Vitiligo and disorders of the retinal pigment epithelium.
The association of vitiligo with inflammation of the uveal tract is well established. The relationship between vitiligo and hypopigmentation and/or degeneration of the retinal pigment epithelium (RPE) not secondary to ocular inflammation has not been adequately investigated. Sixty (27%) of 223 consecutive patients with vitiligo were found to have some evidence of RPE hypopigmentation ranging from mild, focal areas of involvement in most cases to extensive RPE degeneration with a retinitis pigmentosa-like syndrome in one patient. Fifteen (25%) patients complained of night blindness. Only 6 (4%) of 148 patients in a control group had similar funduscopic findings (p less than 0.001). None of these patients were symptomatic. There have been isolated reports of vitiligo occurring with tapetoretinal degeneration. We report 2 patients with both vitiligo and retinitis pigmentosa.


Dual porphyrias revisited.
The porphyrias are clinically and genetically heterogeneous metabolic diseases, which predominantly result from a hereditary dysfunction in the pathway of haeme biosynthesis. Currently, at least eight different forms of porphyrias can be differentiated, all of them characterized by a specific enzyme deficiency that is either inherited in an autosomal-dominant fashion, autosomal recessively or, in the case of porphyria cutanea tarda, might also be acquired. All genes encoding these enzymes have been cloned and several mutations underlying the different types of porphyrias have been reported. Traditionally, the diagnosis of porphyria is made on the basis of clinical symptoms, characteristic biochemical findings and enzyme assays. In some porphyria patients and families, however, these diagnostic tools can reveal simultaneous findings compatible with two different forms of porphyria, a phenomenon referred to as dual porphyria. Here, we give an overview on what is currently known about these peculiar variants of porphyria and suggest that, whenever feasible, molecular genetic analysis should complement the analytical techniques used to characterize patients and families in which a double enzymatic deficiency within the haeme biosynthetic pathway is assumed.


[Biochemical determination of B. thuringiensis thermostabile, exotoxin, using the inhibition of bacterial RNA polymerases].
This method can determine amounts of exotoxin near 1 mug. Used on the autoclaved filtrates of cultures of B. thuringiensis var. thuringiensis (serotype 1 type-strain), it shows an excretion rate of 250 to 300 mug per millilitre. The results on different exotoxin-producer strains give a perfect parallelism with the results obtained by bio-assays on Insects, but the biochemical method is more accurate and reproducible. This biochemical technique allows us, for the first time, to place the exotoxin excretion during the sporulation stage and not during the exponential growth.


Microinjection of morphine into various amygdaloid nuclei differentially affects nociceptive responsiveness and RVM neuronal activity.
The goal of the present study was to identify nuclei of the amygdala in which opioid-sensitive systems can act to recruit nociceptive modulatory circuitry in the rostral ventromedial medulla (RVM) and affect nociceptive responsiveness. In lightly anesthetized rats, 10 microg of morphine was bilaterally microinjected into basolateral, cortical, medial, central, and lateral nuclei of the amygdala to determine the relative influence on the activity of identified ON, OFF and NEUTRAL cells in the RVM and on the latency of the tail flick reflex evoked by noxious radiant heat. Infusions of morphine into the basolateral nuclei resulted in a substantial, naloxone-reversible increase in tail flick latency, and significantly increased ongoing firing of OFF cells and depressed that of ON cells. The reflex-related changes in cell firing were also attenuated. Morphine infusions into the cortical nuclei resulted in a small (approximately 1 s) but significant increase in tail flick latency. As with basolateral microinjections, ongoing activity of the OFF cells was increased, and although the ongoing firing of ON cells was not significantly changed, the reflex-related burst that characterizes these neurons was reduced. Microinjections in the medial nuclei again altered ongoing activity of both ON cells and OFF cells. However, the duration of the OFF cell pause and tail flick latency were unchanged. NEUTRAL cells were not affected by morphine at any site. Morphine applied within the central, medial lateral and dorsal lateral nuclei had no effect on RVM neurons or on the tail flick. Thus, focal application of morphine within the basolateral nucleus of the amygdala produced hypoalgesia and influenced RVM ON and OFF cells in a manner similar to that seen following systemic or RVM opioid administration. Opioid action within the medial and cortical nuclei also influenced RVM cell activity, but did not prevent the reflex-related OFF cell pause, and failed to alter the tail flick substantially. These observations, plus the lack of an opioid-activated influence from the central and lateral nuclei, demonstrate fundamental differences among systems linking the different amygdalar nuclei with the RVM. One way in which the modulatory circuitry of the RVM might be engaged physiologically in behaving animals is via opioid-mediated activation of the basolateral nucleus.


Building New Teams for Late Life Care: Lessons From LifeCourse.
This article details team development within a longitudinal cohort study designed to bring team-based, whole person care early in the course of serious illness. The primary innovation of this approach is the use of nonclinically trained care guides who support patients and family members by focusing care around what matters most to patients, linking to resources, collaborating with other providers, and offering continuity through care transitions. By describing the development of this team, we document the kinds of questions others may ask during the process of team creation.


The PAT randomized clinical trial.
A pragmatic, single-centre, double-blind randomized clinical trial was conducted in a NHS teaching hospital to evaluate whether there is a difference in functional knee scores, quality-of-life outcome assessments, and complications at one-year after intervention between total knee arthroplasty (TKA) and patellofemoral arthroplasty (PFA) in patients with severe isolated patellofemoral arthritis. This parallel, two-arm, superiority trial was powered at 80%, and involved 64 patients with severe isolated patellofemoral arthritis. The primary outcome measure was the functional section of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score at 12 months. Secondary outcomes were the full 24-item WOMAC, Oxford Knee Score (OKS), American Knee Society Score (AKSS), EuroQol five dimension (EQ-5D) quality-of-life score, the University of California, Los Angeles (UCLA) Physical Activity Rating Scale, and complication rates collected at three, six, and 12 months. For longer-term follow-up, OKS, EQ-5D, and self-reported satisfaction score were collected at 24 and 60 months. Among 64 patients who were randomized, five patients did not receive the allocated intervention, three withdrew, and one declined the intervention. There were no statistically significant differences in the patients' WOMAC function score at 12 months (adjusted mean difference, -1.2 (95% confidence interval -9.19 to 6.80); p = 0.765). There were no clinically significant differences in the secondary outcomes. Complication rates were comparable (superficial surgical site infections, four in the PFA group versus five in the TKA group). There were no statistically significant differences in the patients' OKS score at 24 and 60 months or self-reported satisfaction score or pain-free years. Among patients with severe isolated patellofemoral arthritis, this study found similar functional outcome at 12 months and mid-term in the use of PFA compared with TKA. Cite this article: Bone Joint J 2020;102-B(3):310-318.


Concomitant presentation of eosinophilic or oncocytic mucoepidermoid carcinoma, immunoglobulin G4-related disease, and adult-onset asthma and periocular xanthogranuloma: Case report of 3 uncommon clinical entities.
Immunoglobulin (Ig) G4-related disease (IgG4-RD) reportedly has a strong relationship with adult-onset asthma and periocular xanthogranuloma (AAPOX) and may be linked to sclerosing mucoepidermoid carcinoma (MEC). We present a rare case of IgG4-RD and AAPOX occurring in a patient with resected eosinophilic or oncocytic MEC. A 52-year-old woman was referred to our rheumatology clinic in 2020 to be evaluated for suspected IgG4-RD. The patient had diagnoses of periorbital xanthelasmas, worsening glucocorticoid-dependent chronic rhinosinusitis and adult-onset asthma, and cervical lymphadenopathy persisting 2 years after resection of a low-grade MEC of a minor salivary gland. Because the patient's symptomatic relief was glucocorticoid dependent, IgG4-RD was suspected, and she was referred to our medical center. Her amylase and lipase levels were elevated. Serum IgG4 levels were initially within normal limits, but IgG4-RD was diagnosed because of the presence of lymphadenopathy and evidence of pancreatitis, which was shown on positron emission tomography/computed tomography. Furthermore, the IgG4 levels later increased without explanation. After the patient began combination therapy with a glucocorticoid (prednisone) and methotrexate, her symptoms improved but recurred when the daily oral glucocorticoid dosage decreased below 10 mg. An excisional biopsy of her right submandibular gland in 2021 yielded results consistent with IgG4-RD. In addition, AAPOX was diagnosed, given the presence of periocular edema and plaques, adult-onset asthma, and rhinosinusitis. The patient was carcinoma free at last follow-up and was receiving medication to treat the other conditions. The diagnosis of these 3 concomitant, uncommon entities required approximately 7 years of medical investigations. Clinicians should know that IgG4-RD, AAPOX, and MEC may occur together.


[Pulsed secretion of gonadotropins in polycystic ovary syndrome].
Pulsed secretion of gonadotropins was studied in 8 women suffering from polycystic ovarian syndrome, aged 23-28. Data on the time course of LH and FSH levels were processes by Santen and Bardin's method and by harmonic analysis. The results evidence that regular ejections of LH at a frequency higher than circahoralian rhythm (about 2 impulses per h) in such patients may be the cause of the development of the polycystic ovarian syndrome. Therapy with norcolut, carried out for 3 months, resulted in development of a trend to normalization of LH secretion, FSH secretion remaining unchanged.


Metformin loaded non-ionic surfactant vesicles: optimization of formulation, effect of process variables and characterization.
Metformin an oral hypoglycemic has been widely used as a fist line of treatment of Type II Diabetes but in a very high dose 2-3 times a day and moreover suffers from a number of side effects like lactic acidosis, gastric discomfort, chest pain, allergic reactions being some of them. The present work was conducted with the aim of sustaining the release of metformin so as to decrease its side effects and also reduce its dosing frequency using a novel delivery system niosomes (non-ionic surfactant vesicles). Non-ionic surfactant vesicles of different surfactants were prepared using thin film hydration technique and were investigated for morphology, entrapment, in-vitro release, TEM (transmission electron microscopy) and physical stability. Optimized formulation was further studied for the effect of Surfactant concentration, DCP (Dicetyl phosphate), Surfactant: cholesterol ratio and volume of hydration. The release studies data was subjected to release kinetics models. The prepared vesicles were uniform and spherical in size. Optimized formulation MN3 entrapped the drug with 84.50±0.184 efficiency in the vesicles of the size 487.60±2.646 and showed the most sustained release of 73.89±0.126. Also it was resulted that 100 molar concentration of cholesterol and surfactant, Presence of DCP, equimolar ratio of span 60: cholesterol and 15 ml of volume of hydration were found to be optimum for miosome preparation. The present work concluded metformin loaded niosomes to be effective in sustaining the drug release leading to decreased side effects and increased patient compliance.


Metabolic coupling of arsenic, carbon, nitrogen, and sulfur in high arsenic geothermal groundwater: Evidence from molecular mechanisms to community ecology.
Groundwater arsenic (As) poses a global environmental problem and is regulated by complex biogeochemical processes. However, the As biogeochemistry and its metabolic coupling with carbon (C), nitrogen (N), and sulfur (S) in high As geothermal groundwater remain unclear. Here, we reported significant shifts in the geothermal groundwater microbiome and its functional ecological clusters along the flow path with increased As levels and dynamic As-C-N-S biogeochemical cycle from the Guide Basin, China. Strong associations among As(III), NH4+, HCO3-, and corresponding functional microbial taxa suggest that microbe-mediated As transformation, ammonification, and organic carbon biodegradation potentially contributed to the As mobilization in the discharge area. And As oxidizers (coupling with denitrification or carbon fixation) and S oxidizers were closely linked to the transformation of As(III) to immobile As(V) in the recharge area. Our study provides a comprehensive insight into the complex microbial As-C-N-S coupling network and its potential role in groundwater As mobilization under hydrological disturbances.


Social learning of predators in the dark: understanding the role of visual, chemical and mechanical information.
The ability of prey to observe and learn to recognize potential predators from the behaviour of nearby individuals can dramatically increase survival and, not surprisingly, is widespread across animal taxa. A range of sensory modalities are available for this learning, with visual and chemical cues being well-established modes of transmission in aquatic systems. The use of other sensory cues in mediating social learning in fishes, including mechano-sensory cues, remains unexplored. Here, we examine the role of different sensory cues in social learning of predator recognition, using juvenile damselfish (Amphiprion percula). Specifically, we show that a predator-naive observer can socially learn to recognize a novel predator when paired with a predator-experienced conspecific in total darkness. Furthermore, this study demonstrates that when threatened, individuals release chemical cues (known as disturbance cues) into the water. These cues induce an anti-predator response in nearby individuals; however, they do not facilitate learnt recognition of the predator. As such, another sensory modality, probably mechano-sensory in origin, is responsible for information transfer in the dark. This study highlights the diversity of sensory cues used by coral reef fishes in a social learning context.


[Effect of functional exercises on patients with rheumatoid arthritis: a meta-analysis].
To evaluate the effect of functional exercises on disease activity, joint function and quality of life of patients with rheumatoid arthritis (RA). Randomized controlled trials were searched in Cochrane Library, PubMed, China National Knowledge Infrastructure (CNKI), VIP database and Wanfang database with keywords being "rheumatoid arthritis/RA", "function exercise (training)/joint exercise (training)/physical exercise (training)/resistance movement (exercise)/isotonic and isometric/stretching exercise/muscle exercise", and "trials/clinical trials". Then literature selection, extraction and literature quality evaluation were carried out by two of the authors independently following the including and excluding standards. Then the outcome indicators were analyzed with Review Manager 5.3 software. In the study, 2 173 articles were achieved by searching in databases, including 1 522 English papers and 651 Chinese papers. Then 913 duplicated papers were identified and removed using EndNote software. After reading the titles and abstracts, 1 194 papers were excluded that did not satisfy the including standards. Finally, the full texts of these papers were read and papers with insufficient data were excluded, resulting in 13 included papers for systematic review, including 8 English and 5 Chinese papers. A total of 812 cases were studied in these papers, including 426 in the experimental groups and 386 in the conventional groups. For the outcome index in these articles, disease activity score 28 (DAS28) was used in 5 of them, health assessment questionnaire (HAQ) was used in 8 articles, visual analogue scale (VAS) for pain was used in 6 articles, and morning stiffness duration was used in 3 articles. The meta-analysis showed that functional exercises could delay the development of the disease activity of RA patients (mean difference=-0.76; 95%CI: -1.13, -0.38; P<0.001), improve the joint function (mean difference=-0.36; 95%CI: -0.47, -0.24; P<0.001), alleviate the pain of joints (mean difference=-1.75; 95%CI: -1.98, -1.53; P<0.001), and reduce the duration of morning stiffness (mean difference=-17.65; 95%CI: -22.09, -13.21; P<0.001). This study showed the positive effects of functional exercises on alleviating the pain of joints, reducing the morning stiffness duration, and delaying the disease exacerbation of RA patients. It has a positive effect on improving the joint function and improving the quality of life in patients with RA.


Relationship of running intensity to hypertension, hypercholesterolemia, and diabetes.
To estimate the independent relationships of running intensity with antihypertensive, LDL-cholesterol-lowering, and antidiabetic medication use when adjusted for running volume (km x d(-1)). Self-reported medication use was compared cross-sectionally to running pace (m x s(-1) during usual run) in 25,552 male and 29,148 female National Runners' Health Study participants. The men ran a mean +/- SD of 5.2 +/- 3.1 km x d(-1) at 3.3 +/- 0.5 m x s(-1) (8.3 +/- 1.4 min x mile(-1)) and the women 4.7 +/- 2.9 km x wk(-1) at 3.0 +/- 0.4 m x s(-1) (9.2 +/- 1.8 min x mile(-1)). When adjusted for kilometers per day, each meter-per-second increment in intensity in men and women reduced the odds for antihypertensive drug use by 54% and 46%, respectively, reduced the odds for LDL-cholesterol-lowering medication use by 55% and 48%, respectively, and reduced the odds for antidiabetic medication use by 50% and 75%, respectively (all P < 0.0001). Compared with men who ran slower than 10 min x mile(-1), the odds for medication use in those who ran or exceeded a 7-min x mile(-1) pace were 72% less for antihypertensive, 78% less for LDL-cholesterol lowering, and 67% less for antidiabetic medications (the corresponding odds reductions in women were 61%, 64%, and 87%, respectively, for 8 min x mile(-1) or faster versus slower than 11 min x mile(-1)). Although usual running pace correlated significantly with a 10-km performance (male, r = 0.55; females, r = 0.49), usual pace remained significantly related to lower use of all three medications in men and antihypertension and antidiabetic medications in women when adjusted for a 10-km performance. Although these results do not prove causality, they show that exercise intensity is inversely associated with the prevalence of hypertension, hypercholesterolemia, and diabetes independent of exercise volume and cardiorespiratory fitness (10-km performance), suggesting that the more vigorous the exercise, the healthier the health benefits.


Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716.
SR141716, a recently developed CB1 cannabinoid receptor antagonist, blocks acute effects of Delta-9-tetrahydrocannabinol (THC) and other CB1 cannabinoid agonists in vitro and in animals. These findings suggest that CB1 receptors mediate many of the effects of marijuana, but this has not been evaluated in humans. Sixty-three healthy men with a history of marijuana use were randomly assigned to receive oral SR141716 or a placebo in an escalating dose (1, 3, 10, 30, and 90 mg) design. Each subject smoked an active (2.64% THC) or placebo marijuana cigarette 2 hours later. Psychological effects associated with marijuana intoxication and heart rate were measured before and after antagonist and marijuana administration. Single oral doses of SR141716 produced a significant dose-dependent blockade of marijuana-induced subjective intoxication and tachycardia. The 90-mg dose produced 38% to 43% reductions in visual analog scale ratings of "How high do you feel now?" "How stoned on marijuana are you now?" and "How strong is the drug effect you feel now?" and produced a 59% reduction in heart rate. SR141716 alone produced no significant physiological or psychological effects and did not affect peak THC plasma concentration or the area under the time x concentration curve. SR141716 was well tolerated by all subjects. SR141716 blocked acute psychological and physiological effects of smoked marijuana without altering THC pharmacokinetics. These findings confirm, for the first time in humans, the central role of CB1 receptors in mediating the effects of marijuana.


[Management after hepatectomy of colorectal cancer metastases to the liver--intrahepatic arterial infusion chemotherapy and repeated hepatectomy].
Before Dec. 1993, we resected 17 patients with hepatic metastases from colorectal cancer. Hepatic recurrences developed in 82% patients who had been given mitomycin C or doxorubicin by hepatic-artery. The one-, 3- and 5-year survival rate after surgery was, 88%, 18% and 12%, respectively. Therefore, some new types of adjuvant therapy were needed to improve survival after surgery. This is a retrospective study to determine whether preventive intrahepatic artery infusion chemotherapy (HAI) and repeated hepatectomy are of benefit for patients with hepatic metastases from colorectal cancer who underwent hepatectomy. Thirty-five patients with hepatic metastases from colorectal cancer underwent hepatectomy and were administered 1,500 mg of 5-FU 10 times via the hepatic artery for 5 hrs every 1-2 weeks to prevent hepatic recurrence after Jan. 1994. Nine patients underwent repeated hepatectomy, then HAL following the operation. Non-resectable recurrence were treated by HAI. The amounts of the infused 5-FU dose were 8.5-46.5 g (mean 23 g) and 17-31 times HAI (mean 22 times). Survival rates were 81, 67, 67% and 24%, respectively, after 1, 2, 3 and 4 years. Hepatic disease-free interval rates were 49.3% and 32.5%, respectively, after 1 and 2 years. Preventive HAI could not control hepatic recurrence but prognosis after hepatectomy was improved by these modalities compared with treatment before Dec. 1993. Survival rates of 9 patients who underwent repeated hepatectomy were 89, 89% and 37%, respectively, after 1, 3 and 4 years. The prognosis of patients with hepatic metastases from colorectal cancer was improved by HAI and repeated hepatectomy, but further studies should be undertaken to improve preventive HAI.


Positive and negative emotions in dairy cows: Can ear postures be used as a measure?
Applying objective measures to assess the emotional states of animals is an important area of research and essential for improving animal welfare. In this study, we have built upon previous research to test whether ear postures can be used as an indicator of emotional states in dairy cows. By using a positive and negative contrast paradigm, we elicited the emotional states of excitement and frustration in 22 dairy cows. Each cow was first conditioned to expect the delivery of standard feed when a bell was rung. Once they were familiar with the experimental set-up and the delivery of the feed, they were then given concentrates feed instead. As concentrates are highly desired, this was considered to elicit the emotional state of excitement. This was then repeated five times. On the following trial, the cows were given inedible woodchip, and the cows' unfulfilled expectations were considered to elicit a state of frustration. We observed the cows' ear postures and mean heart rate (beats per minute) during 15-minute focal observations, each comprised of 5 min of pre-feeding (baseline), 5 min of feeding, and 5 min of post-feeding. Both the woodchip treatment and the concentrates elicited significantly higher mean heart rates compared with the standard feed, indicating that both treatments elicited a high arousal emotional state. The woodchip and concentrates treatments were also significantly associated with the increased performance of different ear postures, indicating that cows do perform certain ear postures in relation to both positive and negative high arousal emotional states. Our results complement previous research performed with both cows and sheep, and indicate that with training and contextual knowledge, ear postures may be suitable as a reliable measure of emotional state in dairy cows.


Controlled chattering--a new 'cutting-edge' technology for nanofabrication.
Chatters are unwanted random defects on surfaces often generated in cutting samples via microtome for micrographic analysis. In this work, we demonstrate that chatters can actually be controlled for fabrication of uniform periodic wavy patterns on polymethylmethacrylate surfaces. This control in chattering is achieved based on an oscillation cutting mechanism. Pattern sizes ranging from 30 nm to a few micrometers are obtained by fine-tuning cutting speed and oscillating frequency. This simple one-step non-lithographic 'cutting-edge' technology is simple and robust, with no chemical reactions and by-products involved and ease in scaling up for long-range and large-areas patterns.


Further evidence of interrelation between homocysteine and hypertension in stroke patients: a cross-sectional study.
A high total plasma homocysteine level is an independent risk factor for cardiovascular and cerebrovascular disease, but the evidence connecting plasma tHcy level with hypertension is inconsistent. To determine the association between plasma tHcy level and some common risk factors for cerebrovascular disease (recurrent stroke, diabetes mellitus, hypertension, ischemic heart disease and hyperlipidemia) in patients presenting with primary or recurrent acute ischemic strokes. This retrospective cross-sectional chart analysis was conducted in a university-affiliated referral hospital. During an 18 month period we identified 113 acute ischemic stroke patients (mean age 71.2), 25 of whom had a recurrent stroke. Plasma tHcy level, obtained 2-10 days after stroke onset, was determined by the high performance liquid chromatography method with fluorescence detection. A multivariate logistic regression model was used to determine the independent relationship between each potential risk factor and tHcy level above or below the 75th percentile. Hypertension was more frequent among patients with plasma tHcy level above than below the 75th percentile (51.7% vs. 80.8%, respectively, P = 0.012). After adjusting for demographic and clinical variables, the odds ratio for recurrent stroke and hypertension, with tHcy above or below the 75th percentile, was 3.4 (95% confidence interval 1.01-10.4, P = 0.037) and 4.02 (95% CI 1.2-13.9, P = 0.028), respectively. A high plasma tHcy level is associated with history of hypertension and recurrent stroke among patients presenting with acute ischemic stroke. These results were independent of other risk factors such as atrial fibrillation, diabetes and hyperlipidemia. Hypertensive stroke patients with hyperhomocysteinemia should be identified as high risk patients as compared to non-hypertensive stroke patients, and more vigorous measures for secondary prevention may be warranted.


Laser-assisted morphing of complex three dimensional objects.
Morphing refers to the smooth transition from a specific shape into another one, in which the initial and final shapes can be significantly different. A typical illustration is to turn a cube into a sphere by continuous change of shape curvatures. Here, we demonstrate a process of laser-induced morphing, driven by surface tension and thermally-controlled viscosity. As a proof-of-concept, we turn 3D glass structures fabricated by a femtosecond laser into other shapes by locally heating up the structure with a feedback-controlled CO2 laser. We further show that this laser morphing process can be accurately modelled and predicted.


The effect of intraperitoneal administration of zinc aspartate on myringosclerosis in perforated tympanic membranes of rats.
The objective of the present study was to determine the effect of zinc aspartate on myringosclerosis in perforated rat tympanic membrane. Fifteen Sprague-Dawley rats were randomly divided into three groups each containing five rats. Automicroscopic examinations were performed and then all rats were bilaterally myringotomized. Group 1 received no treatment. Group 2 was treated with intraperitoneal injection of physiological saline and group 3 with intraperitoneal injection of zinc aspartate. Tympanic bullas were harvested after 20 days. Histopathological evaluation was carried out under the light microscope. When the groups were compared in the light of the myringosclerotic findings, while there was no significant difference between group 1 and 2 (p=1.00), it was found that there were significant differences between group 1 and 3, and between group 2 and 3 (p<0.03). It appears that zinc aspartat treatment has beneficial effects on prevention or retardation of the development of myringosclerosis, but further studies are needed to clarify this effect.


Oxidative Dissolution of Sulfide Minerals in Single and Mixed Sulfide Systems under Simulated Acid and Metalliferous Drainage Conditions.
Chalcopyrite, galena, and sphalerite commonly coexist with pyrite in sulfidic waste rocks. The aim of this work was to investigate their impact, potentially by galvanic interaction, on pyrite oxidation and acid generation rates under simulated acid and metalliferous drainage conditions. Kinetic leach column experiments using single-minerals and pyrite with one or two of the other sulfide minerals were carried out at realistic sulfide contents (total sulfide <5.2 wt % for mixed sulfide experiments), mimicking sulfidic waste rock conditions. Chalcopyrite was found to be most effective in limiting pyrite oxidation and acid generation with 77-95% reduction in pyrite oxidation over 72 weeks, delaying decrease in leachate pH. Sphalerite had the least impact with reduction of pyrite dissolution by 26% over 72 weeks, likely because of the large band gap and poor conductivity of sphalerite. Galena had a smaller impact than chalcopyrite on pyrite oxidation, despite their similar band gaps, possibly because of the greater extent of oxidation and the significantly reduced surface areas of galena (area reductions of >47% for galena vs <1.5% for chalcopyrite) over 72 weeks. The results are directly relevant to mine waste storage and confirm that the galvanic interaction plays a role in controlling acid generation in multisulfide waste even at low sulfide contents (several wt %) with small probabilities (≤0.23%) of direct contact between sulfide minerals in mixed sulfide experiments.


Altered trafficking and turnover of LAMP-1 in Pompe disease-affected cells.
The lysosome-associated membrane protein (LAMP-1) is elevated in the cells and plasma from lysosomal storage disorder-affected individuals; however, the mechanism of this elevation is not well defined. In this study we have investigated the synthesis, glycoprocessing, trafficking, and turnover of LAMP-1 in human skin fibroblasts from Pompe disease patients and control individuals. There were similar levels of LAMP-1 synthesis in both cell types, but glycoprocessing was retarded in Pompe (T1/2 = 25 min) compared to control (T1/2 = 17 min) fibroblasts. There was also a marked delay in trafficking of LAMP-1 to lysosomes of Pompe (T1/2 = 200 min) compared to control (T1/2 = 100 min) cells. A proportion of newly synthesized LAMP-1 (5.4% in Pompe and 8.5% in controls) was trafficked out of the cell (T1/2 = 3.5 h in controls) and, although significantly smaller than the lysosomal form, still had a transmembrane domain and cytoplasmic tail. In contrast, a soluble lysosomal pool of LAMP-1 had no tail sequence, suggesting that it had been clipped from the membrane. In turnover studies, LAMP-1 was more stable in Pompe (T1/2 = 4.9 days) compared to control (T1/2 = 1. 6 days) cells, implying either reduced proteolysis or lysosomal function, in Pompe cells. These results indicate altered traffic and turnover of LAMP-1 in storage disorders and identify different intracellular and extracellular pools of soluble LAMP-1, suggesting alternative trafficking pathways.


Genome-wide DNA methylation profiles in renal tumors of various histological subtypes and non-tumorous renal tissues.
The aim of this study is to clarify genome-wide DNA methylation profiles in renal tumors of various histological subtypes. Bacterial artificial chromosome (BAC) array-based methylated CpG island amplification was performed using tissue samples of 17 patients with papillary renal cell carcinomas (RCCs), chromophobe RCCs and oncocytomas, and the results were compared with those from 51 patients with clear cell RCCs. Unsupervised hierarchical clustering analysis based on DNA methylation status clustered type 1 and type 2 papillary RCCs into different subclasses. Although chromophobe RCCs and oncocytomas were clustered into the same subclass, the DNA methylation status of 21 BAC clones was able to discriminate chromophobe RCCs from oncocytomas. The number of BAC clones showing DNA methylation alteration in non-tumorous renal tissue from patients with chromophobe RCCs and oncocytomas was smaller than that from patients with clear cell RCCs. Biphasic accumulation of DNA methylation alterations was observed in non-tumorous renal tissue from all 68 patients, and patients showing such alterations on more BAC clones had a poorer outcome than patients showing them on fewer BAC clones. DNA methylation profiles determining the histological subtypes of renal tumors developing in individual patients and/or patient outcome may be already established in non-tumorous renal tissue at the precancerous stage.


The effectiveness of anti-stigma interventions for reducing mental health stigma in young people: A systematic review and meta-analysis.
Experiencing mental health stigma during adolescence can exacerbate mental health conditions, reduce quality of life and inhibit young people's help-seeking for their mental health needs. For young people, education and contact have most often been viewed as suitable approaches for stigma reduction. However, evidence on the effectiveness of these anti-stigma interventions has not been consistent. This systematic review evaluated the effectiveness of interventions to reduce mental health stigma among youth aged 10-19 years. The review followed Cochrane and PRISMA guidelines. Eight databases were searched: PubMed, PsycINFO, MEDLINE, Web of Science, Scopus, EMBASE, British Education Index and CNKI. Hand searching from included studies was also conducted. Randomised controlled trials and experimental designs that included randomised allocation to interventions and control groups were included in the review. Narrative synthesis was employed to analyse the results. A meta-analysis was conducted to determine the effectiveness of included interventions. Twenty-two studies were included in the review. Eight studies reported positive effects, 11 studies found mixed effects and 3 studies reported no effect on indicators of mental health stigma among youth. Seven of the effective studies were education-based. Eleven studies were suitable for meta-analysis, and the multivariate meta-analytic model indicated a small, significant effect at post-intervention (d = .21, p < .001), but not at follow-up (d = .069, p = .347). Interventions to reduce stigma associated with mental health conditions showed small, short-term effects in young people. Education-based interventions showed relatively more significant effects than other types of interventions.


The Effects of p-Azidophenylalanine Incorporation on Protein Structure and Stability.
Functionalization is often needed to harness the power of proteins for beneficial use but can cause losses to stability and/or activity. State of the art methods to limit these deleterious effects accomplish this by substituting an amino acid in the wild-type molecule into an unnatural amino acid, such as p-azidophenylalanine (pAz), but selecting the residue for substitution a priori remains an elusive goal of protein engineering. The results of this work indicate that all-atom molecular dynamics simulation can be used to determine whether substituting pAz for a natural amino acid will be detrimental to experimentally determined protein stability. These results offer significant hope that local deviations from wild-type structure caused by pAz incorporation observed in simulations can be a predictive metric used to reduce the number of costly experiments that must be done to find active proteins upon substitution with pAz and subsequent functionalization.


A patient's decision aid for vascular access placement in the emergency department.
Vascular access device placement is one of the most routinely performed procedures in the emergency department. Despite its high usage, most patients have limited knowledge about vascular access device placement. Patient decision aids have been utilized heavily in non-emergency department settings to provide basic clinical information regarding a patient's medical care options. In this study, we investigated whether exposure to a patient decision aid on vascular access devices and patients' experiences with vascular access devices would influence their vascular access device preference during an acute care episode. Patients in this institutional review board-approved study were enrolled prospectively in the emergency department at a busy level 1 trauma institution. A patient decision aid on vascular access device was constructed using criteria developed by the International Patient Decision Aid Standards. All participants were exposed to the patient decision aid and were asked to complete two questionnaires, and two tests. Fifty subjects (50) were enrolled prospectively in the emergency department. The mean pretest score was 17.2% (95% confidence interval, 0.54-1.18), while the mean post-test score was 72.4% (95% confidence interval, 3.15-4.09). We found that patients who were exposed to the patient decision aid preferred landmark-based peripheral intravenous lines over ultrasound-guided peripheral intravenous lines in this data set. The result from this analysis indicated that most patients visiting the emergency department are not knowledgeable about their options related to vascular access device placement. The observed increase in the average correct responses on the post-test indicates that a patient decision aid can be an effective educational tool in the emergency department.


Perovskenes: two-dimensional perovskite-type monolayer materials predicted by first-principles calculations.
Inspired by the successful transfer of freestanding ultrathin films of SrTiO3 and BiFeO3 onto various substrates without any thickness limitation, in this study, using density functional theory (DFT), we assessed the structural stability of a group of two-dimensional perovskite-type materials which we call perovskenes. Specifically, we analyzed the stability of 2D SrTiO3, SrZrO3, BaTiO3, and BaZrO3 monolayers. Our simulations revealed that the 2D monolayers of SrTiO3, BaTiO3, and BaZrO3 are at least meta-stable, as confirmed by cohesive energy calculations, evaluation of elastic constants, and simulation of phonon dispersion modes. With this information, we proceeded to investigate the electronic, optical, and thermoelectric properties of these perovskenes. To gain insight into their promising applications, we investigated the electronic and optical properties of these 2D materials and found that they are wide bandgap semiconductors with significant absorption and reflection in the ultraviolet (UV) region of the electromagnetic field, suggesting them as promising materials for use in UV shielding applications. In addition, evaluating their thermoelectric factors revealed that these materials become better conductors of electricity and heat as the temperature rises. They can, hence, convert temperature gradients into electrical energy and transport electrical charges, which is beneficial for efficient power generation in thermoelectric devices. This work opens a new window for designing a novel family of 2D perovskite type materials termed perovskenes. The vast variety of different perovskite compounds and their variety of applications suggest deeper studies on the perovskenes materials for use in innovative technologies.


Egg consumption and insulin metabolism in the Insulin Resistance Atherosclerosis Study (IRAS).
To examine the association between egg consumption and measures of insulin sensitivity (SI), acute insulin response (AIR) and metabolic clearance rate of insulin (MCRI). Cross-sectional analysis. Egg consumption, categorized as <1/week, 1 to <3/week, 3 to <5/week and ≥5/week, was measured using a validated FFQ. SI, AIR and MCRI were determined from frequently sampled intravenous glucose tolerance tests. Non-diabetic participants (n 949) in the Insulin Resistance Atherosclerosis Study (IRAS). Egg consumption was inversely associated with SI and MCRI, and positively associated with fasting insulin in regression models adjusted for demographic, socio-economic, lifestyle and dietary factors (β = -0·22, 95 % CI -0·38, -0·045, P = 0·05 for SI; β = -0·20, 95 % CI -0·34, -0·055, P = 0·005 for MCRI; β = 0·35, 95 % CI 0·15, 0·54, P = 0·002 for fasting insulin; all P values for linear trend). These associations remained significant after additionally adjusting for energy intake or dietary saturated fat, although dietary cholesterol and BMI attenuated these associations to non-significance. Egg consumption was not associated with AIR. Dietary cholesterol and BMI appear to mediate the inverse association of egg consumption with insulin sensitivity and clearance. Alternatively, egg consumption may be clustered with other dietary behaviours which increase BMI, hence negatively impacting on insulin sensitivity and clearance.


Antibodies Against the NH2-Terminus of the GluA Subunits Affect the AMPA-Evoked Releasing Activity: The Role of Complement.
Antibodies recognizing the amino-terminal domain of receptor subunit proteins modify the receptor efficiency to controlling transmitter release in isolated nerve endings (e.g., synaptosomes) indirectly confirming their presence in these particles but also allowing to speculate on their subunit composition. Western blot analysis and confocal microscopy unveiled the presence of the GluA1, GluA2, GluA3, and GluA4 receptor subunits in cortical synaptosomes. Functional studies confirmed the presence of presynaptic release-regulating AMPA autoreceptors in these terminals, whose activation releases [3H]D-aspartate ([3H]D-Asp, here used as a marker of glutamate) in a NBQX-dependent manner. The AMPA autoreceptors traffic in a constitutive manner, since entrapping synaptosomes with the pep2-SVKI peptide (which interferes with the GluA2-GRIP1/PICK1 interaction) amplified the AMPA-evoked releasing activity, while the inactive pep2-SVKE peptide was devoid of activity. Incubation of synaptosomes with antibodies recognizing the NH2 terminus of the GluA2 and the GluA3 subunits increased, although to a different extent, the GluA2 and 3 densities in synaptosomal membranes, also amplifying the AMPA-evoked glutamate release in a NBQX-dependent fashion. We then analyzed the releasing activity of complement (1:300) from both treated and untreated synaptosomes and found that the complement-induced overflow occurred in a DL-t-BOA-sensitive, NBQX-insensitive fashion. We hypothesized that anti-GluA/GluA complexes in neuronal membranes could trigger the classic pathway of activation of the complement, modifying its releasing activity. Accordingly, the complement-evoked release of [3H]D-Asp from antiGluA2 and anti-GluA3 antibody treated synaptosomes was significantly increased when compared to untreated terminals and facilitation was prevented by omitting the C1q component of the immunocomplex. Antibodies recognizing the NH2 terminus of the GluA1 or the GluA4 subunits failed to affect both the AMPA and the complement-evoked tritium overflow. Our results suggest the presence of GluA2/GluA3-containing release-regulating AMPA autoreceptors in cortical synaptosomes. Incubation of synaptosomes with commercial anti-GluA2 or anti-GluA3 antibodies amplifies the AMPA-evoked exocytosis of glutamate through a complement-independent pathway, involving an excessive insertion of AMPA autoreceptors in plasma membranes but also affects the complement-dependent releasing activity, by promoting the classic pathway of activation of the immunocomplex. Both events could be relevant to the development of autoimmune diseases typified by an overproduction of anti-GluA subunits.


Gli1 contributes to cellular resistance to cisplatin through altered cellular accumulation of the drug.
Cellular resistance to platinum anticancer compounds is governed by no less than two molecular processes; DNA repair and cellular accumulation of drug. Gli1 is an upstream regulator of nucleotide excision repair, effecting this process through c-jun. We, therefore, investigated whether Gli1 plays a role in cellular accumulation of cisplatin. Using a Gli1-specific shRNA, we explored the role of Gli1 in the cellular accumulation and efflux of cisplatin, in cisplatin-resistant A2780-CP70 human ovarian cancer cells. When Gli1 is inhibited, cellular uptake of cisplatin was approximately 33% of the level of uptake under control conditions. When Gli1 is inhibited, cellular efflux of cisplatin was completely abrogated, over a 12-h period of observation. We assayed nuclear lysates from these cells, for the ability to bind the DNA sequence that is the Gli-binding site (GBS) in the 5'UTR for each of five known cisplatin transmembrane transporters. Four of these transporters are active in cisplatin uptake; and, one is active in cisplatin efflux. In each case, nuclear lysate from A2780-CP70 cells binds the GBS of the respective cisplatin transport gene. We conclude that Gli1 plays a strong role in total cellular accumulation of cisplatin in these cells; and, that the combined effects on cellular accumulation of drug and on DNA repair may indicate a role for Gli1 in protecting cellular DNA from lethal types of DNA damage.


Association of Tp-Te/QT Ratio With Ventricular Tachycardia in Patients With Idiopathic Outflow Tract Ventricular Premature Contraction.
Idiopathic outflow tract ventricular premature contraction (VPC) can evolve into ventricular tachycardia (VT) via triggered activity mechanism. Transmural dispersion of repolarization (TDR) might play a role in idiopathic outflow tract VT by inducing phase 2 early afterdepolarization (EAD) and serve as the functional substrate for VT. Tp-Te/QT ratio as an arrhythmogenesis index has been reported to be associated with the incidence of ventricular arrhythmia. This study aims to investigate the association between Tp-Te/QT ratio with VT incidence in idiopathic outflow tract VPC. Observational research with cross sectional design was conducted. VT episodes were retrospectively tracked from electrocardiogram (ECG), treadmill test (TMT), Holter monitor and electrophysiology study data in Sardjito Hospital of patients with idiopathic outflow tract VPC during September to October 2017. Tp-Te/QT was defined as the time from the peak of T wave to the intersection between the tangent and isoeectric line, divided with QT interval. Tp-Te/QT ratio measurement was performed in leads V4, V5 and V6 by single observer. Tp-Te/QT ratio was categorized into increased (> 0.25) and normal (< 0.25). Chi-square and logistic regression test were performed. Out of 46 patients, there were 28 patients who had VT. Increased Tp-Te/QT ratio of lead V4 was found in 11 patients, the increased ratios in leads V5 and V6 were found in 13 patients. The prevalence ratio (PR) of Tp-Te/QT ratio to VT incidence in lead V4 was 2.059 (95% CI: 1.464 - 2.895; P = 0.007), while in leads V5 and V6 was 2.200 (95% CI: 1.514 - 3.197; P = 0.002). Tp-Te/QT ratios in leads V4, V5 and V6 were not significantly different and equally strong in predicting VT events (P < 0.001; 95% CI). Adjustment of confounding factor hypertension with multivariate test gave insignificant results (PR: 1.290; 95% CI: 0.444 - 3.747). Increased Tp-Te/QT ratio in idiopathic outflow tract VPC patients was associated with higher prevalence ratio for VT, although this was affected by hypertension. Leads V4, V5 and V6 were equally strong in predicting VT events.


Population-Level Relative Effectiveness of the COVID-19 Vaccines and the Contribution of Naturally Acquired Immunity.
Immune protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be induced by natural infection or vaccination or both. Interaction between vaccine-induced immunity and naturally acquired immunity at the population level has been understudied. We used regression models to evaluate whether the impact of coronavirus disease 2019 (COVID-19) vaccines differed across states with different levels of naturally acquired immunity from March 2021 to April 2022 in the United States. Analysis was conducted for 3 evaluation periods separately (Alpha, Delta, and Omicron waves). As a proxy for the proportion of the population with naturally acquired immunity, we used either the reported seroprevalence or the estimated proportion of the population ever infected in each state. COVID-19 mortality decreased as coverage of ≥1 dose increased among people ≥65 years of age, and this effect did not vary by seroprevalence or proportion of the total population ever infected. Seroprevalence and proportion ever infected were not associated with COVID-19 mortality, after controlling for vaccine coverage. These findings were consistent in all evaluation periods. COVID-19 vaccination was associated with a sustained reduction in mortality at state level during the Alpha, Delta, and Omicron periods. The effect did not vary by naturally acquired immunity.


Reproducibility of twitch mouth pressure, sniff nasal inspiratory pressure, and maximal inspiratory pressure.
Twitch mouth pressure (Pmo,tw) during magnetic phrenic nerve stimulation and sniff nasal inspiratory pressure (SNIP) were recently proposed as alternative noninvasive methods for assessing inspiratory muscle strength. This study aimed to compare their reproducibility with maximal inspiratory pressure (MIP) in normal subjects. Ten healthy subjects were studied at functional residual capacity in semirecumbent position. Cervical magnetic phrenic nerve stimulation was performed during gentle expiration against an occlusion incorporating a small leak. Constancy of stimulation was controlled by recording diaphragmatic electromyogram. Within and between-session reproducibility of pressure were studied for Pmo,tw, SNIP, and MIP. The subjects were studied during a session of 10 manoeuvres repeated after 1 day and 1 month. The mean values were 16 cmH2O for Pmo,tw, 118 cmH2O for SNIP, and 115 cmH2O for MIP. For the three tests, the within subject variation was small in relation to between-subject variation, with the intraclass correlation coefficient ranging 0.79-0.90 for Pmo,tw, 0.85-0.92 for SNIP, and 0.88-0.92 for MIP. At 1 day interval, the coefficient of repeatability (2 SD of differences) was 3.6 cmH2O for Pmo,tw, 32 cmH2O for SNIP and 28 cmH2O for MIP. At 1 month interval, the coefficient of repeatability was 5.8 cmH2O for Pmo,tw, 23 cmH2O for SNIP and 21 cmH2O for MIP. We conclude that the within session reproducibility of the new tests twitch mouth pressure and sniff nasal inspiratory pressure is sufficient to be clinically useful. For sniff nasal inspiratory pressure, the between session reproducibility established after 1 day was maintained after 1 month. For twitch mouth pressure, the between session reproducibility declined slightly after 1 month. These characteristics should be considered when using these methods to follow an individual patient over time.


QR-on-a-chip: a computer-recognizable micro-pattern engraved microfluidic device for high-throughput image acquisition.
This study proposes a novel way to achieve high-throughput image acquisition based on a computer-recognizable micro-pattern implemented on a microfluidic device. We integrated the QR code, a two-dimensional barcode system, onto the microfluidic device to simplify imaging of multiple ROIs (regions of interest). A standard QR code pattern was modified to arrays of cylindrical structures of polydimethylsiloxane (PDMS). Utilizing the recognition of the micro-pattern, the proposed system enables: (1) device identification, which allows referencing additional information of the device, such as device imaging sequences or the ROIs and (2) composing a coordinate system for an arbitrarily located microfluidic device with respect to the stage. Based on these functionalities, the proposed method performs one-step high-throughput imaging for data acquisition in microfluidic devices without further manual exploration and locating of the desired ROIs. In our experience, the proposed method significantly reduced the time for the preparation of an acquisition. We expect that the method will innovatively improve the prototype device data acquisition and analysis.


Aspartate aminotransferase isozymes from rabbit liver. Purification and properties.
Cytosolic and mitochondrial isozymes of aspartate aminotransferase (L-aspartate:2-oxoglutarate aminotransferase [EC 18.104.22.168] ) were purified to homogeneity from rabbit liver. The rabbit liver isozymes were closely similar to the corresponding isozymes from other sources, including human heart, pig heart, chicken heart, and rat liver, in their molecular weights, absorption spectra, amino acid compositions, isoelectric points, and Michaelis constants for the substrates. The NH2-terminal amino acid sequences of rabbit liver isozymes were identified up to 30 residues, and showed some differences from those of the corresponding isozymes obtained from other animals so far studied.


Genome-wide identification of lineage and locus specific variation associated with pneumococcal carriage duration.
Streptococcus pneumoniae is a leading cause of invasive disease in infants, especially in low-income settings. Asymptomatic carriage in the nasopharynx is a prerequisite for disease, but variability in its duration is currently only understood at the serotype level. Here we developed a model to calculate the duration of carriage episodes from longitudinal swab data, and combined these results with whole genome sequence data. We estimated that pneumococcal genomic variation accounted for 63% of the phenotype variation, whereas the host traits considered here (age and previous carriage) accounted for less than 5%. We further partitioned this heritability into both lineage and locus effects, and quantified the amount attributable to the largest sources of variation in carriage duration: serotype (17%), drug-resistance (9%) and other significant locus effects (7%). A pan-genome-wide association study identified prophage sequences as being associated with decreased carriage duration independent of serotype, potentially by disruption of the competence mechanism. These findings support theoretical models of pneumococcal competition and antibiotic resistance.


Motility in normal and filamentous forms of Rhodospirillum rubrum.
By suitable choice of medium, Rhodospirillum rubrum has been grown both in normal (length 2 mum) and filamentous (length up to 60 mum) forms. Both forms were highly motile, and negatively-stained preparations showed bipolar flagellated cells, with an average of seven flagella at each pole. Motion consisted of a series of runs and tumbles, the ditribution of run time-lengths being Poissonian. Both forms tumbled in response to dark shock and showed negative chemotaxis to oxygen. The observation that the motility pattern was very similar in normal and filamentous forms makes chemical control of tumbling unlikely and favours a system involving membrane potentials.


Use of high-pressure CO2 for concentrating CrVI from electroplating wastewater by Mg-Al layered double hydroxide.
The desorption of Cr(VI) from Cr(VI)-adsorbed layered double hydroxide (Cr(VI)-LDH) and the recycling of LDH adsorbent are the bottlenecks that limit the practical application of LDH in treating Cr(VI)-containing industrial wastewater. Given the strong affinity of LDH for CO2, we studied desorption and enrichment of Cr(VI) from Cr(VI)-LDH as well as recycling of LDH in the presence of high-pressure CO2. Results showed that Cr(VI) solution with concentration of 500 mg/L could be enriched more than 20 times in each adsorption-desorption cycle. The regenerated LDH maintained the layer structure and the sheets as revealed by XRD and TEM patterns. FT-IR data showed CO2 formed HCO3(-) at high pressure. The transformation from CO2 to HCO3(-) followed by the anion-exchange with CrO4(2-) was the critical factor for Cr(VI) desorption and LDH regeneration. A pilot-scale experiment was carried out with 20 L Cr(VI)-containing electroplating wastewater. The concentration of the desorbed Cr(VI) solution could reach up to 10000 mg/L, which could be used in electroplating after appropriate adjustment. The main advantages of this method are high concentration of Cr(VI), direct reuse of enriched Cr(VI), and efficient regeneration of LDH adsorbent. This method showed promises in recycling Cr(VI) and regenerating LDH in treating industrial wastewater.


Incidence and prevalence of type 2 diabetes mellitus with HIV infection in Africa: a systematic review and meta-analysis.
This systematic review aims to investigate the incidence and prevalence of type 2 diabetes mellitus (T2DM) in patients with HIV infection in African populations. Only studies reporting data from Africa were included. A systematic search was conducted using four databases for articles referring to HIV infection and antiretroviral therapy, and T2DM in Africa. Articles were excluded if they reported data on children, animals or type 1 diabetes exclusively. Incidence of T2DM and prevalence of T2DM. Risk ratios were generated for pooled data using random effects models. Bias was assessed using an adapted Cochrane Collaboration bias assessment tool. Of 1056 references that were screened, only 20 were selected for inclusion. Seven reported the incidence of T2DM in patients with HIV infection, eight reported the prevalence of T2DM in HIV-infected versus uninfected individuals and five reported prevalence of T2DM in HIV-treated versus untreated patients. Incidence rates ranged from 4 to 59 per 1000 person years. Meta-analysis showed no significant differences between T2DM prevalence in HIV-infected individuals versus uninfected individuals (risk ratio (RR) =1.61, 95% CI 0.62 to 4.21, p=0.33), or between HIV-treated patients versus untreated patients (RR=1.38, 95% CI 0.66 to 2.87, p=0.39), and heterogeneity was high in both meta-analyses (I2=87% and 52%, respectively). Meta-analysis showed no association between T2DM prevalence and HIV infection or antiretroviral therapy; however, these results are limited by the high heterogeneity of the included studies and moderate-to-high risk of bias, as well as, the small number of studies included. There is a need for well-designed prospective longitudinal studies with larger population sizes to better assess incidence and prevalence of T2DM in African patients with HIV. Furthermore, screening for T2DM using gold standard methods in this population is necessary. PROSPERO42016038689.


Clinical characteristics of male prolactinoma patients mainly presenting with severe obesity and the metabolic response to dopamine agonist therapy.
To summarize the clinical characteristics of 4 male prolactinoma patients with severe obesity. The clinical data of all the patients were retrospectively analyzed. All the patients visited our hospital for severe obesity at the age of 16-30 years old with their body mass index (BMI) of 37.9-55.9 kg/m2. All the patients were obese since childhood, even at birth. Hyperprolactinemia (72.3-273.0 ng/ml) was found during the etiological screening of obesity and MRI revealed pituitary adenomas. Additionally, all of them had multiple obesity related complications, such as hyperinsulinemia and dyslipidemia. Treatment of dopamine agonists (DAs) effectively normalized their prolactin level and the pituitary MRI reexamination after 6 months of DAs treatment showed the shrinkage of the pituitary adenomas in 3 patients. Their weight also decreased in different degrees (2.70~19.03% lower than the baseline) with improved metabolic profiles. Serum prolactin level should be screened in obese patients, especially those with severe obesity.


Ethnic density and preterm birth in African-, Caribbean-, and US-born non-Hispanic black populations in New York City.
Segregation studies suggest that the health of blacks in the United States is poorer in majority-black compared with mixed-race neighborhoods. However, segregation studies have not examined black immigrants, who may benefit from social support and country-of-origin foods in black immigrant areas. The authors used 1995-2003 New York City birth records and a spatial measure of ethnic density to conduct a cross-sectional investigation of the risks of preterm birth for African-, Caribbean-, and US-born non-Hispanic black women associated with neighborhood-level African-, Caribbean-, and US-born non-Hispanic black density, respectively. Preterm birth risk differences were computed from logistic model coefficients, comparing neighborhoods in the 90th percentile of ethnic density with those in the 10th percentile. African black preterm birth risks increased with African density, especially in more deprived neighborhoods, where the risk difference was 6.1 per 1,000 (95% confidence interval: 1.9, 10.2). There was little evidence of an ethnic density effect among non-Hispanic black Caribbeans. Among US-born non-Hispanic blacks, an increase in preterm birth risk associated with US-born black density was observed in more deprived neighborhoods only (risk difference = 12.5, 95% confidence interval: 6.6, 18.4). Ethnic density seems to be more strongly associated with preterm birth for US-born non-Hispanic blacks than for non-Hispanic black immigrants.


Tight junction proteins claudin-3 and claudin-4 are frequently overexpressed in ovarian cancer but not in ovarian cystadenomas.
Claudin proteins represent a large family of integral membrane proteins crucial for tight junction (TJ) formation and function. Claudins have been shown to be up-regulated in various cancers and have been suggested as possible biomarkers and targets for cancer therapy. Because claudin-3 and claudin-4 have been proposed to be expressed in epithelial ovarian cancer, we have performed a detailed analysis of CLDN3 and CLDN4 expression in a panel of ovarian tumors of various subtypes and cell lines. We also investigated whether high expression of claudin-3 and claudin-4 was associated with TJ function in ovarian cancer cells. RNA was obtained from a panel of 39 microdissected epithelial ovarian tumors of various histological subtypes for real-time reverse transcription-PCR analysis. In addition, a total of 70 cases of ovarian carcinomas, ovarian cysts, and normal ovarian epithelium from a tissue array were analyzed by immunohistochemistry. Finally, a panel of cell lines was used for Western analysis of claudin expression and TJ permeability studies. Although expressed at low levels in some normal human tissues, including the ovary, CLDN3 and CLDN4 are highly up-regulated in epithelial ovarian cancers of all subtypes. Immunohistochemical analyses using our ovarian tissue array confirmed the high level of expression of claudin-3 and claudin-4 in the majority of ovarian carcinomas, including many tumors exhibiting cytoplasmic staining. Ovarian cystadenoma did not frequently overexpress these proteins, suggesting that the expression of these proteins is associated with malignancy. In ovarian cancer cell lines, claudin-3 and claudin-4 expression was not associated with functional TJs as measured by transepithelial electrical resistance. These results show that CLDN3 and CLDN4 are frequently up-regulated in ovarian tumors and cell lines and may represent novel markers for this disease. Overexpression of these genes in ovarian cancer also suggests interesting scenarios for the involvement of TJ in tumorigenesis. A better knowledge of the mechanisms underlying ovarian tumorigenesis will likely result in the development of novel approaches for the diagnosis and therapy of this deadly disease.


The Seniors' Outdoor Survey: An Observational Tool for Assessing Outdoor Environments at Long-Term Care Settings.
To describe the development and psychometric testing of the Seniors' Outdoor Survey (SOS), an instrument for evaluating how well the outdoor space in a long-term care setting supports the preferences and outdoor usage of residents. Content validity of the main SOS items initially was based on relevant literature and preliminary studies in diverse long-term care settings. After conducting a multiregional pilot study with 152 outdoor spaces at 68 assisted living facilities, the instrument was substantially revised and tested for interrater and test-retest reliability with 22 outdoor spaces at 12 long-term care settings, using 2 raters. Validity was examined using content analysis of resident survey responses (N = 1,128) from the multiregional study and specific item validation by subject matter experts (N = 53). The final instrument contains 60 ratable items organized in 5 domains: access to nature (14 items), outdoor comfort and safety (15 items), walking and outdoor activities (14 items), indoor-outdoor connection (11 items), and connection to the world (6 items). Intraclass correlation coefficient (ICC) estimates of interrater reliability were .91 for the overall instrument, ranging from .83 to .98 for the 5 domains. Interrater reliability (ICC) was above .70 for more than 79% of individual items. Test-retest reliability (ICC) was .92, ranging from .81 to .98 for domains. The SOS tool fills a gap in the available environmental assessment instruments, providing a reliable way for researchers, providers, and designers to evaluate and compare the supportive potential of outdoor spaces for long-term care residents.


PICH Activates Cyclin A1 Transcription to Drive S-Phase Progression and Chemoresistance in Gastric Cancer.
The chemotherapeutic agent 5-fluorouracil (5-FU) remains the backbone of postoperative adjuvant treatment for gastric cancer. However, fewer than half of patients with gastric cancer benefit from 5-FU-based chemotherapies owing to chemoresistance and limited clinical biomarkers. Here, we identified the SNF2 protein Polo-like kinase 1-interacting checkpoint helicase (PICH) as a predictor of 5-FU chemosensitivity and characterized a transcriptional function of PICH distinct from its role in chromosome separation. PICH formed a transcriptional complex with RNA polymerase II (Pol II) and ATF4 at the CCNA1 promoter in an ATPase-dependent manner. Binding of the PICH complex promoted cyclin A1 transcription and accelerated S-phase progression. Overexpressed PICH impaired 5-FU chemosensitivity in human organoids and patient-derived xenografts. Furthermore, elevated PICH expression was negatively correlated with survival in postoperative patients receiving 5-FU chemotherapy. Together, these findings reveal an ATPase-dependent transcriptional function of PICH that promotes cyclin A1 transcription to drive 5-FU chemoresistance, providing a potential predictive biomarker of 5-FU chemosensitivity for postoperative patients with gastric cancer and prompting further investigation into the transcriptional activity of PICH. PICH binds Pol II and ATF4 in an ATPase-dependent manner to form a transcriptional complex that promotes cyclin A1 expression, accelerates S-phase progression, and impairs 5-FU chemosensitivity in gastric cancer.


Reconnecting interpretation to reasoning through individual differences.
Computational theories of mind assume that participants interpret information and then reason from those interpretations. Research on interpretation in deductive reasoning has claimed to show that subjects' interpretation of single syllogistic premises in an "immediate inference" task is radically different from their interpretation of pairs of the same premises in syllogistic reasoning tasks (Newstead, 1989, 1995; Roberts, Newstead, & Griggs, 2001). Narrow appeal to particular Gricean implicatures in this work fails to bridge the gap. Grice's theory taken as a broad framework for credulous discourse processing in which participants construct speakers' "intended models" of discourses can reconcile these results, purchasing continuity of interpretation through variety of logical treatments. We present exploratory experimental data on immediate inference and subsequent syllogistic reasoning. Systematic patterns of interpretation driven by two factors (whether the subject's model of the discourse is credulous, and their degree of reliance on information packaging) are shown to transcend particular quantifier inferences and to drive systematic differences in subjects' subsequent syllogistic reasoning. We conclude that most participants do not understand deductive tasks as experimenters intend, and just as there is no single logical model of reasoning, so there is no reason to expect a single "fundamental human reasoning mechanism".


Angiomatosis retinae. An ultrastructural study and lipid analysis.
A nonfamilial case of agiomatosis retinae (retinal hemangioblastoma) was studied by electron microscopy. In addition to the three major types of cells previously identified within the tumor (endothelial cells, pericytes, heavily lipidized stromal cells), fibrous astrocytes in different stages of lipidization were also found. The endothelial cells were fenestrated, providing the basis for the extravasated exudate that is characteristic of the tumor. The pericytes were completely surrounded by casement membranes and displayed no significant lipidization; in a cellular plaque of vasular tissue at the base of the lesion, however, some of the multilaminar pericytes showed evidence of early smooth muscle differentiation. The stromal cells contained abundant lipid vacuoles and a few organelles, and exhibited granular degeneration of cytoplasmic filaments between the lipid vacuoles. There was spotty basement membrane formation where the stromal cells abutted on the vascular elements. No interconversion could be demonstrated among the endothelial cells, pericytes, and stromal cells. A source for the stromal cells was discovered in the early lipisization of fibrous astrocytes. Analysis of the extracted lipid from the tumor by means of infrared spectroscopy, lipid chromatography, and x-ray diffraction disclosed that the lipid was mostly cholestrol stearate, a plasma lipid. It is suggested that in the retinal lesions the leaky (fenestrated) capillaries of the tumor allowed the passive imbibition of plasma lipid by the fibrous astrocytes, leading to their gradual transformation into the fully lipidized stromal cells.


Evidence for Intramolecular Antiparallel Beta-Sheet Structure in Alpha-Synuclein Fibrils from a Combination of Two-Dimensional Infrared Spectroscopy and Atomic Force Microscopy.
The aggregation of the intrinsically disordered protein alpha-synuclein (αS) into amyloid fibrils is thought to play a central role in the pathology of Parkinson's disease. Using a combination of techniques (AFM, UV-CD, XRD, and amide-I 1D- and 2D-IR spectroscopy) we show that the structure of αS fibrils varies as a function of ionic strength: fibrils aggregated in low ionic-strength buffers ([NaCl] ≤ 25 mM) have a significantly different structure than fibrils grown in higher ionic-strength buffers. The observations for fibrils aggregated in low-salt buffers are consistent with an extended conformation of αS molecules, forming hydrogen-bonded intermolecular β-sheets that are loosely packed in a parallel fashion. For fibrils aggregated in high-salt buffers (including those prepared in buffers with a physiological salt concentration) the measurements are consistent with αS molecules in a more tightly-packed, antiparallel intramolecular conformation, and suggest a structure characterized by two twisting stacks of approximately five hydrogen-bonded intermolecular β-sheets each. We find evidence that the high-frequency peak in the amide-I spectrum of αS fibrils involves a normal mode that differs fundamentally from the canonical high-frequency antiparallel β-sheet mode. The high sensitivity of the fibril structure to the ionic strength might form the basis of differences in αS-related pathologies.


Patient perspectives on the impact of fibromyalgia.
The objective of this study was to elicit and assess important symptom domains and the impact of fibromyalgia on patients' quality of life and functioning from a patient's perspective. The intention was to collect this information as part of an overall effort to overcome shortcomings of existing outcome measures in fibromyalgia. This was a qualitative study in which six focus group sessions with 48 women diagnosed with fibromyalgia were conducted to elicit concepts and ideas to assess the impact of fibromyalgia on their lives. The focus groups conducted with fibromyalgia patients identified symptom domains that had the greatest impact on their quality of life including pain, sleep disturbance, fatigue, depression, anxiety, and cognitive impairment. Fibromyalgia had a substantial negative impact on social and occupational function. Patients reported disrupted relationships with family and friends, social isolation, reduced activities of daily living and leisure activities, avoidance of physical activity, and loss of career or inability to advance in careers or education. The findings from the focus groups revealed that fibromyalgia has a substantial negative impact on patients' lives. A comprehensive assessment of the multiple symptoms domains associated with fibromyalgia and the impact of fibromyalgia on multidimensional aspects of function should be a routine part of the care of fibromyalgia patients.


Biomaterial engineered electrodes for bioelectronics.
A series of single-cysteine-containing cytochrome c, Cyt c, heme proteins including the wild-type Cyt c (from Saccharomyces cerevisiae) and the mutants (V33C, Q21C, R18C, G1C, K9C and K4C) exhibit direct electrical contact with Au-electrodes upon covalent attachment to a maleimide monolayer associated with the electrode. With the G1C-Cyt c mutant, which includes the cysteine residue in the polypeptide chain at position 1, the potential-induced switchable control of the interfacial electron transfer was observed. This heme protein includes a positively charged protein periphery that surrounds the attachment site and faces the electrode surface. Biasing of the electrode at a negative potential (-0.3 V vs. SCE) attracts the reduced Fe(II)-Cyt c heme protein to the electrode surface. Upon the application of a double-potential-step chronoamperometric signal onto the electrode, where the electrode potential is switched to +0.3 V and back to -0.3 V, the kinetics of the transient cathodic current, corresponding to the re-reduction of the Fe(III)-Cyt c, is controlled by the time interval between the oxidative and reductive potential steps. While a short time interval results in a rapid interfacial electron-transfer, ket1 = 20 s-1, long time intervals lead to a slow interfacial electron transfer to the Fe(III)-Cyt c, ket2 = 1.5 s-1. The fast interfacial electron-transfer rate-constant is attributed to the reduction of the surface-attracted Fe(III)-Cyt c. The slow interfacial electron-transfer rate constant is attributed to the electrostatic repulsion of the positively charged Cyt c from the electrode surface, resulting in long-range electron transfer exhibiting a lower rate constant. At intermediate time intervals between the oxidative and reductive steps, two populations of Cyt c, consisting of surface-attracted and surface-repelled heme proteins, are observed. Crosslinking of a layered affinity complex between the Cyt c and cytochrome oxidase, COx, on an Au-electrode yields an electrically-contacted, integrated, electrode for the four-electron reduction of O2 to water. Kinetic analysis reveals that the rate-limiting step in the bioelectrocatalytic reduction of O2 by the integrated Cyt c/COx electrode is the primary electron transfer from the electrode support to the Cyt c units.


Angular and position stability of a nanorod trapped in an optical tweezers.
We analyze the trap stiffness and trapping force potential for a nano-cylinder trapped in the optical tweezers against its axial and lateral shift and tilt associated to the natural Brownian motion. We explain the physical properties of the optical trapping by computing and integrating the radiation stress distribution on the nano-cylinder surfaces using the T-matrix approach. Our computation shows that the force stiffness to the lateral shift is several times higher than that to the axial shift of the nano-cylinder, and lateral torque due to the stress on the side-face is 1-2 orders of magnitude higher than that on the end-faces of a nano-cylinder with the aspect ratio of 2 - 20. The torque due to the stress on the nano-cylinder surface is 2-3 orders of magnitude higher than the spin torque. We explain why a nano-cylinder of low aspect ratio is trapped and aligned normal to the trapping beam axis.


Two early vaccinia virus genes encode polypeptides related to protein kinases.
Vaccinia virus particles contain a protein kinase with an Mr of 62K calculated from sedimentation rate. We have sequenced the SalI G restriction fragment of the vaccinia virus genome near to the right inverted terminal repeat and have identified two genes which share 36% amino acid identity with each other and are related to the family of protein kinase genes. One gene, designated B1R, encodes a 34.2K protein which shares 27% identity with a protein kinase encoded by the herpes simplex virus type 1 US3 gene and contains conserved motifs characteristic of protein kinases of serine/threonine specificity. The second gene, B12R, encodes a protein of 33.3K which is poorly related to known protein kinases and lacks specific amino acids at several highly conserved key positions. The deduced partial amino acid sequence of a gene in the corresponding region of the cowpox virus genome is identical to B12R except for one conservative amino acid substitution. Both of the vaccinia virus genes are transcribed towards the right-hand end of the genome early during infection. It is possible that the product of either or both of these genes associates to form a homo- or heterodimer that represents the 62K virion-associated protein kinase.


Epileptic Seizure Prediction Using Big Data and Deep Learning: Toward a Mobile System.
Seizure prediction can increase independence and allow preventative treatment for patients with epilepsy. We present a proof-of-concept for a seizure prediction system that is accurate, fully automated, patient-specific, and tunable to an individual's needs. Intracranial electroencephalography (iEEG) data of ten patients obtained from a seizure advisory system were analyzed as part of a pseudoprospective seizure prediction study. First, a deep learning classifier was trained to distinguish between preictal and interictal signals. Second, classifier performance was tested on held-out iEEG data from all patients and benchmarked against the performance of a random predictor. Third, the prediction system was tuned so sensitivity or time in warning could be prioritized by the patient. Finally, a demonstration of the feasibility of deployment of the prediction system onto an ultra-low power neuromorphic chip for autonomous operation on a wearable device is provided. The prediction system achieved mean sensitivity of 69% and mean time in warning of 27%, significantly surpassing an equivalent random predictor for all patients by 42%. This study demonstrates that deep learning in combination with neuromorphic hardware can provide the basis for a wearable, real-time, always-on, patient-specific seizure warning system with low power consumption and reliable long-term performance.


Toward Transgene-Free Transposon-Mediated Biological Mutagenesis for Plant Breeding.
Genetic diversity is a key factor for plant breeding. The birth of novel genic and genomic variants is also crucial for plant adaptation in nature. Therefore, the genomes of almost all living organisms possess natural mutagenic mechanisms. Transposable elements (TEs) are a major mutagenic force driving genetic diversity in wild plants and modern crops. The relatively rare TE transposition activity during the thousand-year crop domestication process has led to the phenotypic diversity of many cultivated species. The utilization of TE mutagenesis by artificial and transient acceleration of their activity in a controlled mode is an attractive foundation for a novel type of mutagenesis called TE-mediated biological mutagenesis. Here, I focus on TEs as mutagenic sources for plant breeding and discuss existing and emerging transgene-free approaches for TE activation in plants. Furthermore, I also review the non-randomness of TE insertions in a plant genome and the molecular and epigenetic factors involved in shaping TE insertion preferences. Additionally, I discuss the molecular mechanisms that prevent TE transpositions in germline plant cells (e.g., meiocytes, pollen, egg and embryo cells, and shoot apical meristem), thereby reducing the chances of TE insertion inheritance. Knowledge of these mechanisms can expand the TE activation toolbox using novel gene targeting approaches. Finally, the challenges and future perspectives of plant populations with induced novel TE insertions (iTE plant collections) are discussed.


[Mother-infant rooming-in and beginning of breast feeding in a tertiary care hospital].
To establish a mother-baby's rooming-in program (RI) in a hospital that provides a tertiary level of care. Babies born to healthy mothers were included, both delivered vaginally (P) and by cesarean section (C). Information was gathered on the cause for RI suspension, the type of infant's feeding and the mother's opinion about the program. Sixty-eight per cent of P infants and 98% of C infants participated in the program. The time from delivery to RI was uncovered; for P babies it was 5.8 hours and for C babies it was 17 hours. The RI was suspended in 1% of P and 6.7% of C infants, but with no justifiable medical reason in the infants. The mother's opinion about RI was very favorable. Only 50% of the infants started breast feeding within the first 6 hours after birth; however, all of them were breastfed at the time of discharge. It is possible to establish RI and initiate breast feeding in a tertiary care hospital, even in mothers with cesarean section.


CO-oximetry measurements and antioxidant effects of ascorbic acid and methylene blue in equine methemoglobinemic blood.
To determine the effects of time after sampling on CO-oximetry measurements of equine blood samples and the effects of adding ascorbic acid (AscAc) and methylene blue (MetBlue) to samples with methemoglobinemia. Experimental study. University teaching hospital. Thirty healthy adult horses assigned to 5 groups. Repeated CO-oximetry determinations were performed on venous (n = 6) and arterial blood samples (n = 7) stored at 0°C for 48 hours. Methemoglobinemia was induced in vitro in 17 additional blood samples. Six were used as untreated controls, 6 had AscAc added, and 5 had MetBlue added. Total hemoglobin, oxyhemoglobin, carboxyhemoglobin, methemoglobin (MetHb), and oxygen saturation of hemoglobin (SO2 ) were measured. Oxyhemoglobin and SO2 increased from 69.8% ± 10.2% and 90% ± 3% to 82.8% ± 7.9% and 99% ± 3%, respectively, after 8 hours in venous blood (mean ± SD, P < 0.001). There was an effect of treatment (P = 0.032) and of time (interaction P = 0.003) on MetHb% in methemoglobinemic samples. The difference in absolute MetHb% from time 0 was as follows: 7.0% (interquartile range [IQR] = 21.2), -0.2% (IQR = 3.5), and -4.4% (IQR = 5.2) at 48 hours in control, AscAc, and MetBlue groups, respectively (P < 0.05). There was no effect of time on MetHb% in the AscAc group (23% [IQR = 52.6] at time 0 to 23.2% [IQR = 56.9] after 48 h). Storage of blood in ice water to determine O2 Hb and SO2 using a CO-oximeter should not exceed 4 hours. Measurement of MetHb% could be delayed by up to 48 hours if AscAc is added to the sample. MetBlue significantly decreased MetHb% over time. The limitations of this study include the fact that the antioxidant effects of AscAc and MetBlue were evaluated in vitro and not in vivo. Further studies are needed to evaluate different storage temperatures and syringe types.


Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells.
Autosomal-dominant polycystic kidney disease is a multiorgan disease and its vascular manifestations are common and life-threatening. Despite this, little is known about their pathogenesis. Somatic mutations to the normal PKD allele in cystic epithelia and cyst development associated with the unstable Pkd2(WS25) allele suggest a two-hit model of cystogenesis. However, it is unclear if this model can account for the cardiovascular pathology or if haploinsufficiency alone is disease-associated. In the present study, we found a decreased polycystin-2 (PC2, protein encoded by Pkd2 gene) expression in Pkd2( +/-) vessels, roughly half the wild-type level, and an enhanced level of intracranial vascular abnormalities in Pkd2 (+/-) mice when induced to develop hypertension. Consistent with these observations, freshly dissociated Pkd2 (+/-) vascular smooth muscle cells have significantly altered intracellular Ca(2+) homeostasis. The resting [Ca(2+)](i) is 17.1% lower in Pkd2 (+/-) compared with wild-type cells (P=0.0003) and the total sarcoplasmic reticulum Ca(2+) store (emptied by caffeine plus thapsigargin) is decreased (P<0.0001). The store operated Ca(2+) (SOC) channel activity is also decreased in Pkd2 (+/-) cells (P=0.008). These results indicate that inactivation of just one Pkd2 allele is sufficient to significantly alter intracellular Ca(2+) homeostasis, and that PC2 is necessary to maintain normal SOC activity and the SR Ca(2+) store in VSMCs. Based on these findings, and the fact that [Ca(2+)](i) signaling is essential to the regulation of contraction, production and secretion of extracellular matrix, cellular proliferation and apoptosis, we propose that the abnormal intracellular Ca(2+) regulation associated with Pkd2 haploinsufficiency is directly related to the vascular phenotype.


Fabrication of MSC-laden composites of hyaluronic acid hydrogels reinforced with MEW scaffolds for cartilage repair.
Hydrogels are of interest in cartilage tissue engineering due to their ability to support the encapsulation and chondrogenesis of mesenchymal stromal cells (MSCs). However, features such as hydrogel crosslink density, which can influence nutrient transport, nascent matrix distribution, and the stability of constructs during and after implantation must be considered in hydrogel design. Here, we first demonstrate that more loosely crosslinked (i.e. softer, ∼2 kPa) norbornene-modified hyaluronic acid (NorHA) hydrogels support enhanced cartilage formation and maturation when compared to more densely crosslinked (i.e. stiffer, ∼6-60 kPa) hydrogels, with a >100-fold increase in compressive modulus after 56 d of culture. While soft NorHA hydrogels mature into neocartilage suitable for the repair of articular cartilage, their initial moduli are too low for handling and they do not exhibit the requisite stability needed to withstand the loading environments of articulating joints. To address this, we reinforced NorHA hydrogels with polycaprolactone (PCL) microfibers produced via melt-electrowriting (MEW). Importantly, composites fabricated with MEW meshes of 400µm spacing increased the moduli of soft NorHA hydrogels by ∼50-fold while preserving the chondrogenic potential of the hydrogels. There were minimal differences in chondrogenic gene expression and biochemical content (e.g. DNA, GAG, collagen) between hydrogels alone and composites, whereas the composites increased in compressive modulus to ∼350 kPa after 56 d of culture. Lastly, integration of composites with native tissue was assessedex vivo; MSC-laden composites implanted after 28 d of pre-culture exhibited increased integration strengths and contact areas compared to acellular composites. This approach has great potential towards the design of cell-laden implants that possess both initial mechanical integrity and the ability to support neocartilage formation and integration for cartilage repair.


Structural and metabolic cerebral alterations between elderly bipolar disorder and behavioural variant frontotemporal dementia: A combined MRI-PET study.
Elderly bipolar disorder (BD) and behavioural variant of frontotemporal dementia (bvFTD) may exhibit similar symptoms and both disorders are characterized by selective abnormalities in cortical and subcortical regions that are associated with cognitive and emotional impairments. We aimed to investigate common and distinct neural substrates of BD and bvFTD by coupling, for the first time, magnetic resonance imaging (MRI) and positron emission tomography (PET) techniques. 3-Tesla MRI and 18 fluorodeoxyglucose-PET scans were acquired for 16 elderly BD patients, 23 bvFTD patients with mild cognitive impairments and 68 healthy controls (48 for PET and 20 for MRI analyses). BD and bvFTD patients exhibit a different localization of grey matter reductions in the lateral prefrontal cortex, with the first group showing grey matter decrease in the ventrolateral prefrontal cortex and the latter group showing grey matter reductions in the dorsolateral prefrontal cortex as well as unique grey matter and metabolic alterations within the orbitofrontal cortex. The bvFTD group also displayed unique volumetric shrinkage in regions within the temporo-parietal network together with greater metabolic impairments within the temporal cortex and more extensive volumetric and metabolic abnormalities within the limbic lobe. Finally, while the BD group showed greater grey matter volumes in caudate nucleus, bvFTD subjects displayed lower metabolism. This MRI-PET study explored, for the first time to the best of our knowledge, structural and functional abnormalities in bvFTD and elderly BD patients, with the final aim of identifying the specific biological signature of these disorders, which might have important implications not only in prevention but also in differential diagnosis and treatment.


Neural response to monetary loss among youth with disruptive behavior disorders and callous-unemotional traits in the ABCD study.
Etiological models highlight reduced punishment sensitivity as a core risk factor for disruptive behavior disorders (DBD) and callous-unemotional (CU) traits. The current study examined neural sensitivity to the anticipation and receipt of loss, one key aspect of punishment sensitivity, among youth with DBD, comparing those with and without CU traits. Data were obtained from the Adolescent Brain and Cognitive Development (ABCD)SM Study (N = 11,874; Mage = 9.51; 48% female). Loss-related fMRI activity during the monetary incentive delay task was examined across 16 empirically-derived a priori brain regions (e.g., striatum, amygdala, insula, anterior cingulate cortex, medial prefrontal cortex) and compared across the following groups: (1) typically developing (n = 693); (2) DBD (n = 995), subdivided into those (3) with CU traits (DBD + CU, n = 198), and (4) without CU traits (DBD-only, n = 276). Latent variable modeling was also employed to examine network-level activity. There were no significant between-group differences in brain activity to loss anticipation or receipt. Null findings were confirmed with and without covariates, using alternative grouping approaches, and in dimensional models. Network-level analyses also demonstrated comparable activity across groups during loss anticipation and receipt. Findings suggest that differences in punishment sensitivity among youth with DBD are unrelated to loss anticipation or receipt. More precise characterizations of other aspects punishment sensitivity are needed to understand risk for DBD and CU traits.


The effect of gender and social capital on the dual burden of malnutrition: a multilevel study in Indonesia.
The paradoxical phenomenon of the coexistence of overweight and underweight individuals in the same household, referred to as the "dual burden of malnutrition", is a growing nutrition dilemma in low- and middle-income countries (LMICs). The objectives of this study were (i) to examine the extent of the dual burden of malnutrition across different provinces in Indonesia and (ii) to determine how gender, community social capital, place of residency and other socio-economic factors affect the prevalence of the dual burden of malnutrition. The current study utilized data from the fourth wave of the Indonesian Family Life Survey (IFLS) conducted between November 2007 and April 2008. The dataset contains information from 12,048 households and 45,306 individuals of all ages. This study focused on households with individuals over two years old. To account for the multilevel nature of the data, a multilevel multiple logistic regression was conducted. Approximately one-fifth of all households in Indonesia exhibited the dual burden of malnutrition, which was more prevalent among male-headed households, households with a high Socio-economic status (SES), and households in urban areas. Minimal variation in the dual burden of malnutrition was explained by the community level differences (<4%). Living in households with a higher SES resulted in higher odds of the dual burden of malnutrition but not among female-headed households and communities with the highest social capital. To improve household health and reduce the inequality across different SES groups, this study emphasizes the inclusion of women's empowerment and community social capital into intervention programs addressing the dual burden of malnutrition.


Conversion of plasma progesterone to deoxycorticosterone in men, nonpregnant and pregnant women, and adrenalectomized subjects.
During the third trimester of human pregnancy the concentrations of deoxycorticosterone (DOC) in maternal plasma are 4-50 times those in nonpregnant women and men. It has been suggested that the increased amount of DOC in maternal plasma originates in the fetal compartment. We considered an alternate explanation for the high levels of DOC in plasma or near-term pregnant women, viz., that DOC may be derived in part from 21-hydroxylation of maternal plama progesterone. To test this hyposthesis we measured the fractional conversion of plasma progesterone to DOC from the relationship between the 3H:14C ratio of the infused tracers, [3H]progesterone and [14C]-DOC, and the 3H:14C ratio or urinary 3 alpha,21-dihydroxy-5 beta-pregnan-20-one (tetrahydro-DOC). The fractional conversion of plasma progesterone to DOC ([rho](BU)P-DOC), measured in this manner, was 0.007 +/- 0.001 (mean +/- SEM, n = 26) in the subjects of this study. The values for [rho](BU)P-DOC varied widely among subjects (0.002-0.022) but the range of values for [rho](BU)P-DOC was similar among women pregnant with an anencephalic or dead fetus, nonpregnant and adrenalectomized women, and men. The transfer constant of conversion of progesterone to DOC in plasma, [rho](BB)P-DOC, remained constant in a nonpregnant woman during the infusion of nonradiolabeled progesterone at rates of 0-14 mg/h. Based on the results of these studied, we conclude that DOC is formed by extra-adrenal 21-hydroxylation of plasma progesterone and that the rate of formation of DOC by this pathway is proportional to the concentration of progesterone in plasma.


The Sibs Program: A Structured Peer-Mentorship Program to Reduce Burnout for First-Year Medical Students.
This article was migrated. The article was marked as recommended. First-year medical students are at risk for burnout despite resources available to help them manage stress. In 2015, a structured peer-mentorship program was created at our institution for incoming medical students (M1s) by second-year medical students (M2s) with a goal of reducing risk factors for burnout; a secondary goal was to improve the mentoring skills of M2s. Over the course of the year, we surveyed M1s about their anxiety, prioritization skills, and work-life balance; M2s from the previous year's unstructured peer-mentorship program served as a control group. 164 M1s and 164 M2s participated in this program. Among M1s, a structured peer-mentorship program significantly reduced anxiety levels (p=<0.01), improved prioritization skills (p=<0.01), and facilitated greater awareness of the importance of striving to maintain work-life balance (p=<0.01). M2s felt neutral-to-agreeable in their ability to provide guidance, refer students for help, and remain invested in their mentees. A structured peer-mentorship program, therefore, may reduce anxiety, improve prioritization skills, and emphasize the importance of work-life balance among M1s, elements that have been associated with reduced rates of burnout. Furthermore, this program can augment the professional development of M2s by motivating them to maintain longitudinal mentoring relationships with underclassmen.