Calcium gating of H+ fluxes in chloroplasts affects acid-base-driven ATP formation.
In previous work, calcium ions, bound at the lumenal side of the CF0H+ channel, were suggested to keep a H+ flux gating site closed, favoring sequestered domain H+ ions flowing directly into the CF0-CF1 and driving ATP formation by a localized delta approximately mu H+ gradient. Treatments expected to displace Ca++ from binding sites had the effect of allowing H+ ions in the sequestered domains to equilibrate with the lumen, and energy coupling showed delocalized characteristics. The existence of such a gating function implies that a closed-gate configuration would block lumenal H+ ions from entering the CF0-CF1 complex. In this work that prediction was tested using as an assay the dark, acid-base jump ATP formation phenomenon driven by H+ ions derived from succinic acid loaded into the lumen. Chlorpromazine, a photoaffinity probe for many proteins having high-affinity Ca(++)-binding sites, covalently binds to the 8-kDa CF0 subunit in the largest amounts when there is sufficient Ca++ to favor the localized energy coupling mode, i.e., the "gate closed" configuration. Photoaffinity-bound chlorpromazine blocked 50% or more of the succinate-dependent acid-base jump ATP formation, provided that the ionic conditions during the UV photoaffinity treatment were those which favor a localized energy coupling pattern and a higher level of chlorpromazine labeling of the 8-kDa CF0 subunit. Thylakoids held under conditions favoring a delocalized energy coupling mode and less chlorpromazine labeling of the CF0 subunit did not show any inhibition of acid-base jump ATP formation. Chlorpromazine and calmidazolium, another Ca(++)-binding site probe, were also shown to block redox-derived H+ initially released into sequestered domains from entering the lumen, at low levels of domain H+ accumulation, but not at higher H+ uptake levels; ie., the closed gate state can be overcome by sufficiently acidic conditions. That is consistent with the observation that the inhibition of lumenal succinate-dependent ATP formation by photoaffinity-attached chlorpromazine can be reversed by lowering the pH of the acid stage from 5.5 to 4.5. The evidence is consistent with the concept that Ca++ bound at the lumenal side of the CF0 H+ channel can block H+ flux from either direction, consistent with the existence of a molecular structure in the CF0 complex having the properties of a gate for H+ flux across the inner boundary of the CF0. Such a gate could control the expression of localized or delocalized delta approximately mu H+ energy coupling gradients.


Changes in mental health service use among 8-year-old children: a 24-year time-trend study.
The use of children's mental health services has increased, but most children with psychiatric problems are still not in contact with these services. This time-trend study assessed changes in considered and reported service use over a 24-year period and studied the factors associated with it using four cross-sectional studies. Information was gathered on 8-year-old children living in the area covered by Turku University Hospital, Finland, at four time points: 986 children in 1989, 891 in 1999, 930 in 2005, and 942 in 2013. The same study design, methods and school districts were used each year and the participation rates varied between 86 and 95%. Parents and teachers completed questionnaires concerning the child's psychiatric symptoms and service use. The considered and reported service use increased continuously during the study period. In 1989, 2.4% of children had used services and in 2013 this was 11.0% (OR 5.0, 95% CI 3.1-8.0). Reported service use also increased among children with comorbid problems, from 18.3 to 50.7% (OR 5.0, 95% CI 2.1-12.0). Psychiatric problems and some family factors were associated with service use, but the increase was not explained by these factors. The increase in child mental health service use may reflect better public awareness of mental health problems, fewer barriers to accessing care and decrease of stigma. Although more children are using mental health services, there are still a large number of children with mental health problems who have not been in contact with services.


Prevalence of oromucosal lesions in HIV positive patients receiving haart-A prospective clinical study.
To determine the preponderance of oral mucosal lesions and conditions in patients receiving highly active antiretroviral therapy (HAART) for Human Immunodeficiency virus (HIV). Patient tested Seropositive for HIV and on HAART therapy were clinically examined to evaluate prevalence of oral lesions. In the pool of 152 HIV positive patients in the study, age ranged from 7 to 71 years, 67 were males and 85 females. The duration of the HAART medication was 43 months. Oral lesion was present in 51.32% of patients related to infection. Oral lesions seen in descending order of frequency were periodontitis, mucosal hyperpigmentation, acute gingivitis, oral candidiasis, linear gingival erythema, stomatitis, and nonspecific ulcers. Totally, 48.68% of patients had no oral lesions. Majority of the HIV patients on HAART exhibited periodontitis (30.77%), mucosal hyperpigmentation (17.44%), gingivitis (10.77%), anemic stomatitis (11.28%), and other oral lesions accounted to 29.74% which may be attributed to Anti Retro Viral Therapy.


Pretreatment platelet-to-lymphocyte ratio (PLR) as a prognosticating indicator for gastric cancer patients receiving immunotherapy.
Previous investigations suggest that systemic inflammation markers are able to provide prognostic value in several cancers. This study seeks to characterize the ability of pretreatment platelet-to-lymphocyte ratio (PLR) to prognosticate advanced or metastatic gastric cancer patients (AGC or MGC, respectively) receiving immunotherapy. AGC and MGC patients exposed to PD-1 inhibitors from January 2016-August 2021 in the Chinese PLA General Hospital were recruited. Correlations between PLR and overall survival (OS), progression-free survival (PFS), and immunotherapy-associated tumor response rates were determined. 237 patients were enrolled for this retrospective investigation. The 6 month and 12 month PFS based on the area under the curve value was 0.60 and 0.65 (p < 0.05). based on a calculated PLR cut-off value of 139.41, The PLR < 139.41 group has a longer OS in contrast with the PLR ≥ 139.41 group (13.46 m vs 10.71 m, HR = 0.57, 95% CI 0.42-0.78, p = 0.004). The PLR < 139.41 group had a PFS of 7.93 m in contrast to the 4.75 m seen in those with PLR ≥ 139.41 group (HR = 0.57, 95% CI 0.43-0.76, p = 0.002). The disease control rate (DCR) and objective response rate (ORR) were 86.17% and 30.85%, respectively, in the PLR < 139.41 group, but were 82.52% and 32.17%, respectively in the PLR ≥ 139.41 group. Both groups did not show any marked differences in terms of ORR and DCR (p = 0.887, p = 0.476). PLR is an independent prognostic indicator for OS and PFS upon uni- and multivariate analyses (p < 0.05). Pre-treatment PLR correlated significantly with PFS and OS in AGC and MGC patients who received immunotherapy. An elevated PLR may provide guidance on subsequent treatment options.


T helper 17 cells get the NOD.
Interleukin-17 (IL-17)-producing helper T cells play a role in pathogen defense and autoimmunity. In this issue of Immunity, van Beelen et al. (2007) reveal a pathway that elicits potent IL-17 production from memory T cells through activation of the intracellular receptor NOD2.


Synopsis of the hard ticks (Acari: Ixodidae) of Romania with update on host associations and geographical distribution.
The current paper is a synoptic review of the distribution and host associations of the 25 species of hard tick fauna (family Ixodidae) in Romania. In addition to a full literature survey, original data is presented, based on eight years of occasional or targeted sample collection. The literature data on geographical distribution was transposed digitally to the decimal degree coordinate system. For each species, an updated distribution map is given together with all historical data and new host associations. Overall, our paper records 58 new tick-host associations for Romania: 20 for Ixodes ricinus, 1 for I. apronophorus, 6 for I. arboricola, 2 for I. hexagonus, 9 for I. redikorzevi, 1 for I. trianguliceps, 2 for I. vespertilionis, 2 for Haemaphysalis punctata, 1 for H. sulcata, 2 for H. concinna, 1 for D. marginatus, 4 for Rhipicephalus sanguineus sensu lato, 1 for R. bursa and 6 for Hyalomma marginatum.


Urinary versus serum microRNAs in human oxalic acid poisoning: Contrasting signals and performance.
MicroRNAs are key regulators of the normal kidney function and development, and altered in acute kidney injury (AKI). However, there is a lack of studies comparing serum and urine miRNA expression in toxic AKI in humans. We aimed to compare the global signature of urinary and serum microRNAs, with and without kidney injury, after human oxalic acid poisoning. We profiled urinary microRNAs in patients who ingested oxalic acid and developed no injury (No AKI n = 3), moderate injury (AKIN2 n = 3) or severe injury (AKIN3 n = 3) and healthy controls (n = 3). We validated a signature of 30 urinary microRNAs identified in the discovery profiling, in a second cohort of individuals exposed to oxalic acid (No AKI n = 15, AKIN2 n=11 & AKIN3 n= 18) and healthy controls (n=-27) and we compared the results with previously published serum data. Global profiling in toxic AKI patients showed a higher expression of urinary microRNAs and lower expression of serum microRNAs. Most urine microRNA in the validation cohort were significantly upregulated (25/30, fold change >2.8 and p < 0.05) in AKIN2/3 patients compared to No AKI. Four urinary microRNAs (miR-191, miR-19b, miR-20a and miR-30b) had good diagnostic performance (AUC greater than 0.8) to predict AKIN2/3 between 4-8 hours post ingestion. Poisoning irrespective of AKI led to significantly lower expression of many microRNAs in serum but relatively few changes in urinary miRNA expression. In conclusion, urinary microRNA signature provides a stronger measure of AKI in oxalic acid poisoning compared to serum microRNA. Kidney injury has the greatest impact on urinary microRNA, while poisoning itself was better reflected in serum miRNA. Plasma and urinary microRNAs signatures provide complementary information in toxic kidney injury.


AAV9-mediated central nervous system-targeted gene delivery via cisterna magna route in mice.
Current barriers to the use of adeno-associated virus serotype 9 (AAV9) in clinical trials for treating neurological disorders are its high expression in many off-target tissues such as liver and heart, and lack of cell specificity within the central nervous system (CNS) when using ubiquitous promoters such as human cytomegalovirus (CMV) or chicken-β-actin hybrid (CAG). To enhance targeting the transgene expression in CNS cells, self-complementary (sc) AAV9 vectors, scAAV9-GFP vectors carrying neuronal Hb9 and synapsin 1, and nonspecific CMV and CAG promoters were constructed. We demonstrate that synapsin 1 and Hb9 promoters exclusively targeted neurons in vitro, although their strengths were up to 10-fold lower than that of CMV. In vivo analyses of mouse tissue after scAAV9-GFP vector delivery via the cisterna magna revealed a significant advantage of synapsin 1 promoter over both Hb9 variants in targeting neurons throughout the brain, since Hb9 promoters were driving gene expression mainly within the motor-related areas of the brain stem. In summary, this study demonstrates that cisterna magna administration is a safe alternative to intracranial or intracerebroventricular vector delivery route using scAAV9, and introduces a novel utility of the Hb9 promoter for the targeted gene expression for both in vivo and in vitro applications.


Analysis of the Effects of COVID-19 on Hip Fractures in Korea Without Lockdown: Interrupted Time Series Analysis Using a Nationwide Cohort.
The purpose of this study was to investigate the change in the incidence rate, length of hospital stay (LOS), in-hospital mortality rate, and surgical method of hip fractures during the coronavirus disease 2019 (COVID-19) pandemic in South Korea where lockdown restrictions were not implemented. We calculated the expected values of the incidence of hip fractures, in-hospital mortality and LOS of hip fracture patients in 2020 (COVID period) based hip fracture database of the Korean National Health Insurance Review and Assessment (HIRA) during a 9-year period from 2011 to 2019 (pre-COVID period). A generalized estimating equation model with Poisson distribution and logarithmic link function was used to estimate adjusted annual percent change (PC) of incidence rate and 95% confidence intervals (CIs). Then, we compared the annual incidence, in-hospital mortality rate and LOS in 2020 with the expected values. The overall incidence rate of hip fracture in 2020 was not significantly different from the expected value (PC, -5%; 95% CI, -13 to 4; P = 0.280). In women, the incidence rate of hip fracture in age groups over 70 years was smaller than the predicted value (P < 0.001). The in-hospital mortality rate was not significantly different from the expected value (PC, 5%; 95% CI, -8 to 19; P = 0.461). The mean LOS was larger than the expected value by 2% (PC, 2%; 95% CI, 1 to 3; P < 0.001). In intertrochanteric fracture, the proportion of internal fixation was smaller than the predicted value by 2% (PC, -2%; 95% CI, -3 to -1; P < 0.001), and that of hemiarthroplasty was larger than the predicted value by 8% (PC, 8%; 95% CI, 4 to 14; P < 0.001). In 2020, the incidence rate of hip fracture did not significantly decrease, and in-hospital mortality rate did not significantly increase compared to the expected rates, which were projected based on the HIRA hip fracture data from 2011 to 2019. Only LOS increased slightly.


Nutritional effects and feeding behavior in ewes fed with biscuit bran and cashew nut bran, with different energy levels.
This research evaluated the effects of biscuit bran and cashew nut bran as energy source and additional energy level on intake, digestibility, feeding behavior, energy partitioning, N balance, and blood parameters on ewes. Twenty Morada Nova cull ewes breed (average age of 3 years old and initial body weight of 30.1 ± 3.56 kg) were distributed in a completely randomized design in a 2 × 2 factorial scheme of two energy sources (biscuit bran vs. cashew nut bran) and two levels of energy above 10% and 25% of the recommended energy requirements. The inclusion of cashew nut bran above 10% of the recommended energy promoted a lower crude protein (CP) and ethereal extract intake (P < 0.01) than cashew nut bran above 25% of the recommended energy. The interaction between energy source × energy level did not affect digestibility and energy partition on ewes (P > 0.05). The diet containing cashew nut bran above 10% of the recommended energy presented lower metabolizable energy intake and energy balance (P < 0.05). Regarding N balance, the cashew nut bran diet above 10% of the recommended energy decreased Nintake (P = 0.01), Nabsorbed (P < 0.01), and Nbalance (P = 0.04). Partial replacement of corn with the byproduct biscuit bran or cashew nut bran is a possible nutritional strategy. Ewes fed with 210 g/kg of biscuit bran presented greater CP intake and improvement of the protein use with the reduction of plasma levels of urea.


Neurochemical evidence that [Ca2+]o antagonizes the effect of neomycin on acetylcholine release from mouse hemidiaphragm preparation: an attempt to assess the margin to safety.
Although the neuromuscular junction is the most thoroughly studied synapse of any type and has become the model of our understanding of synaptic transmission, some questions remain unanswered; e.g. there has been no direct assessment of the size of margin of safety. In this study the [Ca2+]o-dependent, quantally released acetylcholine measured by a neurochemical method, and the contraction of the mouse hemidiaphragm in response to phrenic nerve stimulation were recorded, and the effect of neomycin was studied. It was found that a much higher concentration of neomycin was needed to depress contractions, than to reduce acetylcholine release to the same extent, and that there was an inverse correlation between [Ca2+]o and the inhibitory effect of neomycin on acetylcholine release. Ninety percent of the release of acetylcholine had to be reduced by neomycin before any reduction in muscle responses could be seen. This indicates that the margin of safety is about 10. In conclusion, at the neuromuscular junction any reduction in ACh release, whatever the mechanism, first produces a reduction in the margin of safety. The nondepolarizing neuromuscular blocking agents block primarily the nicotinic receptors located on the postjunctional site. Many receptors have to be blocked before a reduction of muscle response is observed. This is probably the reason why unexpected clinical problems (e.g. recurarization) have been described when a patients has been treated with antibiotics, even though the dose of muscle relaxant injected was relatively low.


Role of instrument cleaning and maintenance in the development of diffuse lamellar keratitis.
To determine if instrument cleaning techniques affect the rate of diffuse lamellar keratitis (DLK) after laser in situ keratomileusis (LASIK). Retrospective case series. Two hundred ten eyes of 109 patients. A record review was performed of all patients who underwent LASIK at the Jules Stein Eye Institute from April 1 through June 24, 1999. During the first 6 weeks, the instruments used in LASIK surgery were cleaned according to our conventional protocol. At the end of this 6-week period, the cleaning protocol was modified and used for a subsequent 6-week period. For each eye during the two periods, the status of DLK on the first postoperative day was recorded. Presence of DLK. During the first 6-week period, 118 eyes of 60 patients underwent LASIK surgery. In the subsequent 6 weeks, 92 eyes of 49 patients underwent LASIK surgery. The two groups included patients with similar demographic background: gender, age, and target correction. Diffuse lamellar keratitis was present in 13 of 118 eyes (11%) using our conventional protocol. In only 2 of 92 eyes (2%) did DLK develop after the protocol was modified. Using the chi-square test, the difference between the two groups was statistically significant (P = 0.01). Diffuse lamellar keratitis is a fairly uncommon phenomenon after LASIK surgery. Although the cause remains to be elucidated, these results demonstrated a reduced incidence of DLK associated with alteration of cleaning procedures and a decrease in stagnant instrument cleaning fluids. The authors recommend that refractive centers avoid the use of stagnant fluids in their instrument cleaning and sterilizing protocols to minimize the occurrence of DLK outbreaks.


U.S. Nulliparas' Reasons for Expected Provider Type and Childbirth Setting.
The objective of this study was to describe nulliparas' reasons for the type of provider (i.e., midwife, physician) and childbirth setting (i.e., home, hospital, hospital-based birth center) that respondents expected for their births. Data were collected via a cross-sectional, descriptive, self-administered, Web-based survey including both close- and open-ended questions and were analyzed using conventional content analysis. Respondents were 220 nulliparous women aged 18-40 years, living in the United States, and pregnant at 20 or fewer weeks' gestation. Women's reasons were categorized broadly as relating to provider/setting attributes, relationship with provider/setting, normative choices, respondent attributes, and practical considerations. Respondents' reasons highlight misconceptions about childbirth care options, especially regarding midwifery and nonhospital settings, which may be addressed by childbirth education.


Toxic effects of Cr(VI) and Cr(III) on energy metabolism of heterotrophic Euglena gracilis.
To assess the toxic effect of Cr on energy metabolism, heterotrophic Euglena gracilis was grown in a medium that prompts high yield biomass and in the presence of different Cr(VI) or Cr(III) concentrations. The cell growth IC₅₀ value was 12 and >250μM for Cr(VI) and Cr(III), respectively; in these cells chromium was accumulated and a fraction compartmentalized into mitochondria, and synthesis of cysteine and glutathione was induced. Respiration of control isolated mitochondria was strongly inhibited by added Cr(VI) or Cr(III) with L-lactate or succinate as substrates. In turn, cellular and mitochondrial respiration, respiratory Complexes I, III and IV, glycolysis and cytosolic NAD(+)-alcohol and -lactate dehydrogenases from cells cultured with Cr(VI) were significantly lower than control, whereas AOX and external NADH dehydrogenase activities were unaltered or increased, respectively. Addition of Cr(VI) or Cr(III) to isolated mitochondria or cytosol from control- or Cr(VI)-grown cells induced inhibition of respiration, respiratory Complexes III, IV and AOX, and glycolytic pyruvate kinase; whereas Complex I, external NADH dehydrogenase, and other glycolytic enzymes were unaffected. Protein contents of mitochondrial Complexes I, III, IV and V, and ANT were diminished in Cr(VI)-grown cells. Decreased respiration and glycolysis induced by Cr(VI) resulted in lower cellular ATP content. Results suggested that Cr(VI) cytotoxicity altered gene expression (as widely documented) and hence enzyme content, and induced oxidative stress, but it was also related with direct enzyme inhibition; Cr(III) was also cytotoxic although at higher concentrations. These findings establish new paradigms for chromium toxicity: Cr(VI) direct enzyme inhibition and non-innocuous external Cr(III) toxicity.


Lipids, clotting factors, and diabetes: endogenous risk factors for cardiovascular disease.
Theories of intimal injury leading to plaque formation include platelet adhesion and production of growth factors, hypercholesterolemia, smooth muscle cell proliferation, macrophage activity, defective utilization of low-density lipoproteins via deficient receptors, and deficiency in cellular lysosomal enzymes. High levels of low-density lipoproteins and intermediate-density lipoproteins, as well as their apoproteins, are strong risk factors for cardiovascular disease. The lowering of the cholesterol level has been shown to produce significant regression of atherosclerotic lesions. Data also suggest an interaction between lipids and platelets, although the role of coagulation disorders as an independent risk factor for atherosclerosis is difficult to assess. Although much of the data are controversial, there is evidence that platelet survival time is a strong predictor of severe vessel damage. In addition, some studies have reported decreased activity of antithrombin III with coronary artery disease, and there appears to be a direct correlation between fibrinogen and cholesterol levels. Finally, diabetes mellitus (both types I and II) is a significant independent risk factor for atherosclerosis. The risk is not related to the severity or duration of diabetes, and it appears to be greater in women than in men.


Identification and characterization of receptor-interacting protein 2 as a TNFR-associated factor 3 binding partner.
Tumor necrosis factor receptor-associated factor 3 (TRAF3) is a highly versatile immune regulator that positively controls type I interferon production, but negatively regulates the activation of mitogen-activated protein kinase and alternative nuclear factor-κB signaling. The precise function of TRAF3 in different signaling pathways remains unclear. Thus, in a yeast two-hybrid assay, TRAF3 was used as the bait to screen a human spleen cDNA library for TRAF3 interactors that may potentially mediate TRAF3-regulated functions. Receptor-interacting protein 2 (RIP2) was identified as a TRAF3 binding partner. The interaction between TRAF3 and RIP2 was further confirmed by mammalian two-hybrid, co-immunoprecipitation and GST pull-down assays, and this interaction was also verified by immunoprecipitation of endogenous proteins in Ramos cells, a human B lymphoma cell line. RIP2 is an activator of NF-κB. We therefore examined the effect of TRAF3 in RIP2-induced NF-κB activation. The result showed that TRAF3 could inhibit RIP2-induced NF-κB activation. Given the high expression of RIP2 in the B lymphoma cell line and endogenous interaction between TRAF3 and RIP2 in Ramos cells, the role of RIP2 was further studied. The result demonstrated that RIP2 knockdown was capable of increasing the expression of TRAF3 and suppressing the activation of alternative NF-кB pathway in Ramos cells. These findings suggest that functional interactions between RIP2 and TRAF3 may provide some clues to the mechanisms of TRAF3-involvement in both positive and negative regulatory functions.


Localization of cytochrome oxidase (COX) activity and COX mRNA in the hippocampus and entorhinal cortex of the monkey brain: correlation with specific neuronal pathways.
Cytochrome oxidase (COX) activity and COX II mRNA expression were localized in the hippocampal formation and entorhinal cortex of the rhesus monkey brain by means of enzyme histochemistry and in situ hybridization, respectively. Within the hippocampal formation, the terminal field of the perforant pathway showed the highest levels of COX activity, whereas COX II mRNA was localized mainly in neuronal cell bodies. In the entorhinal cortex. COX II mRNA was detected in neuronal cell bodies of layers II and IV. These results indicate that the pattern of localization of COX and its mRNA in entorhinal cortex correlates with the input and output pathways of the hippocampus.


Isolation, identification and characterization of camelpox virus in Iraq.
A virus was isolated from pox-like lesions in camels during an outbreak of camelpox disease which occurred in December 1977 in an area near the Iraqi-Iranian border. It was identified serologically as a virus of the Orthopoxvirus group. The biological properties of the isolate indicated that it was probably identical with strains of camelpox virus isolated from Iran, Egypt, Kenya and the U.S.S.R.


Optimal thresholds, sensitivity, and specificity of long-term pH-metry for the detection of gastroesophageal reflux disease.
Long-term esophageal pH-metry has become the preferred test to quantify acid gastroesophageal reflux, but its accuracy in separating physiologic from pathological reflux is not well defined. To establish optimal thresholds of 24-h pH-metry, we studied 45 patients with clinically proven gastroesophageal reflux disease and 42 healthy volunteers. Twenty-four-hour esophageal pH was measured while the subject was ambulatory, using a combined glass electrode connected to a portable recorder. Percentage of time with esophageal pH less than 4, the number and mean duration of reflux episodes, the number of episodes lasting longer than 5 min, and the duration of the longest episode were calculated for periods of upright and supine body position, respectively. Discriminant analysis and receiver-operating-characteristic analysis were used to define optimal thresholds. A maximum of sensitivity (93.3%) and specificity (92.9%) was obtained using receiver-operating-characteristic analysis with the following criteria. Only percentage of time with esophageal pH less than 4 is considered. A subject is classified as "normal" if both values for the upright and supine body position are below the thresholds, otherwise the subject is classified as "pathological." The thresholds are 10.5% of time with esophageal pH less than 4 for the upright position and 6.0% for the supine position. Within the limits of this retrospective study, it is concluded that rather simple criteria yield a high diagnostic accuracy in the evaluation of long-term esophageal pH-metry. Nevertheless, a prospective and independent confirmation of these criteria is needed.


Stanniocalcin-1 ameliorates cerebral ischemia by decrease oxidative stress and blood brain barrier permeability.
Blood brain barrier (BBB) permeability and oxidative stress have been reported to be important mechanisms for brain damage following ischemic stroke and stanniocalcin-1 (STC-1), a neuroprotective protein, has anti-inflammatory and anti-oxidative stress properties. Herein, we report the effect of STC-1 on BBB permeability and brain oxidative stress after stroke in an animal model. Male Wistar received an intracerebroventricularly injection of human recombinant STC-1 (100 ng/kg) or saline and were subjected to sham procedure or global cerebral ischemia/reperfusion (I/R) model. Six and 24 h after I/R, neurological evaluation was performed; at 24 h brain water content was evaluated in the total brain, and BBB permeability, nitrite/nitrate (N/N) concentration, lipid peroxidation, protein carbonyls formation, superoxide dismutase (SOD) and catalase (CAT) activity were determined in the hippocampus, cortex, prefrontal cortex, striatum and cerebellum. Rats exhibited neurological deficit at 6 and 24 h after I/R and STC-1 reduction at 24 h. After I/R there were an increase of brain water content, BBB permeability in the hippocampus, cortex and pre-frontal cortex and N/N in the hippocampus, and STC-1 decreased this level only in the hippocampus. STC-1 decreased lipid peroxidation in the hippocampus, cortex and prefrontal cortex and protein oxidative damage in the hippocampus and cortex. SOD activity decreased in the hippocampus, cortex and prefrontal cortex after I/R and STC-1 reestablished these levels in the hippocampus and cortex. CAT activity decreased only in the hippocampus and cortex and STC-1 increased the CAT activity in the hippocampus. Our data provide the first experimental demonstration that STC-1 reduced brain dysfunction associated with cerebral I/R in rats, by decreasing BBB permeability and oxidative stress parameters.


Development and reliability of a standard rating system for outcome measurement of foot and ankle disorders I: development of standard rating system.
The aim of this study was to report the five scales comprising the rating system that the Japanese Society for Surgery of the Foot (JSSF) devised (JSSF standard rating system) and the newly offered interpretations and criteria for determinations of each assessment item. We produced the new scales for the JSSF standard system by modifying the clinical rating systems established by the American Orthopaedic Foot and Ankle Society (AOFAS scales) and the Japanese Orthopaedic Association's foot rating scale (JOA scale). We also provided interpretations of each assessment item and the criteria of determinations in the new standard system. We improved the ambiguous expressions and content in the conventional standard rating systems so they would be easily understood by Japanese people. The result was five scales in total. Four were designed for use specifically for ankle-hindfoot, midfoot, hallux metatarsophalangeal-interphalangeal, and lesser metatarsophalangeal-ineterphalangeal sites; and the fifth was for the foot and ankle with rheumatoid arthritis. Furthermore, we described interpretations and criteria for determinations with regard to evaluation items in each scale. Conventionally, the AOFAS scales or the JOA scale have been separately applied depending on the sites or disorders concerned, but it was often difficult to decide on scores during practical evaluations because of differing expressions in different languages and also because of ambiguity in the interpretation of each evaluation item and in scoring standards as well. JSSF improved these scales and added definite interpretations of evaluation items as well as criteria for the rating (to be reported here in part I). Because these steps were expected to improve the reliability of outcomes assessed by each scale, we examined the reliability in scores of the newly developed scales, which are reported in part II (in this issue).


Suppression of ovine lymphocyte activation by Teladorsagia circumcincta larval excretory-secretory products.
Teladorsagia circumcincta is an important pathogenic nematode of sheep. It has been demonstrated previously that stimulation of murine T lymphocytes with excretory-secretory (ES) products derived from fourth stage larvae of T. circumcincta (Tci-L4-ES) results in de novo expression of Foxp3, a transcription factor intimately involved in regulatory T cell function. In the current study, Foxp3⁺ T cell responses in the abomasum and the effects of Tci-L4-ES on ovine peripheral blood mononuclear cells (PBMC) following T. circumcincta infection were investigated. T. circumcincta infection resulted in a significant increase in numbers of abomasal Foxp3⁺ T cells, but not an increase in the proportion of T cells expressing Foxp3. Unlike in mice, Tci-L4-ES was incapable of inducing T cell Foxp3 expression but instead suppressed mitogen-induced and antigen-specific activation and proliferation of ovine PBMC in vitro. This effect was heat labile, suggesting that it is mediated by protein(s). Suppression was associated with up-regulation of interleukin-10 (IL-10) mRNA, and specific monoclonal antibody neutralisation of IL-10 resulted in a 50% reduction in suppression, indicating involvement of the IL-10 signaling pathway. Suppression was significantly reduced in PBMC isolated from T. circumcincta infected vs. helminth-naïve lambs, and this reduction in suppression was associated with an increase in Tci-L4-ES antigen-specific T cells within the PBMC. In conclusion, we have identified a mechanism by which T. circumcincta may modulate the host adaptive immune response, potentially assisting survival of the parasite within the host. However, the impact of Tci-L4-ES-mediated lymphocyte suppression during T. circumcincta infection remains to be determined.


Extended -10 motif is critical for activity of the cspA promoter but does not contribute to low-temperature transcription.
Bacterial promoters belonging to the extended -10 class contain a conserved TGn motif upstream of the -10 promoter consensus element. Open promoter complexes can be formed on some extended -10 Escherichia coli promoters at temperatures as low as 6 degrees C, when complexes on most promoters are closed. The promoter of cspA, a gene that codes for the major cold shock protein CspA of E. coli, contains an extended -10 motif. CspA is dramatically induced upon temperature downshift from 37 to 15 degrees C, and its cold shock induction has been attributed to transcription, translation, and mRNA stabilization effects. Here, we show that though the extended -10 motif is critical for high-level expression of cspA, it does not contribute to low-temperature expression. In fact, transcription from the wild-type cspA promoter is cold sensitive in vitro and in vivo. Thus, transcription appears to play little or no role in low-temperature induction of cspA expression.


Osteoclasts may contribute bone substitute materials remodeling and bone formation in bone augmentation.
Bone augmentation is increasingly important in implantology. Bone substitute materials exert essential roles during bone augmentation process. However, accelerating bone substitute materials remodeling and acquiring high bone architecture quality was still the challenges of bone augmentation. Accumulated studies had suggested osteoclasts is the key cell type to resorb bone or bone substitute materials. Our previous study and other studies suggested osteoclasts contributed to bone formation by promoting osteoblast function and facilitate angiogenesis. We hypothesized that bone substitute materials loaded osteoclastogenic cytokines or osteoclast progenitors will help to bone substitute materials rapid remodeling and subsequent bone formation. Our hypothesis could help to lessen long-term post-bone augmentation period and acquire better bone quality for osseointegration.


Accuracy of response of six pulse oximeters to profound hypoxia.
Oxygen saturation, SpO2%, was recorded during rapidly induced 42.5 +/- 7.2-s plateaus of profound hypoxia at 40-70% saturation by 1 or 2 pulse oximeters from each of six manufacturers (NE = Nellcor N100, OH = Ohmeda 3700, NO = Novametrix 500 versions 2.2 and 3.3 (revised instrumentation), CR = Criticare CSI 501 + version .27 and version .28 in 501 & 502 (revised instrumentation), PC = PhysioControl Lifestat 1600, and MQ = Marquest/Minolta PulseOx 7). Usually, one probe of each pair was mounted on the ear, the other on a finger. Semi-recumbent, healthy, normotensive, non-smoking caucasian or asian volunteers (age range 18-64 yr) performed the test six to seven times each. After insertion of a radial artery catheter, subjects hyperventilated 3% CO2, 0-5% O2, balance N2. Saturation ScO2, computed on-line from mass spectrometer end-tidal PO2 and PCO2, was used to manually adjust FIO2 breath by breath to obtain a rapid fall to a hypoxic plateau lasting 30-45s, followed by rapid resaturation. Arterial HbO2% (Radiometer OSM-3) sampled near the end of the plateau averaged 55.5 +/- 7.5%. ScO2% (from the mass spectrometer) and SaO2% (from pH and PO2, by Corning 178) differed from HbO2% by + 0.2 +/- 3.6% and 0.4 +/- 2.8%, respectively. The mean and SD errors of pulse oximeters (vs. HbO2%) were: (table; see text) The plateaus were always long enough to permit instruments to demonstrate a plateau with ear probes, but finger probes sometimes failed to provide plateaus in subjects with peripheral vasoconstriction. Nonetheless, SpO2 read significantly too low with finger probes at 55% mean SaO2.(ABSTRACT TRUNCATED AT 250 WORDS)


Compliance with American Urological Association Guidelines for Post-Percutaneous Nephrolithotomy Antibiotics Does Not Appear to Increase Rates of Infection.
We compared infection rates after percutaneous nephrolithotomy in a group of patients without a history of infection or struvite calculi who received 24 hours or less of antibiotics postoperatively (ie compliance with AUA guidelines) vs a group that received 5 to 7 days of antibiotics postoperatively. We retrospectively reviewed the records of consecutive percutaneous nephrolithotomy procedures in patients without a history of urinary tract infection. Group 1 received 24 hours or less of antibiotics postoperatively and group 2 received a mean of 6 days of antibiotics postoperatively. A total of 52 patients in group 1 (24 hours or less of antibiotics) and 30 in group 2 (mean 6 days of antibiotics) met study inclusion criteria. In 5 group 1 patients (9.6%) fever developed within 72 hours of percutaneous nephrolithotomy but none demonstrated bacteriuria or bacteremia on cultures. No patient in group 1 was treated for urinary tract infection on postoperative days 3 to 14. In 4 group 2 patients (13.3%) fever developed within 72 hours of percutaneous nephrolithotomy. A single patient showed bacteriuria (less than 10,000 cfu mixed gram-positive bacteria) on culture while no patient demonstrated bacteremia. No patient in group 2 was treated for urinary tract infection on postoperative days 3 to 14. There was no difference in stone-free rates or the need for additional procedures between the 2 groups. In this pilot series compliance with AUA guidelines for antibiotic prophylaxis did not result in higher rates of infection than in a comparable group of 30 patients who received approximately 6 days of antibiotics postoperatively.


Molecular characterization of a novel ovary-specific gene fem-1 homolog from the oriental river prawn, Macrobrachium nipponense.
The feminization-1 (fem-1) gene is characterized by one of the most common protein-protein interaction motifs, ankyrin repeat motifs, displays many expression patterns in vertebrates and invertebrates, and plays an essential role in the sex-determination/differentiation pathway in Caenorhabditis elegans. In this study, a fem-1 homolog, designated as Mnfem-1, was first cloned from the oriental river prawn Macrobrachium nipponense. The prawn Mnfem-1 gene consists of six exons and five introns. The full-length cDNA (2603bp) of Mnfem-1 contains an open reading frame (ORF) encoding a protein of 622 amino acids. The Mnfem-1 RNA and protein are exclusively expressed in the ovary in adult prawns as revealed by RT-PCR and immunofluorescence analysis, respectively. In situ hybridization results showed that strong positive signals were concentrated at the edge of the previtellogenic and vitellogenic oocyte. During embryogenesis, Mnfem-1 is highly expressed in both unfertilized eggs and embryos at cleavage stage and thereafter dropped to a low level from blastula to zoea, indicating that the Mnfem-1 in early embryos is maternal. After hatching, the Mnfem-1 expression significantly increased in the larvae at length of 2cm, an important stage of sex differentiation. Yeast two hybridization results showed that the Mnfem-1 protein can be potentially interactive with cathepsin L and proteins containing the domains of insulinase, ankyrin or ubiquitin. Our results suggested that Mnfem-1 could have roles in prawn ovarian development and sex determination/differentiation.


Surgical experience with diseases of the tricuspid valve. Cross-sectional and Doppler echocardiographic evaluation following DeVega's repair.
Seventy-eight patients undergoing mitral valve surgery with or without replacement of the aortic valve also underwent procedures on the tricuspid valve over a period of 10 years. All patients were in functional class III or IV preoperatively. The procedures were performed in all patients with organic disease of the tricuspid valve (N = 44) and in those with moderate or severe functional tricuspid valvar regurgitation (N = 34). Seventy-one patients underwent DeVega's annuloplasty with or without commissurotomy. The overall mortality was 11.5%. 65 long-term survivors were followed up for a period of 6 months to 10 years (mean 5.3 years). Sixty-three patients were in functional class I or II at the last follow-up. Six patients had clinical evidence of mild to moderate tricuspid regurgitation. Regression of cardiomegaly (as judged by the chest radiograph and right ventricular hypertrophy seen in the electrocardiogram) was evident in most cases. Fifty-one of 54 patients evaluated by cross-sectional echocardiography were reported to have a functionally normal tricuspid valve. Doppler echocardiography in 28 patients showed no significant tricuspid regurgitation or stenosis in 26 patients. Eleven consecutive patients undergoing DeVega's annuloplasty were studied prospectively with pre- and postoperative Doppler echocardiography. Good correlation existed between right ventricular systolic pressures predicted by Doppler with those obtained preoperatively at cardiac catheterization. Postoperative Doppler echocardiography in these 11 patients showed complete restoration of competence of the tricuspid valve as well as normalisation of the right ventricular systolic pressure in 10 patients.


Comparison of phenobarbitone and ursodeoxycholic acid in drug-augmented hepatobiliary scintigraphy for excluding the diagnosis of obstructive cholestasis in neonatal cholestasis syndrome.
Neonatal cholestasis is a common cause of jaundice among newborns. Hepatobiliary scintigraphy plays an important role in the diagnosis of neonatal cholestasis by ruling out extrahepatic biliary atresia, which is one of the common causes. Phenobarbitone and ursodeoxycholic acid (UDCA) have been used to improve the specificity of hepatobiliary scintigraphy in ruling out obstructive causes of neonatal cholestasis syndrome (NCS). The present study was undertaken to compare the utility of phenobarbitone and UDCA in augmenting hepatobiliary scintigraphy in the evaluation of NCS. Seventy-four consecutive patients with NCS referred for hepatobiliary scintigraphy were initially subjected to a baseline scan. Twenty patients showed tracer activity in the intestine within 24 h after injection, thus ruling out obstructive cholestasis. Fifty-four patients who did not show any tracer activity in the intestine were categorized as nonexcretors. Four nonexcretors were lost to follow-up and were excluded from the study. Fifty nonexcretors showing scan features suggestive of obstructive cholestasis were further randomized into those receiving phenobarbitone (n=20), UDCA (n=20), or placebo (n=10). These groups were further evaluated with drug-augmented hepatobiliary scintigraphy, after premedication, for any excretory activity in the intestine. Out of 50 patients who were evaluated with drug-augmented hepatobiliary scintigraphy two patients from the phenobarbitone group and one patient each from UDCA and placebo groups showed a change in excretory pattern from the baseline scan. However, these results were statistically nonsignificant (P=1.00). In the present study, drug-augmented (phenobarbitone or UDCA) hepatobiliary scintigraphy did not seem to improve the results (negative predictive value) for ruling out an obstructive cause of neonatal cholestasis.


"I Don't Want to Go Anywhere Else": Patient Experiences of Abortion in Family Medicine.
Prior studies have demonstrated that most women are comfortable with the option of receiving early abortion care in the family medicine setting, and patients who received early abortion care in this context report satisfaction with their experience. There are few qualitative studies, however, that explore abortion experiences in the family medicine setting. This study aimed to better understand influential factors in women's choices and experiences of their family medicine setting for abortion care. We conducted semi-structured interviews with 15 women who received early abortion care at an urban federally qualified health center offering full-spectrum family medicine. Transcripts were analyzed in NVivo, using editing and immersion/crystallization approaches. Women who received abortion care in this setting were highly satisfied. Though many were surprised when they learned abortion care was available, their responses were favorable, and their experiences were positive. Our results indicate that connection to the clinic setting and to the provider who performed the abortion created a context of trust and comfort. Further, women in our study appreciated the privacy offered by a general medical setting as well as the convenience and continuity of care afforded by accessing abortion care in their accustomed primary care setting. Women in our study reported high levels of satisfaction with care and would recommend this setting to others. In a context of increasing restrictions on abortion, family physicians are well-positioned to increase access by including abortion care in the range of reproductive health services offered in their primary care practice settings.


2-(1H-Benzotriazol-1-yl)-1-(furan-2-yl)ethanol.
In the title compound, C(12)H(11)N(3)O(2), the benzotriazole ring system is approximately planar [maximum deviation = 0.008 (1) Å] and its mean plane is oriented at a dihedral angle of 24.05 (4)° with respect to the furan ring. In the crystal, O-H⋯N hydrogen bonds link the mol-ecules into chains along the ac diagonal. π-π stacking between the furan rings, between the triazole and benzene rings, and between the benzene rings [centroid-centroid distances = 3.724 (1), 3.786 (1) and 3.8623 (9) Å] are also observed.


Prenatal diagnosis of the hemoglobinopathies: ethical issues.
Prenatal diagnosis of the hemoglobinopathies has been increasingly reported. This article discusses those ethical issues stemming from pregnancy studies by fetoscopy or placental aspiration: diagnostic accuracy and safety for mother and fetus, abortion of the fetus diagnosed as homozygous for thalassemia or sickle cell diseases, and access to prenatal diagnosis for those who cannot afford it. The author's position on these issues attempts to mediate between the poles in current ethical debate on abortion in public policy.


Megasonic sonication for cost-effective and automatable elution of Cryptosporidium from filters and membranes.
Sample processing is a highly challenging stage in the monitoring of waterborne pathogens. This step is time-consuming, requires highly trained technicians and often results in low recovery rates of pathogens. In the UK but also in other parts of the world, Cryptosporidium is the only pathogen directly tested for in routine operational monitoring. The traditional sampling process involves the filtration of 1000L of water, semi-automated elution of the filters and membranes with recovery rates of about 30-40% typically. This paper explores the use of megasonic sonication in an attempt to increase recovery rates and reduce both the time required for processing and the number of labour-intensive steps. Results demonstrate that megasonic energy assisted elution is equally effective as the traditional manual process in terms of recovery rates. Major advantages are however offered in terms of reduction of the elution volume enabling the current centrifugation stage to be avoided. This saves time, equipment and staff costs and critically removes the step in the process that would be most challenging to automate, paving the way thereby for highly effective automated solutions to pathogens monitoring.


Flavonoids inhibit the production of cytokines/chemokines and induce apoptosis in human neutrophils.
Neutrophils play an important role in the pathophysiology of inflammatory processes, where their concentration and activity are usually extremely high, due to a variety of soluble factors, namely cytokines and chemokines. Cytokines and chemokines are responsible for the delay of the neutrophils' constitutive apoptotic pathway, contributing for their accumulation at the inflammatory site, potentiating the tissue damage by the continuous production of reactive oxygen species and granule enzymes. Thus, the modulation of neutrophils' apoptosis and the production of cytokines and chemokines are seen as new therapeutic targets.[1] Flavonoids may be considered promising molecules in the resolution of the inflammatory process, due to their potential to interfere with pro-inflammatory signaling pathways. In this study, a series of flavonoids were tested for their capacity to interfere in human neutrophils apoptosis, assessed by flow cytometry after simultaneous staining with Annexin-V labeled with fluorescein and propidium iodide.[2] Their capacity to modulate the production of cytokines and chemokines were also evaluated, in human whole blood, using a commercial ELISA kit.[3] The studied flavonoids showed promising features for simultaneously induce apoptosis and inhibit the cytokines / chemokine's production. Overall, this work reveals promising flavonoids for the modulation of the inflammatory process.


Activation of membrane guanylate cyclase by an invertebrate peptide hormone.
Peptide hormones can stimulate cyclic GMP synthesis through either of two general mechanisms: some peptides activate the cytoplasmic form of guanylate cyclase via a coupling factor called EDRF (endothelium-derived relaxation factor), while others activate the membrane form by interacting directly with an extracellular binding domain of the cyclase molecule itself. We have investigated the mechanism(s) by which crustacean hyperglycemic hormone (CHH), a neuropeptide that regulates energy metabolism in crustaceans, elevates cyclic GMP levels in lobster muscle. Phosphodiesterase inhibitors potentiate the response in intact tissue. This indicates that the primary effect of the peptide is to activate a cyclase rather than inhibit a phosphodiesterase. Methylene blue, a specific inhibitor of the EDRF pathway, does not block the actions of CHH. In addition, nitroprusside, an agent that directly activates the EDRF pathway in vertebrate animals, does not activate guanylate cyclase either in intact or homogenized lobster muscle. This indicates that the EDRF pathway, although prominent in vertebrate muscle, is not found in crustaceans and further suggests that the membrane cyclase is the most likely target of CHH. Membrane and soluble cyclases can be isolated from homogenates of lobster muscle (in a 3.5:1 ratio), and both are stimulated by Mn2+ and inhibited by Ca2+. CHH has no effect on the soluble enzyme. Coupling of CHH receptors to the particulate cyclase, however, remains intact in isolated membranes, thus providing a new model system for the study of receptor/cyclase interactions.


Interferon alpha-2 enhances slow-wave sleep in rabbits.
Interferon alpha-2 (IFN) is a leukocyte product with several biological properties including antiviral activity, pyrogenicity and enhancement of immune functions. We report here that an additional facet of IFN activity is its ability to enhance slow-wave sleep (SWS) without greatly altering other aspects of sleep. Intravenous or cerebral intraventricular injections of human IFN into rabbits induced enhancement of SWS, electroencephalographic slow-wave (0.5-4 Hz) activity and brain temperatures. IFN induced slight reductions in rapid-eye movement sleep. Animal behavior, brain temperature changes that occur during the transition from one arousal state to another, and the cyclic nature of states of vigilance remained undisturbed after IFN treatment. The sleep-promoting activity of IFN may be related to feelings of lassitude and sleepiness that often accompany viral disease and interferon therapy. That IFN and other immunoactive substances, e.g. interleukin-1 and muramyl peptides, can enhance sleep suggests that sleep is linked into the immune response.


Post-traumatic headache due to mild traumatic brain injury: Current knowledge and future directions.
Post-traumatic headache is one of the most common and persistent symptoms following mild traumatic brain injury. The objective of this narrative review is to provide an update on the diagnostic criteria, clinical presentation, epidemiology, pathophysiology, and treatment of post-traumatic headache, and to identify future research priorities. This is a narrative review of the literature regarding post-traumatic headache attributed to mild traumatic brain injury. Onset of post-traumatic headache within 7 days of injury is the only evidence for a causal relationship between the injury and the headache included in the diagnostic criteria. Post-traumatic headache often resolves within the first few days of onset, whereas it persists for at least 3 months in 30-50%. The majority of insights into post-traumatic headache pathophysiology come from pre-clinical animal studies and human imaging studies, which implicate structural, functional, metabolic, and neuroinflammatory mechanisms for post-traumatic headache. There is a paucity of quality evidence for how to best treat post-traumatic headache. Although meaningful progress has been made in the post-traumatic headache field, priorities for future research are numerous, including the optimization of diagnostic criteria, a greater understanding of post-traumatic headache pathophysiology, identifying mechanisms and predictors for post-traumatic headache persistence, and identifying safe, well-tolerated, effective therapies.


Acid proteases from the yolk and the yolk-sac of the hen's egg. Purification, properties and identification as cathepsin D.
Two acid proteases from the yolk and one from the yolk-sac of the hen's egg were purified and characterized. They belong all three to the class of cathepsin D. Mostly, minor differences were found in their properties. Possible endogenous substrates, as some egg-proteins and some other yolk-enzymes, were hydrolysed with variable intensity, in vitro.


Effect of the molecular weight of polyethylene glycol (PEG) on the properties of chitosan-PEG-poly(N-isopropylacrylamide) hydrogels.
Our prior study has shown that polyethylene glycol (PEG) played a crucial role in improving the properties of the physically crosslinked chitosan-PEG-poly(N-isopropylacrylamide) (PNIPAAm) hydrogels. In this paper, we further investigated the effect of the molecular weight (MW) of PEG on the properties of the chitosan-based physical hydrogels. Fourier Transform Infrared Spectroscopy (FTIR) study showed that the interaction between PEG and other components in the physically crosslinked hydrogels became stronger as the MW of PEG increased. The wide angle X-ray diffraction (WAXD) study indicated that the crystallinity of the physical hydrogels decreased with an increase in the MW of PEG. The thermal study using differential scanning calorimetry (DSC) revealed the crystallizability of the physical hydrogels first reduced with an increase in the MW of PEG, but slightly increased thereafter with a further increase in the MW of PEG. The swelling test showed the water uptake capability of the physical hydrogels increased with an increase in the MW of PEG. The results obtained by scanning electron microscope (SEM) found that the morphological changes of the physical hydrogels with MW of PEG were consistent with the results of swelling and thermal properties; and, contrary to pure PNIPAAm hydrogels which showed a compact and dense network structure at a temperature (37 degrees C) above its LCST, the physical chitosan-PEG-PNIPAAm hydrogels exhibited porous network structure at 37 degrees C instead. The mechanical property of the physical hydrogels was initially increased with an increase in PEG MW, but deteriorated with a further increase in PEG MW. Therefore, the MW of PEG played a key role in controlling the property of the chitosan-based physical hydrogels.


Zinc effects on LDH, MDH and alkaline phosphatase from cultures of fathead minnow cells.
1. Three purported zinc metalloenzymes have been investigated from cell cultures of the fathead minnow (Pimephales promelas). 2. With the addition of increasingly higher concentrations of zinc to the tissue culture medium, the specific activity of LDH increased. 3. The results with MDH were equivocal. 4. The specific activity of alkaline phosphatase decreased in the presence of increasing amounts of zinc in the growth medium. 5. Zinc exogenously added to the LDH enzyme assay did not alter the LDH enzyme activity of cells grown without zinc.


[Comparison of antimicrobial susceptibility of 1,217 Escherichia coli isolates from women with hospital and community-acquired urinary tract infections].
The treatment of urinary tract infection (UTI) in women is based mainly on empirical antibiotic therapy. It requires up-to-date knowledge of the susceptibility patterns of the bacteria most commonly identified in that setting. The aim of this prospective study was to measure the antibiotic susceptibility of Escherichia coli isolates responsible for UTIs in women from a single area and to compare it in hospital and community settings. From May 2003 through April 2004, UTI was diagnosed in 1838 women around Rennes (France), 893 of them inpatients admitted to the teaching hospital and 945 outpatients in the community. We determined the susceptibility to 7 antibiotics of the resulting 1217 E. coli isolates. E. coli resistance rates in hospitalized and community patients were respectively 47.9% and 39.2% for aminopenicillins, 47.3% and 25.4% for coamoxiclav, 19.2% and 14.1% for cotrimoxazole, 14.3% and 5.7% for first-generation quinolones, and 8.9% and 3.7% for fluoroquinolones. All these rates were significantly higher among hospitalized patients (p<0.05). Conversely, resistance to injectable third-generation cephalosporins and fosfomycin was similar and infrequent in both groups. Comparisons with previous data show that activity of third-generation cephalosporins and fosfomycin on E. coli appears unchanged, in contrast to the increased resistance rates to other antibiotics usually prescribed for UTI.


Association of clonal T-cell large granular lymphocyte disease and paroxysmal nocturnal haemoglobinuria (PNH): further evidence for a pathogenetic link between T cells, aplastic anaemia and PNH.
There is mounting evidence to suggest that T-cell-mediated suppression of haemopoiesis is a pathogenetic mechanism in three bone marrow failure syndromes: aplastic anaemia (AA), paroxysmal nocturnal haemoglobinuria (PNH) and myelodysplasia (MDS). T-cell microclones can be detected by sensitive polymerase chain reaction (PCR)-based methods in all three disorders. Recently, larger clonal populations of T-cell large granular lymphocytes (T-LGLs) have been observed in some patients with AA and MDS. Here, we report the development of a large clonal T-LGL population in a patient with bona fide PNH. In this patient, we defined part of the sequence of the T-cell receptor (TCR) beta-chain gene, and we have shown that the large T-LGL population emerged from a background of multiple smaller T-cell clones. Thus, T-LGL clones in AA, MDS and PNH probably expand as a result of antigenic stimulation. It is postulated that the antigen driving clonal T-cell proliferations in these disorders exists on haemopoietic stem cells.


Effects of pollen and nitrogen availability on reproduction in a woodland herb, Lysimachia quadrifolia.
Relationships between pollen loads, resource availability, and fruit and seed production were determined for Lysimachia quadrifolia ramets in two adjacent sites (the scrub site and the open site) in 1982, 1983, and 1984. Pollen loads limited % fruit set and seed production in the open site in 1982 and 1983. Reproduction in the scrub site was resource limited in 1982, as shown by an increase in % fruit set when one-half of the flowers on a ramet were removed prior to fruit initiation. In the scrub site in 1983, pollination of one-half of the flowers on a ramet decreased the % fruit set of the remaining, unpollinated flowers. Fruit production in the same site was limited by pollen in 1984. Addition of nitrogen fertilizer to the scrub site in 1984 had no effect on fruit and seed production. There was more variation in fruit set between sites than between years. There was no trend to greater fruit set or number of seeds/fruit on early flowers compared to late flowers on the same ramet. Correlations between measures of reproduction were positive or insignificant. These results demonstrate year-and site-specific variation in the factors that limit plant reproduction.


Pediatric multiple sclerosis.
Recognition of multiple sclerosis (MS) and other acquired demyelinating disorders in children has increased significantly in the last decade. Consensus definitions that characterize the varied clinical presentations of acute demyelination, and proposed clinical and MRI criteria specific for MS in children have aided diagnostic consistency. Care of children with an acute demyelinating attack is influenced by clinical severity, with corticosteroids, immunoglobulin, and plasma exchange being the most commonly employed therapies. Children with confirmed MS are often managed with immunomodulatory therapies (interferon and glatiramer acetate) approved for the treatment of MS in adults. Routine assessment of hepatic and hematological cell indices are important to monitor for safety of interferon therapy. While clinical treatment trials of interferon and glatiramer acetate in pediatric MS have yet to be conducted, case series evidence supports clinical safety and relapse rate reduction in the pediatric MS population. Epidemiological studies have implicated place of residence during childhood as a key determinant of MS risk. As such, pediatric-onset MS provides an opportunity to explore these risk factors contemporaneous with the clinical onset of disease. Studies of vitamin D, microbial exposures, and parental smoking are areas under active investigation. Finally, research exploring primary immunological mechanisms and host responses in patients with pediatric-onset MS, who by virtue of their young age may harbor fewer extraneous immune abnormalities, may yield new insights into the fundamental pathobiology of MS.


Localization of plasma membrane and secretory calcium pumps in the mammary gland.
Until recently the mechanism for the enrichment of milk with calcium was thought to be almost entirely via the secretory pathway. However, recent studies suggest that a plasma membrane calcium ATPase, PMCA2, is the primary mechanism for calcium transport into milk, highlighting a major role for apical calcium transport. We compared the expression of the recently identified secretory calcium ATPase, SPCA2, and SPCA1, in the mouse mammary gland during development. SPCA2 levels increased over 35-fold during lactation with expression localized to luminal secretory cells, while SPCA1 increased only a modest 2-fold and was expressed throughout the cells of the mammary gland. We also observed major differences in the localization of PMCA2 and PMCA1. Our studies highlight the likely specific roles of PMCA2 and SPCA2 in lactation and indicate that calcium transport into milk is a complex interplay between apical and secretory pathways.


Synthesis of Combretastatin-A4 Carboxamidest that Mimic Sulfonyl Piperazines by a Molecular Hybridization Approach: in vitro Cytotoxicity Evaluation and Inhibition of Tubulin Polymerization.
Molecular hybridization approach is a promising structural modification tool to design new chemical entities (NCEs) by mimicking two different pharmacophoric units into one scaffold to enhance the biological properties. With this aim, combretastatin-A4 acids were integrated with sulfonyl piperazine scaffolds as a one molecular platform and evaluated for their in vitro antiproliferative activity against a panel of human cancer lines cell lines namely, lung (A549), mouse melanoma (B16F10), breast (MDA MB-231and MCF-7) and colon (HCT-15) by MTT assay. Amongst which the compound (E)-3-(4-Chlorophenyl)-1-(4-((4-chlorophenyl)sulfonyl)piperazin-1-yl)-2-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (5 ab) displayed significant IC50 values in the range of 0.36 to 7.08 μm against the selected cancer cell lines. Moreover, 5 ab was found to be the most potent member of this series with IC50 0.36±0.02 μm. Further investigations revealed that the compound 5 ab displayed significant inhibition of tubulin assembly with IC50 5.24±0.06 μm and molecular docking studies also disclosed the binding of 5 ab effectively in CA4 binding space at the colchicine binding site. The flow cytometric analysis demonstrated that the compound 5 ab caused cell cycle arrest at G2/M phase in A549 cells. Compound 5 ab induced apoptosis in A549 cells which was further evaluated by different staining assays such as DAPI and AO which undoubtedly speculated, the induction of apoptosis. To study the anti-migration with 5 ab, cell migration/scratch wound assay was performed and the extent of apoptosis was studied by Annexin-V, including mitochondrial potential by JC-1 staining.


The High Prevalence of Vitamin D Insufficiency in Cord Blood in Calgary, Alberta (APrON-D Study).
Vitamin D is important in promoting healthy pregnancy and fetal development. We undertook this study to measure 25-hydroxyvitamin D in maternal and cord blood and to identify maternal factors related to vitamin D status in Calgary. Blood samples collected at the time of delivery from the Alberta Pregnancy Outcomes and Nutrition study cohort (ApronStudy.ca) participants were processed for plasma and assayed using liquid chromatography mass spectrometry methodology for 25(OH)D3. Ninety-two pairs of maternal and cord blood samples were obtained. The prevalence of 25(OH)D3 insufficiency-25(OH)D3 <75 nmol/L-was 38% and 80% in women and neonates, respectively. Vitamin D supplementation was the only clinical factor associated with 25(OH)D3 sufficiency, and the odds of sufficiency were 3.75 (95% CI 1.00 to 14.07) higher for women and 5.27 (95% CI 1.37 to 20.27) when over 2000 IU/day were used. Using liquid chromatography mass spectrometry, we demonstrated a very high prevalence of vitamin D insufficiency in cord blood and that the use of high dose vitamin D was associated with greater odds of sufficiency in pregnant women and cord blood in Alberta.


Integrodifference models for evolutionary processes in biological invasions.
Individual variability in dispersal and reproduction abilities can lead to evolutionary processes that may have significant effects on the speed and shape of biological invasions. Spatial sorting, an evolutionary process through which individuals with the highest dispersal ability tend to agglomerate at the leading edge of an invasion front, and spatial selection, spatially heterogeneous forces of selection, are among the fundamental evolutionary forces that can change range expansions. Most mathematical models for these processes are based on reaction-diffusion equations, i.e., time is continuous and dispersal is Gaussian. We develop novel theory for how evolution shapes biological invasions with integrodifference equations, i.e., time is discrete and dispersal can follow a variety of kernels. Our model tracks how the distribution of growth rates and dispersal ability in the population changes from one generation to the next in continuous space. We include mutation between types and a potential trade-off between dispersal ability and growth rate. We perform the analysis of such models in continuous and discrete trait spaces, i.e., we determine the existence of travelling wave solutions, asymptotic spreading speeds and their linear determinacy, as well as the population distributions at the leading edge. We also establish the relation between asymptotic spreading speeds and mutation probabilities. We observe conditions for when spatial sorting emerges and when it does not and also explore conditions where anomalous spreading speeds occur, as well as possible effects of deleterious mutations in the population.


An aqueous platinum nanotube based fluorescent immuno-assay for porcine reproductive and respiratory syndrome virus detection.
Porcine reproductive and respiratory syndrome virus (PRRSV) has been a significant pathogen towards global swine industry upon its emergence in the late 1980s and since then has exemplified a rapidly evolving, widely spreading pathogen. It is urgently important to develop a simple, rapid and cost effective method to detect this pathogen when virus outbreaks. In the present work, it was found that virus antibody modified platinum nanotubes (Pt-Ab) could act as a superquencher to CdTe:Zn(2+) quantum dots (CdTe:Zn(2+) QDs) fluorescence by Stern-Volmer constants nearly 10(9) M(-1) without any aggregation, the CdTe:Zn(2+) QDs fluorescence will recover as the Pt-Ab goes away by antibody and antigen interaction when virus was added into the probe solution, releasing CdTe:Zn(2+) QDs from the surface of Pt-Ab. By the recovery fluorescence intensity, it can realize qualitative and quantitative detection of PRRSV. This method gives a fast response to PRRSV concentration and provides a sensitive detection limit (2.4 ng/mL). Moreover, it can be applied in infected porcine serum samples and obtain satisfied results.


Stimulation by epinephrine of histamine synthesis by rat peritoneal fluid mast cells in vitro.
In vitro exposure of mast but not of other cells of rat peritoneal fluid to epinephrine leads, within 1 min, to progressing levels of histamine in both fluid and sedimentable phases of the incubates, which present no increase in their free/total histamine ratio. Histamine increase was blocked by alpha-fluoromethyl histidine (alpha FMH), acting after a significant lag period. When compared with controls under the electron microscope, epinephrine-treated mast cells show less electron-dense, swollen intracellular granules, apparent maintenance of cell membrane continuity and an apparent decrease of peripheral finger-like projections. Histamine accumulation by epinephrine-treated mast cells may be the result of an enhanced ability of pre-formed mast cell histidine decarboxylase to attack its cell-borne substrate, consequent to an unfolding of the cell membrane during cell tumefaction evoked by epinephrine.


Trichinella spiralis: differences between "early" and "late" rapid expulsion evident from inhibition studies using cortisone and irradiation.
Cortisone administered once at 100 mg/kg during the first 3 weeks of infection inhibited rapid expulsion. In rats immunized with an abbreviated infection (T/M regime) inhibition averaged approximately 50%, whereas in rats given a complete infection (C.I.) 14% inhibition occurred. Sensitivity to 400 rad whole-body irradiation was greatest 7 days before a challenge infection in all immune rats. Three days after beginning the T/M infection rats were highly susceptible to cortisone but only weakly so to irradiation. Rats immunized by C.I. were equally, but only weakly, susceptible to either cortisone or irradiation 3 days after infection. Acute administration of cortisone 1 or 4 hr prior to challenge did not inhibit rapid expulsion but 60% inhibition occurred when cortisone was given 24 hr prior to challenge. Inhibition of rapid expulsion by irradiation 7 days prior to challenge was not reversed by immune serum and irradiation did not affect antibody titer in treated rats. It was suggested that irradiation 7 days before challenge compromised the intestinal, and not the immunological, component of rapid expulsion. Differences in sensitivity of "early" and "late" rapid expulsion to irradiation and cortisone therapy provide further evidence of functional differences between these rejection processes.


Evolution, development, mechanism and function of IgA in the gut.
Since its discovery as the most abundant Ig produced at mucosal surfaces, IgA has been the subject of continuous studies. The concepts emerged were that the precursors for IgA plasma cells are efficiently generated in follicular organized structures in the gut with the help of CD4 T cells and that secretory IgA provides protection against mucosal pathogens. Novel conceptual advances have been made in the past few years in describing new sites, mechanisms and functions of mucosal IgA synthesis.


Comparison of planar bone scintigraphy and single photon emission computed tomography for diagnosis of active condylar hyperplasia.
The aim of this study was to compare the reliability and correlations with age and gender of two nuclear medicine tests used for diagnosis of active condylar hyperplasia, namely, planar bone scintigraphy versus single photon emission computed tomography (SPECT). This was a descriptive observational study carried out in 61 patients (38 women and 23 men) clinically diagnosed as having facial asymmetry and suspected unilateral condylar hyperplasia. The patients had both planar bone scintigraphy and SPECT diagnostic imaging as well as reference data of the percentage of (99)Tc(m) MDP (methylenediphosphonate) uptake in the condyle, clivus, and fourth lumbar vertebra (L4), respectively, for SPECT and planar scintigraphy calculations. Radioactive counts were measured per region of interest and the respective ratios were calculated. The age range of the patients was 13-50 years (mean ± standard deviation = 21.16 ± 8.75). The two groups were compared by a nonparametric (Mann-Whitney U test. Uptake percentage and delta values had normal distribution and consequently were compared by a Student t test. A total of 61 anterior planar images and 61 SPECT images were compared. Eight patients presented high uptake in planar bone scintigraphy images (13.11%), while 32 patients (52.46%) had high uptake with SPECT. The prevalence of condylar hyperactivity was higher in women than in men both for right condyle (ratio 4:3) and for left condyle (10:1) and the prevalence was significantly higher for the right condyle. The study indicates that SPECT is more sensitive to identify condylar hyperactivity as compared to planar bone scintigraphy in patients with clinical presumptive diagnostic of condylar hyperplasia.


Immunodiagnosis and immunotherapy of childhood malignancies.
Recent advances in immunologic techniques have allowed the generation of monoclonal antibodies against antigens on tumor cells and their normal counterparts. Monoclonal antibodies useful for diagnosing and defining subtypes of acute leukemias and neuroblastoma have been prepared, although the prognostic significance of the subtypes defined by such antibodies remains to be determined. The usefulness of these reagents for therapeutic purposes either ex vivo, in association with autologous bone marrow transplantation, or in vivo, as carriers of cytotoxic agents, is currently under investigation.


Job satisfaction and the work situation of physicians: a survey at a German university hospital.
Job demands and workload of hospital physicians are increasing. The object of this survey was to examine the factors that constitute job satisfaction and to analyse physicians' work situation in the area of in-patient care. 447 physicians at a German University Hospital received questionnaires with regard to work situation, job satisfaction and personal health. Data were analysed by MANOVA and multiple regression models. A first regression model explained 53% of the variance in satisfaction with "work and profession". Among the explanatory variables "superiors and hierarchy" showed the highest beta-weight (beta = -0.49). "Personal health" also determined job satisfaction, for female physicians stronger (beta = -0.31) than for male physicians (beta = -0.11). In a second regression model on satisfaction with "Financial situation" only 18% of the variance was explained, whereby "work condition on the ward", "personal health" and "collaboration between occupational groups" showed the highest beta-weights. Among resident physicians, work conditions, superiors, hierarchy, transparency and participation in decisions are very important variables for job satisfaction. Improvements in these aspects may improve job satisfaction and help to reduce physician shortage in hospitals.


Poor sleep quality is associated with impaired glucose tolerance in women after gestational diabetes.
We analyzed the association of sleep quality and glucose metabolism in women after gestational diabetes (pGDM) and in women after normoglycemic pregnancy (controls). Data during pregnancy and a visit within the first 15 months after delivery were collected from 61 pGDM and 30 controls in a prospective cohort study. This included a medical history, physical examination, questionnaires (Pittsburgh Sleep Quality Index (PSQI), and Perceived Stress Scale (PSS)), and 5-point oral glucose tolerance test with insulin measurements to determine indices of insulin sensitivity and insulin secretion. We used Spearman correlation coefficients and multivariate regression models for analysis.9.3 ± 3.2 months after delivery, pGDM had significantly higher fasting and 2 h glucose levels and lower insulin sensitivity than controls. There was no significant difference in age, BMI and sleep quality as assessed with the PSQI between the two groups. The PSQI score correlated with the ogtt-2 h plasma glucose in pGDM (δ = 0.41; p = 0.0012), but not in controls. This association was confirmed with a multivariate linear regression model with adjustment for age, BMI and months post-delivery. Perceived stress was an independent risk factor (OR 1.12; 95% CI 1.02-1.23) for impaired sleep. Our findings suggest that post-delivery sleep quality significantly influences glucose tolerance in women after GDM and that impaired sleep is associated with increased stress perception. Measures to improve of sleep quality and reduce perceived stress should therefore be tested as additional strategies to prevent progression to type 2 diabetes after GDM.


Methicillin-resistant Staphylococcus aureus in hospitals in Tbilisi, the Republic of Georgia, are variants of the Brazilian clone.
The purpose of this study was to characterise methicillin-resistant Staphylococcus aureus (MRSA) isolates from the Republic of Georgia, part of the former Soviet Union. Thirty-two non-duplicate MRSA isolates were collected in the period from May 2006 to February 2007. The patient data were analysed and the isolates were characterised by staphylococcal protein A (spa) typing, staphylococcal chromosome cassette mec (SCCmec) typing, multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE) and the detection of Panton-Valentine leukocidin (PVL) genes. Only two closely related spa types were found; 29 isolates were of spa type 459 and three were t030. The spa types belonged to sequence type (ST) 239, clonal complex (CC) 8. All isolates were multiresistant, PVL-negative and harboured SCCmec type IIIA. Based on the molecular findings and PFGE, the isolates most closely resembled the pandemic Brazilian clone (ST239-IIIA).


Depression of spontaneous and ionophore-induced transmitter release by ruthenium red at the neuromuscular junction.
The effects on spontaneous and ionophore-induced transmitter release of the inorganic dye, ruthenium red (RuR), a known inhibitor of calcium binding sites, were observed at the frog sartorius neuromuscular junction using intracellular recording techniques. Both crude and purified RuR, at concentrations of 1 and 5 micron depressed or blocked spontaneous release of acetylcholine (ACh) and reduced postsynaptic sensitivity to ACh, the crude dye being more potent than the pure. Pretreatment of muscles with RuR prevented the catastrophic reaction of junctions to 100 micron X537A ionophore. Increased levels of Ca2+ restored spontaneous transmitter release to control levels after depression or blockade by RuR. It was concluded that RuR blocks a critical membrane-bound binding site for calcium which is necessary for quantal release of transmitter.


[Synthesis and Pharmacological Activity of N-Hetaryl-3(5)-Nitropyridines].
Reacting a number chlorosubstituted 3(5)-nitropyridine with some diazoles or 3-chloropyridazin-6-one synthesized previously undescribed various 2-, 4- or 6-substituted hetaryl-3(5)-nitropyridines. Furthermore, pyrazolyl-3-nitropyridine prepared by cyclizing hydrazinopyridine resulting from the nucleophilic substitution of chlorine in chlorosubstituted 3-nitropyridine by hydrazine. It has been shown that these compounds have moderate antibacterial activity against some pathogenic Gram-positive and Gram-negative bacteria (Staphylococcus aureus, Escherichia coli), as well as a strong effect on protistocidal action form Colpoda steinii, surpassing clinically used reference drugs.


Phase Transformations in the High-Tc Superconducting Compounds, Ba2RCu3O7-δ (R = Nd, Sm, Gd, Y, Ho, and Er).
The phase transformation between the orthorhombic and tetragonal structures of six high-T c superconductors, Ba2RCu3O7- δ , where R = Nd, Sm, Gd, Y, Ho, and Er, and δ = 0 to 1, has been investigated using techniques of x-ray diffraction, differential thermal analysis/thermogravimetric analysis (DTA/TGA) and electron diffraction. The transformation from the oxygen-rich orthorhombic phase to the oxygen-deficient tetragonal phase involves two orthorhombic phases. A superlattice cell caused by oxygen ordering, with a' = 2a, was observed for materials with smaller ionic radius (Y, Ho, and Er). For the larger lanthanide samples (Nd, Sm, and Gd), the a' = 2a type superlattice cell was not observed. The structural phase transition temperatures, oxygen stoichiometry and characteristics of the T c plateaus appear to correlate with the ionic radius, which varies based on the number of f electrons. Lanthanide elements with a smaller ionic radius stabilize the orthorhombic phase to higher temperatures and lower oxygen content. Also, the superconducting temperature is less sensitive to the oxygen content for materials with smaller ionic radius. The trend of dependence of the phase transformation temperature on ionic radius across the lanthanide series can be explained using a quasi-chemical approximation (QCA) whereby the strain effect plays an important role on the order-disorder transition due to the effect of oxygen content on the CuO chain sites.


Tandem reporter assay for myristoylated proteins post-translationally (TRAMPP) identifies novel substrates for post-translational myristoylation: PKCε, a case study.
Myristoylation, the addition of a 14-carbon fatty acid to the N-terminal glycine of a protein, is key to protein-membrane and protein-protein interactions. Typically, myristoylation occurs cotranslationally; however, post-translational myristoylation of caspase-cleaved proteins is now emerging as a well-established protein modification and as a novel regulator of apoptosis. To identify additional post-translationally myristoylated proteins, we engineered a plasmid vector encoding for a caspase-cleavable reporter protein named tandem reporter assay for myristoylation of proteins post-translationally (TRAMPP). pTRAMPP consists of tdTomato-DEVD-"test myristoylation sequence"-enhanced green fluorescent protein (EGFP). After induction of apoptosis, the reporter protein is cleaved by caspases, which frees a new N-terminal glycine residue attached to EGFP that can be myristoylated. We used pTRAMPP in appropriately transfected cells to identify 7 post-translationally myristoylated proteins. First, we confirmed the post-translational myristoylation of two previously identified putative substrates, cytoplasmic dynein intermediate chain 2A and PKCε (ctPKCε), and identified 5 more caspase-cleaved potential substrates for myristoylation that include the antiapoptotic regulator of apoptosis, Mcl-1, and the causative agent of Huntington's disease, huntingtin protein. Further investigation revealed that post-translationally myristoylated ctPKCε localized to membranes and increased Erk signaling and degradation of the proapoptotic protein Bim, which prevented a significant loss of mitochondrial potential of 17% over nonmyristoylated ctPKCε in HeLa cells in the presence of apoptotic stimuli. Taken together, these findings suggest a possible antiapoptotic role for post-translationally myristoylated caspase-cleaved ctPKCε.


Disulphide reaction staining for the identification of integumental elastic fibres.
Based on specific methods (Sippel-APM-chromotropic acid technique; IC3-PE-maleimide fluorescence reaction) and skin samples of four domesticated mammals (dog, cattle, horse, pig), disulphide groups were demonstrated in the elastic component of the basement membrane of the epidermis, the elastic fibre system of the dermis, the elastic components of the connective tissue sheath of hair follicles, apocrine tubular glands, and sebaceous glands, and of the connective tissue surrounding the cutaneous muscle. The results are discussed regarding the relation of this reaction staining to the presence of microfibrils (fibrillin) in the elastic fibres.


Neuronal On- and Off-type heterogeneities improve population coding of envelope signals in the presence of stimulus-induced noise.
Understanding the mechanisms by which neuronal population activity gives rise to perception and behavior remains a central question in systems neuroscience. Such understanding is complicated by the fact that natural stimuli often have complex structure. Here we investigated how heterogeneities within a sensory neuron population influence the coding of a noisy stimulus waveform (i.e., the noise) and its behaviorally relevant envelope signal (i.e., the signal). We found that On- and Off-type neurons displayed more heterogeneities in their responses to the noise than in their responses to the signal. These differences in heterogeneities had important consequences when quantifying response similarity between pairs of neurons. Indeed, the larger response heterogeneity displayed by On- and Off-type neurons made their pairwise responses to the noise on average more independent than when instead considering pairs of On-type or Off-type neurons. Such relative independence allowed for better averaging out of the noise response when pooling neural activities in a mixed-type (i.e., On- and Off-type) than for same-type (i.e., only On-type or only Off-type), thereby leading to greater information transmission about the signal. Our results thus reveal a function for the combined activities of On- and Off-type neurons towards improving information transmission of envelope stimuli at the population level. Our results will likely generalize because natural stimuli across modalities are characterized by a stimulus waveform whose envelope varies independently as well as because On- and Off-type neurons are observed across systems and species.


Building capacity: a cross-sectional evaluation of the US Training Institute for Dissemination and Implementation Research in Health.
In 2011, the National Institute of Health (NIH) initiated the Training in Dissemination and Implementation Research in Health (TIDIRH) program. Over its first 5 years, TIDIRH provided an in-person, week-long training to 197 investigators who were new to the dissemination and implementation (D&I) field. This paper evaluates the long-term impact of TIDIRH on trainees' use of D&I methods, collaborations, and research funding. Trainees were selected to participate through a competitive process. We compared the 197 trainees to 125 unselected applicants (UAs) whose application score was within one standard deviation of the mean for all trainees' scores for the same application year. A portfolio analysis examined electronic applications for NIH peer-reviewed funding submitted by trainees and UAs between 2011 and 2019. A survey of trainees and UAs was conducted in 2016, as was a faculty survey among the 87 individuals who served as TIDIRH instructors. A major goal of TIDIRH was to build the field, at least in part through networking and collaboration. Thirty-eight percent of trainees indicated they had extensive contact with faculty following the training, and an additional 38% indicated they had at least limited contact. Twenty-four percent of trainees had extensive collaboration with other fellows post-TIDIRH, and 43% had at least limited contact. Collaborative activities included the full range of academic activities, including manuscript development, grant writing, and consultation/collaboration on research studies. The portfolio analysis combining grant mechanisms showed that overall, TIDIRH trainees submitted more peer-reviewed NIH grants per person than UA and had significantly better funding outcomes (25% vs 19% funded, respectively). The greatest difference was for large research project, program/center, and cooperative agreement grants mechanisms. Overall, this evaluation found that TIDIRH is achieving its three primary goals: (1) building a pipeline of D&I investigators, (2) creating a network of scholars to build the field, and (3) improving funding outcomes for D&I grants.


Medicinal plants used by the villagers of a Sundanese community in West Java, Indonesia.
Based on the authors' fieldwork in a Sundanese village, Indonesia, this paper aimed to elucidate the roles of herbal medicine in treatment of illnesses and to report medicinal plants and their uses, comparing with those mentioned in the encyclopedic book series of Plant Resources of South-East Asia (PROSEA). Interview survey was conducted for all of the 19 herbalist healers about their therapies for the past 1-month period, and the medicinal plants used were botanically identified. For 70 non-healer households, treatments for all members' illness episodes in the past 1-month period were asked. Medicinal plants were used in two-thirds of illness cases, either through the villagers' self-treatment (60.9%) or by the healers (6.5%). The healers made 96 therapies for illnesses (classified into 23 categories), using 117 plant species. There were 257 types of illness-plant pairs, and only 114 of them (44.4%) were judged conformed to those mentioned in the PROSEA. Sundanese villagers have depended heavily on herbal medicine, and high proportion of non-conformed illness-plant pairs suggests necessity of further studies about Sundanese medicinal plants, particularly their pharmacological effects.


Pyrrolidin-2-one linked benzofused heterocycles as novel small molecule monoacylglycerol lipase inhibitors and antinociceptive agents.
Eighteen pyrrolidin-2-one linked benzothiazole, and benzimidazole derivatives (10-27) were designed and synthesized. The structure of the compounds was confirmed by elemental and spectral (IR, 1 H-NMR and MS) data analysis. All the compounds were screened by human monoacylglycerol lipase (hMAGL) inhibition assay. Three benzimidazole compounds, 22 (4-Cl phenyl), 23 (3-Cl,4-F phenyl) and 25 (4-methoxy phenyl) were found to be the most potent, having an IC50 value of 8.6, 8.0 and 9.4 nm, respectively. Among them, the halogen-substituted phenyl derivatives, compound 22 (4-Cl phenyl) and compound 23 (3-Cl,4-F phenyl), showed micromolar potency against fatty acid amide hydrolase (FAAH), having an IC50 value of 35 and 24 µm, respectively. Benzimidazole derivative having 4-methoxyphenyl substitution (compound 25) was found to be a selective MAGL inhibitor (IC50 = 9.4 nm), with an IC50 value above 50 µm against FAAH. In the formalin-induced nociception test, compound 25 showed a dose-dependent reduction of pain response in both acute and late phases. At 30 mg/kg dose, it significantly reduced the pain response and showed greater potency than the reference drug gabapentin (GBP).


Event-related potentials reflect spectral differences in speech and non-speech stimuli in children and adults.
Event-related brain potentials (ERP) may provide tools for examining normal and abnormal language development. To clarify functional significance of auditory ERPs, we examined ERP indices of spectral differences in speech and non-speech sounds. Three Spectral Items (BA, DA, GA) were presented as three Stimulus Types: syllables, non-phonetics, and consonant-vowel transitions (CVT). Fourteen 7- to 10-year-old children and 14 adults were presented with equiprobable Spectral Item sequences blocked by Stimulus Type. Spectral Item effect appeared as P1, P2, N2, and N4 amplitude variations. The P2 was sensitive to all Stimulus Types in both groups. In adults, the P1 was also sensitive to transitions while the N4 was sensitive to syllables. In children, only the 50-ms CVT stimuli elicited N2 and N4 spectral effects. In both groups, non-phonetic stimuli elicited larger N1-P2 amplitudes while speech stimuli elicited larger N2-N4 amplitudes. Auditory feature processing is reflected by P1-P2 and N2-N4 peaks and matures earlier than supra-sensory integrative mechanisms, reflected by N1-P2 peaks. Auditory P2 appears to pertain to both processing types. These results delineate an orderly processing organization whereby direct feature mapping occurs earlier in processing and, in part, serves sound detection whereas relational mapping occurs later in processing and serves sound identification.


A Global Analysis of Associations between Fine Particle Air Pollution and Cardiovascular Risk Factors: Feasibility Study on Data Linkage.
This paper presents a feasibility study of data linkage between global air pollution data and clinical medical data to assess the associations of PM2.5 with cardiovascular risk factors. Cardiovascular risk factor data were obtained from the SUrvey of Risk Factors (SURF) for coronary heart disease (CHD) patients from 10 countries in Europe, Asia, and the Middle-East. Annual average PM2.5 concentrations were estimated using recent global WHO PM2.5 maps combining satellite and surface monitoring data for the location of the 71 participating centers. Associations of PM2.5 with risk factors were assessed by mixed-effect generalized estimation equation models adjusted by sex, age, exercise, body mass index, and smoking. In the final model there was further adjustment for country. Linkage between cardiovascular risk factor data and PM2.5 via the postal address of participating hospitals was shown to be feasible, however with several limitations noted.Eight thousand three hundred and ninety two patients (30% women) were included. Globally, an increase of 10 μg/m3 in PM2.5 was significantly associated with decreased BP and increased glucose. After controlling for country, an increase of 10 μg/m3 in PM2.5 was associated with decreased BP and increased LDL (SBP: -0.45 mmHg [95% CI: -0.85, -0.06]; DBP: -0.47 mmHg [-0.73, -0.20]; LDL: 0.04 mmol/L [0.01, 0.08]). The association with glucose attenuated (0.08 mmol/L [-0.23, 0.16]). It is feasible to link PM2.5 and cardiovascular risk factors but it is still challenging to interpret these observed associations due to unavailability of potential confounders. After country adjustment, PM2.5 was associated with small increases in LDL and small decreases in BP. - There are limited studies on the association between air pollution and cardiovascular risk factors for patients with established coronary heart disease in low- and middle-income countries;- Data linkage is an efficient and cost-effective method to maximize the use of existing data to investigate more health related research questions;- It is feasible to determine global associations of air pollution and cardiovascular risk factors by data linkage but it is still challenging in terms of interpretation.


Peripartum Pubic Symphysis Diastasis.
Peripartum separation of the pubic symphysis is a rare but potentially severe complication of childbirth, which may lead to prolonged immobilization. Thus, prompt diagnosis and treatment are paramount. The purpose of this review is to define peripartum separation of the pubic symphysis and provide a thorough review of its etiology, clinical manifestations, diagnostic imaging techniques, management, and prognosis. This was a literature review using PubMed and Google Scholar. Peripartum pubic symphysis separation is defined as disruption of the pubic symphysis joint and ligamentous structures with greater than 1 cm of separation during delivery. Risk factors include fetal macrosomia, nulliparity, and precipitous labor. Patients often present with a sensation of something "giving way" in the pubic symphysis area at the time of delivery, or with severe pain in the pubic symphysis region with attempted mobilization postpartum. In severe cases, associated hematomas, pelvic fractures, sacroiliac joint disruption, and urinary tract injury may be seen. Imaging such as x-ray or ultrasound may be used to confirm the diagnosis. Although most patients recover well with conservative management, orthopedic surgical intervention may be indicated in more severe or unresolved cases. Pubic symphysis separation is increasingly identified peripartum due enhanced accessibility and utilization of imaging modalities. It can be debilitating and lead to prolonged immobility postpartum. Therefore, early recognition and diagnosis are important, as this can guide decision-making for management. A multidisciplinary team approach, including coordination with obstetrics, orthopedic surgery, physical therapy, and occupational therapy should be used for early detection and treatment to ensure optimal patient outcomes.