAP1 p.R120W mutation can display a wide range of clinical severity. We investigated the JPH1 gene as a genetic modifier of clinical expression variability because junctophilin-1 (JPH1) is a good positional and functional candidate. We demonstrated that the JPH1-GDAP1 cluster forms a paralogon and is conserved in vertebrates. Moreover, both proteins play a role in Ca(2+) homeostasis, and we demonstrated that JPH1 is able to restore the store-operated Ca(2+) entry (SOCE) activity in GDAP1-silenced cells. After the mutational screening of JPH1 in a series of 24 CMT2K subjects who harbour the GDAP1 p.R120W mutation, we characterized the JPH1 p.R213P mutation in one patient with a more severe clinical picture. JPH1(p.R213P) cannot rescue the SOCE response in GDAP1-silenced cells. We observed that JPH1 colocalizes with STIM1, which is the activator of SOCE, in endoplasmic reticulum-plasma membrane puncta structures during Ca(2+) release in a GDAP1-dependent manner. However, when GDAP1(p.R120W) is expressed, JPH1 seems to be retained in mitochondria. We also established that the combination of GDAP1(p.R120W) and JPH1(p.R213P) dramatically reduces SOCE activity, mimicking the effect observed in GDAP1 knock-down cells. In summary, we conclude that JPH1 and GDAP1 share a common pathway and depend on each other; therefore, JPH1 can contribute to the phenotypical consequences of GDAP1 mutations.


No evidence for genetic association or linkage of the cathepsin D (CTSD) exon 2 polymorphism and Alzheimer disease.
Two recent case-control studies have suggested a strong association of a missense polymorphism in exon 2 of the cathepsin D gene (CTSD) and Alzheimer disease (AD). However, these findings were not confirmed in another independent study. We analyzed this polymorphism in two large and independent AD study populations and did not detect an association between CTSD and AD. The first sample was family-based and included 436 subjects from 134 sibships discordant for AD that were analyzed using the sibship disequilibrium test (SDT, p = 0.68) and the sib transmission/disequilibrium test (Sib-TDT, p = 0.81). The second sample of 200 AD cases and 182 cognitively normal controls also failed to show significant differences in the allele or genotype distribution in cases versus controls (chi2, p = 0.91 and p = 0.88, respectively). In addition, two-point linkage analyses in an enlarged family sample (n = 670) did not show evidence for linkage of the chromosomal region around CTSD. Thus, our analyses on more than 800 subjects suggest that if an association between the CTSD exon 2 polymorphism and AD exists, it is likely to be smaller than previously reported.


Psychopharmacological treatment of neurocognitive deficits in people with schizophrenia: a review of old and new targets.
Neurocognitive impairments significantly contribute to disability and the overall clinical picture in schizophrenia spectrum disorders. There has therefore been a concerted effort, guided by the discovery of neurotransmitter and synaptic systems in the central nervous system, to develop and test compounds that may ameliorate neurocognitive deficits. The current article summarizes the results of efforts to test neurocognitive-enhancing agents in schizophrenia. Overall, existing clinical trials provide little reason to be enthusiastic about the benefits of psychopharmacological agents at enhancing neurocognition in schizophrenia-a state of affairs that may reflect the inadequacy of single neurotransmitter or receptor models. The etiologic and phenomenological complexity of neurocognitive deficits in schizophrenia may be better served by psychopharmacological agents that (i) target neurotransmitter systems proximal in the causal chain to neurocognitive deficits; (ii) enhance distal survival processes in the central nervous system-neurogenesis, neuronal growth, synaptogenesis, and connectivity; and (iii) counteract the negative effects of aberrant neurodevelopment in schizophrenia, such as neuroinflammation and oxidative stress. Future efforts to develop psychopharmacological agents for neurocognitive impairment in schizophrenia should reflect the knowledge of its complex etiology by addressing aberrations along its causal chain. Clinical trials may benefit methodologically from (i) an appreciation of the phenomenological heterogeneity of neurocognitive deficits in schizophrenia; (ii) a characterization of the predictors of treatment response; and (iii) a recognition of issues of sample size, statistical power, treatment duration, and dosing.


[Pro-inflammatory cytokines in Alzheimer's disease].
Alzheimer's disease (AD), the most common progressive neurodegenerative disorder in the elderly, is clinically characterized by progressive impairment of cognitive functions, including reduced critical capacity, weakness of decision-making and problem orientation, while in the more advanced stages it is accompanied by behavioral disorders and impaired verbal ability. Neuropathological characteristics of the disease are the neurofibrillary tangles (NFT), the neuritic plaques (NP), the prominent synaptic loss and eventually the neuronal loss. The presence of inflammatory process seems to be playing important role in the progression of the disease. This process is directed by the activated glial cells and it leads to the overproduction of acute phase proteins, complement factors activation and induction of inflammatory enzyme systems. These inflammatory factors can contribute to neuronal dysfunction and cell death. Cytokines belong to the acute phase proteins, which are secreted from glial cells. They can either strengthen the inflammatory reaction or suppress it, adjusting the intensity and duration of the immune response. In the category of cytokines belong several interleukins (ILs) and various factors (TNF-α, TGF-β). Interleukins are involved in complex intercellular interactions among neurons, microglia and astrocytes, as well as intracellular signal transduction events, which are necessary to promote the inflammatory cascade characteristic of AD neuropathology. It has been observed that increased levels of pro- inflammatory cytokines, including tumor necrosis factor (TNF), interleukin 1β (IL-1β), interleukin 6 (IL-6) and interferon γ (IFN-γ), may suspend phagocytosis of amyloid Aβ in brains of patients with AD. Thus, it may interfere with the effective removal of plaque from microglia, promote astrogliosis and neural death. Normally, during immune surveillance, a balance is maintained between pro- and antiinflammatory influences. Yet, during AD, the abnormal accumulation of soluble amyloid oligomers triggers excessive release of pro inflammatory factors, such as cytokines and other acute-phase reactants, out of proportion to the regulatory components, such as IL-4, IL-10, receptor antagonists, interleukin inhibitors and others, ultimately leading to neuronal and synaptic injury and loss and cognitive decline. These changes in the brain parenchyma are often accompanied by changes in levels of these inflammatory proteins in peripheral blood. Even though literature is presenting conflicting studies, efforts are being made for the detection of cytokines in peripheral blood and association of their levels with the progression of AD. Inflammatory pathways, involving the signaling of cytokines, could be potential targets for the prevention of AD and the development of new therapies. The aim of the present work is to review studies indicating a correlation between these inflammatory agents and AD pathogenesis.


Diagnosing testicular lumps in primary care.
Although the incidence of testicular cancer has increased over the past few decades, testicular tumours are still rare and many GPs will only see one or two new diagnoses in their career. In one UK study, out of 845 patients who had been referred with testicular lumps or pain, only 33 (4%) were diagnosed with testicular cancer. Epididymal cysts, or spermatoceles when containing sperm, were the most common finding, and were found in 228 patients (27%). The second most common finding was hydrocele, a fluid collection between the parietal and visceral layers of the tunica vaginalis, which was found in 96 patients (11%). The vast majority (95-98%) of testicular cancers are germ cell tumours. In Western Europe, five-year survival for testicular cancer is approximately 95%. It is almost 100% for stage 1 seminomas, but falls to 48% in the poorest prognostic group – non-seminomatous tumours with metastases at diagnosis.When examining scrotal swellings, the key question is whether the lump is intra- or extra-testicular, as palpable intra-testicular lesions are highly likely (around 90%) to be malignant, whereas those lying outside the testis are usually benign. NICE recommends that men with non-painful enlargement or change in shape or texture of the testis should be referred via the two-week wait cancer pathway. Any painful or tender mass within the body of the testis which is not suggestive of infection should also be referred. GPs should refer patients for an urgent ultrasound if they are aged 20-40 with a hydrocele; if there is uncertainty as to whether the mass is intra-testicular or extra-testicular; or if the testis cannot be fully palpated.


Endotracheal intubation results in acute tracheal damage induced by mtDNA/TLR9/NF-κB activity.
Tracheitis secondary to placement of an endotracheal tube (ETT) is characterized by neutrophil accumulation in the tracheal lumen, which is generally associated with epithelial damage. Mitochondrial DNA (mtDNA), has been implicated in systemic inflammation and organ dysfunction following trauma; however, less is known about the effects of a foreign body on local trauma and tissue damage. We hypothesized that tracheal damage secondary to the ETT will result in local release of mtDNA at sufficient levels to induce TLR9 and NF-κB activation. In a swine model we compared the differences between uncoated, and chloroquine (CQ) and N-acetylcysteine (NAC) coated ETTs as measured by tracheal lavage fluids (TLF) over a period of 6 h. The swine model allowed us to recreate human conditions. ETT presence was characterized by neutrophil activation, necrosis, and release of proinflammatory cytokines mediated by TLR9/NF-κB induction. Amelioration of the tracheal damage was observed in the CQ and NAC coated ETT group as shown in tracheal tissue specimens and TLF. The role of TLR9/NF-κB dependent activity was confirmed by HEK-Blue hTLR9 reporter cell line analysis after coincubation with TLF specimens with predetermined concentrations of NAC or CQ alone or TLR9 inhibitory oligodeoxynucleotide (iODN). These findings indicate that therapeutic interventions aimed at preventing mtDNA/TLR9/NF-κB activity may have benefits in prevention of acute tracheal damage.


Regional grey and white matter changes in heavy male smokers.
Cigarette smoking is highly prevalent in the general population but the effects of chronic smoking on brain structures are still unclear. Previous studies have found mixed results regarding regional grey matter abnormalities in smokers. To characterize both grey and white matter changes in heavy male smokers, we investigated 16 heavy smokers and 16 matched healthy controls, using both univariate voxel-based morphometry (VBM) and multivariate pattern classification analysis. Compared with controls, heavy smokers exhibited smaller grey matter volume in cerebellum, as well as larger white matter volume in putamen, anterior and middle cingulate cortex. Further, the spatial patterns of grey matter or white matter both discriminated smokers from controls in these regions as well as in other brain regions. Our findings demonstrated volume abnormalities not only in the grey matter but also in the white matter in heavy male smokers. The multivariate analysis suggests that chronic smoking may be associated with volume alternations in broader brain regions than those identified in VBM analysis. These results may better our understanding of the neurobiological consequence of smoking and inform smoking treatment.


Carbonyl-Stabilized Phosphorus Ylide as an Organocatalyst for Cyanosilylation Reactions Using TMSCN.
We report carbonyl-stabilized phosphorus ylides as general and efficient catalysts for the cyanosilylation of ketones. The N,N-diethylacetamide derived phosphorane is identified as an extremely efficient catalyst for the cyanosilylation of dialkyl ketones, alkyl aryl ketones, diaryl ketones, and α,β-unsaturated enones with catalyst loading down to 0.005 mol %, the lowest ever known for ketone cyanosilylation. Aldehydes, aldimines, and ketimines are also viable substrates. By NMR and React IR analysis, as well as electrical conductivity experiments, it is proposed that the phosphorane acts as a Lewis base in order to mediate the reaction via the desilylative nucleophilic activation of TMSCN.


The cofactor role of protein S in the acceleration of whole blood clot lysis by activated protein C in vitro.
The effect of purified human activated protein C (APC) and protein S on fibrinolysis was studied by using an in vitro blood clot lysis technique. Blood clots were formed from citrated blood (supplemented with 125I-fibrinogen) by adding thrombin and Ca2+-ions; lysis of the clots was achieved by adding tissue-type plasminogen activator. The release of labeled fibrin degradation products from the clots into the supernatant was followed in time. We clearly demonstrated that APC accelerates whole blood clot lysis in vitro. The effect of APC was completely quenched by antiprotein C IgG, pretreatment of APC with diisopropylfluorophosphate, and preincubation of the blood with antiprotein S IgG. This demonstrates that both the active site of APC and the presence of the cofactor, protein S, are essential for the expression of the profibrinolytic properties. At present, the substrate of APC involved in the regulation of fibrinolysis is not yet known. Analysis of the radiolabeled fibrin degradation products demonstrated that APC had no effect on the fibrin cross-linking capacity of factor XIII.


Calcium oxalate monohydrate aggregation induced by aggregation of desialylated Tamm-Horsfall protein.
Tamm-Horsfall protein (THP) is thought to protect against calcium oxalate monohydrate (COM) stone formation by inhibiting COM aggregation. Several studies reported that stone formers produce THP with reduced levels of glycosylation, particularly sialic acid levels, which leads to reduced negative charge. In this study, normal THP was treated with neuraminidase to remove sialic acid residues, confirmed by an isoelectric point shift to higher pH. COM aggregation assays revealed that desialylated THP (ds-THP) promoted COM aggregation, while normal THP inhibited aggregation. The appearance of protein aggregates in solutions at ds-THP concentrations ≥1 μg/mL in 150 mM NaCl correlated with COM aggregation promotion, implying that ds-THP aggregation induced COM aggregation. The aggregation-promoting effect of the ds-THP was independent of pH above its isoelectric point, but was substantially reduced at low ionic strength, where protein aggregation was much reduced. COM aggregation promotion was maximized at a ds-THP to COM mass ratio of ~0.025, which can be explained by a model wherein partial COM surface coverage by ds-THP aggregates promotes crystal aggregation by bridging opposing COM surfaces, whereas higher surface coverage leads to repulsion between adsorbed ds-THP aggregates. Thus, desialylation of THP apparently abrogates a normal defensive action of THP by inducing protein aggregation, and subsequently COM aggregation, a condition that favors kidney stone formation.


Enzyme-linked immunosorbent assays for Snow Mountain and Norwalk agents of viral gastroenteritis.
Enzyme-linked immunosorbent assays (ELISAs) for antigen detection and blocking ELISAs for serum antibody rises were developed for the Snow Mountain and Norwalk agents of viral gastroenteritis. The ELISAs were as sensitive as the existing radioimmunoassays and were specific for the Snow Mountain or Norwalk agent. The blocking ELISAs detected the same number of significant rises in antibodies to these agents as did the existing blocking radioimmunoassays.


Empty Sella Is a Sign of Symptomatic Lateral Sinus Stenosis and Not Intracranial Hypertension.
Empty sella has been reported in patients with idiopathic intracranial hypertension and is thought to be a sign of elevation of intracranial pressure. However, it can also be found in patients with lateral sinus stenosis presenting with isolated pulsatile tinnitus without signs of intracranial hypertension. We hypothesized that the volume of the sella turcica would be similar in both groups of patients undergoing stent placement for lateral sinus stenosis. Consecutive patients with idiopathic intracranial hypertension or isolated venous pulsatile tinnitus and undergoing lateral sinus stent placement from January 2012 to December 2017 were included. The primary outcome was the estimated volume of the sella turcica based on preoperative CTA measurements. The ratio of the pituitary gland height/sellar height was calculated on preoperative MR imaging. Sellar volumes were compared among the 3 groups: pulsatile tinnitus, idiopathic intracranial hypertension, and a control group, matched by age and sex. Eighty-eight patients underwent lateral sinus stent placement. The median age was 37 years, and 94% were women. No difference in age, sex, or body mass index was found among the groups. Patients undergoing venous stent placement had significantly higher sellar volumes than the control group (P < 0.001). There was no difference in the sellar volumes (P = .63) or gland/sellar height ratios (P = .25) between the pulsatile tinnitus and idiopathic intracranial hypertension groups. Empty sella is found in 2 differing groups of patients undergoing lateral sinus stent placement, suggesting that it is a radiologic sign of symptomatic hemodynamic lateral sinus stenosis rather than elevated intracranial pressure.


The asymmetric distribution of the essential histidine kinase PdhS indicates a differentiation event in Brucella abortus.
Many organisms use polar localization of signalling proteins to control developmental events in response to completion of asymmetric cell division. Asymmetric division was recently reported for Brucella abortus, a class III facultative intracellular pathogen generating two sibling cells of slightly different size. Here we characterize PdhS, a cytoplasmic histidine kinase essential for B. abortus viability and homologous to the asymmetrically distributed PleC and DivJ histidine kinases from Caulobacter crescentus. PdhS is localized at the old pole of the large cell, and after division and growth, the small cell acquires PdhS at its old pole. PdhS may therefore be considered as a differentiation marker as it labels the old pole of the large cell. Moreover, PdhS colocalizes with its paired response regulator DivK. Finally, PdhS is able to localize at one pole in other alpha-proteobacteria, suggesting that a polar structure associating PdhS with one pole is conserved in these bacteria. We propose that a differentiation event takes place after the completion of cytokinesis in asymmetrically dividing alpha-proteobacteria. Altogether, these data suggest that prokaryotic differentiation may be much more widespread than expected.


New triorganotin (IV) derivatives of dipeptides as models for metal-protein interactions: synthesis, structural characterization and biological studies.
New non-electrolytic triorganotin(IV) derivatives of dipeptides with general formulae R3Sn(HL), where R = Ph and HL = monoanion of glycylisoleucine (H2L-1), valylvaline (H2L-2), alanylvaline (H2L-3), leucylalanine (H2L-4), leucylleucine (H2L-5); R = n-Bu and HL = monoanion of glycylisoleucine (H2L-1) and leucylalanine (H2L-4); and R = Me and HL = monoanion of leucylalanine (H2L-4) have been synthesized and characterized on the basis of infrared, multinuclear 1H, 13C and 119Sn NMR and 119Sn Mössbauer spectroscopic studies. These investigations suggest that all the ligands in R3Sn(HL) act as monoanionic bidentates coordinating through the COO- and NH2 groups. The 119Sn Mössbauer studies, together with the NMR data, indicate that, for these polymeric derivatives, the polyhedron around tin in R3Sn(HL) is a trigonal-bipyramid with the three organic groups in the equatorial positions, while the axial positions are occupied by a carboxylic oxygen and the amino nitrogen atom from the adjacent molecule. The anti-inflammatory and cardiovascular activities and toxicity of all these compounds have been determined. Four of the complexes have also been screened against some of the chosen bacterial and fungal strains. The Ph3Sn(IV) compounds exhibit better anti-inflammatory and cardiovascular activities in comparison to the Me3Sn(IV) and n-Bu3Sn(IV) analogues. n-Bu3Sn(Gly-Ile) and Ph3Sn(Ala-Val) exhibit good antibacterial activity against all the chosen strains.


Leucocyte esterase-nitrite screening method for pyuria and bacteriuria.
The value of the one minute leucocyte esterase-nitrite chemical strips as a screening procedure for detecting appreciable levels of pyuria and bacteriuria was assessed by comparison with microscopy and culture results. The likelihood that a negative leucocyte esterase result indicated less than 10 white cells/cu mm by microscopy (the negative predictive value), was 90.1% and that a negative nitrite result indicated less than 10(5) organisms/ml was 91.3%. There were many false positive results with both tests, however, and the overall predictive value of a positive leucocyte esterase or nitrite test, or both, was low. The leucocyte esterase-nitrite strip was neither sufficiently sensitive nor specific enough to be used as a cost effective method for screening urines in the laboratory.


Some improved methods in P22 transduction.
Recent refinements simplify methods for P22 transduction in Salmonella and allow improved recovery of phage-free transductional clones. The methods include use of: integration- and lysis-defective phage mutants, heat-killed bacteria to eliminate free phage, direct plating of phage and bacteria, replica-plating for detection of phage content of individual clones, improved broth for phage growth, and procurement of high titer phage from P22 lysogens.


A review of dynamic network models with latent variables.
We present a selective review of statistical modeling of dynamic networks. We focus on models with latent variables, specifically, the latent space models and the latent class models (or stochastic blockmodels), which investigate both the observed features and the unobserved structure of networks. We begin with an overview of the static models, and then we introduce the dynamic extensions. For each dynamic model, we also discuss its applications that have been studied in the literature, with the data source listed in Appendix. Based on the review, we summarize a list of open problems and challenges in dynamic network modeling with latent variables.


The in-vitro effect of a titanium implant on oral microflora: comparison with other metallic compounds.
Dental implant research has been mostly concerned with the biocompatibility of materials for implantation. In this study the effects of titanium dioxide and other metallic salts on seven bacterial species commonly found in dental plaque, two which are uncommon, and a yeast, were determined by agar incorporation and diffusion techniques, and compared with the effects of a titanium implant abutment. Neither the titanium dioxide nor the implant abutment demonstrated any inhibitory activity, although other compounds such as cobalt used in dental alloys had some effects.


Obesity genetics: insights from the Pakistani population.
The Pakistani population is extensively diverse, indicating a genetic admixture of European and Central/West Asian migrants with indigenous South Asian gene pools. Pakistanis are organized in different ethnicities/castes based on cultural, linguistic and geographical origin. While Pakistan is facing a rapid nutritional transition, the rising prevalence of obesity is driving a growing burden of health complications and mortality. This represents a unique opportunity for the research community to study the interplay between obesogenic environmental changes and obesity predisposing genes in the time frame of one generation. This review recapitulates the ancestral origins of Pakistani population, the societal determinants of the rise in obesity and its governmental management. We describe the contribution of syndromic, monogenic non-syndromic and polygenic obesity genes identified in the Pakistani population. We then discuss the utility of gene identification approaches based on large consanguineous families and original gene × environment interaction study designs in discovering new obesity genes and causal pathways. Elucidation of the genetic basis of obesity in the Pakistani population may result in improved methods of obesity prevention and treatment globally.


Methylome and proteome integration in human skeletal muscle uncover group and individual responses to high-intensity interval training.
Exercise is a major beneficial contributor to muscle metabolism, and health benefits acquired by exercise are a result of molecular shifts occurring across multiple molecular layers (i.e., epigenome, transcriptome, and proteome). Identifying robust, across-molecular level targets associated with exercise response, at both group and individual levels, is paramount to develop health guidelines and targeted health interventions. Sixteen, apparently healthy, moderately trained (VO2 max = 51.0 ± 10.6 mL min-1 kg-1 ) males (age range = 18-45 years) from the Gene SMART (Skeletal Muscle Adaptive Responses to Training) study completed a longitudinal study composed of 12-week high-intensity interval training (HIIT) intervention. Vastus lateralis muscle biopsies were collected at baseline and after 4, 8, and 12 weeks of HIIT. DNA methylation (~850 CpG sites) and proteomic (~3000 proteins) analyses were conducted at all time points. Mixed models were applied to estimate group and individual changes, and methylome and proteome integration was conducted using a holistic multilevel approach with the mixOmics package. A total of 461 proteins significantly changed over time (at 4, 8, and 12 weeks), whilst methylome overall shifted with training only one differentially methylated position (DMP) was significant (adj.p-value < .05). K-means analysis revealed cumulative protein changes by clusters of proteins that presented similar changes over time. Individual responses to training were observed in 101 proteins. Seven proteins had large effect-sizes >0.5, among them are two novel exercise-related proteins, LYRM7 and EPN1. Integration analysis showed bidirectional relationships between the methylome and proteome. We showed a significant influence of HIIT on the epigenome and more so on the proteome in human muscle, and uncovered groups of proteins clustering according to similar patterns across the exercise intervention. Individual responses to exercise were observed in the proteome with novel mitochondrial and metabolic proteins consistently changed across individuals. Future work is required to elucidate the role of these proteins in response to exercise.


Concurrent use of antidepressants and propranolol: case report and theoretical considerations.
The therapeutic indications for propranolol have been steadily increasing in recent years. Propranolol and other beta-adrenergic blocking agents are now generally acknowledged to be helpful in the management of hypertension, certain cardiac arrhythmias, migraine, essential tremor, angina pectoris, and most recently, immediately after myocardial infarction (Frishman, 1981; Norwegian Multicenter Study Group, 1982). Because of the myriad clinical settings in which propranolol has been found to be of benefit, the interactions of these drugs with other commonly utilized pharmacological agents is of great pragmatic interest. In this report we describe the successful concomitant clinical use of propranolol and an antidepressant drug. This finding is also of interest because of recent theories concerning the mechanism of action of antidepressant drugs. Because propranolol readily penetrates into the CNS, it blocks beta-adrenergic receptors in both the periphery and the CNS (Weiner, 1980). Much attention has been focused recently on the effects of long-term antidepressant therapy on central beta-adrenergic receptors in the brain as a possible mechanism of action of these drugs. The concurrent use of propranolol and an antidepressant drug in the patient described in this report did not attenuate the therapeutic effects of the antidepressant.


An Integral Recognition and Signaling for Electrochemical Assay of Protein Kinase Activity and Inhibitor by Reduced Graphene Oxide-Polydopamine-Silver Nanoparticle-Ti4+ Nanocomposite.
A novel electrochemical biosensing method for protein kinase (PKA) activity was demonstrated by using a reduced graphene oxide-polydopamine-silver nanoparticle-Ti4+ (rGO-PDA-AgNPs-Ti4+) nanocomposite. The obtained nanocomposite possessed an integral capability for phosphopeptide recognition and signal readout. The polydopamine modified reduced graphene oxide (rGO-PDA) was firstly prepared based on a self-polymerization method of dopamine. The silver ions were adsorbed onto polydopamine (PDA) layer and directly reduced into silver nanoparticles (AgNPs), which was used for electrochemical signal reporting. Then, the Ti4+ cations were attached onto the PDA layer for phosphopeptide recognition according to the strong coordination ability of PDA with Ti4+ and phosphate group. The prepared rGO-PDA-AgNPs-Ti4+ nanocomposites were characterized with different methods. The developed rGO-PDA-AgNPs-Ti4+ nanocomposites were then employed for electrochemical analysis of PKA-catalyzed kemptide phosphorylation. The sensitive detection toward PKA activity was realized with an experimental detection limit of about 0.01 U/mL. It may be also extended for the inhibitor evaluation. Thus, it provided a facile and sensitive means for electrochemical analysis of PKA activity and inhibitor screening.


Frenulate siboglinids at high Arctic methane seeps and insight into high latitude frenulate distribution.
Frenulate species were identified from a high Arctic methane seep area on Vestnesa Ridge, western Svalbard margin (79°N, Fram Strait) based on mitochondrial cytochrome oxidase subunit I (mtCOI). Two species were found: Oligobrachia haakonmosbiensis, and a new, distinct, and undescribed Oligobrachia species. The new species adds to the cryptic Oligobrachia species complex found at high latitude methane seeps in the north Atlantic and the Arctic. However, this species displays a curled tube morphology and light brown coloration that could serve to distinguish it from other members of the complex. A number of single tentacle individuals were recovered which were initially thought to be members of the only unitentaculate genus, Siboglinum. However, sequencing revealed them to be the new species and the single tentacle morphology, in addition to thin, colorless, and ringless tubes indicate that they are juveniles. This is the first known report of juveniles of northern Oligobrachia. Since the juveniles all appeared to be at about the same developmental stage, it is possible that reproduction is either synchronized within the species, or that despite continuous reproduction, settlement, and growth in the sediment only takes place at specific periods. The new find of the well-known species O. haakonmosbiensis extends its range from the Norwegian Sea to high latitudes of the Arctic in the Fram Strait. We suggest bottom currents serve as the main distribution mechanism for high latitude Oligobrachia species and that water depth constitutes a major dispersal barrier. This explains the lack of overlap between the distributions of northern Oligobrachia species despite exposure to similar current regimes. Our results point toward a single speciation event within the Oligobrachia clade, and we suggest that this occurred in the late Neogene, when topographical changes occurred and exchanges between Arctic and North Atlantic water masses and subsequent thermohaline circulation intensified.


"Low-age, low-frequency" lung cancer screening strategies maybe adaptable to the situation in China.
The object was to compare changes in patients undergoing lung surgery before and after COVID-19 outbreak, and to explore the impact of COVID-19 on lung surgery and its coping strategies. A retrospective review of patients undergoing thoracic surgery at a single institution was conducted. Group A included patients treated between January 23, 2019, and January 23, 2020, while Group B included patients treated between June 1, 2020, and June 1, 2021, at our center. We compared the reasons of seeking medical treatment, the general characteristics of patients, imaging features, pathological features, surgical methods and postoperative recovery. Compared to Group A, the number of patients with pulmonary nodules screened by routine check-up increased in Group B (57.6% vs 46.9%, p < 0.05). Female patient increased (55.2%vs 44.7%). Patient without smoking history or with family history of lung cancer increased (70.7% vs 60.7%) (10.1%vs 7.8%). Early stage lung cancer increased. Lobectomy decreased (53.4% vs 64.1%). Segmental resection increased (33.3% vs 12.7%). Patients without postoperative comorbidities increased (96.1%vs 85.7%). In the case of patients with Ground Glass Opacity(GGO), their age was comparatively lower (52 ± 9.9 vs. 55 ± 10.7), the female patients increased, patient without smoking history, tumor history, family history of tumor increased, small GGO increased. Lobectomy decreased (35.2% vs 49.7%). Segmental resection increased (49.6% vs 21.2%). Patients without postoperative comorbidities increased (96.5% vs 87.4%). Since COVID-19 outbreak, more young, non-smoking, female lung cancers, more Ground Glass Opacity, none high risk patients have been detected through screening, suggesting that our current screening criteria for lung cancer may need to be revised. Higher requirements, including the selection of the timing of nodular surgery, surgical methods were put forward for thoracic surgeons' skills.


Risk of death, hospitalization and intensive care unit admission by SARS-CoV-2 variants in Peru: a retrospective study.
Peru has had the highest death toll from the pandemic worldwide; however, it is not clear what the effects of the different variants on these outcomes are. The study aimed to evaluate the risk of death, hospitalization, and intensive care unit (ICU) admission rates of COVID-19 according to the SARS-CoV-2 variants detected in Peru from March 2020-February 2022. Retrospective study using open-access databases were published by the Peruvian Ministry of Health. Databases of genomic sequencing, death, COVID-19 cases, hospitalization and ICU, and vaccination were used. Crude and adjusted Cox proportional hazards regressions with clustered variances were modeled to calculate the hazard ratio (HR) of outcomes by variant. Lambda variant had the highest risk of death (HR 1.92, 95% CI 1.37-2.68), whereas the Delta variant had the lowest risk (HR 0.50, 95% CI 0.31-0.82). Mu variant had the highest risk of hospitalization (HR: 2.39, 95% CI 1.56-3.67), Omicron the lowest (HR 0.45, 95%CI 0.23-0.90), and Gamma had the highest ICU admission rate (HR 1.95, 95%CI 1.40-2.71). SARS-CoV-2 variants showed distinctive risks of clinical outcomes, which could have implications for the management of infected persons during the pandemic.


Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins.
Eukaryotic members of the CLC gene family function as plasma membrane chloride channels, or may provide neutralizing anion currents for V-type H(+)-ATPases that acidify compartments of the endosomal/lysosomal pathway. Loss-of-function mutations in the endosomal protein ClC-5 impair renal endocytosis and lead to kidney stones, whereas loss of function of the endosomal/lysosomal protein ClC-7 entails osteopetrosis and lysosomal storage disease. Vesicular CLCs have been thought to be Cl- channels, in particular because ClC-4 and ClC-5 mediate plasma membrane Cl- currents upon heterologous expression. Here we show that these two mainly endosomal CLC proteins instead function as electrogenic Cl-/H+ exchangers (also called antiporters), resembling the transport activity of the bacterial protein ClC-e1, the crystal structure of which has already been determined. Neutralization of a critical glutamate residue not only abolished the steep voltage-dependence of transport, but also eliminated the coupling of anion flux to proton counter-transport. ClC-4 and ClC-5 may still compensate the charge accumulation by endosomal proton pumps, but are expected to couple directly vesicular pH gradients to Cl- gradients.


Engineering of a Self-Regulatory Bidirectional DNA Assembly Circuit for Amplified MicroRNA Imaging.
The engineering of catalytic hybridization DNA circuits represents versatile ways to orchestrate a complex flux of molecular information at the nanoscale, with potential applications in DNA-encoded biosensing, drug discovery, and therapeutics. However, the diffusive escape of intermediates and unintentional binding interactions remain an unsolved challenge. Herein, we developed a compact, yet efficient, self-regulatory assembly circuit (SAC) for achieving robust microRNA (miRNA) imaging in live cells through DNA-templated guaranteed catalytic hybridization. By integrating the toehold strand with a preblocked palindromic fragment in the stem domain, the proposed miniature SAC system allows the reactant-to-template-controlled proximal hybridization, thus facilitating the bidirectional-sustained assembly and the localization-intensified signal amplification without undesired crosstalk. With condensed components and low reactant complexity, the SAC amplifier realized high-contrast intracellular miRNA imaging. We anticipate that this simple and template-controlled design can enrich the clinical diagnosis and prognosis toolbox.


The Effect of Neonates' Exposure to Their Mother's Scent on Weight Gain: A Randomized Controlled Study.
Objective: The aim of this study was to determine the effect of newborns' exposure to their mother's scent in the intensive care unit on their weight gain. Materials and Methods: This is an experimental randomized controlled study. One hundred and four neonates were included in the study. Two groups were observed in the research: the first group consisting of those exposed to their mother's scent (n = 52) and a second control group (n = 52). Data were collected with a data collection form and an infant body weight monitoring form. Significance for the study was accepted as p < 0.05. Results: Among the neonates, 61.5% were males, the gestational week of the infants was 38.49 ± 1.24, their mean weight was 3,213.32 ± 468.67 grams (g); the two groups were similar in terms of these characteristics (p > 0.05). The neonates exposed to their mother's scent at the beginning of the study were weighed, averaging 3,105.38 ± 487.69 g; at the end of Day 1 and Day 2, their mean weight was 3,150.77 ± 493.07 and 3,197.50 ± 489.06 g, respectively. It was seen that there were significant differences in the weight of the group of neonates exposed to their mother's scent before the experiment, on Day 1 and on Day 2 (p < 0.05). The neonates in the control group were weighed at the beginning of the experiment, exhibiting a mean of 3,119.42 ± 452.85 g. Their mean weight was 3,107.12 ± 463.30 g at the end of Day 1 and 3,116.63 ± 471.09 g at the end of Day 2. These differences, however, were not statistically significant (p > 0.05). Conclusion: We found that the newborns exposed to their mother's scent in the intensive care unit registered a higher increase in weight. Our recommendation is that a mother's scent be routinely factored into neonatal care in intensive care units.


Geographic diversity in tuberculosis trends and directly observed therapy, New York City, 1991 to 1994.
The New York City tuberculosis (TB) case rate declined from 1991 to 1994 following more than a decade of increases. The present study investigated TB trends in New York City neighborhoods and their association with neighborhood-specific rates of application of directly observed therapy (DOT). Using Poisson regression models, TB trends in each of New York City's 30 health districts were classified as increasing, decreasing, or stable, as indicated respectively by significant positive, negative, or nonsignificant regression coefficient. Case counts increased in four health districts, decreased in 10, and were stable in 16. Decreasing TB was associated with a higher rate of application of DOT. TB cases among foreign-born persons increased in 12 health districts and were stable in 18, whereas cases among persons born in the United States decreased in 19 and were stable in 11 districts. Among the foreign-born, increasing TB was not associated with a lesser rate of application of DOT. These data provide some support for the role of DOT in containing TB, but also suggest that the application of DOT among foreign-born residents is less effective than among United States-born residents. This may be due to a greater proportion of TB cases among the foreign-born being due to reactivation of TB rather than new infection.


Evaluation of the consequences associated with diffuse vascular disease history in patients diagnosed with peripheral arterial disease: estimates from Saskatchewan health data.
Peripheral arterial disease (PAD) is caused by narrowing of the arteries in the lower extremities. Limited data exist concerning the impact of diffuse vascular disease (DVD) on prognosis and costs. Thus, the objective of this study is to estimate the impact of DVD on morbidity, mortality and costs. PAD was identified between 1985 and 1995 and classified by extent of DVD at diagnosis: none (PAD only, reference group), prior myocardial infarction (MI), prior stroke, prior MI and stroke (MI + stroke), prior transient ischemic attack (TIA). Deaths and hospitalizations were identified through December 2000. Hospitalization costs were estimated from the Ontario Case Cost Project, reported in 2002 $CAD. Proportional hazards analyses measured the impact of vascular involvement on mortality while controlling for risk factors (e.g., age, cardiovascular history). Overall, 16,439 patients with PAD were included; 14.8% had a prior MI, 10.2% a prior stroke, 2.6% prior MI + stroke, 6.4% prior TIA, two-thirds had PAD only. Median survival was shorter for patients with prior MI (9.3 yrs), TIA (6.3), stroke (4.7), and MI+stroke (4.1) versus the reference group (9.9, p < 0.05, all comparisons). Analyses revealed that the death risk was 60% higher in patients with prior stroke and 84% higher for MI + stroke. Atherothrombotic and bleeding event-related costs were $712, $337, $268, and $170 higher per patient/year of follow-up in patients with a history of MI+stroke, MI, stroke, and TIA, respectively. Patients diagnosed with PAD with DVD have higher risk of poor outcomes and increased costs.


The American centennial of brain tumor surgery.
Early in 1887 the first well-documented total removal of an unequivocal brain tumor in America was carried out in New York City by Robert F. Weir. The patient died during the immediate postoperative period. Later in the same year in Philadelphia, W.W. Keen also removed a large meningioma; his patient lived many years. In 1886, a Dr. Morse in California had probably performed a partial removal of a glioma from a patient who died shortly after the operation. To celebrate the centennial of Keen's triumph, it is worthwhile as well to contemplate the efforts of his contemporaries.


Inwardly rectifying potassium channels (Kir) in central nervous system glia: a special role for Kir4.1 in glial functions.
Glia in the central nervous system (CNS) express diverse inward rectifying potassium channels (Kir). The major function of Kir is in establishing the high potassium (K+) selectivity of the glial cell membrane and strongly negative resting membrane potential (RMP), which are characteristic physiological properties of glia. The classical property of Kir is that K+ flows inwards when the RMP is negative to the equilibrium potential for K+ (E(K)), but at more positive potentials outward currents are inhibited. This provides the driving force for glial uptake of K+ released during neuronal activity, by the processes of "K+ spatial buffering" and "K+ siphoning", considered a key function of astrocytes, the main glial cell type in the CNS. Glia express multiple Kir channel subtypes, which are likely to have distinct functional roles related to their differences in conductance, and sensitivity to intracellular and extracellular factors, including pH, ATP, G-proteins, neurotransmitters and hormones. A feature of CNS glia is their specific expression of the Kir4.1 subtype, which is a major K+ conductance in glial cell membranes and has a key role in setting the glial RMP. It is proposed that Kir4.1 have a primary function in K+ regulation, both as homomeric channels and as heteromeric channels by co-assembly with Kir5.1 and probably Kir2.0 subtypes. Significantly, Kir4.1 are also expressed by oligodendrocytes, the myelin-forming cells of the CNS, and the genetic ablation of Kir4.1 results in severe hypomyelination. Hence, Kir, and in particular Kir4.1, are key regulators of glial functions, which in turn determine neuronal excitability and axonal conduction.


International academic mobility: the experience of undergraduate nursing students.
To understand/reveal the experiences of undergraduate students of the Nursing School of the Universidade de São Paulo in international academic mobility. A cross-sectional, descriptive study with a qualitative approach conducted between February and July 2017. Data were collected using a semi-structured interview and submitted to content analysis. Twenty-two (22) students participated in the study. Five analytical categories emerged from the analysis of the interviews: Interinstitutional Relationships Dimension, Personal Dimension, Professional Dimension, Academic Dimension and Cultural Dimension. There are many advantages that international mobility can bring to vocational training. Greater governmental and institutional investment is considered necessary, but with mutual planning and monitoring by the institutions in order for it to contribute to the development of Nursing and the Country.


Outcomes in patients with clinical stage III NSGCT who achieve complete clinical response to chemotherapy at extraretroperitoneal disease site.
To compare the survival outcomes of patients with advanced nonseminoma and extraretroperitoneal (ERP) disease observed for a clinical complete response (CCR) with those demonstrating a pathologic complete response (PCR). From 1989 to 2003, 237 patients with clinical Stage III nonseminoma underwent induction chemotherapy followed by retroperitoneal lymph node dissection. After chemotherapy, 107 demonstrated a CCR to treatment at the ERP disease site. Of the remaining 130 patients with radiographic evidence of residual ERP disease, 86 (66%) had fibrosis only on pathologic review (ie, PCR). The probability of progression-free and disease-specific survival was estimated using the Kaplan-Meier method. Cox proportional hazards regression analysis was used to determine the prognostic significance of risk factors for progression and survival. The median follow-up was similar for both CCR and PCR patients (44.5 and 50.7 months, respectively). Overall, the 5-year probability of freedom from progression (93% vs 72%, respectively; P = .0005) and disease-specific survival (96% vs 87%, respectively; P = .08) rates were far better for men with a PCR. The predictors of disease progression included residual retroperitoneal nodal size after chemotherapy (P = .05), and resection of the residual disease at the ERP site was protective (P = .02). A CCR at the ERP disease site is associated with a greater likelihood of relapse compared with a PCR, underscoring the limitations of radiographic imaging after chemotherapy in detecting microscopic residual disease and need for rigorous monitoring of patients observed after a CCR. Furthermore, until more accurate clinical predictors of ERP histologic features are identified, we advocate for complete surgical resection of all sites of residual disease, when feasible.


Studies on a lipoproteinase of group A streptococci.
The opalescence produced in serum by group A streptococci has been investigated. The development of opalescence is shown to be initiated by an enzyme attached to the bacterial cell which acts upon the alpha(1)-lipoprotein fraction of serum liberating the lipids from the protein. This enzyme has been termed a lipoproteinase. Evidence is presented which suggests that the degree of opalescence which develops following lipoproteinase activity is influenced not only by factors attached to the bacterial cell but also by substances present in serum. The lipoproteinase is antigenic and many human sera contain specific antibodies which inhibit the action of the enzyme.


Sulforaphane epigenetically demethylates the CpG sites of the miR-9-3 promoter and reactivates miR-9-3 expression in human lung cancer A549 cells.
Increasing evidence suggests that epigenetic aberrations contribute to the development and progression of cancers such as lung cancer. The promoter region of miR-9-3 was recently found to be hypermethylated in lung cancer, resulting in down-regulation of miR-9-3 and poor patient prognosis. Sulforaphane (SFN), a natural compound that is obtained from cruciferous vegetables, has potent anticancer activities. In this study, we aimed to investigate the effect of SFN on restoring the miR-9-3 level in lung cancer A549 cells through epigenetic regulation. DNA methylation of the miR-9-3 promoter was examined using bisulfite genomic sequencing and methylated DNA immunoprecipitation analysis. The expression levels of miR-9-3 and several epigenetic modifying enzymes were measured using quantitative real-time polymerase chain reaction and Western blotting, respectively. The transcriptional activity of the miR-9-3 promoter was evaluated by patch methylation, and histone modifications were analyzed using chromatin immunoprecipitation (ChIP) assays. We found that CpG methylation was reduced in the miR-9-3 promoter and that miR-9-3 expression was increased after 5 days of treatment with SFN. In vitro methylation analysis showed that the methylated recombinant construct exhibited lower luciferase reporter activity than the unmethylated counterpart. ChIP assays revealed that SFN treatment increased H3K4me1 enrichment at the miR-9-3 promoter. Furthermore, SFN treatment attenuated enzymatic DNMT activity and DNMT3a, HDAC1, HDAC3, HDAC6 and CDH1 protein expression. Taken together, these findings indicate that SFN may exert its chemopreventive effects partly through epigenetic demethylation and restoration of miR-9-3.


Acute chest pain: the role of MR imaging and MR angiography.
MR imaging (MRI) and MR angiography (MRA) have gained a high level of diagnostic accuracy in cardiovascular disease. MRI in cardiac disease has been established as the non-invasive standard of reference in many pathologies. However, in acute chest pain the situation is somewhat special since many of the patients presenting in the emergency department suffer from potentially life-threatening disease including acute coronary syndrome, pulmonary embolism, and acute aortic syndrome. Those patients need a fast and definitive evaluation under continuous monitoring of vital parameters. Due to those requirements MRI seems to be less suitable compared to X-ray coronary angiography and multislice computed tomography angiography (CTA). However, MRI allows for a comprehensive assessment of all clinically stable patients providing unique information on the cardiovascular system including ischemia, inflammation and function. Furthermore, MRI and MRA are considered the method of choice in patients with contraindications to CTA and for regular follow-up in known aortic disease. This review addresses specific features of MRI and MRA for different cardiovascular conditions presenting with acute chest pain.


[Current trends in the treatment and outcome of acute myocardial infarction (MI)].
Current trends in the treatment and outcome of acute myocardial infarction were studied in a trial entering 2411 patients with macrofocal myocardial infarction (MI) treated in 1993-1998. There were many cases of severe and repeated MI. The age of the patients tends to increase. Lethal outcomes' probability is very high in multiple stenosis of the coronary arteries. This condition is associated with a high risk of cardiac insufficiency progression because of inadequate blood supply to necrosis-free myocardial zones. Thrombolytic therapy (TLT), ACE inhibitors reduce lethality but their use is limited by such factors as concurrent diseases, time from MI onset, rethrombosis risk. As a result, only 1/5 of the patients received pharmacological treatment. Balloon angioplasty is indicated in contraindications to TLT, in TLT failure or large residual stenosis. ACE inhibitors slow down the progression of cardiac insufficiency giving time for surgical revascularization. Updated treatment of MI improved its outcomes, but further progress in lowering MI lethality will be insignificant unless efficient methods providing adequate blood supply to the myocardium are introduced.


Exploring Game Dynamics in Padel: Implications for Assessment and Training.
Courel-Ibáñez, J, Sánchez-Alcaraz Martinez, BJ, and Muñoz Marín, D. Exploring game dynamics in padel: implications for assessment and training. J Strength Cond Res 33(7): 1971-1977, 2019-A better understanding of in-game competition demands potentially improved coaching strategy and quality. However, there is very limited information about game patterns in padel, a very modern racket sport born in the 70s. The purpose of this study was therefore to quantify and classify game dynamics during the match in professional padel players through a multivariate decision tree approach including technical, spatial, and effectiveness indicators. The results determined 3 main game styles strongly defined by the court zone (net, middle, and baseline). In addition, particular technical, spatial, and effectiveness indicators were identified in each zone. In net and middle areas (offense) stood the use of volleys and overhead strokes on the center lane to both keep a positional advantage and solve the point. Conversely in the baseline (defense), the use of corner side walls and the domain of lobs showed to be relevant. The high rate of backhand groundstrokes, involving over 4 of 10 actions, is also remarkable. This information may have relevant implications for coaches working in padel by providing a novel hierarchically organization of game dynamics, which helps in designing training and conditioning programs close to real competitive situations.


Systematic review of biological effects of exposure to static electric fields. Part II: Invertebrates and plants.
The construction of high-voltage direct current (HVDC) lines for the long-distance transport of energy is becoming increasingly popular. This has raised public concern about potential environmental impacts of the static electric fields (EF) produced under and near HVDC power lines. As the second part of a comprehensive literature analysis, the aim of this systematic review was to assess the effects of static EF exposure on biological functions in invertebrates and plants and to provide the basis for an environmental impact assessment of such exposures. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was used to guide the methodological conduct and reporting. Thirty-three studies - 14 invertebrate and 19 plant studies - met the eligibility criteria and were included in this review. The reported behavioral responses of insects and planarians upon exposure strongly suggest that invertebrates are able to perceive the presence of a static EF. Many other studies reported effects on physiological functions that were expressed as, for example, altered metabolic activity or delayed reproductive and developmental stages in invertebrates. In plants, leaf damage, alterations in germination rates, growth and yield, or variations in the concentration of essential elements, for example, have been reported. However, these physiological responses and changes in plant morphology appear to be secondary to surface stimulation by the static EF or caused by concomitant parameters of the electrostatic environment. Furthermore, all of the included studies suffered from methodological flaws, which lowered credibility in the results. At field levels encountered from natural sources or HVDC lines (< 35kV/m), the available data provide reliable evidence that static EF can trigger behavioral responses in invertebrates, but they do not provide evidence for adverse effects of static EF on other biological functions in invertebrates and plants. At far higher field levels (> 35kV/m), adverse effects on physiology and morphology, presumably caused by corona-action, appear to be more likely. Higher quality studies are needed to unravel the role of air ions, ozone, nitric oxide and corona current on alterations in physiological functions and morphology.


Positive and negative regulation of transcription by a cleavage product of Ada protein.
The 39,000 Mr Ada protein of Escherichia coli that carries two distinct methyltransferase activities and activity to promote transcription of the ada and the alkA genes is cleaved by a cellular proteinase. As a result, the 20,000 and the 19,000 Mr proteins are formed, which are derived from the N-terminal and the C-terminal halves of the protein, respectively. To elucidate the molecular mechanism of transcriptional control by Ada protein, the N-terminal 20,000 Mr protein was overproduced by manipulating the cloned ada gene. The protein possessed an activity to transfer a methyl group from the methylphosphotriester of the alkylated DNA to its own molecule and retained the potential to promote transcription of the alkA gene. The methylated form of the 20,000 Mr proteins binds to the proper alkA regulatory sequence, as does the intact Ada protein, and facilitates further binding of RNA polymerase to the promoter, thus forming an active transcription initiation complex. The non-methylated 20,000 Mr protein was incapable of binding itself or supporting RNA polymerase binding to the alkA promoter. When the 20,000 Mr protein was produced under the control of the lac promoter in E. coli and then exposed to a methylating agent, a considerable amount of 3-methyladenine-DNA glycosylase II, the product of the alkA gene, was formed. Thus, the results obtained in in vitro experiments were confirmed by the events observed in vivo. The methylated 20,000 Mr protein also binds to the ada promoter; however, it does not facilitate further binding of RNA polymerase to the promoter nor does it promote ada transcription in vitro. These findings indicate that the N-terminal half of Ada protein is mainly responsible for recognition of and binding to alkA and the ada regulatory sequence. The methylated 20,000 Mr protein occupies the same region of the ada promoter to which the intact Ada protein would bind, thereby suggesting that it acts as a repressor for expression of the ada gene. The ada transcription promoted by the Ada protein was greatly inhibited by the methylated, but not the non-methylated, form of the 20,000 Mr protein. In an in vivo system, formation of the 20,000 Mr protein leads to inhibition of transcription from the ada promoter. We suggest that termination of the adaptive response may come about by proteolytic cleavage of the Ada protein, the result being a loss of the activator as well as formation of the repressor for ada transcription.


[Action of the nurse with peripherally inserted central catheter in the newborn infant].
Technological advances in Neonatology have benefited the infant newborn who need a safe venous access. This study aimed at investigating the actions of the nurse regarding Peripherally Inserted Central Catheter (PICC) in the Neonatal Intensive Care Unit in Fortaleza, CE. The sample was composed by 17 nurses; the data were collected from July to August 2004 through a structured questionnaire. In the results, it was verified that 09 nurses reported the basilic vein as the most indicated for puncture; 17 reported the washing the hands before and after handling the catheter and washing it before and after the drug administration as the most important care. It was concluded that handling this device requires knowledge and hability on the part of the professionals.


A rapid in vivo assay system for analyzing the organogenetic capacity of human kidney cells.
Transplantation of human kidney-derived cells is a potential therapeutic modality for promoting regeneration of diseased renal tissue. However, assays that determine the ability of candidate populations for renal cell therapy to undergo appropriate differentiation and morphogenesis are limited. We report here a rapid and humane assay for characterizing tubulogenic potency utilizing the well-established chorioallantoic membrane CAM) of the chick embryo. Adult human kidney-derived cells expanded in monolayer were suspended in Matrigel and grafted onto the CAM. After a week, grafts were assessed histologically. Strikingly, many of the renal cells self-organized into tubular structures. Host blood vessels penetrated and presumably fed the grafts. Immuno- and histochemical staining revealed that tubular structures were epithelial, but not blood vessels. Some of the cells both within and outside the tubules were dividing. Analysis for markers of proximal and distal renal tubules revealed that grafts contained individual cells of a proximal tubular phenotype and many tubules of distal tubule character. Our results demonstrate that the chick CAM is a useful xenograft system for screening for differentiation and morphogenesis in cells with potential use in renal regenerative medicine.


IgA pemphigus foliaceus: a case report.
An 84-year-old male with a 4-week history of vesiculobullous eruptions was diagnosed clinically and pathologically to suffer from pemphigus foliaceus. Amazingly, direct immunofluorescence demonstrated intercellular IgA deposits in the whole epidermis. The patient did not respond to a regimen of fluocortolone and azathioprine but rapidly improved under dapsone. The few reported dermatoses with intraepidermal IgA deposits do not form a homogeneous group. In the following, their spectrum will be outlined. It is important to distinguish these dermatoses from IgG pemphigus, since they require a different therapy.


GABA transporters regulate inhibition in the retina by limiting GABA(C) receptor activation.
Inhibition is mediated by two classes of ionotropic receptors in the retina, GABA(A) and GABA(C) receptors. We used the GABA transport blocker NO-711 to examine the role of GABA transporters in shaping synaptic responses mediated by these two receptors in the salamander retinal slice preparation. Focal applications (puffs) of GABA onto GABA(C) receptors on bipolar cells terminals or GABA(A) receptors on ganglion cells elicited currents that were enhanced by NO-711, demonstrating the presence of transporters in the inner plexiform layer (IPL). IPSCs were evoked in bipolar and ganglion cells by puffing kainate into the IPL. NO-711 enhanced the IPSCs only in bipolar cells, suggesting that, when GABA uptake was blocked, the GABA(C) receptors were more strongly activated by spillover transmission than the GABA(A) receptors on ganglion cells. NO-711 enhanced the light-evoked IPSCs mediated by GABA(C) receptors on bipolar cell axon terminals, which resulted in reduced transmission between bipolar and ganglion cells. NO-711 also shifted the intensity-response relationship of the ganglion cell, reducing its sensitivity to light. Surround illumination has been shown by others to produce similar shifts in ganglion cell light sensitivity. Our results show that GABA transporters limit the extent of inhibitory transmission at the inner retina during light-evoked signal processing.


Coupled waveguide modes in hexagonal photonic crystals.
We investigate the modes of coupled waveguides in a hexagonal photonic crystal. We find that for a substantial parameter range the coupled waveguide modes have dispersion relations exhibiting multiple intersections, which we explain both intuitively and using a rigorous tight-binding argument.


Phage display-derived peptides for osteosarcoma imaging.
Osteosarcoma represents the most common malignant primary bone tumor in childhood; however, the survival rate has remained unchanged for the past 20 years. To improve existing diagnosis and treatment methods and broaden the spectrum of imaging agents that can be used for early detection and assessment of tumor response to therapy, we performed a phage display-based screening for peptide sequences that bind specifically to osteosarcoma cells. From the Ph.D.-12 phage display peptide library composed of 2.7 x 10(9) different displayed peptides, one peptide was enriched after four rounds of in vitro selection in 143B osteosarcoma tumor cells with 293T human embryonic kidney cells as a control. Both the peptide and the phage clone displaying the peptide were conjugated with fluorescent dyes for in vitro cell and ex vivo tumor tissue stainings. The peptide was further labeled with (18)F for positron emission tomography imaging studies. Cell uptake and efflux and ex vivo biodistribution were also done with (18)F-labeled osteosarcoma specific peptide. ASGALSPSRLDT was the dominant sequence isolated from biopanning and named as OSP-1. OSP-1 shares a significant homology with heparinase II/III family protein, which binds and reacts with heparan sulfate proteoglycans. The fluorescence staining showed that FITC-OSP-1-phage or Cy5.5-OSP-1 had high binding with a panel of osteosarcoma cell lines, much less binding with UM-SCC1 human head and neck squamous cell carcinoma cells, and almost no binding with 293T cells, whereas the scrambled peptide OSP-S had virtually no binding to all the cell lines. (18)F-OSP-1 had significantly higher accumulation in 143B tumor cells both in vitro and in vivo than (18)F-OSP-S. (18)F-OSP-1 also had higher uptake in 143B tumors than in UM-SCC-1 tumors. Our data suggest that OSP-1 peptide is osteosarcoma specific, and the binding site of OSP-1 might be related to heparan sulfate proteoglycans. Appropriately labeled OSP-1 peptide has the potential to serve as a novel probe for osteosarcoma imaging.


Evaluation of intensity-modulated electron FLASH radiotherapy in a clinical setting using veterinary cases.
The increased normal tissue tolerance for FLASH radiotherapy (FLASH-RT), as compared to conventional radiotherapy, was first observed in ultra-high dose rate electron beams. Initial clinical trials in companion animals have revealed a high risk of developing osteoradionecrosis following high-dose single-fraction electron FLASH-RT, which may be related to inhomogeneities in the dose distribution. In the current study, we aim to evaluate the possibilities of intensity-modulated electron FLASH-RT in a clinical setting to ensure a homogeneous dose distribution in future veterinary and human clinical trials. Our beam model in the treatment planning system electronRT (.decimal, LLC, Sanford, FL, USA) was based on a 10-MeV electron beam from a clinical linear accelerator used to treat veterinary patients with FLASH-RT in a clinical setting. In electronRT, the beam can be intensity-modulated using tungsten island blocks in the electron block cutout, and range-modulated using a customized bolus with variable thickness. Modulations were first validated in a heterogeneous phantom by comparing measured and calculated dose distributions. To evaluate the impact of intensity modulation in superficial single-fraction FLASH-RT, a treatment planning study was conducted, including eight canine cancer patient cases with simulated tumors in the head-and-neck region. For each case, treatment plans with and without intensity modulation were created for a uniform bolus and a range-modulating bolus. Treatment plans were evaluated using a target dose homogeneity index (HI), a conformity index (CI), the near-maximum dose outside the target ( D 2 % , Body - PTV ${D_{2{\mathrm{\% }},{\mathrm{\ Body}} - {\mathrm{PTV}}}}$ ), and the near-minimum dose to the target ( D 98 % ${D_{98\% }}$ ). By adding intensity modulation to plans with a uniform bolus, the HI could be improved (p = 0.017). The combination of a range-modulating bolus and intensity modulation provided a further significant improvement of the HI as compared to using intensity modulation in combination with a uniform bolus (p = 0.036). The range-modulating bolus also improved the CI compared to using a uniform bolus, both with an open beam (p = 0.046) and with intensity modulation (p = 0.018), as well as increased the D 98 % ${D_{98\% }}$ (p = 0.036 with open beam and p = 0.05 with intensity modulation) and reduced the median D 2 % , Body - PTV ${D_{2\% ,{\mathrm{\ Body}} - {\mathrm{PTV}}}}$ (not significant). By using intensity-modulated electron FLASH-RT in combination with range-modulating bolus, the target dose homogeneity and conformity in canine patients with simulated tumors in complex areas in the head-and-neck region could be improved. By utilizing this technique, we hope to decrease the dose outside the target volume and avoid hot spots in future clinical electron FLASH-RT studies, thereby reducing the risk of radiation-induced toxicity.


Systematic review of low-income and middle-income country perceptions of visiting surgical teams from high-income countries.
The shortage of surgeons, anaesthesiologists and obstetricians in low-income and middle-income countries (LMICs) is occasionally bridged by foreign surgical teams from high-income countries on short-term visits. To advise on ethical guidelines for such activities, the aim of this study was to present LMIC stakeholders' perceptions of visiting surgical teams from high-income countries. We performed a systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines in November 2021, using standardised search terms in PubMed/Medline (National Library of Medicine), EMBASE (Elsevier), Global Health Database (EBSCO) and Global Index Medicus, and complementary hand searches in African Journals Online and Google Scholar. Included studies were analysed thematically using a meta-ethnographic approach. Out of 3867 identified studies, 30 articles from 15 countries were included for analysis. Advantages of visiting surgical teams included alleviating clinical care needs, skills improvement, system-level strengthening, academic and career benefits and broader collaboration opportunities. Disadvantages of visiting surgical teams involved poor quality of care and lack of follow-up, insufficient knowledge transfers, dilemmas of ethics and equity, competition, administrative and financial issues and language barriers. Surgical short-term visits from high-income countries are insufficiently described from the perspective of stakeholders in LMICs, yet such perspectives are essential for quality of care, ethics and equity, skills and knowledge transfer and sustainable health system strengthening. More in-depth studies, particularly of LMIC perceptions, are required to inform further development of ethical guidelines for global surgery and support ethical and sustainable strengthening of LMIC surgical systems.


Evaluation of antibiotic susceptibility in wound infections: A pilot study from Bangladesh.
Introduction: Infections due to antibiotic resistant bacteria have increased alarmingly in both developed and developing countries. Unrestrained and rapidly spreading bacterial growth has turned the management of wound infections into a serious challenge. This study aimed to determine the prevalence of different bacterial pathogens and their antibiotic susceptibility in various types of wound infections. Methods: A cross-sectional study was conducted to collect 105 wound swabs. All isolated bacteria were identified based on colony characteristics, gram stain and standard biochemical tests, and antibiotic susceptibility testing (AST) with the disc diffusion method. Descriptive statistics were used to present the study findings, and all analyses were performed using Stata Version 13. Results: The rate of isolation of bacteria was 92.3%. Staphylococcus aureus was found to be the most frequent isolate (55.7%), followed by Escherichia coli (23.7%), Pseudomonas spp. (8.2%), and Streptococcus pyogenes (7.2%). Gram-positive bacteria were mostly (60%) found sensitive to vancomycin, azithromycin, gentamicin, imipenem, cefixime, and ceftriaxone in this study. Among the Gram-negative bacteria, Escherichia coli (>60%) showed sensitivity to cefixime, azithromycin, cefuroxime, ceftriaxone, cefotaxime, gentamycin, and ceftazidime. Conclusions: The diversity of isolated bacteria and their susceptibility patterns signify a need to implement a proper infection control strategy, which can be achieved by carrying out antibiotic sensitivity tests of the isolates.


Requirements for the import of neisserial Omp85 into the outer membrane of human mitochondria.
β-Barrel proteins are present only in the outer membranes of Gram-negative bacteria, chloroplasts and mitochondria. Fungal mitochondria were shown to readily import and assemble bacterial β-barrel proteins, but human mitochondria exhibit certain selectivity. Whereas enterobacterial β-barrel proteins are not imported, neisserial ones are. Of those, solely neisserial Omp85 is integrated into the outer membrane of mitochondria. In this study, we wanted to identify the signal that targets neisserial β-barrel proteins to mitochondria. We exchanged parts of neisserial Omp85 and PorB with their Escherichia coli homologues BamA and OmpC. For PorB, we could show that its C-terminal quarter can direct OmpC to mitochondria. In the case of Omp85, we could identify several amino acids of the C-terminal β-sorting signal as crucial for mitochondrial targeting. Additionally, we found that at least two POTRA (polypeptide-transport associated) domains and not only the β-sorting signal of Omp85 are needed for its membrane integration and function in human mitochondria. We conclude that the signal that directs neisserial β-barrel proteins to mitochondria is not conserved between these proteins. Furthermore, a linear mitochondrial targeting signal probably does not exist. It is possible that the secondary structure of β-barrel proteins plays a role in directing these proteins to mitochondria.


Patient reported outcomes in the assessment of premature ejaculation.
The term 'Patient Reported Outcome', abbreviated as PRO, was introduced by the US Food and Drug Administration (FDA) which proposed guidance on the development and validation of PROs. Previously PROs were known as self-report diaries, event-logs, self-administered questionnaires, and clinician administered rating scales. PROs seek to capture the subjective perceptions of patients and/or partner's related to their specific symptoms, degree of bother, efficacy of a medication or psychotherapy intervention, and quality of life issues related to a specific condition. This article reviews the essential psychometric and regulatory agency requirements in the development of PROs. The constructs of reliability, various forms of validity, sensitivity, and specificity as well as concerns with translating a PRO into a different language are reviewed. Three PROs, the Premature Ejaculation Profile (PEP), the Index of Premature Ejaculation (IPE) and the Premature Ejaculation Diagnostic Tool (PEDT) all used in the assessment of premature ejaculation (PE) are discussed. These questionnaires meet or exceed all the psychometric requirements and have been employed in clinical trials and observational studies of men with PE. The article concludes on discussing some of the limitations of PRO use and recommendations for the future.


Participatory model building for suicide prevention in Canada.
Suicide is a behaviour that results from a complex interplay of factors, including biological, psychological, social, cultural, and environmental factors, among others. A participatory model building workshop was conducted with fifteen employees working in suicide prevention at a federal public health organization to develop a conceptual model illustrating the interconnections between such factors. Through this process, knowledge emerged from participants and consensus building occurred, leading to the development of a conceptual model that is useful to organize and communicate the complex interrelationships between factors related to suicide. A model building script was developed for the facilitators to lead the participants through a series of group and individual activities that were designed to elicit participants' implicit models of risk and protective factors for suicide in Canada. Participants were divided into three groups and tasked with drawing the relationships between factors associated with suicide over a simplified suicide process model. Participants were also tasked with listing prevention levers that are in use in Canada and/or described in the scientific literature. Through the workshop, risk and prevention factors and prevention levers were listed and a conceptual model was drafted. Several "lessons learned" which could improve future workshops were generated through reflection on the process. This workshop yielded a helpful conceptual model contextualising upstream factors that can be used to better understand suicide prevention efforts in Canada.


Lake-depth related pattern of genetic and morphological diatom diversity in boreal Lake Bolshoe Toko, Eastern Siberia.
Large, old and heterogenous lake systems are valuable sources of biodiversity. The analysis of current spatial variability within such lakes increases our understanding of the origin and establishment of biodiversity. The environmental sensitivity and the high taxonomic richness of diatoms make them ideal organisms to investigate intra-lake variability. We investigated modern intra-lake diatom diversity in the large and old sub-arctic Lake Bolshoe Toko in Siberia. Our study uses diatom-specific metabarcoding, applying a short rbcL marker combined with next-generation sequencing and morphological identification to analyse the diatom diversity in modern sediment samples of 17 intra-lake sites. We analysed abundance-based compositional taxonomic diversity and generic phylogenetic diversity to investigate the relationship of diatom diversity changes with water depth. The two approaches show differences in taxonomic identification and alpha diversity, revealing a generally higher diversity with the genetic approach. With respect to beta diversity and ordination analyses, both approaches result in similar patterns. Water depth or related lake environmental conditions are significant factors influencing intra-lake diatom patterns, showing many significant negative correlations between alpha and beta diversity and water depth. Further, one near-shore and two lagoon lake sites characterized by low (0-10m) and medium (10-30m) water depth are unusual with unique taxonomic compositions. At deeper (>30m) water sites we identified strongest phylogenetic clustering in Aulacoseira, but generally much less in Staurosira, which supports that water depth is a strong environmental filter on the Aulacoseira communities. Our study demonstrates the utility of combining analyses of genetic and morphological as well as phylogenetic diversity to decipher compositional and generic phylogenetic patterns, which are relevant in understanding intra-lake heterogeneity as a source of biodiversity in the sub-arctic glacial Lake Bolshoe Toko.


Synergy of sulbactam and ampicillin against methicillin-resistant staphylococci.
Methicillin resistance in staphylococci is an increasing problem both for Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE), which cause infections of the heart and after central nervous system surgery. Resistance seems to be due primarily to production of altered penicillin-binding proteins. The present study determined whether a combination of beta-lactamase inhibitor sulbactam and ampicillin or sulbactam and cefazolin would inhibit MRSA and MRSE. Sulbactam, ampicillin and cefazolin at 32 micrograms/ml did not inhibit MRSA or MRSE. At 8 micrograms/ml of each agent all isolates were inhibited. Synergy of sulbactam and ampicillin could be demonstrated against MRSA by the agar fixed ratio method, checkerboard dilution and by killing curves. This suggests that in certain situations MRSA and MRSE may be effectively eliminated by this method.


Use of polymorphic DNA probes to test the lymph nodes of infants and fetuses for spontaneous chimerism.
Spontaneous chimerism is rare, but it has been observed in infants who have received intrauterine transfusions, or in those infants who have severe combined immunodeficiency disease. The site of maternal cell engraftment has not been identified in these cases, but it is apparently not the bone marrow. Lymph nodes have not been investigated. Based on recent experimental data that showed that foreign cells grow in the lymph nodes, but not in the marrows of perinatally inoculated mice, the decision was made to use highly specific polymorphic DNA probes to assay for the presence of maternal DNA in the nodes that were removed from three infants and two fetuses. No evidence for the engraftment of maternal cells was detected at a 5% level of sensitivity. These results were in accord with findings from previous work that has shown that the placenta and host-resistance mechanisms combine to make spontaneous chimerism a rare event. The results also showed that similar tests for maternal cell engraftment in lymph nodes and other sites, not previously evaluated, are feasible and perhaps indicated in infants with congenital and acquired immunodeficiencies, such as severe combined immunodeficiency disease and acquired immunodeficiency syndrome.


Longitudinal study of the relationship between coffee consumption and type 2 diabetes in Chinese adult residents: Data from China Health and Nutrition Survey.
Increasing coffee intake was inversely associated with risk of type 2 diabetes in Western countries. However, in China where coffee consumption and diabetes population has been growing fast in recent years, studies on the impact of coffee intakes on the onset of type 2 diabetes are lacking. This study attempts to determine the associations between coffee consumption and type 2 diabetes in Chinese adults. This longitudinal study analyzed 10447 adults who had participated in at least two rounds of the China Health and Nutrition Survey (CHNS), which is a survey database of multistage, random cluster process during 1993-2011. Coffee consumption and type 2 diabetes incidence were measured in the survey. Body mass index (BMI), age, sex, place of residence, waves, education level, smoking, drinking alcohol and tea drinking frequency were adjusted as covariate. We used longitudinal fixed effects regression models to assess changes within person. After adjusting confounding factors, lower risk of diabetes is observed among Chinese adults who drink coffee occasionally (Adjusted Odds Ratio (AOR) = 0.13, 95% CI = 0.05, 0.34) and drink almost every day (AOR = 0.61, 95% CI = 0.45, 0.83), compared with those who do not or hardly drink. In the subgroup analysis, among women aged 45-59 who drink coffee one to three times a week (AOR = 0.21, 95% CI = 0.08, 0.52) and men over 60 who drink coffee almost every day (AOR = 0.19, 95% CI = 0.07, 0.53), protective effects were found. For young men aged 19-29, drinking coffee almost every day showed a risk effect (AOR = 20.21, 95% CI = 5.96-68.57). Coffee drinking habit is an independent protective factor for adult on type 2 diabetes in China. And it varies among people with different ages and genders. The rapid growth of coffee consumption in China in recent years may help reduce the risk of type 2 diabetes, but at the same time, the risk of type 2 diabetes in adolescents needs attention.