Anticholinergic drugs versus non-drug active therapies for non-neurogenic overactive bladder syndrome in adults.
Overactive bladder syndrome is defined as urgency with or without urgency incontinence, usually with frequency and nocturia. Pharmacotherapy with anticholinergic drugs is often the first line medical therapy, either alone or as an adjunct to various non-pharmacological therapies after conservative options such as reducing intake of caffeine drinks have been tried. Non-pharmacologic therapies consist of bladder training, pelvic floor muscle training with or without biofeedback, behavioural modification, electrical stimulation and surgical interventions. To compare the effects of anticholinergic drugs with various non-pharmacologic therapies for non-neurogenic overactive bladder syndrome in adults. We searched the Cochrane Incontinence Group Specialised Register (searched 4 September 2012), which includes searches of the Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE, and the reference lists of relevant articles. All randomised or quasi-randomised, controlled trials of treatment with anticholinergic drugs for overactive bladder syndrome or urgency urinary incontinence in adults in which at least one management arm involved a non-drug therapy. Trials amongst patients with neurogenic bladder dysfunction were excluded. Two authors evaluated the trials for appropriateness for inclusion and risk of bias. Two authors were involved in the data extraction. Data extraction was based on predetermined criteria. Data analysis was based on standard statistical approaches used in Cochrane reviews. Twenty three trials were included with a total of 3685 participants, one was a cross-over trial and the other 22 were parallel group trials. The duration of follow up varied from two to 52 weeks. The trials were generally small and of poor methodological quality. During treatment, symptomatic improvement was more common amongst those participants on anticholinergic drugs compared with bladder training in seven small trials (73/174, 42% versus 98/172, 57% not improved: risk ratio 0.74, 95% confidence interval 0.61 to 0.91). Augmentation of bladder training with anticholinergics was also associated with more improvements than bladder training alone in three small trials (23/85, 27% versus 37/79, 47% not improved: risk ratio 0.57, 95% confidence interval 0.38 to 0.88). However, it was less clear whether an anticholinergic combined with bladder training was better than the anticholinergic alone, in three trials (for example 74/296, 25% versus 95/306, 31% not improved: risk ratio 0.80, 95% confidence interval 0.62 to 1.04). The other information on whether combining behavioural modification strategies with an anticholinergic was better than the anticholinergic alone was scanty and inconclusive. Similarly, it was unclear whether these complex strategies alone were better than anticholinergics alone.In this review, seven small trials comparing an anticholinergic to various types of electrical stimulation modalities such as Intravaginal Electrical Stimulation (IES), transcutaneous electrical nerve stimulation (TENS), the Stoller Afferent Nerve Stimulation System (SANS) neuromodulation and percutaneous posterior tibial nerve stimulation (PTNS) were identified. Subjective improvement rates tended to favour the electrical stimulation group in three small trials (54% not improved with the anticholinergic versus 28/86, 33% with electrical stimulation: risk ratio 0.64, 95% confidence interval 1.15 to 2.34). However, this was statistically significant only for one type of stimulation, percutaneous posterior tibial nerve stimulation (risk ratio 2.21, 95% confidence interval 1.13 to 4.33), and was not supported by significant differences in improvement, urinary frequency, urgency, nocturia, incontinence episodes or quality of life.The most commonly reported adverse effect among anticholinergics was dry mouth, although this did not necessarily result in withdrawal from treatment. For all comparisons there were too few data to compare symptoms or side effects after treatment had ended. However, it is unlikely that the effects of anticholinergics persist after stopping treatment. The use of anticholinergic drugs in the management of overactive bladder syndrome is well established when compared to placebo treatment. During initial treatment of overactive bladder syndrome there was more symptomatic improvement when (a) anticholinergics were compared with bladder training alone, and (b) anticholinergics combined with bladder training were compared with bladder training alone. Limited evidence from small trials might suggest electrical stimulation is a better option in patients who are refractory to anticholinergic therapy, but more evidence comparing individual types of electrostimulation to the most effective types of anticholinergics is required to establish this. These results should be viewed with caution in view of the different classes and varying doses of individual anticholinergics used in this review. Anticholinergics had well recognised side effects, such as dry mouth.


Adventures in the pathophysiology of brain ischemia: penumbra, gene expression, neuroprotection: the 2002 Thomas Willis Lecture.
The pathophysiology of cerebral ischemia is well studied in small-animal models, which offer reproducibility and control of confounding variables-factors essential to hypothesis-testing. This presentation first highlights insights into the ischemic penumbra enabled by a multimodal experimental approach; second, discusses gene expression in ischemia; and third, confronts the challenges of neuroprotectant therapy. The ischemic penumbra: Transient (2-hour) middle cerebral artery suture-occlusion in anesthetized rats gives rise to highly consistent neurological and histopathological sequelae. Autoradiographic local cerebral blood flow (LCBF) studies at 2 hours of occlusion define the penumbra as a region of intermediate CBF depression (20% to 40% of control) surrounding the densely ischemic core (5% to 20% of control) and constituting one half of the entire lesion. Local glucose metabolic rate in the acute penumbra is not reduced despite the critical CBF reduction, so that the penumbral metabolism/blood flow ratio is markedly elevated. In contrast, following 1 hour of recirculation, glucose metabolism throughout the previously ischemic hemisphere has become markedly depressed, and the metabolism/flow ratio has pseudonormalized. By correlating these data with histopathology using multimodal image analysis, the probability of infarction is shown to be highly determined by the degree of antecedent CBF reduction. These animal data agree strikingly with published results in patients with acute stroke studied by positron emission tomography. This remarkable correspondence belies the assertion that data from lower species may not be relevant to human stroke. Gene expression: Perfusion gradients also determine differential patterns of gene expression in ischemia. This can be demonstrated by correlating in situ hybridization autoradiographs for gene expression with autoradiographic LCBF data and histological infarct maps derived from replicate series. In other studies, DNA microarray technology is used to screen for thousands of expressed genes. In the 2-hour middle cerebral artery occlusion model with 3-hour recirculation, we have identified 28 known ischemia-hypoxia response genes that are upregulated and 6 that are downregulated, together with 35 upregulated and 41 downregulated genes newly connected with ischemia. These findings underscore the enormous complexity of ischemic biology and suggest possible novel mechanisms for future exploration. NEUROPROTECTION: A desirable neuroprotectant would, in theory, antagonize multiple injury mechanisms. We have explored 2 such therapies of particular promise. Mild brain hypothermia (32 degrees C target temperature, for 5 hours) is highly neuroprotective even when initiated at the onset of recirculation. Another highly protective agent is human albumin, administered in doses of 1.25 to 2.5 g/kg--a therapy that reduces infarct volume in this ischemia model by 60% to 65%, markedly diminishes brain swelling, and has a therapeutic window extending to 4 hours. The careful study of rodent ischemia models can yield valuable, clinically relevant insights into the pathophysiology of ischemic stroke.


Inflammation and chemerin in colorectal cancer.
Chemerin is expressed mainly in the adipose tissue. It is an agonist of chemokine-like receptor-1, which is expressed by the immune system cells. Chemerin stimulates the chemotaxis of the immune system cells, and this indicates the function of chemerin and chemokine-like receptor-1 in the immune response. The tumor microenvironment is very important for determining cancer cell growth and spreading. Therefore, we aimed to investigate the association between colorectal cancer, inflammation, and adipokines including chemerin, adiponectin, and vaspin. The study group consisted of patients with colon cancer, whereas the control subjects consisted of patients with benign conditions, diagnosed with colonoscopy. The two groups were compared in terms of the C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, adiponectin, chemerin, and vaspin. A total of 41 (28 men, 13 women) patients with confirmed colon cancer, and 27 (15 men, 12 women) controls without, confirmed by colonoscopy, were enrolled. The median chemerin levels were found significantly higher in the study group than the controls (390 vs. 340 ng/mL, p = 0.032), whereas the mean vaspin and adiponectin levels were not significantly different. The median values for the CRP, fibrinogen, and ESR were significantly higher in the patients with colon cancer, when compared to the control group (6.08 vs. 1.4 mg/L, p < 0.0001; 408 vs. 359 mg/dL, p = 0.002; and 30 vs. 8 mm/h, p < 0.0001, respectively). Our results show that higher levels of circulating chemerin, CRP, fibrinogen, and ESR are associated with an increased risk of developing colorectal cancer.


Humpback whale populations share a core skin bacterial community: towards a health index for marine mammals?
Microbes are now well regarded for their important role in mammalian health. The microbiology of skin--a unique interface between the host and environment--is a major research focus in human health and skin disorders, but is less explored in other mammals. Here, we report on a cross-population study of the skin-associated bacterial community of humpback whales (Megaptera novaeangliae), and examine the potential for a core bacterial community and its variability with host (endogenous) or geographic/environmental (exogenous) specific factors. Skin biopsies or freshly sloughed skin from 56 individuals were sampled from populations in the North Atlantic, North Pacific and South Pacific oceans and bacteria were characterized using 454 pyrosequencing of SSU rRNA genes. Phylogenetic and statistical analyses revealed the ubiquity and abundance of bacteria belonging to the Flavobacteria genus Tenacibaculum and the Gammaproteobacteria genus Psychrobacter across the whale populations. Scanning electron microscopy of skin indicated that microbial cells colonize the skin surface. Despite the ubiquity of Tenacibaculum and Psychrobater spp., the relative composition of the skin-bacterial community differed significantly by geographic area as well as metabolic state of the animals (feeding versus starving during migration and breeding), suggesting that both exogenous and endogenous factors may play a role in influencing the skin-bacteria. Further, characteristics of the skin bacterial community from these free-swimming individuals were assembled and compared to two entangled and three dead individuals, revealing a decrease in the central or core bacterial community members (Tenacibaculum and Psychrobater spp.), as well as the emergence of potential pathogens in the latter cases. This is the first discovery of a cross-population, shared skin bacterial community. This research suggests that the skin bacteria may be connected to humpback health and immunity and could possibly serve as a useful index for health and skin disorder monitoring of threatened and endangered marine mammals.


Marine water quality assessment at Mumbai West Coast.
In recent past, Mumbai Municipal corporation was not able to keep pace with required infrastructural facilities due to unprecedented population growth. Sewage disposal is one of the major issues, which needed immediate attention because huge quantity of sewage with only preliminary treatment is disposed into the nearby coastal areas and has deteriorated the water quality of the near coastal region. World Bank assisted Bombay Sewage Disposal Project (BSDP) undertaken by the Municipal Corporation of Bruhan Mumbai (MCBM) envisaged sewage discharges through marine outfalls at Worli and Bandra and treatment by aerated lagoons for other areas before disposal in creeks. During BSDP programme, studies were undertaken on water quality assessment along the west coast of Mumbai before and after commissioning of the Worli outfall. A pre- and post-commissioning water quality database for selected parameters was generated for near shore as well as west coast region up to 5 km seaward distance to assess the efficacy of the Worli outfall and delineate the areas affected around diffuser location of the outfall due to sewage disposal. This paper presents observations of the coastal studies at Mumbai and the impact zone of Worli outfall.


Study of hybrid membrane filtration and photocatalysis for removal of perfluorooctanoic acid (PFOA) in groundwater.
Groundwater contamination in Thailand from leaking of leachate due to improper solid waste disposal can cause contamination by PFOA (one of the perfluorinated compounds). This study proposed a new idea for the removal of PFOA from groundwater using a combination of membrane filtration and photocatalysis. Spiked groundwater samples were treated by nanofiltration and the rejected part was sent to a UV contact tank for photocatalysis. All samples were analyzed by high-performance liquid chromatography-tandem mass spectrometer (HPLC-MS/MS). The results showed that the removal efficiency of nanofiltration was 99.62%, and the rejected part was degraded by photocatalysis at an efficiency of 59.64%. Thus, the contaminants released to the environment were only 34.23%, which is around three times lower than nanofiltration alone. The results of this technical feasibility study proved that hybrid membrane filtration and photocatalysis are able to remove and degrade the contaminants in the rejected part significantly before being released to the environment, which has been the biggest gap in the processing of membrane filtration, and should be studied further in other aspects, such as fouling effects, energy consumption, and operating costs in a long-term pilot run.


Changes in plasma renin activity and blood pressure after acute and chronic administration of beta-adrenergic receptor-blocking drugs.
1. Prindolol and propranolol chronically cause a fall in mean blood pressure and mean plasma renin activity, but no correlation was observed between the two variables. 2. The response of blood pressure to prindolol and propranolol was not predicted by the basal plasma renin activity. 3. Propranolol administered acutely caused the plasma renin activity to fall with no acute change in blood pressure, whereas prindolol caused the blood pressure to fall with no change in plasma renin activity. 4. The effects of beta-adrenergic-blocking drugs on plasma renin activity and blood pressure can be dissociated and it is unlikely that their hypotensive action is mediated through the renin-angiotensin system. 5. Basal plasma renin activity does not identify the patients who will respond to beta-adrenergic-blocking drugs.


Reflecting the relative values of community, faculty, and students in the admissions tools of medical school.
In defining the characteristics of medical students that society and the medical profession find desirable, little effort has been spent assessing the relative value of the dozens of characteristics that have been identified. Furthermore, many institutions go to great lengths to ensure equal representation across stakeholder groups in an effort to maximize the heterogeneity of the pool of students accepted to study medicine; however, the extent to which different stakeholders value different characteristics has yet to be determined. This study was an attempt to assess the relative value of the characteristics of medical students that society and the medical profession find desirable. Using documents created internationally to identify the core competencies of medical personnel, a series of 7 characteristics were generated for inclusion in a study that adopted the paired comparison technique. Of 347 surveyed, 292 respondents indicated the rank ordering they would assign to each characteristic by circling the more important characteristic in all possible pairings. Overwhelmingly, "ethical" was deemed to be the most important characteristic on which selection tools should be based. Surprisingly, the pattern of responses was highly consistent regardless of stakeholder group and degree of affiliation with the undergraduate medical program. The generalizable features of this study not only include the empirical findings but also demonstrate useful survey protocol that can be adapted by any admission committee to guide the generation of an institution-specific admissions blueprint. A novel protocol that provides the necessary flexibility is discussed.


Market forces affect patterns of polygyny in Uganda.
Polygynous marriage is generally more beneficial for men than it is for women, although women may choose to marry an already-married man if he is the best alternative available. We use the theory of biological markets to predict that the likelihood of a man marrying polygynously will be a function of the level of resources that he has, the local sex ratio, and the resources that other men in the local population have. Using records of more than 1 million men in 56 districts from the 2002 Ugandan census, we show that polygynously married men are more likely to own land than monogamously married men, that polygynous marriages become more common as the district sex ratio becomes more female biased, that owning land is particularly important when men are abundant in the district, and that a man's owning land most increases the odds of polygyny in districts where few other men own land. Results are discussed with reference to models of the evolution of polygyny.


Role of cytokines in the pathogenesis and suppression of thyroid autoimmunity.
Autoimmune thyroid diseases (AITD) are one of the most common organ-specific autoimmune disorders, of which Hashimoto's thyroiditis (HT) and Graves' disease (GD) are 2 of the most common clinical expressions. HT is characterized by hypothyroidism that results from the destruction of the thyroid by thyroglobulin-specific T cell-mediated autoimmune response. In contrast, GD is characterized by hyperthyroidism due to excessive production of thyroid hormone induced by thyrotropin receptor-specific stimulatory autoantibodies. Cytokines play a crucial role in modulating immune responses that affect the balance between maintenance of self-tolerance and initiation of autoimmunity. However, the role of cytokines is often confusing and is neither independent nor exclusive of other immune mediators. A regulatory cytokine may either favor induction of tolerance against thyroid autoimmune disease or favor activation and/or exacerbation of autoimmune responses. These apparently contradictory functions of a given cytokine are primarily influenced by the nature of co-signaling delivered by other cytokines. Consequently, a thorough understanding of the role of a particular cytokine in the context of a specific immune response is essential for the development of appropriate strategies to modulate cytokine responses to maintain or restore health. This review provides a summary of recent research pertaining to the role of cytokines in the pathogenesis of AITD with a particular emphasis on the therapeutic applications of cytokine modulation.


Sequence diversity in genes of lipid metabolism.
Elevated plasma lipoprotein levels play a crucial role in the development of coronary artery disease. Genetic factors strongly influence the levels of plasma lipoproteins, but the genes and sequence variations contributing to the most common forms of dyslipidemias are not known. We used GeneChip probe arrays to resequence the coding regions of 10 key genes of lipid metabolism. The sequences of these genes were analyzed in 80 dyslipidemic individuals. Fourteen nonsynonymous and twenty-two synonymous single nucleotide changes were identified that could be confirmed by conventional sequencing. Seven of the fourteen nonsynonymous sequence variants were polymorphisms with allele frequency >1% in the general population. The remaining seven were not found in normolipidemic controls (25 Caucasians and 25 African-Americans). The relationship between nonsynonymous sequence variations and various dyslipidemias was explored in association and family studies. No evidence was found for coding sequence variations in any of the 10 genes contributing to dyslipidemia. Only a single sequence variation, a missense mutation in the low density lipoprotein receptor gene, co-segregated with hyperlipidemia in the proband's family. This study illustrates some of the difficulties associated with identifying sequence variations contributing to complex traits.


Use of rigid and flexible bronchoscopy among pediatric otolaryngologists.
To explore how rigid and flexible bronchoscopy are used in pediatric otolaryngologic practice. Survey. Members of the American Society of Pediatric Otolaryngology who practice in the United States and Canada and were listed in the membership directory were eligible. Of the 206 members, 24 practicing outside the United States or Canada and 11 without an e-mail address or a fax machine were excluded. Hence, a questionnaire was e-mailed or faxed to 171 pediatric otolaryngologists. Questions concerned the practice setting, type and number of bronchoscopies, indications, complications, and medicolegal cases. Responses were received from 120 subjects (70.2%), with 3 retired and 2 practicing only otology, leaving 115 respondents who completed at least some of the questionnaire. Rigid and flexible bronchoscopy were performed by 72.7% (56/77) of those in academic settings and by 71.1% (27/38) of those in group or solo practices. In the last 12 months, approximately 10 454 total bronchoscopies were performed, with 2052 flexible and 9117 rigid bronchoscopies. Stridor, suspected foreign body inhalation, and laryngomalacia were the most common indications for bronchoscopy. Of the 83 respondents practicing rigid and flexible bronchoscopy, 25 (30.1%) used both instruments to manage complex or repeated foreign bodies, 25 (30.1%) used both to manage patients with cystic fibrosis, and 15 (18.1%) used both to manage simple foreign bodies. Complications were reported by 15.7% of the respondents, the most common being arrhythmia. Familiarity with a case resulting in medicolegal action was reported by 32.2% of the respondents. Rigid and flexible bronchoscopy have multiple uses in pediatric otolaryngologic practice. Also, flexible bronchoscopy appears to be emerging as a more frequently used diagnostic and therapeutic tool.


Recombinant coagulation factor VIIa for rapid preoperative correction of warfarin-related coagulopathy in patients with acute subdural hematoma.
Intracranial hemorrhage, either spontaneous or traumatic is a well-known and potentially lethal complication of Warfarin treatment. Patients with Warfarin-related intracranial hemorrhage need urgent reversal of anticoagulation that must be especially rapid if surgical intervention is indicated. The traditional treatment with fresh frozen plasma (FFP) and vitamin K often fails to achieve the desired correction of coagulopathy in urgent neurosurgical settings. In the present case Recombinant Coagulation Factor VIIa (rFVIIa) was used for preoperative reversal of Warfarin-related coagulopathy. The patient was a fifty two years old man, mechanic valve recipient with Warfarin-induced coagulopathy: International Normalization Ratio (INR) of 6.39, who suffered from acute subdural hematoma and needed urgent neurosurgical intervention. He received a single dose of rFVIIa 120 mg/kg and immediately underwent craniotomy and evacuation of the hematoma. Appropriate hemostasis was achieved during surgery and coagulation test taken two hours after rFVIIa injection revealed INR of 1.25. The INR remained normalized for additional 14 hours. To the best of our knowledge, this is the first report on the use of rFVIIa in the preoperative management of Warfarin-induced intracranial hemorrhage. Recombinant Coagulation Factor VIIa provides rapid correction of coagulation to a level that allows safe neurosurgical intervention without significant delay. This agent is safe and effective; and should be considered for reversal of Warfarin-induced coagulopathy in cases of intracranial hemorrhage, especially when urgent surgical intervention is required.


Does caregiving cause psychological distress? The case for familial and genetic vulnerabilities in female twins.
Informal caregiving can be deleterious to mental health, but research results are inconsistent and may reflect an interaction between caregiving and vulnerability to stress. We examined psychological distress among 1,228 female caregiving and non-caregiving twins. By examining monozygotic and dizygotic twin pairs discordant for caregiving, we assessed the extent to which distress is directly related to caregiving or confounded by common genes and environmental exposures. Caregiving was associated with distress as measured by mental health functioning, anxiety, perceived stress, and depression. The overall association between caregiving and distress was confounded by common genes and environment for mental health functioning, anxiety, and depression. Common environment also confounded the association of caregiving and perceived stress. Vulnerability to distress is a factor in predicting caregivers' psychosocial functioning. Additional research is needed to explicate the mechanisms by which common genes and environment increase the risk of distress among informal caregivers.


Temporal dynamics of motor cortex excitability during perception of natural emotional scenes.
Although it is widely assumed that emotions prime the body for action, the effects of visual perception of natural emotional scenes on the temporal dynamics of the human motor system have scarcely been investigated. Here, we used single-pulse transcranial magnetic stimulation (TMS) to assess motor excitability during observation and categorization of positive, neutral and negative pictures from the International Affective Picture System database. Motor-evoked potentials (MEPs) from TMS of the left motor cortex were recorded from hand muscles, at 150 and 300 ms after picture onset. In the early temporal condition we found an increase in hand motor excitability that was specific for the perception of negative pictures. This early negative bias was predicted by interindividual differences in the disposition to experience aversive feelings (personal distress) in interpersonal emotional contexts. In the later temporal condition, we found that MEPs were similarly increased for both positive and negative pictures, suggesting an increased reactivity to emotionally arousing scenes. By highlighting the temporal course of motor excitability during perception of emotional pictures, our study provides direct neurophysiological support for the evolutionary notions that emotion perception is closely linked to action systems and that emotionally negative events require motor reactions to be more urgently mobilized.


"Goalkeeper's hip": acute haematogenous osteomyelitis secondary to apophyseal fractures.
We report two cases of acute haematogenous osteomyelitis in the anterior superior iliac spine (ASIS) in adolescent goalkeepers following trauma of the iliac crest apophysis. Both patients complained of pain over their right ASIS and were pyrexial. They were given antibiotics and were discharged from follow up without complication 64 and 90 days after starting treatment.


Microfluidic electroporation for cellular analysis and delivery.
Electroporation is a simple yet powerful technique for breaching the cell membrane barrier. The applications of electroporation can be generally divided into two categories: the release of intracellular proteins, nucleic acids and other metabolites for analysis and the delivery of exogenous reagents such as genes, drugs and nanoparticles with therapeutic purposes or for cellular manipulation. In this review, we go over the basic physics associated with cell electroporation and highlight recent technological advances on microfluidic platforms for conducting electroporation. Within the context of its working mechanism, we summarize the accumulated knowledge on how the parameters of electroporation affect its performance for various tasks. We discuss various strategies and designs for conducting electroporation at the microscale and then focus on analysis of intracellular contents and delivery of exogenous agents as two major applications of the technique. Finally, an outlook for future applications of microfluidic electroporation in increasingly diverse utilities is presented.


Simultaneous measurement of group refractive index and thickness of optical samples using optical coherence tomography.
Optical coherence tomography (OCT), based on a Michelson interferometer and utilizing low coherence light as the optical source, is a novel technique for the noninvasive imaging of optical scattering media. A simple OCT scheme based on a 3 x 3 fiber coupler is presented for the simultaneous measurement of the refractive index and thickness of optical samples. The proposed system enables the refractive index and thickness to be determined without any prior knowledge of the sample parameters and is characterized by a simple and compact configuration, a straightforward measurement procedure, and a low cost. The feasibility of the proposed approach is demonstrated experimentally using BK7 and B270 optical glass samples.


A Modified Chromogenic Assay for Determination of the Ratio of Free Intracellular NAD+/NADH in Streptococcus mutans.
Nicotinamide adenine dinucleotide is a coenzyme present in all kingdoms of life and exists in two forms: oxidized (NAD+) and reduced (NADH). NAD(H) is involved in a multitude of essential metabolic redox reactions, providing oxidizing or reducing equivalents. The ratio of free intracellular NAD+/NADH is fundamentally important in the maintenance of cellular redox homeostasis (Ying, 2008). Various chromogenic cycling assays have been used to determine the ratio of NAD+/NADH in both bacterial and mammalian cells for more than forty years (Bernofsky and Swan, 1973; Nisselbaum and Green, 1969). Here, we describe in detail an assay to determine the ratio of free intracellular NAD+ to NADH in Streptococcus mutans. This cycling assay is a modified version of the protocol first described by Bernofsky and Swan (Bernofsky and Swan, 1973), using the extraction buffer described by Frezza et al. (2011), followed by the reduced MTT precipitation described by Gibbon and Larher (Gibon and Larher, 1997). As depicted in Figure 1, alcohol dehydrogenase is used to drive a series of redox reactions utilizing exogenously added ethanol and NAD+ from sample extracts as initial substrates, phenazine ethosulfate (PES) as an electron carrier, and thiazolyl blue tetrazolium bromide (MTT) as a terminal electron acceptor. 6 M NaCl is used to stop the reaction. The reduced MTT (formazan dye) is purple in color and can be quantified by measuring absorbance at 570 nm. This protocol is divided into three steps: A. Preparation of cell pellets of S. mutans; B. Preparation of deproteinated cell extracts containing NADtotal or NADH; C. NAD+/NADH cycling assay. This method has proven robust in measuring the NAD+/NADH ratio in S. mutans under a variety of conditions, and should be applicable to other Gram-positive bacteria.


Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level.
Antigen-specific T cell immunity is HLA-restricted. Human immunodeficiency virus-type 1 (HIV-1) mutations that allow escape from host immune responses may therefore be HLA allele-specific. We analyzed HIV-1 reverse transcriptase sequences from a large HLA-diverse population of HIV-1-infected individuals. Polymorphisms in HIV-1 were most evident at sites of least functional or structural constraint and frequently were associated with particular host HLA class I alleles. Absence of polymorphism was also HLA allele-specific. At a population level, the degree of HLA-associated selection in viral sequence was predictive of viral load. These results support a fundamental role for HLA-restricted immune responses in driving and shaping HIV-1 evolution in vivo.


Serum lipid concentrations and blood pressure in obese women.
In 70 obese women no correlation was found between body weight and serum cholesterol or triglyceride concentrations, but there was a significant correlation between weight and blood pressure. Weight reduction by diet or jejunoileal shunt was not accompanied by any significant change in serum lipid concentrations other than the decrease in serum cholesterol expected after intestinal bypass. Twelve months after bypass surgery was carried out on 14 patients, however, both systolic and diastolic blood pressures were significantly reduced and at levels appropriate to the patients' new weights. These results suggest that obesity in women cannot be taken to indicate the presence of hyperlipidaemia and that sustained weight loss may lower blood pressure.


ROS signalling--specificity is required.
Reactive oxygen species (ROS) production increases in plants under stress. ROS can damage cellular components, but they can also act in signal transduction to help the cell counteract the oxidative damage in the stressed compartment. H(2)O(2) might induce a general stress response, but it does not have the required specificity to selectively regulate nuclear genes required for dealing with localized stress, e.g. in chloroplasts or mitochondria. Here we argue that peptides deriving from proteolytic breakdown of oxidatively damaged proteins have the requisite specificity to act as secondary ROS messengers and regulate source-specific genes and in this way contribute to retrograde ROS signalling during oxidative stress. Likewise, unmodified peptides deriving from the breakdown of redundant proteins could help coordinate organellar and nuclear gene expression.


Peroxide-modified titanium dioxide: a chemical analog of putative Martian soil oxidants.
Hydrogen peroxide chemisorbed on titanium dioxide (peroxide-modified titanium dioxide) is investigated as a chemical analog to the putative soil oxidants responsible for the chemical reactivity seen in the Viking biology experiments. When peroxide-modified titanium dioxide (anatase) was exposed to a solution similar to the Viking labeled release (LR) experiment organic medium, CO2 gas was released into the sample cell headspace. Storage of these samples at 10 degrees C for 48 hr prior to exposure to organics resulted in a positive response while storage for 7 days did not. In the Viking LR experiment, storage of the Martian surface samples for 2 sols (approximately 49 hr) resulted in a positive response while storage for 141 sols essentially eliminated the initial rapid release of CO2. Heating the peroxide-modified titanium dioxide to 50 degrees C prior to exposure to organics resulted in a negative response. This is similar to, but not identical to, the Viking samples where heating to approximately 46 degrees C diminished the response by 54-80% and heating to 51.5 apparently eliminated the response. When exposed to water vapor, the peroxide-modified titanium dioxide samples release O2 in a manner similar to the release seen in the Viking gas exchange experiment (GEx). Reactivity is retained upon heating at 50 degrees C for three hours, distinguishing this active agent from the one responsible for the release of CO2 from aqueous organics. The release of CO2 by the peroxide-modified titanium dioxide is attributed to the decomposition of organics by outer-sphere peroxide complexes associated with surface hydroxyl groups, while the release of O2 upon humidification is attributed to more stable inner-sphere peroxide complexes associated with Ti4+ cations. Heating the peroxide-modified titanium dioxide to 145 degrees C inhibited the release of O2, while in the Viking experiments heating to this temperature diminished but did not eliminated the response. Although the thermal stability of the titanium-peroxide complexes in this work is lower than the stability seen in the Viking experiments, it is expected that similar types of complexes will form in titanium containing minerals other than anatase and the stability of these complexes will vary with surface hydroxylation and mineralogy.


SorLA signaling by regulated intramembrane proteolysis.
The single-transmembrane receptor SorLA/LR11 contains binding domains typical for lipoprotein receptors and a VPS10 domain, which binds the neuropeptide head-activator. This undecapeptide enhances proliferation of neuronal precursor cells in a SorLA-dependent manner. Using specific inhibitors we found previously that head activator activates shedding of SorLA by the metalloprotease TACE close to the transmembrane domain releasing the large extra-cellular part of the receptor. Here we show that the remaining COOH-terminal membrane fragment of SorLA is processed by gamma-secretase. Inhibition of gamma-secretase by specific inhibitors or overexpression of dominant negative presenilin mutants and knock out of the presenilin genes led to accumulation of the SorLA membrane fragment and also of full-length SorLA in the membrane. In an in vitro assay we observed the gamma-secretase-dependent release of the two soluble cleavage products, the SorLA cytoplasmic domain and the SorLA beta-peptide. These processing steps are reminiscent of a novel signaling pathway that has been described for the notch receptor. Here, the notch cytoplasmic domain is released into the cytoplasm by the gamma-secretase and migrates to the nucleus where it acts as a transcriptional regulator. In parallel we found that a fusion protein of the released cytoplasmic tail of SorLA with EGFP located to the nucleus only if the nuclear localization signal of SorLA was intact. In a reporter gene assay the cytoplasmic domain of SorLA acted as a transcriptional activator indicating that SorLA might directly regulate transcription after activation by gamma-secretase.


In situ viscoelastic properties and chain conformations of heavily hydrated carboxymethyl dextran layers: a comparative study using OWLS and QCM-I chips coated with waveguide material.
Hydration, viscoelastic properties and dominant structure of thin polymer layers on the surface of waveguide material were evaluated using optical waveguide lightmode spectroscopy (OWLS) and quartz crystal microbalance (QCM) methods. The fundamentally different principles of the two applied label-free biosensors enable to examine analyte layers from complementary aspects, e.g. to determine the amount of bound water in hydrated layers. In this study, a new QCM instrument with impedance measurement (QCM-I) is introduced. Its specially designed sensor chips, covered by thin film of waveguide material, supply identical surface as used in OWLS sensors, thus enabling to perform parallel measurements on the same type of surface. Viscoelastic analysis of the measured data was performed by our evaluation code developed in MATLAB environment, using the Voinova's Voigt-based model. In situ deposition experiments on the ultrathin films of poly(L-lysine)-graft-poly(ethylene glycol) (PLL-g-PEG) were conducted for instrumental and code validation. Additionally, a novel OWLS-QCM data evaluation methodology has been developed based on the concept of combining hydration and viscoelastic data with optical anisotropy results from OWLS measurements. This methodology provided insight into the time-dependent chain conformation of heavily hydrated nano-scaled layers, resulting in unprecedented structural, hydration and viscoelastic information on covalently grafted ultrathin carboxymethyl dextran (CMD) films. The measured mass values as well as hydration and viscoelastic properties were compared with the characteristics of PLL-g-PEG layers.


Day case inguinal hernia surgery in Nigerian children: prospective study.
There has been an increase in day case surgery for children worldwide, but there have been few reports of the practice (most of them being retrospective) by many of the surgical sub-specialties in the sub-region. The aim of this study was to document our experience with day case inguinal hernia surgery in a developing economy. This was a prospective study of uncomplicated inguinal hernias treated as day case at OAUTHC between April 2004 and December 2004. Data were collected and analysed. Eighty-eight patients were recruited into the study and none defaulted. There were 88 patients, (M:F = 16.6:1). A majority (n = 54) of the hernias occurred on the right side, while just a few (n = 18) occurred on the left. There were 5 cases of wound infections giving an infection rate of 4.8%. In all, the morbidity following day case inguinal hernia surgery was slight and no patient required readmission into the hospital. Day case inguinal hernia surgery in children is safe and well accepted by patients and parents alike. Health institutions in which children with inguinal hernias still queue for long periods for space on the operation list need to adopt day case surgery for inguinal hernia in order to forestall the risk of their obstruction.


Cryptococcus extracellular vesicles properties and their use as vaccine platforms.
Whereas extracellular vesicle (EV) research has become commonplace in different biomedical fields, this field of research is still in its infancy in mycology. Here we provide a robust set of data regarding the structural and compositional aspects of EVs isolated from the fungal pathogenic species Cryptococcus neoformans, C. deneoformans and C. deuterogattii. Using cutting-edge methodological approaches including cryogenic electron microscopy and cryogenic electron tomography, proteomics, and flow cytometry, we revisited cryptococcal EV features and suggest a new EV structural model, in which the vesicular lipid bilayer is covered by mannoprotein-based fibrillar decoration, bearing the capsule polysaccharide as its outer layer. About 10% of the EV population is devoid of fibrillar decoration, adding another aspect to EV diversity. By analysing EV protein cargo from the three species, we characterized the typical Cryptococcus EV proteome. It contains several membrane-bound protein families, including some Tsh proteins bearing a SUR7/PalI motif. The presence of known protective antigens on the surface of Cryptococcus EVs, resembling the morphology of encapsulated virus structures, suggested their potential as a vaccine. Indeed, mice immunized with EVs obtained from an acapsular C. neoformans mutant strain rendered a strong antibody response in mice and significantly prolonged their survival upon C. neoformans infection.


Overexpression and functional characterization of an ABC (ATP-binding cassette) transporter encoded by the genes drrA and drrB of Mycobacterium tuberculosis.
The genes encoding ATP-binding cassette (ABC) transporters occupy 2.5% of the genome of Mycobacterium tuberculosis. However, none of these putative ABC transporters has been characterized so far. We describe the development of expression systems for simultaneous expression of the ATP-binding protein DrrA and the membrane integral protein DrrB which together behave as a functional doxorubicin efflux pump. Doxorubicin uptake in Escherichia coli or Mycobacterium smegmatis expressing DrrAB was inhibited by reserpine, an inhibitor of ABC transporters. The localization of DrrA to the membrane depended on the simultaneous expression of DrrB. ATP binding was positively regulated by doxorubicin and daunorubicin. At the same time, DrrB appeared to be sensitive to proteolysis when expressed alone in the absence of DrrA. Simultaneous expression of the two polypeptides was essential to obtain a functional doxorubicin efflux pump. Expression of DrrAB in E. coli conferred 8-fold increased resistance to ethidium bromide, a cationic compound. 2',7'-bis-(2-Carboxyethyl)-5(6)-carboxyfluorescein (BCECF), a neutral compound, also behaved as a substrate of the reconstituted efflux pump. When expressed in M. smegmatis, DrrAB conferred resistance to a number of clinically relevant, structurally unrelated antibiotics. The resistant phenotype could be reversed by verapamil and reserpine, two potent inhibitors of ABC transporters.


Assessment of acute injuries and chronic intimal thickening of the radial artery after transradial coronary intervention by optical coherence tomography.
Transradial coronary intervention (TRI) introduces a trauma to the radial artery (RA), possibly influencing quality as a bypass conduit if subsequently used. We sought to determine the acute and chronic effects of TRI on the RA by optical coherence tomography (OCT). Immediately after TRI completion, 73 RAs in 69 patients were examined. The sheath was pulled back 2 cm distal to the puncture site, and OCT imaging was performed. The acute injuries and intimal thickening were compared between first-TRI RAs and repeat-TRI RAs. Intimal tears were observed in 49 RAs (67.1%) and were more frequent in the distal than in the proximal RA (P = 0.001). Medial dissections were not uncommon (26 RAs, 35.6%). The frequency of acute injury was significantly higher in repeat-TRI RAs (P < 0.001). Intima/medial area, the maximum intimal thickness/medial thickness ratio, and per cent narrowing were all significantly greater in repeat-TRI RAs in the distal and proximal RA. Multivariate analysis revealed that a repeated TRI procedure was the only independent predictor of intimal thickening. Optical coherence tomography clearly demonstrated significant acute injuries and chronic intimal thickening of RA after TRI. Further study should evaluate the impact of these effects when TRI RAs are subsequently used as conduits, on long-term graft patency and on clinical outcomes after bypass surgery.


Micropatterned Biphasic Nanocomposite Platform for Maintaining Chondrocyte Morphology.
One major limitation hindering the translation of in vitro osteoarthritis research into clinical disease-modifying therapies is that chondrocytes rapidly spread and dedifferentiate under standard monolayer conditions. Current strategies to maintain rounded morphologies of chondrocytes in culture either unnaturally restrict adhesion and place chondrocytes in an excessively stiff mechanical environment or are impractical for use in many applications. To address the limitations of current techniques, we have developed a unique composite thin-film cell culture platform, the CellWell, to model articular cartilage that utilizes micropatterned hemispheroidal wells, precisely sized to fit individual cells (12-18 μm diameters), to promote physiologically spheroidal chondrocyte morphologies while maintaining compatibility with standard cell culture and analytical techniques. CellWells were constructed of 15-μm-thick 5% agarose films embedded with electrospun poly(vinyl alcohol) (PVA) nanofibers. Transmission electron microscope (TEM) images of PVA nanofibers revealed a mean diameter of 60.9 ± 24 nm, closely matching the observed 53.8 ± 29 nm mean diameter of human ankle collagen II fibers. Using AFM nanoindentation, CellWells were found to have compressive moduli of 158 ± 0.60 kPa at 15 μm/s indentation, closely matching published stiffness values of the native pericellular matrix. Primary human articular chondrocytes taken from ankle cartilage were seeded in CellWells and assessed at 24 h. Chondrocytes maintained their rounded morphology in CellWells (mean aspect ratio of 0.87 ± 0.1 vs three-dimensional (3D) control [0.86 ± 0.1]) more effectively than those seeded under standard conditions (0.65 ± 0.3), with average viability of >85%. The CellWell's design, with open, hemispheroidal wells in a thin film substrate of physiological stiffness, combines the practical advantages of two-dimensional (2D) culture systems with the physiological advantages of 3D systems. Through its ease of use and ability to maintain the physiological morphology of chondrocytes, we expect that the CellWell will enhance the clinical translatability of future studies conducted using this culture platform.


Inducing iPSCs to escape the dish.
Induced pluripotent stem cells (iPSCs) hold great promise for autologous cell therapies, but significant roadblocks remain to translating iPSCs to the bedside. For example, concerns about the presumed autologous transplantation potential of iPSCs have been raised by a recent paper demonstrating that iPSC-derived teratomas were rejected by syngeneic hosts. Additionally, the reprogramming process can alter genomic and epigenomic states, so a key goal at this point is to determine the clinical relevance of these changes and minimize those that prove to be deleterious. Finally, thus far few studies have examined the efficacy and tumorigenicity of iPSCs in clinically relevant transplantation scenarios, an essential requirement for the FDA. We discuss potential solutions to these hurdles to provide a roadmap for iPSCs to "jump the dish" and become useful therapies.


Discharge planning of stroke patients: the relatives' perceptions of participation.
To describe relatives' perceived participation in discharge planning for patients with stroke and identify correlates to perceived participation. Stroke affects both patients and their relatives and previous research shows that relatives were often dissatisfied with their perceived involvement in discharge planning and the information they get. Prospective cross-sectional study. The study comprised 152 consecutively enrolled relatives (mean age = 60.8 years) of acute stroke patients admitted to a stroke unit in southern Sweden during 2003-2005. Data were collected through interviews 2-3 weeks after discharge using 'Relative's Questionnaire about Participation in Discharge planning'. This instrument measures perceived participation in three subscales: R-Information-Illness, R-Information-Care/support, and R-Goals and Needs. The Overall Rating of Relative's Perceived Participation in Discharge Planning was measured by a visual analogue scale (VAS) (1-10 score). Among the relatives, 56-68% reported positively according to R-Information-Illness, but 46-53% perceived that they did not receive any information about care/medication/rehabilitation/support. About 80% perceived no participation at all in goals and needs. The mean value of the VAS was 3.89 (SD 3.40) score. Regression analyses revealed that longer stay at hospital, patients with higher education, and relatives of female patients and female relatives were associated with relatives' perceptions of higher participation in discharge planning. Relatives perceived that they needed more information and knowledge about stroke and care/medication/rehabilitation/support. They also needed to be more involved in goal-setting and in identifying patient needs. Professionals should take into consideration these associated variables to improve relatives' perceived participation. Clinicians should give more attention to the altered situation of stroke patients' relatives when planning for continuing care and when setting postdischarge goals for the patients. The professionals need to develop strategies to involve relatives in sharing information, goal-setting and needs assessment in discharge planning.


Design, synthesis, and traveling wave ion mobility mass spectrometry characterization of iron(II)- and ruthenium(II)-terpyridine metallomacrocycles.
New metallomacrocycles composed of 2,2':6',2″-terpyridine (tpy) ligands and Ru(II) or Fe(II) transition metal ions were prepared by stepwise directed assembly and characterized by 2D diffusion NMR spectroscopy (DOSY), electrospray ionization traveling wave ion mobility mass spectrometry (ESI TWIM MS), and molecular modeling. The supramolecular polymers synthesized include a homonuclear all-Ru hexamer as well as heteronuclear hexamer and nonamer with alternating Ru/Ru/Fe metal centers. ESI MS yields several charge states from each supramacromolecule. If ESI is interfaced with TWIM MS, overlapping charge states and the isomeric components of an individual charge state are separated based on their unique drift times through the TWIM region. From experimentally measured drift times, collision cross-sections can be deduced. The collision cross-sections obtained for the synthesized supramacromolecules are in good agreement with those predicted by molecular modeling for macrocyclic structures. Similarly, the hydrodynamic radii of the synthesized complexes derived from 2D DOSY NMR experiments agree excellently with the radii calculated for macrocyclic architectures, confirming the ESI TWIM MS finding. ESI TWIM MS and 2D DOSY NMR spectroscopy provide an alternative approach for the structural analysis of supramolecules that are difficult or impossible to crystallize, such as the large macrocyclic assemblies investigated. ESI TWIM MS will be particularly valuable for the characterization of supramolecular assemblies not available in the quantity or purity required for NMR studies.


Comparison of lisinopril versus digoxin for congestive heart failure during maintenance diuretic therapy. The Lisinopril-Digoxin Study Group.
Lisinopril 5-20 mg once daily was compared with digoxin 0.125-0.375 mg once daily in a double-blind, randomized, parallel-group study involving 217 patients with mild-to-moderate heart failure (New York Heart Association [NYHA] grades II-III) who were maintained on optimized diuretic therapy. After 6 weeks of treatment, digoxin and lisinopril had increased exercise duration by 18 seconds (p = 0.015) and 32 seconds (p = 0.0007), respectively, versus the baseline run-in period. The difference between treatments was not statistically significant (p = 0.1343). After 12 weeks, digoxin and lisinopril had increased exercise duration by 29 seconds and 51 seconds, respectively. The effect of digoxin compared with the baseline value was not significant but that for lisinopril was (p = 0.0027). The difference between treatments approached statistical significance (p = 0.0813). There was no difference between lisinopril and digoxin with regard to their effects on the frequency of ventricular ectopic counts, couplets, or nonsustained ventricular tachycardia. Blood pressures were not significantly different between treatments, although both systolic and diastolic blood pressure were consistently lower in the lisinopril group throughout randomized treatment. The proportions of patients demonstrating an improvement in NYHA grading were similar for both lisinopril and digoxin. Both treatments had similar effects on the symptoms of heart failure. Both drugs appeared to be equally well tolerated with a similar frequency of adverse events reported for both drugs (30% for lisinopril vs 29% for digoxin). Withdrawals from treatment were of a similar frequency for both treatments.(ABSTRACT TRUNCATED AT 250 WORDS)


Cicero Predicts cis-Regulatory DNA Interactions from Single-Cell Chromatin Accessibility Data.
Linking regulatory DNA elements to their target genes, which may be located hundreds of kilobases away, remains challenging. Here, we introduce Cicero, an algorithm that identifies co-accessible pairs of DNA elements using single-cell chromatin accessibility data and so connects regulatory elements to their putative target genes. We apply Cicero to investigate how dynamically accessible elements orchestrate gene regulation in differentiating myoblasts. Groups of Cicero-linked regulatory elements meet criteria of "chromatin hubs"-they are enriched for physical proximity, interact with a common set of transcription factors, and undergo coordinated changes in histone marks that are predictive of changes in gene expression. Pseudotemporal analysis revealed that most DNA elements remain in chromatin hubs throughout differentiation. A subset of elements bound by MYOD1 in myoblasts exhibit early opening in a PBX1- and MEIS1-dependent manner. Our strategy can be applied to dissect the architecture, sequence determinants, and mechanisms of cis-regulation on a genome-wide scale.


A 7-day high-fat, high-calorie diet induces fibre-specific increases in intramuscular triglyceride and perilipin protein expression in human skeletal muscle.
We have recently shown that a high-fat, high-calorie (HFHC) diet decreases whole body glucose clearance without impairing skeletal muscle insulin signalling, in healthy lean individuals. These diets are also known to increase skeletal muscle IMTG stores, but the effect on lipid metabolites leading to skeletal muscle insulin resistance has not been investigated. This study measured the effect of 7 days' HFHC diet on (1) skeletal muscle concentration of lipid metabolites, and (2) potential changes in the perilipin (PLIN) content of the lipid droplets storing intramuscular triglyceride (IMTG). The HFHC diet increased PLIN3 protein expression and redistributed PLIN2 to lipid droplet stores in type I fibres. The HFHC diet increased IMTG content in type I fibres, while lipid metabolite concentrations remained the same. The data suggest that the increases in IMTG stores assists in reducing the accumulation of lipid metabolites known to contribute to skeletal muscle insulin resistance. A high-fat, high-calorie (HFHC) diet reduces whole body glucose clearance without impairing skeletal muscle insulin signalling in healthy lean individuals. HFHC diets also increase skeletal muscle lipid stores. However, unlike certain lipid metabolites, intramuscular triglyceride (IMTG) stored within lipid droplets (LDs) does not directly contribute to skeletal muscle insulin resistance. Increased expression of perilipin (PLIN) proteins and colocalisation to LDs has been shown to assist in IMTG storage. We aimed to test the hypothesis that 7 days on a HFHC diet increases IMTG content while minimising accumulation of lipid metabolites known to disrupt skeletal muscle insulin signalling in sedentary and obese individuals. We also aimed to identify changes in expression and subcellular distribution of proteins involved in IMTG storage. Muscle biopsies were obtained from the m. vastus lateralis of 13 (11 males, 2 females) healthy lean individuals (age: 23 ± 2.5 years; body mass index: 24.5 ± 2.4 kg m-2 ), following an overnight fast, before and after consuming a high-fat (64% energy), high-calorie (+47% kcal) diet for 7 days. After the HFHC diet, IMTG content increased in type I fibres only (+101%; P < 0.001), whereas there was no change in the concentration of either total diacylglycerol (P = 0.123) or total ceramides (P = 0.150). Of the PLINs investigated, only PLIN3 content increased (+50%; P < 0.01) solely in type I fibres. LDs labelled with PLIN2 increased (+80%; P < 0.01), also in type I fibres only. We propose that these adaptations of LDs support IMTG storage and minimise accumulation of lipid metabolites to protect skeletal muscle insulin signalling following 7 days' HFHC diet.


Semianalytical estimation of the four-wave mixing noise based on extreme value theory.
Four-wave mixing (FWM) is one the limiting factors for existing and future wavelength division multiplexed optical networks. A semianalytical method based on Monte Carlo and Extreme Value theory is proposed and applied to study the influence of the FWM noise on the performance of WDM systems. The statistical behavior of the FWM noise is investigated while the Bit-Error rate is calculated for various combinations of the design parameters and for both single and multiple span WDM systems. The semianalytical method is also compared to the Multicanonical Monte Carlo (MCMC) method showing the same efficiency and accuracy with the former providing however the advantage of deriving closed-form approximations for the cumulative distribution functions of the photocurrents in the mark and the space state and the BER.


Spontaneous postpartum clearance of Plasmodium falciparum parasitemia in pregnant women, Benin.
The question of malaria in the postpartum period is controversial. Malaria was investigated during a randomized trial of intermittent preventive treatment in pregnancy in Benin. Women infected at delivery were tested for parasitemia in the early postpartum period; they had not received treatment unless they were symptomatic. Among the 35 of 1,346 infected women, parasitologic follow-up results could not be interpreted in 15 because they were treated for symptoms, 18 cleared parasitemia spontaneously within five days postpartum, and 2 had a strong decrease in parasitemia before being treated. Because the placenta is the privileged site for sequestration of parasites, it facilitates their persistence during pregnancy, and its elimination may rapidly induce their clearance.


Statistical controversies in clinical research: data access and sharing-can we be more transparent about clinical research? Let's do what's right for patients.
Calls for greater transparency and 'open data access' in clinical research are widespread, from sources including the Executive Office of the President, which in 2013 called for increased access to the results of federally funded research. In 2015, The Institute of Medicine issued a report advocating for a multi-stakeholder effort to foster responsible data sharing, and there are many others. Open science is good for researchers, good for innovation, and good for patients. The question at the center of the open-science efforts for clinical trials should not be whether data should be shared, but rather how we can usher in responsible methods for doing so. Unfortunately, there remain numerous perceived barriers to complete transparency around clinical trial data. This paper reviews the current status of data disclosure, the barriers to achieving it and a suggestion for the future.


TGF-betas and TGF-beta receptors in atherosclerosis.
Based on diverse evidence in animals and humans, it has been hypothesized that atherosclerosis, and other injury-induced hyperplasias such as restenosis, may result from a failure in endogenous inhibitory systems that normally limit wound repair and induce regression of wound repair cells. A key defect in one of these inhibitory pathways, the TGF-beta system, has been identified and characterized in both animal models and in human lesions and lesion-derived cells. Cells derived from human lesions are resistant to the antiproliferative and apoptotic effects of TGF-beta, while their normal counterparts from the vascular media are potently inhibited and killed. Both cell types increase PAI-1 production, switch actin phenotypes in response to TGF-beta1, and produce similar levels of TGF-beta activity. Membrane cross-linking of (125)I-TGF-beta1 indicates that normal human SMC express Type I, II and III receptors. The Type II receptor is strikingly decreased in lesion cells, with little change in the Type I or III receptors. RT-PCR confirmed that the Type II TGF-beta1 receptor mRNA is reduced in lesion cells. Subsequent analysis of human lesion vs normal tissues confirmed that the Type I receptor was consistently present in the lesion, while the Type II receptor was much more variable, and commonly absent in both coronary artery and carotid artery lesions. Transfection of the Type II receptor into lesion cells partially restores the growth inhibitory response to TGF-beta1, implying that signaling remains intact. A subset of patients, and cells derived from their lesions, exhibit acquired mutations in the Type II receptor that would explain their resistance, though the majority of cells are resistant without obvious mutational defects. Thus, it is currently being tested whether transcriptional defects or abnormalities in receptor processing may explain the low levels of the Type II receptor. Because TGF-beta1 is overexpressed in fibroproliferative vascular lesions, receptor-negative cells would be allowed to grow in a slow, but uncontrolled fashion, while overproducing extracellular matrix components.


Equine embryos and embryonic stem cells: defining reliable markers of pluripotency.
Cartilage and tendon injuries are a significant source of animal wastage and financial loss within the horse-racing industry. Moreover, both cartilage and tendon have limited intrinsic capacity for self-repair, and the functionally inferior tissue produced within a lesion may reduce performance and increase the risk of reinjury. Stem cells offer tremendous potential for accelerating and improving tissue healing, and adult mesenchymal stem cells (MSCs) are already used to treat cartilage and tendon injuries in horses. However, MSCs are scarce in the bone marrow isolates used, have limited potential for proliferation and differentiation in vitro, and do not appear to noticeably improve long-term functional repair. Embryonic stem cells (ESCs) or induced pluripotent stem (iPS) cells could overcome many of the limitations and be used to generate tissues of value for equine regenerative medicine. To date, six lines of putative ESCs have been described in the horse. All expressed stem cell-associated markers and exhibited longevity and pluripotency in vitro, but none have been proven to exhibit pluripotency in vivo. Moreover, it is becoming clear that the markers used to characterize the putative ESCs were inadequate, primarily because studies in domestic species have revealed that they are not specific to ESCs or the pluripotent inner cell mass, but also because the function of most in the maintenance of pluripotency is not known. Future derivation and validation of equine embryonic or other pluripotent stem cells would benefit greatly from a reliable panel of molecular markers specific to pluripotent cells of the developing horse embryo.


Influence of the macromolecular architecture on the self-assembly of amphiphilic copolymers based on poly(N,N-dimethylamino-2-ethyl methacrylate) and poly(epsilon-caprolactone).
The self-assembly of amphiphilic copolymers consisting of poly( N, N-dimethylamino-2-ethyl methacrylate) (PDMAEMA) and poly(-caprolactone) (PCL) segments arranged in graft and linear diblock architectures was investigated in this work by means of dynamic light scattering (DLS) in aqueous solution and by atomic force microscopy (AFM) on thin deposits. The solid-state deposits of the micelles were generated by a "freeze-drying" technique that preserves the initial micelle morphology in solution. A comparison between the morphological properties of graft copolymers with corresponding diblock copolymers was established to demonstrate the effect of the copolymer architecture on the micelle structure and organization.


Resolving the evolution of extant and extinct ruminants with high-throughput phylogenomics.
The Pecorans (higher ruminants) are believed to have rapidly speciated in the Mid-Eocene, resulting in five distinct extant families: Antilocapridae, Giraffidae, Moschidae, Cervidae, and Bovidae. Due to the rapid radiation, the Pecoran phylogeny has proven difficult to resolve, and 11 of the 15 possible rooted phylogenies describing ancestral relationships among the Antilocapridae, Giraffidae, Cervidae, and Bovidae have each been argued as representations of the true phylogeny. Here we demonstrate that a genome-wide single nucleotide polymorphism (SNP) genotyping platform designed for one species can be used to genotype ancient DNA from an extinct species and DNA from species diverged up to 29 million years ago and that the produced genotypes can be used to resolve the phylogeny for this rapidly radiated infraorder. We used a high-throughput assay with 54,693 SNP loci developed for Bos taurus taurus to rapidly genotype 678 individuals representing 61 Pecoran species. We produced a highly resolved phylogeny for this diverse group based upon 40,843 genome-wide SNP, which is five times as many informative characters as have previously been analyzed. We also establish a method to amplify and screen genomic information from extinct species, and place Bison priscus within the Bovidae. The quality of genotype calls and the placement of samples within a well-supported phylogeny may provide an important test for validating the fidelity and integrity of ancient samples. Finally, we constructed a phylogenomic network to accurately describe the relationships between 48 cattle breeds and facilitate inferences concerning the history of domestication and breed formation.


Home care services for older clients with and without cognitive impairment in Sweden.
Little is known about the types of home care services granted to older clients in Sweden. The objectives of this study were to: (a) identify and describe the range of granted home care services and service hours; (b) compare services granted for clients with and without documented cognitive impairment; and (c) examine associations between the range of granted home care services and factors related to cognitive impairment and demographical characteristics. The study design was descriptive and cross-sectional. The data, included records of granted home care services for clients age 65+ with (n = 43) and without (n = 88) cognitive impairment documented by the local municipality assessors, collected from one agency in Sweden during a 2-month period in 2015. Data analyses resulted in an overview of the range of home care services divided into two categories: personal care and service. In the personal care category, the median was 3 for types of services (range 0-12), and shower (n = 69; 52.7%) was the most common service. In the service category, the median was 5 for types of services (range 0-10), and cleaning the household (n = 103; 78.6%) was the most common service. The median for service hours was 27 hr per month (range 2.5-127.5). Logistic regression models revealed that cognitive impairment was associated with a higher number of services in the personal care category and a higher number of hours per month. Living alone was associated with a higher number of services in the service category. In conclusion, a wide range of home care services were provided for clients who have complex needs in daily life. Home care services were granted to clients with cognitive impairment and to a greater extent with clients who were living alone.


Protective effects of nebivolol on oxygen free radical-induced vasoconstrictions in vitro.
Disturbed ocular hemodynamics and vasospasms might be involved in the pathogenesis of glaucoma. On a clinical level there are indications for an optimization of ocular perfusion parameters in hypertensive glaucoma patients by switching a beta-adrenoceptor-antagonist therapy to nebivolol. Aim of the present study is to investigate vasoactive properties of nebivolol on ocular vasculature in vitro. Besides vasorelaxing effects, the impact of nebivolol on oxygen free radical-induced vasoconstrictions is studied. The experiments were carried out with ring preparations from porcine ciliary arteries. The preparations were placed in a myograph system and were kept under physiological conditions (pH 7.4, 37 degrees C, Krebs-Henseleit-Buffer, 1.75 mM Ca2+) and were stimulated by K+ depolarizations. The experiments were performed at a Nernst potential of -41 mV, which reflects half-maximal activation. For radical exposure, the preparations were superfused for 20 s in a specifically designed set-up with hydroxyl radicals generated by the Fenton reaction from H2O2 and Fe3+. NO synthase activity was modulated by adding L-arginine to the buffer. At a concentration of 10-5 M nebivolol leads to a reduction of vascular tone by -8.5+/-3.4% (n=11; P=0.016) vs. +2.6+/-1.9% (n=11; n.s.) in presence of its solvent DMSO. Nebivolol (10-5 M) reduces hydroxyl radical-induced vasoconstrictions by 53+/-10% (n=11; P<0.001). Stimulation of the NO synthase by L-arginine saturation potentiates this effect. Nebivolol combines vasorelaxing properties with protection against oxidative stress-induced vasoconstrictions. Both effects may be attributed to NO-releasing properties of nebivolol independently of its beta-adrenoceptor-blocking effect.


BRAIN MITOCHONDRIA. I. ISOLATION OF BOVINE BRAIN MITOCHONDRIA.
Two methods of preparing a mitochondrial fraction from beef brain cortex are described. Data are presented on the rate of oxidation of substrates, P/O and respiratory control ratios, cholinesterase activity, and DNA content. Electron micrographs of isolated mitochondria and mitochondria in situ are shown. Comparisons are drawn between these preparations and mitochondria prepared in 0.25 M sucrose. The data on enzymic properties and contamination by non-mitochondrial material indicate that mitochondrial fractions which compare favorably with those from other tissues can be prepared from brain tissue.


Methodological issues in a prospective study on plasma concentrations of persistent organic pollutants and pancreatic cancer risk within the EPIC cohort.
The use of biomarkers of environmental exposure to explore new risk factors for pancreatic cancer presents clinical, logistic, and methodological challenges that are also relevant in research on other complex diseases. First, to summarize the main design features of a prospective case-control study -nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort- on plasma concentrations of persistent organic pollutants (POPs) and pancreatic cancer risk. And second, to assess the main methodological challenges posed by associations among characteristics and habits of study participants, fasting status, time from blood draw to cancer diagnosis, disease progression bias, basis of cancer diagnosis, and plasma concentrations of lipids and POPs. Results from etiologic analyses on POPs and pancreatic cancer risk, and other analyses, will be reported in future articles. Study subjects were 1533 participants (513 cases and 1020 controls matched by study centre, sex, age at blood collection, date and time of blood collection, and fasting status) enrolled between 1992 and 2000. Plasma concentrations of 22 POPs were measured by gas chromatography - triple quadrupole mass spectrometry (GC-MS/MS). To estimate the magnitude of the associations we calculated multivariate-adjusted odds ratios by unconditional logistic regression, and adjusted geometric means by General Linear Regression Models. There were differences among countries in subjects' characteristics (as age, gender, smoking, lipid and POP concentrations), and in study characteristics (as time from blood collection to index date, year of last follow-up, length of follow-up, basis of cancer diagnosis, and fasting status). Adjusting for centre and time of blood collection, no factors were significantly associated with fasting status. Plasma concentrations of lipids were related to age, body mass index, fasting, country, and smoking. We detected and quantified 16 of the 22 POPs in more than 90% of individuals. All 22 POPs were detected in some participants, and the smallest number of POPs detected in one person was 15 (median, 19) with few differences by country. The highest concentrations were found for p,p'-DDE, PCBs 153 and 180 (median concentration: 3371, 1023, and 810 pg/mL, respectively). We assessed the possible occurrence of disease progression bias (DPB) in eight situations defined by lipid and POP measurements, on one hand, and by four factors: interval from blood draw to index date, tumour subsite, tumour stage, and grade of differentiation, on the other. In seven of the eight situations results supported the absence of DPB. The coexistence of differences across study centres in some design features and participant characteristics is of relevance to other multicentre studies. Relationships among subjects' characteristics and among such characteristics and design features may play important roles in the forthcoming analyses on the association between plasma concentrations of POPs and pancreatic cancer risk.


Cytochrome P450 inhibitory action of Echinacea preparations differs widely and co-varies with alkylamide content.
Echinacea preparations are one of the best selling herbal medicinal products with a well established therapeutic use in the prophylaxis of upper respiratory tract infections. Their consumption is increasing, but information about their ability to inhibit cytochrome P450 enzymes (CYP) is fragmentary. The picture is further complicated by a lack of phytochemical characterization of previously tested preparations. Due to its well characterized immunomodulatory activity, the standardized Swiss registered Echinacea purpurea (L.) Moench Echinaforce extract was selected for detailed study. With the single baculovirus-expressed CYP isoforms 1A2, 2C19, 2D9 and 3A4, inhibitory actions were measured by monitoring fluorescent metabolites derived from enzyme substrates (supersome assay). The Echinaforce extract induced mild inhibition of all these isoforms, with CYP 3A4 being the most, and CYP 2D6 the least sensitive enzyme. To assess whether CYP inhibition might be a general feature of Echinacea preparations, an additional nine commercially available preparations were screened using CYP 3A4. All tested preparations were able to inhibit CYP 3A4, but inhibitory potencies (expressed as median inhibitory concentration, IC50) varied by a factor of 150. The alkylamides are thought to be responsible for the immunomodulatory activity of Echinacea, and so the concentration of 2E,4E,8Z,10E/Z-tetranoic acid isobutylamide (1) and total alkylamide content were determined in all preparations, and the latter was found to be associated with their CYP 3A4 inhibitory potency. The chemically pure alkylamides dodeca-2E,4E,8Z,10E/Z-tetranoic acid isobutylamide (1) and dodeca-2E,4E-dieonoic acid isobutylamide (2) showed inhibitory activity on CYP 2C19, 2D6 and 3A4. However, unlike the Echinaforce extract, the alkylamides did not induce CYP 1A2 inhibition. Thus, other, as yet unidentified constituents also contribute to the overall weak inhibitory effects seen with Echinacea preparations in-vitro.


A Conceptual Model for Youth-Led Programs as a Promising Approach to Early Childhood Care and Education.
The international community has set forth global targets that include calls for universal access to high-quality early childhood care and education (ECCE), as indicated in the United Nations' Sustainable Development Goals. One major impediment to achieving this target is the lack of a skilled workforce. In this paper, we argue the case for leveraging youth as an untapped resource for supplying the workforce the ECCE system needs. Youth comprise a large proportion of the global population, and historically, although youth experience higher unemployment rates than their adult counterparts, youth are important agents of social awareness, social transformation, and community mobilization in multiple global contexts. We provide a conceptual model based on developmental theories and program examples to leverage the discourse of youth-led ECCE programs as a viable option to address workforce gaps while benefiting both young children and youth.


Missed opportunities during family conferences about end-of-life care in the intensive care unit.
Improved communication with family members of critically ill patients can decrease the prolongation of dying in the intensive care unit (ICU), but few data exist to guide the conduct of this communication. Our objective was to identify missed opportunities for physicians to provide support for or information to family during family conferences. We identified ICU family conferences in four hospitals that included discussions about withdrawing life support or delivery of bad news. Fifty-one conferences were audiotaped, including 214 family members. Thirty-six physicians led the conferences and some physicians led more than one. We used qualitative methods to identify and categorize missed opportunities, defined as an occurrence when the physician had an opportunity to provide support or information to the family and did not. Fifteen family conferences (29%) had missed opportunities identified. These fell into three categories: opportunities to listen and respond to family; opportunities to acknowledge and address emotions; and opportunities to pursue key principles of medical ethics and palliative care, including exploration of patient preferences, explanation of surrogate decision making, and affirmation of nonabandonment. The most commonly missed opportunities were those to listen and respond, but examples from other categories suggest value in being aware of these opportunities. Identification of missed opportunities during ICU family conferences provides suggestions for improving communication during these conferences. Future studies are needed to demonstrate whether addressing these opportunities will improve quality of care.


Circulating opioids and plasma renin activity in insulin-dependent diabetics with renal haemodynamic alterations.
Circulating opioids were studied in insulin-dependent diabetics with renal haemodynamic alterations. Higher circulating beta-endorphin (beta-EP) and lower beta-lipotropin (beta-LPH) levels were found in patients with glomerular hyperfiltration than in diabetics with normal glomerular filtration rate (GFR) and controls. Moreover, significantly positive correlations between beta-EP and GFR, and between beta-EP and renal plasma flow were demonstrated in these patients. On the contrary, reduced beta-EP levels were observed in diabetics with impaired GFR and overt nephropathy. Plasma renin activity was increased in diabetics with glomerular hyperfiltration and reduced in diabetics with overt nephropathy. Circulating opioids might, therefore, play a role in renal haemodynamic alterations, both in patients with early and advanced glomerular changes.


Non-invasive evaluation of orthotopic heart transplant rejection by echocardiography.
Heart transplant recipients require frequent myocardial biopsies to screen for acute rejection. The purpose of this study was to identify demographic and echocardiographic factors associated with transplant rejection and develop a predictive model, which may reduce the number of cardiac biopsies. From January 1998 to December 2001, we performed 406 echocardiographic studies on 264 heart transplant patients who had biopsies performed on the same day. Two-dimensional, pulsed and tissue Doppler echocardiographic variables were compared between patients with and without rejection, and their predictive ability for detecting rejection was determined by uni- and multivariate analyses. In 268 biopsies there was no significant rejection (ISHLT Grade <==II), whereas 138 showed rejection (ISHLT Grade > or =IIIa). By multivariate analysis, pericardial effusion, isovolumic relaxation time (IVRT) <90 milliseconds and mitral inflow E/A ratio >1.7, diameter of inferior vena cava and duration of pulmonary vein atrial reversal were independently associated with rejection. Because the odds ratios were similar for all 5 predictors, a simplified model was developed based on the sum of the number of abnormal predictors present (0 to 5). The probability of rejection increased from 15.9%, in the absence of any predictor, to 39.7%, 52.0% and 71.1%, if 1, 2 or 3 predictors were present, respectively. Recipient age, pericardial effusion, IVRT and ratio of pulsed Doppler E/A are significant predictors of acute cardiac allograft rejection. However, no single predictor or combination of predictors were powerful enough to eliminate surveillance endomyocardial biopsies.


Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline.
To update the "Testosterone Therapy in Men With Androgen Deficiency Syndromes" guideline published in 2010. The participants include an Endocrine Society-appointed task force of 10 medical content experts and a clinical practice guideline methodologist. This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. One group meeting, several conference calls, and e-mail communications facilitated consensus development. Endocrine Society committees and members and the cosponsoring organization were invited to review and comment on preliminary drafts of the guideline. We recommend making a diagnosis of hypogonadism only in men with symptoms and signs consistent with testosterone (T) deficiency and unequivocally and consistently low serum T concentrations. We recommend measuring fasting morning total T concentrations using an accurate and reliable assay as the initial diagnostic test. We recommend confirming the diagnosis by repeating the measurement of morning fasting total T concentrations. In men whose total T is near the lower limit of normal or who have a condition that alters sex hormone-binding globulin, we recommend obtaining a free T concentration using either equilibrium dialysis or estimating it using an accurate formula. In men determined to have androgen deficiency, we recommend additional diagnostic evaluation to ascertain the cause of androgen deficiency. We recommend T therapy for men with symptomatic T deficiency to induce and maintain secondary sex characteristics and correct symptoms of hypogonadism after discussing the potential benefits and risks of therapy and of monitoring therapy and involving the patient in decision making. We recommend against starting T therapy in patients who are planning fertility in the near term or have any of the following conditions: breast or prostate cancer, a palpable prostate nodule or induration, prostate-specific antigen level > 4 ng/mL, prostate-specific antigen > 3 ng/mL in men at increased risk of prostate cancer (e.g., African Americans and men with a first-degree relative with diagnosed prostate cancer) without further urological evaluation, elevated hematocrit, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, myocardial infarction or stroke within the last 6 months, or thrombophilia. We suggest that when clinicians institute T therapy, they aim at achieving T concentrations in the mid-normal range during treatment with any of the approved formulations, taking into consideration patient preference, pharmacokinetics, formulation-specific adverse effects, treatment burden, and cost. Clinicians should monitor men receiving T therapy using a standardized plan that includes: evaluating symptoms, adverse effects, and compliance; measuring serum T and hematocrit concentrations; and evaluating prostate cancer risk during the first year after initiating T therapy.


Semi-automatic segmentation and classification of Pap smear cells.
Cytologic screening has been widely used for detecting the cervical cancers. In this study, a semiautomatic PC-based cellular image analysis system was developed for segmenting nuclear and cytoplasmic contours and for computing morphometric and textual features to train support vector machine (SVM) classifiers to classify four different types of cells and to discriminate dysplastic from normal cells. A software program incorporating function, including image reviewing and standardized denomination of file names, was also designed to facilitate and standardize the workflow of cell analyses. Two experiments were conducted to verify the classification performance. The cross-validation results of the first experiment showed that average accuracies of 97.16% and 98.83%, respectively, for differentiating four different types of cells and in discriminating dysplastic from normal cells have been achieved using salient features (8 for four-cluster and 7 for two-cluster classifiers) selected with SVM recursive feature addition. In the second experiment, 70% (837) of the cell images were used for training and 30% (361) for testing, achieving an accuracy of 96.12% and 98.61% for four-cluster and two-cluster classifiers, respectively. The proposed system provides a feasible and effective tool in evaluating cytologic specimens.


"This Treatment Can Really Help Me"-A Longitudinal Analysis of Treatment Readiness and Its Predictors in Patients Undergoing Alcohol and Drug Rehabilitation Treatment.
There is evidence that patients entering alcohol or drug treatment have different levels of treatment readiness and change their motivation differently over time. Nonetheless, existing studies mainly use single measures of motivation and do not consider individual differences. This study addresses 2 questions: (i) How does treatment readiness change in patients with alcohol and drug use dependence over the course of an inpatient rehabilitation treatment?; and (ii) Can changes in treatment readiness be explained by sociodemographic and substance use-related characteristics? Data from 177 alcohol-dependent patients and 152 drug-dependent patients were collected in 2 inpatient rehabilitation centers in Germany. Three single-item indicators of treatment readiness were assessed weekly over the course of the treatment. Sociodemographic and substance use-related characteristics were assessed at baseline. To model developments of treatment readiness that may be different for each patient, multilevel analyses for longitudinal data were used. The overall effect of time on treatment readiness was not significant, indicating that average motivation across all patients did not change over the course of the treatment. However, individuals showed different initial states and different rates of change. School education, employment status, earlier substance use treatments, and craving predicted treatment readiness. Interactions with time were found for craving and marital status. The results suggest that it is necessary to consider individual differences when evaluating treatment motivation in alcohol- and drug-dependent patients. The identification of variables predicting motivation may help to improve substance abuse treatment contents and outcomes.


A theoretical method for estimating small vessel distensibility in humans.
A simple theoretical approach is presented for estimating vascular distensibility of small blood vessels from noninvasively obtained pressure-flow data in the hand and forearm of human subjects. To the extent that Poiseuille's law applies to blood flow in these vascular beds, conductance (the reciprocal of vascular resistance) can be calculated from these data as the ratio of blood flow to mean arterial pressure. The fourth root of the conductance is proportional to the radius of the vascular bed. The slope of the relation between the logarithm of the radius of the vascular bed and the transmural pressure is proportional to the vascular extensibility (E), which, in turn, for small deformations and constant vascular length, is proportional to the distensibility of small blood vessel. Data obtained from the hands of six hypertensive subjects were compared with that obtained from six normotensive subjects, all with their vascular beds in a maximally dilated state. Also compared were data obtained from four normal subjects with their vascular beds in the resting state and when the beds were maximally dilated. The results indicate that 1) in the hypertensive subjects, the small blood vessels of the maximally dilated vascular bed of the hand are significantly (p less than 0.02) less distensible (E = 0.126 +/- 0.034/mm Hg) than those in the normotensive subjects (E = 0.272 +/- 0.047/mm Hg) and 2) the small blood vessels of the normal forearm at resting levels of vasomotor tone are more distensible (E = 1.00 +/- 0.38/mm Hg) than in the maximally dilated state (E = 0.51 +/- 0.08/mm Hg).


Detection of hepatitis B surface antigen among Scottish blood donors: evaluation of sensitive tanned-cell haemagglutination-inhibition test.
A total of 70 224 blood donations were tested at three Scottish blood transfusion centres for hepatitis B surface antigen /HBsAg) by an economical haemagglutination-inhibition method (E.H.A.I.) and the results compared with those of counterelectrophoresis (C.E.P.). A further 4086 donations were tested using the Wellcome turkey cell haemagglutination test, C.E.P., and E.H.A.I.E.H.A.I. was also compared with commercial haemagglutination and radioimmunoassay reagents for sensitivity and specificity against several established antigen panels and used to reinvestigate counterelectrophoresis-negative blood donations implicated in post-transfusion hepatitis. E.H.A.I. combines the inherent specificity of an inhibition reaction with a sensitivity equal to that of commercial radioimmunoassay and haemagglutination kits but at a fraction of the cost. The assessment of 70 224 blood donations in three regions showed that E.H.A.I. detected more antigen-positive blood donations than C.E.P. Results of retesting more than 100 blood donors implicated in 10 cases of post-transfusion hepatitis suggested that the use of E.H.A.I. or a test of similar sensitivity in place of C.E.P. may significantly reduce the incidence of this complication.


Associations of Coffee Consumption with the Circulating Level of Alanine Aminotransferase and Aspartate Aminotransferase. A Meta-Analysis of Observational Studies.
Background: The associations of coffee consumption with the circulating level of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) remains controversial. We conducted a meta-analysis of observational studies to sum up the existing evidence about this matter.Methods: A comprehensive literature-search up to January 2020, using PubMed, Embase and Web of Science databases, was conducted to identify the relevant observational studies that examined the associations of coffee consumption with the circulating level of ALT and AST. The standard mean difference (SMD) for the level of ALT and AST, odds ratio (OR) for the elevated ALT and AST and their corresponding 95% CIs for the highest versus lowest categories of coffee intake were determined.Results: A total of 19 observational studies, which involved 222,067 individuals, were included in this meta-analysis. The combined SMD suggested that coffee consumption was associated with a lower level of ALT (SMD = -0.14, 95% CI: -0.22 to -0.06; p = 0.001) and AST (SMD = -0.17, 95% CI: -0.20 to -0.13; p < 0.001), respectively. Meanwhile, the overall multivariable adjusted OR showed that coffee consumption was inversely associated with the elevated ALT (OR = 0.69, 95% CI: 0.60 to 0.79; p < 0.001) and AST (OR = 0.62, 95% CI: 0.48 to 0.81; p < 0.001), respectively.Conclusion: The results of this meta-analysis suggest that coffee consumption is inversely associated with the circulating level of ALT and AST, and elevated ALT and AST. More randomized controlled trials are needed to elaborate the concerned issues.


Multimodal Analgesia in the Hip Fracture Patient.
Hip fracture is one of the most common injuries among the elderly and, because the population is aging, it is expected to remain a major clinical challenge and public health problem for the foreseeable future. The clinical importance of early mobilization and prompt participation in physical therapy after hip fracture surgery is now widely recognized. Because postoperative pain can impair mobility and delay physical therapy, much attention is now being paid to finding more effective ways of controlling pain after hip fracture. Oversedation with opioid drugs inhibits communication between the patient and the health care team, can delay ambulation and rehabilitation therapy, and may increase the probability of the patient requiring a skilled nursing facility, which adds further cost to the overall health care system. Multiple pain pathways contribute to the perception of postoperative pain, and although opioids are highly effective in blocking nociceptive pain through inhibition of the mu receptors, they do not block other pain pathways. Multimodal analgesia involves the use of several anesthetic and analgesic modalities that are strategically combined to block pain perception at different sites in the peripheral and central nervous systems. This balanced, multifaceted approach provides more effective control of postoperative pain than opioid drugs alone, allows lower doses of opioids to be used as part of the multimodal regimen (thereby reducing the risk of opioid-related adverse events and complications), and may facilitate more rapid recovery and improve certain outcome measures related to recovery time. One prospective randomized study evaluating the clinical value of multimodal pain management in elderly patients undergoing bipolar hip hemiarthroplasty found that a multimodal regimen, including preemptive pain medication and intraoperative periarticular injections, reduced pain on postoperative days 1 and 4, and reduced overall opioid use. This article describes an effective multimodal pain management regimen for hip fracture patients.


Locus of control, cognitive appraisal, and coping in stressful episodes.
Evidence suggests that internals and externals differ in the nature and effectiveness of their coping behavior. This study investigated locus of control and coping processes in relation to specific stressful episodes reported by 171 female student nurses. Scores on each of three measures (General Coping, Direct Coping, and Suppression) that were derived from the "Ways of Coping" Questionnaire were analyzed to examine the role of appraisal (in terms of the extent to which the situation was perceived as amenable to control) and the perceived importance of the episode as mediators of the relation between locus of control and coping. The results showed significant interactions between locus of control and appraisal for each of the measures. Further examination of the interactions showed that the patterns of coping reported by internals were potentially more adaptive in relation to types of appraisal than those of externals. The perceived importance of the episode was significantly related, negatively, to suppression, but the interaction with locus of control was not significant.