Renal functional responses to centrally administered ouabain in anesthetized rabbits.
The effects of intracerebroventricularly administered ouabain on renal function were studied in rabbits. Ouabain, when given intracerebroventricularly in doses ranging from 0.1 to 10 micrograms/kg, dose-dependently produced antidiuretic, antinatriuretic and antikaliuretic effects, along with decreases in renal perfusion and glomerular filtration rate. Systemic blood pressure also increased significantly in a dose-related fashion. No increase in free water reabsorption was noted. Intravenously administered ouabain (10 micrograms/kg) caused less pronounced antidiuresis and antinatriuresis, with the renal hemodynamics tending slightly to decrease. No significant increment of systemic blood pressure with intravenous ouabain was observed. In rabbits with one kidney denervated and the contralateral left intact, ouabain 10 micrograms/kg i.c.v. produced the typical renal effects on the intact kidney, while the denervated kidney responded with prominent natriuresis and diuresis, showing the maximal response in the second 10-min period after administration. Renal nerve activity increased significantly upon administration of ouabain 10 micrograms/kg i.c.v. and reached a peak at around 10 to 20 min after drug administration, a period in which the most remarkable antidiuresis and antinatriuresis is produced by i.c.v. ouabain. These observations suggest that the antidiuresis and antinatriuresis elicited by centrally administered ouabain results mainly from the decrease of renal hemodynamics, which is caused by the increased renal nerve activity.


Liver laceration in an intercollegiate football player.
Serious abdominal injuries in athletics, including liver trauma, are relatively rare. When they do occur, the athletic trainer and the team physician must be able to recognize the signs and symptoms and employ the appropriate first aid and follow-up care. In this paper, we present a case study of a football player who suffered a lacerated liver as a result of a forceful blow to the right side of the chest. Although his case was typical of most isolated liver injuries and he did not experience massive internal bleeding, the potential for life-threatening exsanguination exists and must be recognized by by sports health care practitioners. Most isolated liver injuries can be treated nonsurgically. However, those patients with multiple organ trauma, deteriorating vital signs, or diminishing hemodynamic stability generally require immediate surgery. Athletes with persistent right upper quadrant pain, especially when accompanied by referred pain to the right shoulder, abdominal rigidity, guarding, or rebound pain should be considered to have a liver injury until ruled out by CT scan and liver enzyme studies. Our subject was typical of most athletic liver patients and he was able to resume light exercise after 5 weeks and full activity after 3 months.


Herpes simplex activation prolongs recovery from severe burn injury and increases bacterial infection risk.
Recovery from severe burn injury is complicated by infections that are result of immune suppression created by massive inflammatory states. One indication of immune suppression may be activation of viruses like herpes simplex virus (HSV), which may negatively impact recovery. A 5-year retrospective review was performed of adult patients with ≥30% TBSA burn injury. TBSA burn injury, length of hospital stay, ventilator days, mortality, and cultures were reviewed. Twenty-one patients had cutaneous HSV activation (HSV+) and 50 did not (HSV-). Age (44.2 vs 39.8 years) and TBSA burn injury (45.9 vs 45.5%) did not differ between the groups. Length of hospital stay (60.9 vs 39.8 days, P < .05) and ventilator days (34.9 vs 22.2 days, P < .05) were greater in HSV+ patients. HSV activation increased hospital stay (odds ratio [OR] 1.6, confidence interval [CI] 1.08-2.39, P < .05) and mechanical ventilation (OR 1.02, CI 1.00-1.05, P < .05). HSV activation increased the risk of developing positive Acinetobacter baumannii pulmonary cultures (OR 6.4, CI 1.8-22.3, P < .05) and methicillin-resistant Staphylococcus aureus wound cultures (OR 3.3, CI 1.2-9.6, P < .05). HSV activation also increased the risk of developing any positive A. baumannii cultures (OR 9.1, CI 1.9-44, P < .05). HSV activation during severe burn injury is associated with increased length of mechanical ventilation and hospital stay. In addition, these patients have an increased risk of infections from opportunistic bacteria.


Dual-Stream Spatiotemporal Networks with Feature Sharing for Monitoring Animals in the Home Cage.
This paper presents a spatiotemporal deep learning approach for mouse behavioral classification in the home-cage. Using a series of dual-stream architectures with assorted modifications for optimal performance, we introduce a novel feature sharing approach that jointly processes the streams at regular intervals throughout the network. The dataset in focus is an annotated, publicly available dataset of a singly-housed mouse. We achieved even better classification accuracy by ensembling the best performing models; an Inception-based network and an attention-based network, both of which utilize this feature sharing attribute. Furthermore, we demonstrate through ablation studies that for all models, the feature sharing architectures consistently outperform the conventional dual-stream having standalone streams. In particular, the inception-based architectures showed higher feature sharing gains with their increase in accuracy anywhere between 6.59% and 15.19%. The best-performing models were also further evaluated on other mouse behavioral datasets.


Passively acquired anti-SSA/Ro antibodies are required for congenital heart block following ovodonation but maternal genes are not.
Anti-SSA/Ro antibodies are necessary but not sufficient to provoke autoimmune-associated congenital heart block (CHB). Genetic factors are likely contributory. Accordingly, HLA-related candidates and single-nucleotide polymorphisms in the promoter region of tumor necrosis factor α and codon 10 in transforming growth factor β1 (TGFβ1) were evaluated in a unique family: the surrogate mother (anti-SSA/Ro positive), the biologic father, and the CHB-affected child (product of ovodonation). There was an HLA mismatch between the affected child and the surrogate mother. However, both the biologic and the surrogate mothers shared DQ2 and the profibrosing leucine polymorphism at codon 10 of TGFβ. In conclusion, we observed that CHB can develop in a genetically unrelated child exposed in utero to anti-SSA/Ro antibodies. Testing for anti-SSA/Ro antibodies might be considered in women undergoing artificial fertilization. It is possible that there is no direct association of maternal genes beyond a contributory role in generating the autoantibody.


Hepatic differentiation of amniotic epithelial cells.
Hepatocyte transplantation to treat liver disease is largely limited by the availability of useful cells. Human amniotic epithelial cells (hAECs) from term placenta express surface markers and gene characteristics of embryonic stem cells and have the ability to differentiate into all three germ layers, including tissues of endodermal origin (i.e., liver). Thus, hAECs could provide a source of stem cell-derived hepatocytes for transplantation. We investigated the differentiation of hAECs in vitro and after transplantation into the livers of severe combined immunodeficient (SCID)/beige mice. Moreover, we tested the ability of rat amniotic epithelial cells (rAECs) to replicate and differentiate upon transplantation into a syngenic model of liver repopulation. In vitro results indicate that the presence of extracellular matrix proteins together with a mixture of growth factors, cytokines, and hormones are required for differentiation of hAECs into hepatocyte-like cells. Differentiated hAECs expressed hepatocyte markers at levels comparable to those of fetal hepatocytes. They were able to metabolize ammonia, testosterone, and 17α-hydroxyprogesterone caproate, and expressed inducible fetal cytochromes. After transplantation into the liver of retrorsine (RS)-treated SCID/beige mice, naïve hAECs differentiated into hepatocyte-like cells that expressed mature liver genes such as cytochromes, plasma proteins, transporters, and other hepatic enzymes at levels equal to adult liver tissue. When transplanted in a syngenic animal pretreated with RS, rAECs were able to engraft and generate a progeny of cells with morphology and protein expression typical of mature hepatocytes. Amniotic epithelial cells possess the ability to differentiate into cells with characteristics of functional hepatocytes both in vitro and in vivo, thus representing a useful and noncontroversial source of cells for transplantation.


In vivo modulation of connexins 43 and 26 of human epidermis by topical retinoic acid treatment.
After 14 weeks of topical application of 0.1% all-trans-retinoic acid to the napes of volunteers, we observed a 2.5-fold increase in the thickness of epidermis, owing to an increase (p < 0.001) in the number and size of keratinocytes and the induction of keratin 6. These changes in the differentiation of epidermal keratinocytes were paralleled by an increase in the amount of Cx43, a connexin that is normally expressed in human epidermis, and by the massive induction of Cx26, which is barely detectable in normal interfollicular epidermis, as judged at both the transcript (Northern blotting) and the protein level (immunolabeling). In contrast, retinoic acid treatment did not alter the morphology and connexin pattern of hair follicles or of sebaceous and sweat glands, and did not induce the expression of other connexins (C32, Cx37, Cx40) in either skin adnexae or epidermis. These observations suggest that the expression of two distinct connexins by interfollicular keratinocytes is related to selective changes in the differentiation program of epidermis that are induced by retinoic acid.


Structure of mammalian metallothionein.
All mammalian metallothioneins characterized contain a single polypeptide chain of 61 amino acid residues, among them 20 cysteines providing the ligands for seven metal-binding sites. Native metallothioneins are usually heterogeneous in metal composition, with Zn, Cd, and Cu occurring in varying proportions. However, forms containing only a single metal species, i.e., Zn, Cd, Ni, Co, Hg, Pb, Bi, have now been prepared by in vitro reconstitution from the metal-free apoprotein. By spectroscopic analysis of such derivatives it was established that all cysteine residues participate in metal binding, that each metal ion is bound to four thiolate ligands, and that the symmetry of each complex is close to that of a tetrahedron. To satisfy the requirements of the overall Me7(Cys-)20 stoichiometry, the complexes must be combined to form metal-thiolate cluster structures. Experimental proof for the occurrence of such clusters comes from the demonstration of metal-metal interactions by spectroscopic and magnetic means. Thus, in Co(II)7-metallothionein, the Co(II)-specific ESR signals are effectively suppressed by antiferromagnetic coupling of juxtaposed paramagnetic metal ions. By monitoring changes in ESR signal size occurring on stepwise incorporation of Co(II) into the protein, it is possible to follow the building up of the clusters. This process is biphasic. Up to binding of four equivalents of Co(II), the ESR amplitude increases in proportion to the metal content, indicating generation of magnetically noninteracting high-spin complexes. However, upon addition of the remaining three equivalents of Co(II), these features are progressively suppressed, signaling the formation of clusters. The same mode of cluster formation has also been documented for Cd and Hg. The actual spatial organization of the clusters and the polypeptide chain remains to be established. An attractive possibility is the arrangement of the tetrahedral metal-thiolates in adamantane-like structures surrounded by properly folded segments of the chain providing the ligands. 1H-NMR data and infrared absorption measurements are consistent with a tightly folded structure rich in beta-type conformation.


Vocal fold augmentation with injectable calcium hydroxylapatite: short-term results.
Symptoms of unilateral vocal fold paralysis are improved significantly by augmenting the paralyzed vocal fold via vocal fold injection. In this trial, augmentation with a new calcium hydroxylapatite implant was evaluated. In addition, two different phonosurgical injection techniques were used, and these procedures were compared for accuracy and reliability. A total of 11 terminal patients with unilateral vocal fold paralysis underwent vocal fold injection with calcium hydroxylapatite. Efficacy of the implant was evaluated by comparing results from the Voice Handicap Index (VHI) and mean airflow measurements before and 6 months after injection. Surgeon evaluations determined the comparative benefits of either endoscopic direct vocal fold injection or percutaneous vocal fold injection. Six-month data were obtained for a cohort of five patients. VHI scores improved for all five patients available for full evaluation and four of the five achieved improvements in mean airflow rates. Of the remaining patients, one later had a medialization laryngoplasty, two died from their terminal diseases before the 6-month follow-up, and two of the remaining three reported satisfaction with the results via telephone follow-up. Vocal fold injection via endoscopic, direct laryngoscopy was found to be a more reliable procedure for vocal fold injection than percutaneous injection. Slight overinjection (10% to 15%) was found to provide optimum results. Vocal fold injection of calcium hydroxylapatite for unilateral vocal fold paralysis improved voice quality and reduced mean airflow rates in this patient group with short-term results. Long-term studies are needed to confirm the durability of these findings.


[Effects of hyper- and dyslipidemias on activity of angiotensin-converting enzyme (biochemical disturbances in metabolic syndrome)].
To study influence of lipoprotein complexes on activity of angiotensin-converting enzyme (ACE). Material and methods. Lipoproteins fraction was isolated from the serum of 53 healthy males and females and was studied for lipoproteins action on ACE in vitro. In addition, the examination covered 783 individuals. The data were analysed mathematically for relationships between ACE activity and parameters of lipid metabolism. It was found that blood serum lipoproteins inhibit activity of soluble ACE. Serum ACE activity depends on concentration of total cholesterol (TC) and triglycerides. Maximal activity of ACE is observed in TC 9.41 mM/l and TG concentration 3.05 mM/l. Albumin-related free fatty acids affect ACE activity neither in aqueous solution nor in the presence of lipoprotein complexes. . Development of most common atherogenic hyperlipidemias raises 2-fold plasma ACE activity. Elevated ACE activity may be an integral component of biochemical disturbances in metabolic syndrome.


Effects of a continuum of care intervention on frail older persons' life satisfaction: a randomized controlled study.
The aim of this study was to analyse effects of a comprehensive continuum of care (intervention group) on frail older persons' life satisfaction, as compared to those receiving usual care (control group). The intervention included geriatric assessment, case management, interprofessional collaboration, support for relatives and organising of care-planning meetings in older persons' own homes. Improvements in older persons' subjective well-being have been shown in studies including care planning and coordination by a case manager. However, effects of more complex continuum of care interventions on frail older persons' life satisfaction are not well explored. Randomised controlled study. The validated LiSat-11 scale was used in face-to-face interviews to assess older persons' life satisfaction at baseline and at three, six and 12 months after the baseline. The odds ratio for improving or maintaining satisfaction was compared for intervention and control groups from baseline to three-month, three- to six-month as well as six- to 12-month follow-ups. Older persons who received the intervention were more likely to improve or maintain satisfaction than those who received usual care, between 6 and 12 month follow-ups, for satisfaction regarding functional capacity, psychological health and financial situation. A comprehensive continuum of care intervention comprising several components had a positive effect on frail older persons' satisfaction with functional capacity, psychological health and financial situation. Frail older persons represent a great proportion of the persons in need of support from the health care system. Health care professionals need to consider continuum of care interventions' impact on life satisfaction. As life satisfaction is an essential part of older persons' well-being, we propose that policy makers and managers promote comprehensive continuum of care solutions.


Stomach cancer history in the siblings of patients with gastric carcinoma.
A case-control study in the population of the Eastern Black Sea region of Turkey was conducted to learn the incidence of stomach cancer in the siblings of patients with gastric carcinoma. Among 1240 patients with gastric carcinoma, 168 had sibling(s) with a history of stomach cancer versus 19 cases in the control group matched according to age and gender (OR 10.07, P < 0.0001). The frequency of a history of stomach cancers and cancer of other organs in first- to third-degree relatives was 60.7% and 38.0%, respectively, of 168 sibling cases with gastric carcinoma (P < 0.0001). Fifty-two point three per cent of sibling cases having a history of cancer in other organs in their relatives also reported stomach cancer in the same-degree relatives. The number of stomach cancers in the first- to third-degree relatives of sibling cases was higher than the number of other organ cancers in the same-degree relatives (P < 0.01). Familial clustering of stomach cancer was reported in 12.5% of sibling cases. The study of stomach cancer history in the siblings suggests: the presence of a genetic susceptibility, high risk of the disease occurrence in the siblings of patients, higher predisposition to gastric than to other organ cancers in the relatives, and not infrequent familial clustering.


Radioprotective effect of abana, a polyherbal drug following total body irradiation.
Effects of 20 mg/kg body weight of abana (ABE) on radiation-induced sickness and mortality in mice exposed to 7 Gy to 12 Gy of gamma irradiation were studied. Treatment of mice with abana 1 h before irradiation delayed the onset of mortality and reduced the symptoms of radiation sickness when compared with the non-drug treated irradiated controls (double distilled water, DDW). Abana provided protection against both the gastrointestinal and haemopoietic deaths. However, animals of both the ABE+irradiation and DDW+irradiation groups did not survive up to 30 days post-irradiation beyond 11 Gy irradiation. The LD(50/30) was found to be 8.5 Gy for the DDW+irradiation group and 10.3 Gy for ABE+irradiation group. The administration of abana resulted in an increase in radiation tolerance by 1.8 Gy, and the dose modification factor (DMF) was found to be 1.2. The irradiation of animals resulted in a dose dependent elevation in lipid peroxidation, and a reduction in glutathione (GSH) concentration on day 31 post-irradiation. Treatment of mice with abana before irradiation caused a significant depletion in lipid peroxidation followed by a significant elevation in GSH concentration in the liver of mice at day 31 post-irradiation. Abana scavenged (*)OH, DPPH, ABTS(*+) and NO(*) in a concentration dependent manner in vitro. Our results indicate that the radioprotective activity of abana may be due to free radical scavenging and increased GSH level in irradiated mice.


From ER to Eph receptors: new roles for VAP fragments.
Dominantly inherited mutations in an endoplasmic reticulum protein called VAPB have been found in a subset of patients with a rare familial form of amyotrophic lateral sclerosis (ALS). In this issue, Tsuda et al. (2008) identify a secreted form of VAPB that binds directly to Eph receptors inducing their activation and signaling, providing fresh insights into ALS pathogenesis, including non-neuronal aspects of this disorder.


Effect of an Educational Intervention on Therapeutic Inertia in Neurologists With Expertise in Multiple Sclerosis: A Randomized Clinical Trial.
Therapeutic inertia (TI) is the failure to escalate therapy when treatment goals are unmet and is associated with low tolerance to uncertainty and aversion to ambiguity in physician decision-making. Limited information is available on how physicians handle therapeutic decision-making in the context of uncertainty. To evaluate whether an educational intervention decreases TI by reducing autonomic arousal response (pupil dilation), a proxy measure of how physicians respond to uncertainty during treatment decisions. In this randomized clinical trial, 34 neurologists with expertise in multiple sclerosis (MS) practicing at 15 outpatient MS clinics in academic and community institutions from across Canada were enrolled. Participants were randomly assigned to receive an educational intervention that facilitates treatment decisions (active group) or to receive no exposure to the intervention (usual care [control group]) from December 2017 to March 2018. Participants listened to 20 audio-recorded simulated case scenarios as pupil responses were assessed by eye trackers. Autonomic arousal was assessed as pupil dilation in periods in which critical information was provided (first period [T1]: clinical data, second period [T2]: neurologic status, and third period [T3]: magnetic resonance imaging data). Data were analyzed from September 2018 to March 2020. The traffic light system (TLS)-based educational intervention vs usual care (unexposed). The TLS (use of established associations between traffic light colors and actions to stop or proceed) assists participants in identifying factors associated with worse prognosis in MS care, thereby facilitating the treatment decision-making process by use of established associations between red, green, and yellow colors and risk levels, and actions (treatment decisions). Pupil assessment was the primary autonomic outcome. To test the treatment effect of the educational intervention (TLS), difference-in-differences models (also called untreated control group design with pretest and posttest) were used. Of 38 eligible participants, 34 (89.4%) neurologists completed the study. The mean (SD) age was 44.6 (11.6) years; 38.3% were female and 20 (58.8%) were MS specialists. Therapeutic inertia was present in 50.0% (17 of 34) of all participants and was associated with greater pupil dilation. For every additional SD of pupil dilation, the odds of TI increased by 51% for T1 (odds ratio, 1.51; 95% CI, 1.12-2.03), by 31% for T2 (odds ratio, 1.31; 95% CI, 1.08-1.59), and by 49% for T3 (odds ratio, 1.49; 95% CI, 1.13-1.97). The intervention significantly reduced TI (risk reduction, 31.5%; 95% CI, 16.1%-47.0%). Autonomic arousal responses mediated 29.0% of the effect of the educational intervention on TI. In this randomized clinical trial, the TLS intervention decreased TI as measured by pupil dilation, which suggests that individual autonomic arousal is an indicator of how physicians handle uncertainty when making live therapeutic decisions. Pupil response, a biomarker of TI, may eventually be useful in medical education. ClinicalTrials.gov Identifier: NCT03134794.


Human Derived Immortalized Dermal Papilla Cells With a Constant Expression of Testosterone Receptor.
Androgenetic alopecia (AGA) is the most common type of hair loss, and is mainly caused by the biological effects of testosterone on dermal papilla cells (DPCs). In vitro culturing of DPCs might be a useful tool for the screening of target molecule of AGA. However, primary DPCs cannot continuously proliferate owing to cellular senescence and cell culture stress. In this study, we introduced mutant cyclin-dependent kinase 4 (CDK4), Cyclin D1, and telomerase reverse transcriptase (TERT) into DPCs. We confirmed protein expression of CDK4 and Cyclin D1, and enzymatic activity of TERT. Furthermore, we found the established cell line was free from cellular senescence. We also introduced the androgen receptor gene using a recombinant retrovirus, to compensate the transcriptional suppressed endogenous androgen receptor in the process of cell proliferation. Furthermore, we detected the efficient nuclear translocation of androgen receptor into the nucleus after the treatment of dihydrotestosterone, indicating the functionality of our introduced receptor. Our established cell line is a useful tool to identify the downstream signaling pathway, which activated by the testosterone.


Repeated high blood pressure at 6 and 11 years at the Pelotas 2004 birth cohort study.
We evaluated the prevalence and the factors associated with repeated high systolic (SBP) and diastolic blood pressure (DBP) at 6- and 11-year follow-ups of children from the Pelotas (Brazil) 2004 Birth Cohort. All live births to mothers living in the urban area of Pelotas were enrolled in the cohort. Blood pressure (BP) values were transformed into Z-scores by sex, age, and height. High SBP and DBP were defined as repeated systolic and diastolic BP Z-scores on the ≥95th percentile at the two follow-ups. Prevalence (95% confidence interval) of repeated high SBP, DBP, and both (SDBP) were calculated. Associations with maternal and child characteristics were explored in crude and adjusted logistic regression analyses. A total of 3182 cohort participants were analyzed. Prevalence of repeated high SBP, DBP and SDBP was 1.7% (1.2-2.1%), 2.3% (1.8-2.9%) and 1.2% (0.9-1.6%), respectively. Repeated high SBP was associated with males, gestational diabetes mellitus (2.92; 1.13-7.58) and obesity at 11 years (2.44; 1.29-4.59); while repeated high DBP was associated with females, family history of hypertension from both sides (3.95; 1.59-9.85) and gestational age < 34 weeks (4.08; 1.52-10.96). Repeated high SDBP was not associated with any of the characteristics investigated. Prevalence of repeated high SBP, DBP, and SDBP were within the expected distribution at the population level. Nonetheless, gestational diabetes mellitus, obesity, family history of hypertension, and prematurity increased the risk of repeated high blood pressure measured at two occasions 5 years apart.


Phosphodiesterase A1, a regulator of cellulose synthesis in Acetobacter xylinum, is a heme-based sensor.
The phosphodiesterase A1 protein of Acetobacter xylinum, AxPDEA1, is a key regulator of bacterial cellulose synthesis. This phosphodiesterase linearizes cyclic bis(3'-->5')diguanylic acid, an allosteric activator of the bacterial cellulose synthase, to the ineffectual pGpG. Here we show that AxPDEA1 contains heme and is regulated by reversible binding of O(2) to the heme. Apo-AxPDEA1 has less than 2% of the phosphodiesterase activity of holo-AxPDEA1, and reconstitution with hemin restores full activity. O(2) regulation is due to deoxyheme being a better activator than oxyheme. AxPDEA1 is homologous to the Escherichia coli direct oxygen sensor protein, EcDos, over its entire length and is homologous to the FixL histidine kinases over only a heme-binding PAS domain. The properties of the heme-binding domain of AxPDEA1 are significantly different from those of other O(2)-responsive heme-based sensors. The rate of AxPDEA1 autoxidation (half-life > 12 h) is the slowest observed so far for this type of heme protein fold. The O(2) affinity of AxPDEA1 (K(d) approximately 10 microM) is comparable to that of EcDos, but the rate constants for O(2) association (k(on) = 6.6 microM(-)(1) s(-)(1)) and dissociation (k(off) = 77 s(-)(1)) are 2000 times higher. Our results illustrate the versatility of signal transduction mechanisms for the heme-PAS class of O(2) sensors and provide the first example of O(2) regulation of a second messenger.


Microplastic-induced damage in early embryonal development of sea urchin Sphaerechinus granularis.
Two microplastic sets, polystyrene (PS) and polymethyl methacrylate (PMMA), were tested for adverse effects on early life stages of Sphaerechinus granularis sea urchins. Microparticulate PS (10, 80 and 230 μm diameter) and PMMA (10 and 50 μm diameter) were tested on developing S. granularis embryos from 10 min post-fertilisation (p-f) to the pluteus larval stage (72 h p-f), at concentrations ranging from 0.1 to 5 mg L-1. Both PS and PMMA exposures resulted in significant concentration-related increase of developmental defects and of microplastic uptake in plutei. Moreover, embryo exposures to PS and PMMA (5 and 50 mg L-1) from 10 min to 5 h p-f resulted in a significant increase of cytogenetic abnormalities, expressed as significantly increased mitotic aberrations, while mitotoxicity (as % embryos lacking active mitoses) was observed in embryos exposed to PS, though not to PMMA. When S. granularis sperm suspensions were exposed for 10 min to PS or to PMMA (0.1-5 mg L-1), a significant decrease of fertilisation success was observed following sperm exposure to 0.1 mg L-1 PS, though not to higher PS concentrations nor to PMMA. Sperm pretreatment, however, resulted in significant offspring damage, as excess developmental defects in plutei, both following sperm exposure to PS and PMMA, thus suggesting transmissible damage from sperm pronuclei to the offspring. The overall results point to relevant developmental, cytogenetic and genotoxic effects of PS and PMMA microplastics to S. granularis early life stages, warranting further investigations of other microplastics and other target biota.


Serologic response to meningococcal vaccination in patients with paroxysmal nocturnal hemoglobinuria (PNH) chronically treated with the terminal complement inhibitor eculizumab.
Eculizumab is indicated for the therapy of patients with symptomatic paroxysmal nocturnal hemoglobinuria (PNH). Due to inhibition of terminal complement cascade, patients on eculizumab are susceptible to Neisseria meningitidis infections. The two mainstays to reduce the risk of infection are vaccination and antibiotic prophylaxis. In this retrospective study, serologic response was analyzed after vaccination with a meningococcal vaccine in 23 PNH patients (median age 36 years; range 25 - 88 years; 15 males, 8 females) by measuring serum bactericidal assay (SBA) using rabbit complement (rSBA) titers against meningococcal serogroups A, C, W, and Y. Serologic protection was defined by an rSBA titer ≥1:8. Forty-three percent (10/23) were vaccinated more than once due to chronic eculizumab treatment. Overall serologic response for the meningococcal serogroups was A: 78% (18/23), C: 87% (20/23), W: 48% (11/23), and Y: 70% (16/23). No meningococcal infections have been observed. As immunological response to vaccines varies, the use of serologic response analyses is warranted. Re-vaccination with a tetravalent conjugate vaccine under eculizumab therapy every 3 years is essential or should be based on response rates. If meningococcal infection is suspected, standby therapy with ciprofloxacin and immediate medical evaluation are recommended. The novel vaccines covering serogroup B may even further reduce the risk for infection.


Links between mothers' and fathers' perceptions of infant temperament and coparenting.
This study examined the contributions of infant temperament, marital functioning, and the division of parenting on the quality of the coparenting relationship for couples parenting 6-month-old infants. Marital functioning was assessed prenatally. When infants were 6 months old, infant temperamental characteristics (i.e., distress to limits, distress to novelty, and soothability), division of parenting, and coparenting were rated by parents. Results indicated that the reactivity dimension of temperament was only associated with reduced coparenting quality if other stressors were present and these effects were different for mothers and fathers. Mothers who perceived their infants as more reactive only reported more negative coparenting if their infants were also not easily soothed or if mothers were dissatisfied with how parenting tasks were divided and performed given their prior expectations. Whereas fathers reported more negative coparenting when faced with a more reactive infant and they reported a low quality marital relationship.


Simvastatin strongly reduces levels of Alzheimer's disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo.
Recent epidemiological studies show a strong reduction in the incidence of Alzheimer's disease in patients treated with cholesterol-lowering statins. Moreover, elevated Abeta42 levels and the varepsilon4 allele of the lipid-carrier apolipoprotein E are regarded as risk factors for sporadic and familial Alzheimer's disease. Here we demonstrate that the widely used cholesterol-lowering drugs simvastatin and lovastatin reduce intracellular and extracellular levels of Abeta42 and Abeta40 peptides in primary cultures of hippocampal neurons and mixed cortical neurons. Likewise, guinea pigs treated with high doses of simvastatin showed a strong and reversible reduction of cerebral Abeta42 and Abeta40 levels in the cerebrospinal fluid and brain homogenate. These results suggest that lipids are playing an important role in the development of Alzheimer's disease. Lowered levels of Abeta42 may provide the mechanism for the observed reduced incidence of dementia in statin-treated patients and may open up avenues for therapeutic interventions.


Telemedicine in Chronic Wound Management: Systematic Review And Meta-Analysis.
Chronic wounds have been a great burden to patients and the health care system. The popularity of the internet and smart devices, such as mobile phones and tablets, has made it possible to adopt telemedicine (TM) to improve the management of chronic wounds. However, studies conducted by different researchers have reported contradictory results on the effect of TM on chronic wound management. The aim of this work was to evaluate the efficacy and safety of TM in chronic wound management. We systematically searched multiple electronic databases (MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials [CENTRAL]) to identify eligible studies published from inception to June 12, 2019. Inclusion criteria were randomized controlled trials (RCTs) and interventional cohort studies that investigated the use of TM in chronic wound management. RCT and observational data were analyzed separately. A meta-analysis and qualitative analysis were conducted to estimate endpoints. A total of 6 RCTs and 6 cohort studies including 3913 patients were included. Of these, 4 studies used tablets or mobile phones programmed with apps, such as Skype and specialized interactive systems, whereas the remaining 8 studies used email, telephone, and videoconferencing to facilitate the implementation of TM using a specialized system. Efficacy outcomes in RCTs showed no significant differences in wound healing (hazard ratio [HR] 1.16, 95% CI 0.96-1.39; P=.13), and wound healing around 1 year (risk ratio [RR] 1.05, 95% CI 0.89-1.23; P=.15). Noninferiority criteria of TM were met. A decreased risk of amputation in patients receiving TM was revealed (RR 0.45, 95% CI 0.29-0.71; P=.001). The result of cohort studies showed that TM was more effective than standard care (HR 1.74, 95% CI 1.43-2.12; P<.001), whereas the outcome efficacy RR of wound healing around 1 year (RR 1.21, 95% CI 0.96-1.53; P=.56) and 3 months (RR 1.24, 95% CI 0.47-3.3; P=.67) was not significantly different between TM and standard care. Noninferiority criteria of TM were met for wound healing around 1 year in cohort studies. Currently available evidence suggests that TM seems to have similar efficacy and safety, and met noninferiority criteria with conventional standard care of chronic wounds. Large-scale, well-designed RCTs are warranted.


Mapping Acute Coronary Syndrome Registries to SNOMED CT. A Comparative Study between Malaysia and Sweden.
Malaysia and Sweden have mapped their acute coronary syndrome registries using SNOMED CT. Since similar-purposed patient registries can be expected to collect similar data, these data should be mapped to the same SNOMED CT codes despite the different languages used. Previous studies have however shown variations in mapping between different mappers but the reasons behind these variations and the influence of different mapping approaches are still unknown. To analyze similar-purposed registries and their registry-to-SNOMED CT maps, using two national acute coronary syndrome registries as examples, to understand the reasons for mapping similarities and differences as well as their implications. The Malaysian National Cardiovascular Disease - Acute Coronary Syndrome (NCVD-ACS) registry was compared to the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA). The structures of NCVD-ACS and RIKS-HIA registry forms and their distributions of headings, variables and values were studied. Data items with equivalent meaning (EDIs) were paired and their mappings were categorized into match, mismatch, and non-comparable mappings. Reasons for match, mismatch and non-comparability of each paired EDI were seen as factors that contributed to the similarities and differences between the maps. The registries and their respective maps share a similar distribution pattern regarding the number of headings, variables and values. The registries shared 101 EDIs, whereof 42 % (42) were mapped to SNOMED CT. 45 % (19) of those SNOMED CT coded EDIs had matching codes. The matching EDIs occurred only in pre-coordinated SNOMED CT expressions. Mismatches occurred due to challenges arising from the mappers themselves, limitations in SNOMED CT, and complexity of the registries. Non-comparable mappings appeared due to the use of other coding systems, unmapped data items, as well as requests for new SNOMED CT concepts. To ensure reproducible and reusable maps, the following three actions are recommended: (i) develop a specific mapping guideline for patient registries; (ii) openly share maps; and (iii) establish collaboration between clinical research societies and the SNOMED CT community.


A Sport Education Fitness Season's Impact on Students' Fitness Levels, Knowledge, and In-Class Physical Activity.
The purpose of this study was to determine the extent to which a sport education season of fitness could provide students with recommended levels of in-class moderate-to-vigorous physical activity (MVPA) while also increasing students' fitness knowledge and fitness achievement. One hundred and sixty-six 5th-grade students (76 boys, 90 girls) participated in a 20-lesson season called "CrossFit Challenge" during a 4-week period. The Progressive Aerobic Cardiovascular Endurance Run, push-ups, and curl-ups tests of the FITNESSGRAM® were used to assess fitness at pretest and posttest, while fitness knowledge was assessed through a validated, grade-appropriate test of health-related fitness knowledge (HRF). Physical activity was measured with Actigraph GT3X triaxial accelerometers. Results indicated a significant time effect for all fitness tests and the knowledge test. Across the entire season, the students spent an average of 54.5% of lesson time engaged in MVPA, irrespective of the type of lesson (instruction, free practice, or competition). The results suggest that configuring the key principles of sport education within a unit of fitness is an efficient model for providing students with the opportunity to improve fitness skill and HRF knowledge while attaining recommended levels of MVPA.


Antibodies against sialophorin (CD43) enhance the capacity of dendritic cells to cluster and activate T lymphocytes.
CD43 is a leukocyte membrane glycoprotein rich in negatively charged sialic acid residues that may act as an anti-adhesion molecule. In this study, we analyzed the expression and function of CD43 on epidermal Langerhans cells (LC) and dendritic cells derived from adherent peripheral blood monocytes treated with granulocyte-macrophage CSF and IL-4 (Mo-DC). Both freshly isolated LC (fLC) and Mo-DC expressed uniformly high amounts of membrane CD43, with levels unchanged in 48-h cultured LC or in TNF-alpha-treated Mo-DC. When fLC or Mo-DC were transiently preincubated with anti-CD43 mAb or neuraminidase, they formed much larger clusters with T cells as compared with cells incubated with control mAb. Moreover, a significantly increased proliferation of naive allogeneic T cells in a primary MLR assay was induced. Anti-CD43-treated Mo-DC also presented tetanus toxoid to primed T cells more efficiently. Immunofluorescence and immunogold electron microscopy showed that following Ab cross-linking and warming to 37 degrees C, CD43 is progressively removed from the cell surface and is internalized within endosomes and vacuoles. In addition, fLC and Mo-DC incubated with anti-CD43 mAb increased expression of HLA-DR, ICAM-1, B7-1, B7-2, CD40, and CD83 after 24 h, and this was partially prevented by culturing cells in the presence of cycloheximide. We thus postulate that membrane CD43, other than serving as anti-adhesion molecule, can mediate activation signals in immature DC, leading to augmented expression of adhesion/costimulatory molecules and Ag-presenting function.


Selected Columns of the Density Matrix in an Atomic Orbital Basis I: An Intrinsic and Non-iterative Orbital Localization Scheme for the Occupied Space.
In this work, we extend the selected columns of the density matrix (SCDM) methodology [J. Chem. Theory Comput. 2015, 11, 1463-1469]─a non-iterative and real-space procedure for generating localized occupied orbitals for condensed-phase systems─to the construction of local molecular orbitals (LMOs) in systems described using non-orthogonal atomic orbital (AO) basis sets. In particular, we introduce three different theoretical and algorithmic variants of SCDM (referred to as SCDM-M, SCDM-L, and SCDM-G) that can be used in conjunction with the AO basis sets used in standard quantum chemistry codebases. The SCDM-M and SCDM-L variants are based on a pivoted QR factorization of the Mulliken and Löwdin representations of the density matrix and are tantamount to selecting a well-conditioned set of projected atomic orbitals (PAOs) and projected (symmetrically-) orthogonalized atomic orbitals, respectively, as proto-LMOs that can be orthogonalized to exactly span the occupied space. The SCDM-G variant is based on a real-space (grid) representation of the wavefunction, and therefore has the added flexibility of considering a large number of grid points (or δ functions) when selecting a set of well-conditioned proto-LMOs. A detailed comparative analysis across molecular systems of varying size, dimensionality, and saturation level reveals that the LMOs generated by these three non-iterative/direct SCDM variants are robust, comparable in orbital locality to those produced with the iterative Boys or Pipek-Mezey (PM) localization schemes, and completely agnostic toward any single orbital locality metric. Although all three SCDM variants are based on the density matrix, we find that the character of the generated LMOs can differ significantly between SCDM-M, SCDM-L, and SCDM-G. In this regard, only the grid-based SCDM-G procedure (like PM) generates LMOs that qualitatively preserve σ-π symmetry (in systems such as s-trans alkenes), and are well-aligned with chemical (i.e., Lewis structure) intuition. While the direct and standalone use of SCDM-generated LMOs should suffice for most chemical applications, our findings also suggest that the use of these orbitals as an unbiased and cost-effective (initial) guess also has the potential to improve the convergence of iterative orbital localization schemes, in particular for large-scale and/or pathological molecular systems.


Whole-body 3D water/fat resolved continuously moving table imaging.
To study the feasibility of three-dimensional (3D) whole-body, head-to-toe, water/fat resolved MRI, using continuously moving table imaging technology. Experiments were performed on nine healthy volunteers, acquiring 3D whole-body head-to-toe data under continuous motion of the patient table. Two different approaches for water/fat separation have been studied. Results of a three-point chemical shift encoding and a spectral presaturation technique were compared with respect to image quality and performance. Furthermore, fast, low-resolution, whole-body water/fat imaging was performed in two minutes total scan time to derive patient-specific parameters such as the total water/fat ratio, the intraperitoneal/extraperitoneal fat ratio, and the body mass index (BMI). Good water/fat separation with decent image quality was obtained in all cases. The three-point chemical shift encoding approach was found to be more efficient with respect to signal-to-noise ratio (SNR) and acquisition time. Whole-body water/fat sensitive MRI using continuous table motion is feasible and could be of interest for clinical practice. Some improvements of the method are desirable.


TEG-guided resuscitation is superior to standardized MTP resuscitation in massively transfused penetrating trauma patients.
For nearly a decade, our center performed thromboelastograms (TEGs) to analyze coagulation profiles, allowing rapid data-driven blood component therapy. After consensus recommendations for massive transfusion protocols (MTPs), we implemented an MTP in October 2009 with 1:1:1 ratio of blood (red blood cells [RBC]), plasma (fresh-frozen plasma [FFP]), and platelets. We hypothesized that TEG-directed resuscitation is equivalent to MTP resuscitation. All patients receiving 6 units (U) or more of RBC in the first 24 hours for 21 months before and after MTP initiation in an urban Level I trauma center were examined. Demographics, mechanism of injury (MOI), Injury Severity Score (ISS), 24-hour volume of RBC, FFP, platelets, crystalloid, and 30-day mortality were compared, excluding patients with traumatic brain injuries. Variables were analyzed using Student's t-test and χ2 or Fisher's exact test. For the preMTP group, there were 165 patients. In the MTP group, there were 124 patients. There were no significant differences in ISS, age, or sex. PreMTP patients with 6U or more RBC had significantly more penetrating MOI (p = 0.017), whereas preMTP patients with 10U or more RBC had similar MOIs. All patients received less crystalloid after MTP adoption (p < 0.001). There was no difference in volume of blood products or mortality in patients receiving 6U or more RBC. Blunt trauma MTP patients who received 10U or more RBC received more FFP (p = 0.02), with no change in mortality. Penetrating trauma patients who received 10U or more RBC received a similar volume of FFP; however, mortality increased from 54.1% for MTP versus 33.3% preMTP (p = 0.04). TEG-directed resuscitation is equivalent to standardized MTP for patients receiving 6U or more RBC and for blunt MOI patients receiving 10U or more RBC. MTP therapy worsened mortality in penetrating MOI patients receiving 10U or more RBC, indicating a continued need for TEG-directed therapy. A 1:1:1 strategy may not be adequate in all patients. Therapeutic study, level IV.


Immunological investments reflect parasite abundance in island populations of Darwin's finches.
The evolution of parasite resistance can be influenced by the abundance of parasites in the environment. However, it is yet unresolved whether vertebrates change their investment in immune function in response to variation in parasite abundance. Here, we compare parasite abundance in four populations of small ground finches (Geospiza fuliginosa) in the Galapagos archipelago. We predicted that populations exposed to high parasite loads should invest more in immune defence, or alternatively use a different immunological defence strategy. We found that parasite prevalence and/or infection intensity increased with island size. As predicted, birds on large islands had increased concentrations of natural antibodies and mounted a strong specific antibody response faster than birds on smaller islands. By contrast, the magnitude of cell-mediated immune responses decreased with increasing parasite pressure, i.e. on larger islands. The data support the hypothesis that investments into the immune defence are influenced by parasite-mediated selection. Our results are consistent with the hypothesis that different immunological defence strategies are optimal in parasite-rich and parasite-poor environments.


Defective adhesion to extracellular matrix leads to altered social behaviour in cultured fibroblasts.
We describe the properties of variant mouse fibroblasts selected for poor adhesion to growth substratum containing subcellular matrix accumulated by adherent cells at confluence. The variant cells adhere to virgin plastic and grow normally to confluence in the presence of serum. After subculture and reseeding onto the same surface the cells initially adhere, but after a further 2 days of growth they retract into aggregates and detach. If the aggregates are dispersed and cells reseeded onto the same surface they remain rounded. However, if the same cells are added back to virgin plastic they adhere and grow normally. The retraction can be abolished by treating the subcellular matrix-coated plastic with papain. This behaviour therefore reflects the ability of the cells to modify the composition of the underlying substratum during growth. The variant cells also exhibit retraction 2 days after seeding on a surface previously containing wild-type cells at confluence, while wild-type cells do not retract on subcellular matrix deposited by variants. This shows that the variant behaviour arises not from a deficiency in the subcellular matrix, but from an alteration in the adhesive capacity of the cells. The results are interpreted in terms of three putative adhesion mechanisms: cell-cell adhesion in confluent monolayers and aggregates; 'early' type cell-substratum adhesion, which occurs during culture on virgin plastic; and 'late' type cell-substratum adhesion occurring on surfaces containing accumulated subcellular matrix. The variant phenotype is characterized by a deficiency in the last of these. It is also associated with an increased ability to grow in suspension culture at high dilution.


Esophago-bronchial fistula in a patient with rheumatoid arthritis.
A 58-year-old woman with active rheumatoid arthritis developed an esophago-bronchial fistula in close temporal proximity to the eruption of subcutaneous nodules and a worsening of her joint symptoms. Possible mechanisms to explain the fistula formation are discussed.


UPL1 and 2, two 405 kDa ubiquitin-protein ligases from Arabidopsis thaliana related to the HECT-domain protein family.
The ubiquitin/26S proteasome pathway is a major route for degrading abnormal and important short-lived regulatory proteins in eukaryotes. Covalent attachment of ubiquitin, which triggers entry of target proteins into the pathway, is accomplished by an ATP-dependent reaction cascade involving the sequential action of three enzymes, E1s, E2s and E3s. Although much of the substrate specificity of the pathway is determined by E3s (or ubiquitin-protein ligases, UPLs), little is known about these enzymes in plants and how they choose appropriate targets for ubiquitination. Here, we describe two 405 kDa E3s (UPL1 and 2) from Arabidopsis thaliana related to the HECT-E3 family that is essential in yeast and animals. UPL1 and 2 are encoded by 13 kbp genes 26 cM apart on chromosome I, that are over 95% identical within both the introns and exons, suggesting that the two loci arose from a recent gene duplication. The C-terminal HECT domain of UPL1 is necessary and sufficient to conjugate ubiquitin in vitro in a reaction that requires the positionally conserved cysteine within the HECT domain, E1, and an E2 of the UBC8 family. Given that HECT E3s help define target specificity of the ubiquitin conjugation, a continued characterization of UPL1 and 2 should be instrumental in understanding the functions of ubiquitin-dependent protein turnover in plants and for identifying pathway substrates.


Single-copy nuclear genes recover cretaceous-age divergences in bees.
We analyzed the higher level phylogeny of the bee family Halictidae based on the coding regions of three single-copy nuclear genes (long-wavelength [LW] opsin, wingless, and elongation factor 1-alpha [EF-1 alpha]). Our combined data set consisted of 2,234 aligned nucleotide sites (702 base pairs [bp] for LW opsin, 405 bp for wingless, and 1,127 bp for EF-1 alpha) and 779 parsimony-informative sites. We included 58 species of halictid bees from 33 genera, representing all subfamilies and tribes, and rooted the trees using seven outgroups from other bee families: Colletidae, Andrenidae, Melittidae, and Apidae. We analyzed the separate and combined data sets by a variety of methods, including equal weights parsimony, maximum likelihood, and Bayesian methods. Analysis of the combined data set produced a strong phylogenetic signal with high bootstrap and Bremer support and high posterior probability well into the base of the tree. The phylogeny recovered the monophyly of the Halictidae and of all four subfamilies and both tribes, recovered relationships among the subfamilies and tribes congruent with morphology, and provided robust support for the relationships among the numerous genera in the tribe Halictini, sensu Michener (2000). Using our combined nucleotide data set, several recently described halictid fossils from the Oligocene and Eocene, and recently developed Bayesian methods, we estimated the antiquity of major clades within the family. Our results indicate that each of the four subfamilies arose well before the Cretaceous-Tertiary boundary and suggest that the early radiation of halictid bees involved substantial African-South American interchange roughly coincident with the separation of these two continents in the late Cretaceous. This combination of single-copy nuclear genes is capable of recovering Cretaceous-age divergences in bees with high levels of support. We propose that LW opsin, wingless, and EF-1 alpha(F2 copy) may be useful in resolving relationships among bee families and other Cretaceous-age insect lineages.


Identification of a potential signature to predict the risk of postmenopausal osteoporosis.
Postmenopausal osteoporosis (PMOP) is related to the elevated risk of fracture in postmenopausal women. Thus, to effectively predict the occurrence of PMOP, we explored a novel gene signature for the prediction of PMOP risk. The WGCNA analysis was conducted to identify the PMOP-related gene modules based on the data from GEO database (GSE56116 and GSE100609). The "limma" R package was applied for screening differentially expressed genes (DEGs) based on the data from GSE100609 dataset. Next, LASSO Cox algorithm were applied to identify valuable PMOP-related risk genes and construct a risk score model. GSEA was then conducted to analyze potential signaling pathways between high-risk (HR) score and low-risk (LR) score groups. A novel risk model with five PMOP-related risk genes (SCUBE3, TNNC1, SPON1, SEPT12 and ULBP1) was developed for predicting PMOP risk status. RT-qPCR and western blot assays validated that compared to postmenopausal non-osteoporosis (non-PMOP) patients, SCUBE3, ULBP1, SEPT12 levels were obviously elevated, and TNNC1 and SPON1 levels were reduced in blood samples from PMOP patients. Additionally, PMOP-related pathways such as MAPK signaling pathway, PI3K-Akt signaling pathway and HIF-1 signaling pathway were significantly activated in the HR-score group compared to the LR-score group. The circRNA-gene-miRNA and gene-transcription factor networks showed that 533 miRNAs, 13 circRNAs and 40 TFs might be involved in regulating the expression level of these five PMOP-related genes. Collectively, we developed a PMOP-related gene signature based on SCUBE3, TNNC1, SPON1, SEPT12 and ULBP1 genes, and higher risk score indicated higher risk suffering from PMOP.


Circulating concentrations of interleukin (IL)-17 in patients with multiple sclerosis: Evaluation of the effects of gender, treatment, disease patterns and IL-23 receptor gene polymorphisms.
Background: Interleukin (IL)-17/IL-23 axis performs a prominent role in the pathogenesis of several autoimmune disorders. This study aimed to investigate the concentrations of IL-17 in patients with multiple sclerosis (MS) and its relationship with gender, medication, disease forms and single nucleotide polymorphisms (SNP) in IL-23R gene, including rs11209026 and rs1004819. Methods: The blood specimens were obtained from 135 healthy individuals and 135 MS patients. The patients exhibited relapsing-remitting (RRMS; n = 65), primary progressive (PPMS; n = 19), secondary progressive (SPMS; n = 35) or progressive relapsing (PRMS; n = 14) MS. The DNA was analyzed for SNPs using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and IL-17 concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Results: We have observed elevated serum IL-17 concentrations in MS patients compared with healthy individuals (P < 0.001). The men with MS had higher IL-17 concentrations than women patients (P < 0.050). Untreated patients had significantly higher IL-17 concentrations than healthy individuals and treated patients (P < 0.001 and P < 0.010, respectively). The IL-17 concentrations were significantly decreased in patients treated with interferon-β (IFN-β), methylprednisolone or both drugs as compared with untreated MS patients (P < 0.050, P < 0.020 and P < 0.050, respectively). The IL-17 concentrations were also significantly higher in patients with RRMS and PRMS compared with healthy individuals (P < 0.005 and P < 0.010, respectively). The genetic variations at SNPs rs11209026 and rs1004819 were not significantly different between healthy individuals and patients. The IL-17 concentrations were not influenced by genetic variations at investigated SNPs. Conclusion: These results indicated higher levels of IL-17 in MS patients that may be influenced by disease patterns, medication and gender. No association was observed between investigated SNPs and MS.


How exposure to body neutrality content on TikTok affects young women's body image and mood.
Body neutrality aims to encourage a non-judgmental attitude towards the body and prioritize functionality over appearance. This study examined the impact of exposure to TikTok body neutrality content on young women's body image and mood. The sample comprised 189 undergraduate women (Mage = 19.25, SD = 1.98) who were randomly assigned to view one of three compilation TikTok videos on body neutrality, thin ideal, or art. Controlling for pre-test measures, results showed that women in the body neutrality group reported higher functionality appreciation and body satisfaction than women in the thin ideal and art control groups. Higher levels of positive mood and fewer upward appearance comparisons were reported by women in the body neutrality group relative to the thin ideal group. Although women in the body neutrality and thin ideal groups thought about their appearance and what they were wearing whilst viewing the videos, women in the body neutrality group reported that those thoughts were more positive than those in the thin ideal group. Findings demonstrate that brief exposure to body neutrality content on TikTok may induce immediate positive body image and mood in young women whilst providing a useful alternative to the unrealistic beauty standards popularized on such platforms.


[Care ethics committees].
The author, who in 1976 started the first Healthcare Ethics Committees in Spain, analyses the advantages of being able to count, from the outset, on a moral community of strongly motivated health professionals at a public, university, maternal-infant hospital of reference, privately managed by the Order of San Juan de Dios. From his perspective, he considers that the evolution of these committees shows patterns of similar conflicts in overcoming the ethical-philosophical conflicts of scientific and ethical-religious reductionisms. He considers that only interdisciplinary and transdisciplinary dialogue makes it possible, in our plural society, to find--through deliberation--the best route for solving ethical conflicts respecting the dignity of the patients and the health professionals. He opted for an autonomous ethics in a context of faith. He considers it to be an error to replace interdisciplinary dialogue within the hospital with consulting groups or persons specialising in professional ethics, the self-denominated "bioethical consultants", whether they be doctors or lawyers. He is very critical of the widespread error of confusing criteria of positive evaluation of the "Joint Commission" with criteria of careful deliberation, and he schematises models for analysing problems and placing them in context.


Acute osteomyelitis in children: combined Tc-99m and Ga-67 imaging.
This retrospective study was done to determine the value of combined bone (technetium-99m methylene-diphosphonate) and gallium-67 citrate imaging in selected children with complicated clinical situations. Thirty-one children were evaluated for suspected osteomyelitis by bone scan followed within 4 days by a gallium scan. These 31 children represented a subpopulation in whom the Tc-99m scan is known to be potentially unreliable in diagnosing acute osteomyelitis. Eight children had acute osteomyelitis by strict criteria, while 23 did not. The bone scan successfully identified five of the eight with osteomyelitis but was positive in ten of the other 23. The gallium scan correctly identified all eight with osteomyelitis but was positive in seven of the other 23. The gallium scan was significantly less specific when the suspected lesion was in the extremities compared with central locations; causes of false-positive gallium scans included fracture and juvenile rheumatoid arthritis. Combined gallium and bone scanning increased accuracy of the scintigraphic diagnosis of acute osteomyelitis. Both tests may, however, be abnormal in conditions other than osteomyelitis. These findings emphasize the importance of correlating all imaging studies in detection of osteomyelitis.


Lactoferrin attenuates lipopolysaccharide-stimulated inflammatory responses and barrier impairment through the modulation of NF-κB/MAPK/Nrf2 pathways in IPEC-J2 cells.
Lactoferrin (LF) plays critical roles in various physiological processes. However, its protective effects on small intestinal epithelial cells remain poorly understood. This study aimed to investigate its protective effects and underlying mechanisms in vitro on lipopolysaccharide (LPS)-challenged intestinal porcine epithelial cells (IPEC-J2 cells). The IPEC-J2 cells were treated with or without LPS and LF for 24 h and analyzed using various assays. The results indicated that the LPS treatment induced the secretion of pro-inflammatory cytokines [interleukin (IL)-1β, IL-8, and TNF-α], increased cell permeability, and enhanced reactive oxygen species (ROS) production. The LF treatment decreased the secretion and gene expression of IL-1β and downregulated the phosphorylation levels of NF-κB, IκB, P38, and ERK1/2 in LPS-challenged cells. Moreover, the LF treatment decreased cell permeability, enhanced the expression of claudin-1 protein, and inhibited the expression of the myosin light-chain kinase (MLCK) protein in LPS-challenged cells. It also reduced the ROS and MDA production as well as upregulated the GSH-Px activity and the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) protein. Taken together, these results suggested that LF alleviated the LPS-induced cellular inflammation through the attenuation of nuclear factor kappa B (NF-κB)/mitogen-activated protein kinase (MAPK) pathways, maintaining cellular barrier integrity and mitigating oxidative stress.


Preferences of people living with HIV for differentiated care models in Kenya: A discrete choice experiment.
To improve retention on HIV treatment in Africa, public health programs are promoting a family of innovations to service delivery-referred to as "differentiated service delivery" (DSD) models-which seek to better meet the needs of both systems and patients by reducing unnecessary encounters, expanding access, and incorporating peers and patients in patient care. Data on the relative desirability of different models to target populations, which is currently sparse, can help guide prioritization of specific models during scale-up. We conducted a discrete choice experiment to assess patient preferences for various characteristics of treatment services. Clinically stable people living with HIV were recruited from an HIV clinic in Kisumu, Kenya. We selected seven attributes of DSD models drawn from literature review and previous qualitative work. We created a balanced and orthogonal design to identify main term effects. A total of ten choice tasks were solicited per respondent. We calculated relative utility (RU) for each attribute level, a numerical representation of the strength of patient preference. Data were analyzed using a Hierarchical Bayesian model via Sawtooth Software. One hundred and four respondents (37.5% men, 41.1 years mean age) preferred receiving care at a health facility, compared with home-delivery or a community meeting point (RU = 69.3, -16.2, and -53.1, respectively; p << 0.05); receiving those services from clinicians and pharmacists-as opposed to lay health workers or peers (RU = 21.5, 5.9, -24.5; p < 0.05); and preferred an individual support system over a group support system (RU = 15.0 and 4.2; p < 0.05). Likewise, patients strongly preferred longer intervals between both clinical reviews (RU = 40.1 and -50.7 for 6- and 1-month spacing, respectively; p < 0.05) and between ART collections (RU = 33.6 and -49.5 for 6- and1-month spacing, respectively; p < 0.05). Although health systems find community- and peer-based DSD models attractive, clinically stable patients expressed a preference for facility-based care as long as clinical visits were extended to biannual. These data suggest that multi-month scripting and fast-track models best align with patient preferences, an insight which can help prioritize use of different DSD models in the region.


Physiological stress reactivity and recovery related to behavioral traits in dogs (Canis familiaris).
This study investigated whether stress responsiveness (in one context) can be used to predict dog behavior in daily life. On two occasions (NT1 = 32 puppies; NT2 = 16 young adults), dogs' physiological stress response after a behavioral test at home was measured in terms of reactivity (10 min post-test) and recovery (40 min post-test) for three salivary markers: cortisol, chromogranin A (CgA) and secretory immunoglobulin A (sIgA). For each marker, it was determined whether dogs with a strong physiological response displayed different behavior in daily life compared to dogs with a weaker physiological response. The results revealed three main findings: first, for CgA and cortisol, different patterns were identified according to sample time. High reactivity related to desirable traits, whereas slow recovery after the behavioral test related to undesirable traits. The findings suggest that increased levels of CgA and cortisol 10 minutes after the behavioral test reflected an adaptive stress response, whereas elevated levels 40 minutes after the test reflected unsuccessful coping. Second, patterns for sIgA differed from CgA and cortisol: significant associations were only found with behavioral traits at T2, mostly considered desirable and related to Trainability. Possibly, the delayed reaction pattern of sIgA caused this difference between markers, as sIgA reflects the (secondary) immune response to stress, due to immunosuppressive effects of cortisol. Third, predictive capacity of puppies' physiological stress response (T1) was inconclusive, and contrary relations were found with behavioral traits at T2, suggesting that developmental factors play an important role. This study provides new insights about the relation between stress physiology and behavioral traits, and methodological advice is given to study these patterns further. In conclusion, physiological markers could provide additional insights in dogs' tendencies to display certain behaviors, especially at the young adult stage. Further studies are needed to confirm these patterns.


[Variables associated with cognitive deterioration in Parkinson's disease].
The relation between Parkinson s disease (EP) and dementia is both complex and controversial in definition, epidemiology and pathology. Data on the prevalence of dementia in EP vary widely owing to the different populations studied and differences in the definitions used. However, the large population studies (> 200,000 persons), with details of the clinical features of the cases reviewed, show a prevalence of nearly 30%. We wished to investigate whether certain clinical variables in patients with Parkinson s disease, with or without cognitive deterioration might affect the development of neurodegenerative conditions in these patients. The 23 patients with Parkinson s disease included in this study were selected on the clinico-diagnostic criteria of idiopathic Parkinson s disease, namely on the following clinical characteristics: resting tremor, bradykinesia, rigidity and postural instability; we considered that the patients had cognitive deterioration when they obtained scores below 28 points on the cognitive mini-examination, a Spanish adaptation of the Mini Mental State Examination, which has a maximum possible score of 35 points. The results show significant differences in some of the variables studied. We wished to show which variables, such as the age of onset of symptoms and degree of severity of the extrapyramidal disorder in patients with EP, are risk factors for development of neurodegenerative conditions in these patients.


Validation of semi-automated flow-mediated dilation measurement in healthy volunteers.
Flow-mediated dilation (FMD) is a non-invasive imaging modality used to measure endothelial function but has significant intra- and inter-observer variability. The use of semi-automated FMD devices could overcome this limitation. We assessed the reproducibility of same-day semi-automated FMD measurements by investigators who received basic training on the correct use of the device. Forty-three healthy volunteers had two brachial artery FMD measurements performed 20 minutes apart using the UNEX EF 38G device, and automated outputs were produced. Images were also manually analysed using edge-detection software. The reproducibility of repeat FMD measurements within individuals was compared for automated and manual readings, and the correlation between analytical techniques was calculated. Twenty-five percent of scans were of non-diagnostic quality (n = 32). Automated analyses demonstrated sub-optimal reproducibility and measurement variability [intraclass correlation coefficient (ICCC) = 0.334, coefficient of variation (CV) = 45.87%]. In contrast, manually analysed scans had excellent reproducibility and low measurement variance (ICCC = 0.815, CV = 11.40%). FMD values obtained from automated and manual analysis correlated poorly (r = 0.164), whereas resting (r = 0.955) and maximal brachial artery diameters demonstrated excellent correlation (r = 0.867). Manually evaluated serial UNEX EF readings have good reproducibility and therefore, the optimal FMD workflow involves manual analyses prior to independent automated interrogation. The high non-diagnostic scan rate is most likely the result of insufficient training and indicates that semi-automatic devices such as UNEX EF should be used by experienced investigators to achieve optimal results.


Knowledge resource preferences of family physicians.
Because of the pivotal role of medical knowledge in clinical problem solving, it is important to understand how clinicians decide to seek additional knowledge for patient care decisions and how they choose among the resources available to them. Using a self-administered questionnaire, 126 family physicians reported their use of 11 types of knowledge resources for answering patient-specific questions arising in clinical practice. They reported almost daily use of the Physicians' Desk Reference and more often than weekly use of colleagues. There was little use reported of Index Medicus or computer-based bibliographic retrieval systems. The research literature of medicine was used infrequently and rated among the lowest of resources in terms of credibility, availability, searchability, understandability, and applicability. In deciding among a subset of knowledge resources for answering a clinical practice question, resource cost variables related to clinical availability and applicability of the information to the problem at hand appeared to be more influential in the minds of physicians than factors related to quality of the resource. These findings have important implications for the development and deployment of knowledge resources intended to be useful and used in clinical practice.


Regression of papillomas induced by cottontail rabbit papillomavirus is associated with infiltration of CD8+ cells and persistence of viral DNA after regression.
Cottontail rabbit papillomavirus (CRPV) is a highly oncogenic papillomavirus and has been successfully used as a model to develop protective vaccines against papillomaviruses. Papillomas induced by the virus may spontaneously regress, suggesting that CRPV can also serve as a model to develop therapeutic vaccines. As a first step toward this goal, we have analyzed immunologic and viral aspects associated with papilloma regression and have identified several features unique to regression. Immunohistochemical staining of biopsies from growing and regressing papillomas and from sites after complete regression showed infiltration of CD8+ cells into the basal and suprabasal layers of the epidermis only during active regression. In situ hybridizations with mRNA-specific probes were strongly positive for E6 and E7 mRNAs during regression, but no late mRNA was present. Viral DNA was detected by in situ hybridization during regression but not after regression. However, analysis by PCR revealed persistence of viral DNA for several months at the majority of regression sites. The results suggest that stimulation of a strong CD8+ response to virus-infected cells is important for an effective therapeutic vaccine and that special attention should be given to the suppression of latent infection.


Apparent transverse relaxation rates in systems with coupled carbon-13 spins.
In systems with homonuclear scalar couplings, the envelopes of spin echoes obtained with simple refocusing pulses or trains of such pulses are normally modulated so that it is difficult to extract transverse relaxation rates. It has been shown recently that echo modulations can be quenched by cumulative pulse errors that arise after applying a large number of refocusing pulses with moderate rf amplitudes. The resulting unmodulated decays allow one to extract apparent transverse relaxation rates. Early work on systems comprising only two nitrogen-15 nuclei or two carbon-13 spins has recently been extended to systems with coupled protons. This work focuses on systems with three coupled carbon-13 spins, which in turn are coupled to several neighbouring protons. Unmodulated echo trains can be obtained by optimizing the pulse interval, the carrier frequency and the rf amplitude of the refocusing pulses.


Feline vaccine-associated fibrosarcoma: morphologic distinctions.
Forty-four primary feline vaccine-associated fibrosarcomas and 16 recurrences were examined histologically for detailed morphologic characterization with emphasis on tumor grade, presence of neoplastic multinucleated giant cells, presence and proportion of T and B lymphocytes within the tumor, and thin and intermediate filament contents of neoplastic and stromal cells. The microvascularity and proliferation rates of central and peripheral areas of the tumors were also quantified by computerized image analysis. For primary fibrosarcomas, 11 of 44 (25%) were grade I, 21 of 44 (47.7%) were grade II, and 12 of 44 (27.3%) were grade III. The recurrences followed a similar pattern: 4 of 16 (25%) were grade I, 8 of 16 (50%) were grade II, and 4 of 16 (25%) were grade III. A positive correlation was found between the presence of neoplastic multinucleated giant cells and tumor grade. These cells were present in 9 of 12 (75%) of grade III and none of the grade I tumors. Prominent peritumoral lymphoid aggregates or follicles were present in 59% of the tumors, and many contained high proportions of T lymphocytes, varying from 19 to 87%. All fibrosarcomas were immunoreactive for vimentin and 28 of 44 (64%) were reactive for alpha-smooth muscle actin. The actin-positive cells were either part of the tumor or formed a capsule around tumor nodules. The peripheral vascularity was significantly higher than the central vascular density but no difference was found in tumor cell proliferation rates between the two areas. Centrally located, fluid-filled micro- or macrocavitations were frequently observed in the large vaccine sarcomas and probably formed secondary to rapid tumor growth and central necrosis.


Influence of Beta-1 Adrenergic Receptor Genotype on Cardiovascular Response to Exercise in Healthy Subjects.
The beta-1 adrenergic receptor (ADRB1) has been shown to play a functional role in cardiomyocyte function and accounts for up to 80% of the cardiac tissue adrenergic receptors with ADRB1 stimulation increasing cardiac rate, contractility and work. Multiple polymorphisms of the ADRB1 have been identified such as the Gly49 polymorphism that includes at least one glycine (Gly) for serine (Ser) at amino acid 49 resulting in either homozygous for Gly (Gly49Gly) or heterozygous for Gly (Gly49Ser) polymorphisms. Heart failure patients with this polymorphism (Gly49) have been shown to have improved cardiac function and decreased mortality risk, but if there is an effect in healthy subjects is less clear. The purpose of this study was to determine the effects of the Gly/Ser polymorphism at position 49 of the ADRB1on the cardiovascular response to exercise in healthy subjects. We performed genotyping of the ADRB1 (amino acid 49) and high-intensity, steady-state exercise on 71 healthy subjects (Ser49Ser = 52, Gly49Ser = 19). There were no differences between genotype groups in age, height, weight, body mass index (BMI), or watts achieved (age = 28.9 ± 5.6 years (yrs.), 30.6 ± 6.4yrs., height = 173.6 ± 9.9 cm, 174 ± 7.5 cm, weight = 74.4 ± 13.3 kg, 71.9 ± 13.5 kg, BMI = 24.6 ± 3.5, 23.6 ± 3.3, and watts = 223.8 ± 76.8, 205 ± 49.4, for Ser49Ser and Gly49Ser respectively). Additionally, there were no differences for genotype groups for cardiac output (CO), systolic blood pressure (BPsys), or diastolic blood pressure (BPdias) at rest, maximal exercise, or in change from rest to maximal exercise. The genotype groups differed significantly in heart rate (HRmax) at maximal exercise and cardiac index at rest (CI) (HRmax = 184.2 ± 9.5 bpm, 190.7 ± 10.6 bpm, CI = 0.063 ± 0.014, 0.071 ± 0.013, for Ser49Ser and Gly49Ser respectively). There was a trend towards significance (P = 0.058) for the change in stroke volume from rest to peak exercise (ΔSV) (0.016 ± 0.018 L, 0.0076 ± 0.012 L, for Ser49Ser and Gly49Ser respectively). These data suggest genetic variations of the ADRB1 may influence cardiovascular responses to exercise in healthy subjects.


Calcific diseases. A concept.
New observations portray calcification processes as similar whether occurring normally or pathologically. Most forms of calcification are initiated by membranous organelles, ie, extracellular, calcifying "matrix vesicles" or intracellular mitochondria. Matrix vesicles promote calcification through calcium-binding phospholipids and phosphatase activity. Mitochondria use a forceful, inwardly directed Ca and phosphate transport mechanism. After mineral initiation, the proliferation of mineral crystals is dependent on regulatory factors, such as extracellular Ca2+ and PO4(3-) and other mineral inhibitors and promoters. Calcific diseases are defined as those in which (1) Ca uptake is early, (2) calcification is importantly related to dysfunction, and (3) the control of calcification may lead to decreased morbidity or enhanced diagnostic capability. Calcific diseases include such well-known entities as crystal deposition arthritis, atherosclerosis, calcific valvular sclerosis, tumor calcification, dental plaque, and dysfunctional calcification occurring in implanted cardiovascular devices.


Regional differences in cardiovascular mortality in Kazakhstan: further evidence for the 'Russian mortality paradox'?
The role of alcohol consumption in patterns of CVD mortality in Central Asia is still largely unexplored. Previous research in Kazakhstan and Kyrgyzstan has found that ethnic Russians have higher adult mortality rates than native ethnic groups, despite their higher socio-economic status. This has been termed the 'Russian mortality paradox'. We calculated age-standardized CVD mortality data by gender and region of Kazakhstan, based on mortality data obtained from the Ministry of Health and population data from the State Agency for Statistics. We analysed data on self-reported alcohol consumption from the nationally representative 5th National Behavior Study. We found substantial differences in CVD mortality rates across regions, as well as between males and females. With the exception of Almaty and Astana cities, mortality rates are highest in the country's North-Eastern regions and lowest in South-Western regions, despite the fact that North-Eastern regions have higher income levels. Patterns of self-reported alcohol consumption and alcohol sales follow a similar pattern. One explanation could be related to higher self-reported drinking prevalence among ethnic Russians who live predominantly in the country's North-Eastern regions. Hazardous alcohol consumption seems to be highest in Kazakhstan's North-Eastern regions, which might be related to different patterns of alcohol consumption among different ethnic groups. However, more detailed analyses are required to corroborate these assumptions. The high overall rates suggest the need for population-based measures, such as increasing taxes on alcohol, in particular spirits such as vodka, and strengthening the capacity of primary health care.


[Sociomedical characteristics of the family of a child with tuberculosis].
In 2001-2003, the authors conducted a randomized study at the "Zhemchuzhina" (Pearl) tuberculosis sanatorium (Saint Petersburg) delivering a therapeutic-and-prophylactic care to preschool children infected with Mycobacterium tuberculosis (MBT) and to patients with tuberculosis. Their parents were questioned by a specially complied questionnaire including open and close questions and the data were copied from the children's medical records. The sample amounted to 390 parents of the children aged 4 to 7 years; of them 70% were infected with MBT and 30% were ill with tuberculosis. Boys and girls accounted for 46 and 54%, respectively. Their mothers (67.7%), grandmothers (18.7%), fathers (12%), and other relatives (1.6%) filled in the questionnaire, by indicating the size of family, living and material conditions, education, and parents' occupation, nutrition pattern, family relations, a possibility of spending time on a child. Particular attention was given to the epidemiological characteristics of a family and to the level of knowledge of tuberculosis. The study has demonstrated the parents' low awareness of tuberculosis, which has been established through rumors, their repetition of stereotypes, such as their recognition of the role of a diet alone in the treatment and prevention of tuberculosis infection, with rather high assurance of their knowledge and unwillingness of enriching it. This leads to the fact that parents begin to ignore the problems associated with their child's health as to tuberculosis, thus having a negative impact on the physical and mental health of the parents themselves.


Nitric oxide and atherosclerosis.
Endothelial dysfunction has been shown in a wide range of vascular disorders including atherosclerosis and related diseases. Here, we examine and address the complex relationship among nitric oxide (NO)-mediated pathways and atherogenesis. In view of the numerous pathophysiological actions of NO, abnormalities could potentially occur at many sites: (a) impairment of membrane receptors in the arterial wall that interact with agonists or physiological stimuli capable of generating NO; (b) reduced concentrations or impaired utilization of l-arginine; (c) reduction in concentration or activity both of inducible and endothelial NO synthase; (d) impaired release of NO from the atherosclerotic damaged endothelium; (e) impaired NO diffusion from endothelium to vascular smooth muscle cells followed by decreased sensitivity to its vasodilator action; (f) local enhanced degradation of NO by increased generation of free radicals and/or oxidation-sensitive mechanisms; and (g) impaired interaction of NO with guanylate cyclase and consequent limitation of cyclic GMP production. Therefore, one target for new drugs should be the preservation or restoration of NO-mediated signaling pathways in arteries. Such novel therapeutic strategies may include administration of l-arginine/antioxidants and gene-transfer approaches.


Polybivalency and disordered proteins in ordering macromolecular assemblies.
Intrinsically disordered proteins (IDPs) are prevalent in macromolecular assemblies and are thought to mediate protein recognition in complex regulatory processes and signaling pathways. The formation of a polybivalent scaffold is a key process by which IDPs drive early steps in macromolecular assemblies. Three intrinsically disordered proteins, IC, Swallow and Nup159, are core components, respectively, of cytoplasmic dynein, bicoid mRNA localization apparatus, and nuclear pore complexes. In all three systems, the hub protein LC8 recognizes on the IDP, short linear motifs that are fully disordered in the apo form, but adopt a β-strand when bound to LC8. The IDP/LC8 complex forms a bivalent scaffold primed to bind additional bivalent ligands. Scaffold formation also promotes self-association and/or higher order organization of the IDP components at a site distant from LC8 binding. Rigorous thermodynamic analyses imply that association of additional bivalent ligands is driven by entropic effects where the first binding event is weak but subsequent binding of additional ligands occurs with higher affinity. Here, we review specific examples of macromolecular assemblies in which polybivalency of aligned IDP duplexes not only enhances binding affinity and results in formation of a stable complex but also compensates unfavorable steric and enthalpic interactions. We propose that polybivalent scaffold assembly involving IDPs and LC8-like proteins is a general process in the cell biology of a class of multi-protein structures that are stable yet fine-tuned for diverse cellular requirements.


Identification and sequence composition characterization of chondroitin sulfate-binding peptides through peptide array screening.
Chondroitin sulfate (CS) is an important glycosaminoglycan that has been implicated in several disease processes, such as cancer and spinal cord injury. However, few studies have characterized CS-binding protein and peptide sequences for diagnostic and therapeutic use. In this study, peptide array screening, affinity capillary electrophoresis, and statistical analysis were used to both identify and characterize C6S-binding peptides for sequence composition. The compositional characterization results showed that Phe, Arg, and Tyr all had a significantly high rate of occurrence in the "high binding" affinity peptides, while tryptophan and lysine were significantly underrepresented in this population. Peptides modified with alanine point mutations for Phe, Arg, and Tyr all had lower C6S-binding affinities than the original peptides, demonstrating that these amino acids are all important for C6S binding. Several peptides were designed that substituted Arg for Lys and Phe or Tyr for Trp to create peptides with higher binding affinity. The peptides with the Arg substitution all had improved binding affinities while the Phe/Tyr substitution decreased C6S-binding affinity. Further analysis showed that the increased occurrence of Phe and Tyr in the "high affinity" peptides was dependent upon their positions both within the peptide sequence and in relation to other critical amino acids. Finally, a motif (ABBAA) was suggested for C6S-binding peptides where A represents any aromatic amino acid and B any basic amino acid. The results demonstrate that the methodology developed in this study for sequence composition analysis is an effective technique for the characterization of the interaction between peptides and CS.


Seven years of patient-controlled epidural analgesia in a Swedish hospital: a prospective survey.
Epidural analgesia for postoperative pain relief needs to be monitored regularly in order to evaluate benefits and avoid potential hazards. To evaluate efficacy and safety profile of a ward-based regimen for postoperative epidural analgesia combining patient-controlled epidural analgesia (PCEA) and continuous epidural infusion (CEI). We conducted a prospective survey in all patients who received postoperative epidural analgesia between March 2004 and February 2011. We analysed 4663 patients undergoing elective and acute surgery. University hospital in Sweden. The median level of catheter insertion ranged from T8 in high abdominal surgery to T11 in gynaecological surgery. Mean infusion rate was 5.4 ± 1.6 ml h and was adjusted for age. Mean duration was 3.3 ± 2.1 days. Eighty-seven percent of the patients rated satisfaction 8 to 10 out of 10 on a post-treatment scale. Reasons for termination were elective in 77.1%, due to inadequate pain relief in 11.4%, due to suspected infection in 0.7% and due to other causes in 10.9%. Of the latter, dislodgement of the catheter (4.0%) and leakage from the puncture site (1.4%) dominated. Catheter reinsertion was performed in 5.3% of the patients, and in 5.0%, the treatment was converted into an intravenous (i.v.) morphine patient-controlled analgesia regimen. The incidence of motor blockade was 1.7%, sedation 2.1%, nausea 12.8% and pruritus 18.8%. Bolus doses accounted for 16% of the total infusion volume. No epidural haematoma was seen. One epidural abscess requiring antibiotic treatment occurred. Our prospective survey indicates that PCEA in combination with CEI is effective and relatively well tolerated. The incidence of side effects is generally low and severe adverse events very rare.


Marriage, monogamy and HIV: a profile of HIV-infected women in south India.
A retrospective study was conducted on 134 HIV-infected females evaluated at an HIV/AIDS centre in south India to characterize their sociodemographics, HIV risk factors and initial clinical presentations. The mean age was 29 years; 81% were housewives; 95% were currently or previously married; 89% reported heterosexual sex as their only HIV risk factor; and 88% reported a history of monogamy. The majority were of reproductive age, thus the potential for vertical transmission of HIV and devastating impacts on families is alarming. Nearly half of these women initially presented asymptomatically implying that partner recruitment can enable early HIV detection. Single partner heterosexual sex with their husband was the only HIV risk factor for the majority of women. HIV prevention and intervention strategies need to focus on married, monogamous Indian women whose self-perception of HIV risk may be low, but whose risk is inextricably linked to the behaviour of their husbands.


miR-224 Regulates the Aggressiveness of Hepatoma Cells Through the IL-6/STAT3/SMAD4 Pathway.
Previous studies have shown that miR-224 regulates the progression of liver cancer. The aim of this study was to investigate the underlying mechanisms. The miR-224, p-STAT3 and SMAD4 expression levels were checked with tissue or/and serum samples of HCC patients by qRT-PCR or IHC methods. The regulatory role of IL-6 in p-STAT3 and SMAD4 was investigated by Western-blot. The targeted gene of miR-224 was verified by both Western-blot and luciferase reporter assay. Furthermore, the carcinogenesis of miR-224 in HCC was investigated by cell experiments in vitro and mouse xenograft model and in vivo imaging in vivo. It was found miR-224 was elevated in both tissue and serum of HCC patients. The p-STAT3 expression was higher but the SMAD4 was lower in the HCC tumor tissues. Moreover, IL-6 can induce the p-STAT3/STAT3 and miR-224 expression in HCC cells and STAT3 played the bridge role between IL-6 and miR-224. Target gene studies found miR-224 targeted the 3'UTR of SMAD4. Finally, the promoting roles of miR-224in the growth, proliferation, invasion and migration of HCC were discovered by in vitro and in vivo studies. It implies that miR-224 may potentially represent a new target for developing novel anti-HCC therapeutics.


Leaky modes in multilayer uniaxial optical waveguides.
The propagation characteristics of the leaky modes in planar anisotropic waveguides with a multilayer structure have been investigated by means of a compact rigorous formalism. The leakage losses and leaky transition angle have been studied for the fundamental and first hybrid modes. An inhomogeneous waveguide and buffered step index type structure have been discussed. Particular attention has been devoted to the variation of the loss coefficient of the leaky modes as a function of buffer thickness and buffer refractive index. A notably different behavior has been obtained for various configurations.


Independent evolution of the sexes promotes amphibian diversification.
Classic ecological theory predicts that the evolution of sexual dimorphism constrains diversification by limiting morphospace available for speciation. Alternatively, sexual selection may lead to the evolution of reproductive isolation and increased diversification. We test contrasting predictions of these hypotheses by examining the relationship between sexual dimorphism and diversification in amphibians. Our analysis shows that the evolution of sexual size dimorphism (SSD) is associated with increased diversification and speciation, contrary to the ecological theory. Further, this result is unlikely to be explained by traditional sexual selection models because variation in amphibian SSD is unlikely to be driven entirely by sexual selection. We suggest that relaxing a central assumption of classic ecological models-that the sexes share a common adaptive landscape-leads to the alternative hypothesis that independent evolution of the sexes may promote diversification. Once the constraints of sexual conflict are relaxed, the sexes can explore morphospace that would otherwise be inaccessible. Consistent with this novel hypothesis, the evolution of SSD in amphibians is associated with reduced current extinction threat status, and an historical reduction in extinction rate. Our work reconciles conflicting predictions from ecological and evolutionary theory and illustrates that the ability of the sexes to evolve independently is associated with a spectacular vertebrate radiation.


Comparative Analysis of Private Retail Community Pharmacies' Participation in the National Health Insurance Scheme of Nigeria and Ghana: Implications for Access to Essential Medicines.
Frequent stock-out of drugs in the public hospitals causes National Health Insurance Scheme (NHIS) enrollees to purchase most of their medicines out-of-pocket in community pharmacies, thereby imposing financial constraints on them against the main objective of the scheme. The objectives of this study were to determine and compare the level of participation of private retail community pharmacies (PRCPs) in the NHIS of Nigeria and Ghana, to describe their spatial distribution, and to highlight from literature major factors that would influence the participation of these pharmacies in the scheme. PRCPs data were collected from the Nigerian NHIS active secondary healthcare providers list of 1st July 2017 and the Ghanaian NHIS active providers online list of 2018. PRCPs densities at the national levels were calculated from last published national coverage data for each country. The total number of PRCP accredited by NHIS of both Nigeria and Ghana is 964(639[66.3% versus 325[33.7%]). NHIS accredited PRCPs densities for Nigeria and Ghana were 1 PRCP per 9, 390 enrollees and 1 PRCP per 33, 108 enrollees respectively. Across the Nigerian States, it was noted that Lagos State has the highest proportion (21.4%, n = 137) of community pharmacy participation in the scheme whereas, in Ghan, Greater Accra Region has the highest participation (34.2%, n = 111). This study revealed low participation of PRCPs and skewed spatial distribution between urban and rural areas of both countries, although there was higher participation of these pharmacies in Nigeria due to Nigerian lower NHIS coverage data compared to Ghana.


Hypoxanthine-guanine phosphoribosyltransferase deficiency: activity in normal, mutant, and heterozygote-cultured human skin fibroblasts.
Cultured skin fibroblasts from patients deficient for the enzyme hypoxanthine-guanine phosphoribosyltransferase (PRT) activity show very low but nevertheless significant levels of apparent PRT enzyme despite absence of detectable activity (<0.004% of normal) in erythrocytes of the same patients. In fibroblasts this mutant enzyme is more heat labile than the normal enzyme. These findings indicate that PRT deficiency in this disorder is not due to a deletion mutation of the PRT locus.Individual cultured skin fibroblasts from heterozygote females for PRT deficiency show normal, intermediate, or very low levels of PRT activity. The mosaicism demonstrated in the heterozygotes for this X-linked disorder accounts for the cells with normal and very low activities of PRT. Intermediate activity can best be explained by the phenomenon of metabolic cooperation presumably from the transfer of either PRT enzyme or messenger RNA, from normal to mutant cells.