Impact of increasing parenteral protein loads on amino acid levels and balance in critically ill anuric patients on continuous renal replacement therapy.
We wanted to establish optimum protein and glucose intakes during total parenteral nutrition by using a constant caloric but changing protein intake in critically ill, ventilated, anuric patients on continuous renal replacement therapy and measuring amino acid and glucose losses across the hemofilter. Eleven consecutive, critically ill patients (eight male, age, 43.5 +/- 21.8 y; Acute Physiology and Chronic Health Evaluation II score, 20.5 +/- 7.0; Acute Physiology and Chronic Health Evaluation risk of death: 36.5% +/- 23.0 and 6 +/- 1 impaired organ systems) entered this study. Patients were fed by continuous infusion of a total parenteral mixture consisting of Synthamin (a mixture of essential and non-essential amino acids), 50% dextrose, and intralipid (long-chain triglycerides) to meet caloric requirements as predicted by Schofield's equation corrected by stress factors. The amount of protein infused was varied (1 to 2.5 g. kg(-1). d(-1)) by increments of 0.25 g. kg(-1). d(-1). Patients were stabilized on each feeding regimen for at least 24 h before paired samples of blood and dialysate were taken for amino acid and glucose measurements. Continuous renal replacement therapy was performed by using a blood pump with a blood flow of 100 to 175 mL/min. Dialysate was pumped in and out counter-currently to the blood flow at 2 L/h. A biocompatible polyacrylonitrile hemofilter was used in all cases. With protein intakes below 2.5 g. kg(-1). d(-1), blood levels of 14% to 57% of the measured amino acids were below the lower limits of the normal range. At 2.5 g. kg(-1). d(-1), all measured amino acids were within the normal range. Amino acid balance became more positive as protein input increased (P = 0.0001). Glucose and amino acid losses were dependent on blood concentration. Overall, 17% (range, 13% to 24%) of infused amino acids and 4% of infused glucose were lost in the dialysate. This study of critically ill, ventilated, anuric patients on continuous renal replacement therapy suggested that increases in protein and glucose are required to account for the increased losses across the hemofilter. A protein intake of 2.5 g. kg(-1). d(-1) appeared to optimize nitrogen balance and correct amino acid deficiencies.


A kinematic analysis of distractor interference effects during visually guided action in spatial neglect.
Patients with left spatial neglect following right hemisphere damage may show anomalies in ipsilesional-limb movements directed to targets on their affected side, in addition to their characteristic perceptual deficits. In this study we examined the extent to which visually guided movements made by neglect patients are susceptible to interference from concurrent visual distractors on the contralesional or ipsilesional side of a designated target. Eleven right hemisphere patients with visual neglect, plus 11 matched healthy controls, performed a double-step movement task upon a digitizing tablet, using their ipsilesional hand to respond. On each double-step trial the first component of the movement was cued to a common central target, whereas the second component was cued unpredictably to a target on either the contralesional or ipsilesional side. On separate trials lateral targets either appeared alone or together with a concurrent distractor in an homologous location in the opposite hemispace. In addition to being significantly slower and more error prone than controls, neglect patients also exhibited a number of interference effects from ipsilesional distractors. They often failed to move to left targets in the presence of a right-sided distractor, or else they moved to the distractor itself rather than to a contralesional target. The initial accelerative phase of their movements to contralesional targets tended to be interrupted prematurely, and they spent significantly more time in the terminal guidance phase of movements to contralesional targets in the presence of an ipsilesional distractor. In contrast, contralesional distractors had little effect on patients' movements to ipsilesional targets. We conclude that right hemisphere damage induces a competitive bias that favors actions to ipsilesional targets. This bias affects multiple stages of processing within the visuomotor system, from initial programming through to the final stages of terminal guidance.


SRSF2 plays an unexpected role as reader of m5C on mRNA, linking epitranscriptomics to cancer.
A common mRNA modification is 5-methylcytosine (m5C), whose role in gene-transcript processing and cancer remains unclear. Here, we identify serine/arginine-rich splicing factor 2 (SRSF2) as a reader of m5C and impaired SRSF2 m5C binding as a potential contributor to leukemogenesis. Structurally, we identify residues involved in m5C recognition and the impact of the prevalent leukemia-associated mutation SRSF2P95H. We show that SRSF2 binding and m5C colocalize within transcripts. Furthermore, knocking down the m5C writer NSUN2 decreases mRNA m5C, reduces SRSF2 binding, and alters RNA splicing. We also show that the SRSF2P95H mutation impairs the ability of the protein to read m5C-marked mRNA, notably reducing its binding to key leukemia-related transcripts in leukemic cells. In leukemia patients, low NSUN2 expression leads to mRNA m5C hypomethylation and, combined with SRSF2P95H, predicts poor outcomes. Altogether, we highlight an unrecognized mechanistic link between epitranscriptomics and a key oncogenesis driver.


Lysine Methyltransferase Inhibitors Impair H4K20me2 and 53BP1 Foci in Response to DNA Damage in Sarcomas, a Synthetic Lethality Strategy.
Chromatin is dynamically remodeled to adapt to all DNA-related processes, including DNA damage responses (DDR). This adaptation requires DNA and histone epigenetic modifications, which are mediated by several types of enzymes; among them are lysine methyltransferases (KMTs). KMT inhibitors, chaetocin and tazemetostat (TZM), were used to study their role in the DDR induced by ionizing radiation or doxorubicin in two human sarcoma cells lines. The effect of these KMT inhibitors was tested by the analysis of chromatin epigenetic modifications, H4K16ac and H4K20me2. DDR was monitored by the formation of γH2AX, MDC1, NBS1 and 53BP1 foci, and the induction of apoptosis. Chaetocin and tazemetostat treatments caused a significant increase of H4K16 acetylation, associated with chromatin relaxation, and increased DNA damage, detected by the labeling of free DNA-ends. These inhibitors significantly reduced H4K20 dimethylation levels in response to DNA damage and impaired the recruitment of 53BP1, but not of MDC1 and NBS1, at DNA damaged sites. This modification of epigenetic marks prevents DNA repair by the NHEJ pathway and leads to cell death. KMT inhibitors could function as sensitizers to DNA damage-based therapies and be used in novel synthetic lethality strategies for sarcoma treatment.


Investigating in vivo knee volumetric bone mineral density and walking gait mechanics in healthy people.
The aim of this study was to investigate if the distribution of subchondral volumetric bone mineral density (vBMD) from peripheral quantitative computed tomography (pQCT) is related to estimates of knee joint loads calculated during walking gait in healthy young people. We recruited 19 young (age 18-40 years) healthy people with no self-reported knee pain or pathology. For all participants we collected two forms of data: (1) pQCT data at 2% of tibia length (from the proximal joint line) using a Stratec XCT3000 scanner at 0.2 × 0.2 mm in plane resolution; and (2) indices of joint loading, specifically external joint moment, at the indexed knee during walking gait. Joint moments were calculated from motion capture and ground reaction force data. pQCT scans were performed immediately prior to gait analysis. A sub-group of 9 participants attended a second scanning session to establish the reproducibility of the pQCT workflow. vBMD was extracted for four sub-regions (anteromedial, anterolateral, posteromedial and posterolateral). Reproducibility of the pQCT workflow was good to excellent (ICCs 0.832-0.985) with minimal detectable differences ranging from 2.3-39.5 mg HA/cm3. Significant independent correlations were identified between the external rotation moment and the medial-to-lateral (r = 0.517), posteromedial-to-posterolateral (r = 0.627) and posteromedial-to-anterolateral (r = 0.518) vBMD ratios, and between the knee adduction moment and the medial-to-lateral (r = -0.476) and posteromedial-to-posterolateral (r = -0.497) vBMD ratios. There appear to be significant relationships between measures of vBMD from pQCT and indices of joint loading in healthy people. These data are the first to combine imaging at the resolution available with pQCT and indices of joint loading in the same cohort.


Mammographic Breast Density and Breast Cancer Molecular Subtypes: The Kenyan-African Aspect.
Data examining mammographic breast density (MBD) among patients in Sub-Saharan Africa are sparse. We evaluated how MBD relates to breast cancer characteristics in Kenyan women undergoing diagnostic mammography. This cross-sectional study included women with pathologically confirmed breast cancers (n = 123). Pretreatment mammograms of the unaffected breast were assessed to estimate absolute dense area (cm2), nondense area (cm2), and percent density (PD). Relationships between density measurements and clinical characteristics were evaluated using analysis of covariance. Median PD and dense area were 24.9% and 85.3 cm2. Higher PD and dense area were observed in younger women (P < 0.01). Higher dense and nondense areas were observed in obese women (P-trend < 0.01). Estrogen receptor (ER) positive patients (73%) had higher PD and dense area than ER-negative patients (P ≤ 0.02). Triple negative breast cancer (TNBC) patients (17%) had lower PD and dense area (P ≤ 0.01) compared with non-TNBCs. No associations were observed between MBD and tumor size and grade. Our findings show discordant relationships between MBD and molecular tumor subtypes to those previously observed in Western populations. The relatively low breast density observed at diagnosis may have important implications for cancer prevention initiatives in Kenya. Subsequent larger studies are needed to confirm these findings.


Does a bursary scheme for students in low- to middle-income countries influence outcomes in a master's programme in Public Health?
This article was migrated. The article was marked as recommended. Introduction The People's Open Access Education Initiative (Peoples-uni) provides online education for health professionals in Public Health at the master's level. Although fees are low due to the use of volunteers and Open Educational Resources, a bursary scheme is provided to waive all or some of the fees. This study tests the hypothesis that student outcomes of completing and passing modules are higher among those given a bursary than others. Methods Data were retrieved for all students enrolling between 2009-2017, including demographics and module outcomes, where available. Multivariable logistic regression was used to identify factors associated with a successful bursary application, as well as to elicit whether a successful bursary application was associated with ever completing, or ever passing, a module. Results Data were obtained from 1499 students. Of these, 624 (42%) had ever completed a module, and 513 (34%) had ever passed a module. 503 students (34%) had applied for a bursary, of whom 285 (57%) were successful. After adjusting for demographic variables, employment status and education level, students who were given a bursary were more likely to ever pass a module (adjusted odds ratio [aOR] 2.3, 95% CI 1.7,3.3), as were those who applied for a bursary but were unsuccessful (aOR 1.9, 95% CI 1.3,2.8), compared with students who had not applied for a bursary. Similar results were obtained for the outcome of completing a module. Conclusions Students who were successful in gaining a bursary, as well as those who were not but still able to enroll, were more likely to complete or pass a module than those who did not apply. These results point to the success of the bursary scheme and give us confidence to continue to offer bursaries, in order to sustain the mission of improving population health through capacity building in low resource settings.


Mandibular first and second molars with three mesial canals: a case series.
Adequate cleaning, shaping and filling of the root canal system are mandatory for successful root canal treatment. Thorough knowledge of root canal morphology and unusual anatomy of the tooth is critical for the practitioner. The occurrence and location of the third mesial canal (Middle Mesial Canal) in mandibular first and second molars in relation to other two mesial canals that were treated in private practice were studied. In 27 clinical cases, the presence of a middle mesial canal was demonstrated. The third canal was located in the middle of the distance between the mesiobuccal and mesiolingual canals. This canal configuration was found in six second lower molars and twenty one first molars. Middle mesial canal in all of our cases joined to mesiobuccal or mesiolingual canals. None of the teeth consisted of three independent canals with three apical foramina. In conclusion, every attempt should be made to find and treat all root canals of a tooth.


Ecteinascidin-743: a marine-derived compound in advanced, pretreated sarcoma patients--preliminary evidence of activity.
To report the activity of the chemotherapeutic agent ecteinascidin-743 (ET-743) in advanced pretreated sarcoma patients observed during a phase I study and a named-patient basis, compassionate use program. Twenty-nine pretreated, advanced soft tissue sarcoma (STS) and bone sarcoma patients consecutively seen in our centers were included, 12 from a phase I trial and 17 from a compassionate use program cohort. Patients were treated every 3 weeks at either 1,200 microg/m(2) (six patients), 1,500 microg/m(2) (the recommended dose, 22 patients), or 1,800 microg/m(2) (the maximum-tolerated dose, one patient), given as a 24-hour infusion every 3 to 4 weeks. Fifteen men and 14 women were treated. The median patient age was 46 years (range, 16 to 71 years), with a median World Health Organization performance status of 1 (range, 0 to 2). Twenty-five patients had STS, three had osteosarcoma, and one had Ewing's sarcoma, and all had progressive disease at accrual. Fifteen patients had bulky disease, and 14 had clinical resistance to anthracyclines. A total of 136 treatment cycles were administered (median per patient, five cycles; range, one to 12 cycles). Transient grade 3 and 4 transaminitis was reported in 24% and 5% of cycles, respectively, grade 3 to 4 neutropenia occurred in 32% of cycles, with concomitant sporadic grade 3 to 4 thrombocytopenia in 5.1% of cycles. Grade 2 to 3 asthenia occurred in 21% of cycles. There were two partial responses (PRs) in STS patients and two PRs in osteosarcoma patients. Two minor responses and 10 disease stabilizations were seen. Median duration of response was 10.5 months (range, 2.8 to 15 months), and mean duration of stabilization was 5.2 months. ET-743 has activity in advanced, highly pretreated STS and osteosarcoma patients and warrants further trials to establish the extent of its activity in this setting.


A quinine-activated cationic conductance in vertebrate taste receptor cells.
The chincona alkaloid quinine is known to be a bitter tasting substance for various vertebrates. We examined the effects of quinine on isolated taste receptor cells from the bullfrog (Rana catesbeiana). Membrane currents were recorded by whole-cell recording, while quinine hydrochloride was applied extracellularly from a puffer pipette. At the resting potential (-77 +/- 9 mV, mean +/- SD, n = 49 cells), taste cells generated inward currents in response to quinine stimulation (> 1 mM), indicating a depolarizing response in the taste cells. Two types of current responses were observed; a newly found quinine-activated cationic conductance and a previously reported blocking effect of quinine on K+ conductances. The cationic current was isolated from the K+ current by using a Cs(+)-containing patch pipette. The relative permeabilities (Pion) of the quinine-activated cationic conductance were: PNa/PK/PCs = 1:0.5:0.42. The quinine dose-response relation was described by the Hill equation with the K1/2 of 3.6 mM and Hill coefficient of 5.3. When extracellular [Ca2+] (1.8 mM) was reduced to nominally free, the conductance was enhanced by about sixfold. This property is consistent with observations on quinine responses recorded from the gustatory nerve, in vivo. The quinine-induced cationic current was decreased with an application of 8-bromo-cAMP. We conclude that the bitter substance quinine activates a cation channel in taste receptor cells and this channel plays an important role in bitter taste transduction.


Descriptive Analysis of Forces Applied by Trained Clinicians During Two-Handed Instrument-Assisted Soft Tissue Mobilization.
Instrument-assisted soft tissue mobilization (IASTM) is a common intervention among clinicians. Despite the popularity, little is known about the forces applied by the clinician with the instruments during treatment. The purpose of this investigation was to examine the forces applied by trained clinicians using IASTM instruments during a simulated treatment. Eleven IASTM trained (Graston Technique, Técnica Gavilán, or RockBlades) clinicians (Physical Therapist = 2, Chiropractor = 2, Athletic Trainer = 7) participated in the study. Each clinician performed 75 two-handed strokes distributed evenly across five different IASTM instruments on a skin simulant attached to a force plate. IASTM stroke application was analyzed for peak normal forces (Fpeak) and mean normal forces (Fmean) by stroke. We observed an average Fpeak of 8.9N and Fmean of 6.0N across all clinicians and instruments. Clinicians and researchers may use the descriptive values as a reference for application of IASTM in practice and research.


Plasma steroid dynamics in late- and near-term naturally and artificially conceived bovine pregnancies as elucidated by multihormone high-resolution LC-MS/MS.
The plasma levels of corticosteroids and sex steroids during pregnancy are key indicators of mammalian placental function and the onset of parturition. Steroid hormones are believed to be disturbed in pregnancies produced using assisted reproductive technologies (ARTs) due to placental dysfunction and the frequently observed lack of parturition signals. To elucidate the plasma steroid dynamics, a liquid chromatography-tandem mass spectrometry method was developed and used to determine the levels of corticosteroids (corticosterone, 11-deoxycortisol, and cortisol) and their direct precursors (progesterone and 17α-OH-progesterone) as well as sex steroids (androstenedione, estrone, estrone sulfate, testosterone, and 17β-estradiol) in bovine plasma. The levels of these 10 steroids in recipient cows carrying naturally conceived (control), in vitro fertilized (IVF), or cloned (somatic cell nuclear transfer) conceptuses were compared during late-term pregnancy (30 days before parturition), during near-term pregnancy (1 day before parturition), and on the day of parturition (day 0). Significant differences were observed among the corticosteroid levels: higher levels of corticosterone, 11-deoxycortisol, and cortisol were detected in cloned pregnancies at day 30; lower levels of corticosterone were observed in ART-derived pregnancies at days 1 and 0; and estrone and estradiol levels were higher in IVF pregnancies throughout the final development. These results suggested an upregulation of the P450C11 and P450C21 enzymes 30 days before parturition in somatic cell nuclear transfer pregnancies and an overactivation of the aromatase enzyme in IVF pregnancies. Taken together, the monitoring of multiple steroid hormones revealed that the pregnancies obtained using ART exhibited plasma steroid concentration dynamics compatible with the dysregulation of steroidogenic tissues.


Fatty Acid and Proximate Composition of Bee Bread.
Palynological spectrum, proximate and fatty acid (FA) composition of eight bee bread samples of different botanical origins were examined and significant variations were observed. The samples were all identified as monofloral, namely Castanea sativa (94.4%), Trifolium spp. (85.6%), Gossypium hirsutum (66.2%), Citrus spp. (61.4%) and Helianthus annuus (45.4%). Each had moisture content between 11.4 and 15.9%, ash between 1.9 and 2.54%, fat between 5.9 and 11.5%, and protein between 14.8 and 24.3%. A total of 37 FAs were determined with most abundant being (9Z,12Z,15Z)-octadeca-9,12,15-trienoic, (9Z,12Z)- -octadeca-9,12-dienoic, hexadecanoic, (Z)-octadec-9-enoic, (Z)-icos-11-enoic and octadecanoic acids. Among all, cotton bee bread contained the highest level of ω-3 FAs, i.e. 41.3%. Unsaturated to saturated FA ratio ranged between 1.38 and 2.39, indicating that the bee bread can be a good source of unsaturated FAs.


Prevalence of Patent Foramen Ovale in Ischaemic Stroke in Italy: Results of SISIFO Study.
Although several authors have studied the association between patent foramen ovale (PFO) and ischaemic stroke, the matter is still controversial; few have suggested an association between cryptogenetic stroke and PFO, while others have denied this association. The aim of this study was to evaluate PFO prevalence in the whole ischaemic stroke population, independently from age and stroke subtypes and to identify the characteristics associated with the presence of PFO. SISIFO study was a multicenter, prospective, single-wave, cross-sectional survey conducted on consecutive patients with acute ischemic stroke admitted to selected clinical centres. Data regarding vascular risk factors were registered for each patient; all patients underwent computed tomography scan and/or magnetic resonance imaging of the brain; an electrocardiogram and standard laboratory blood tests were performed. A Doppler ultrasound study of extra-cranial arteries was performed too. The cases were classified according to TOAST and OCSP criteria. Each patient underwent transcranial Doppler or transcranial color-coded duplex sonography with bubble test as diagnostic tool for right-to-left-shunt. Where right-to-left shunt was detected, PFO presence was confirmed by echocardiography. 1,130 consecutive patients were included. We found a PFO in 247 (21.9%; 95% CI, 19.5-24.3%) patients; PFO was present in 23.5% of patients with cryptogenic stroke and in 21.3% of patients with stroke of known causes; this difference was not statistically significant. At the univariate analysis, decreasing age, hypertension, diabetes mellitus, and atrial fibrillation, and stroke characteristics such as NIHSS, OCSP and TOAST were predictors of PFO presence. At the multivariate analysis, we found a significant interaction between age and OCSP syndrome. Being LACI the reference category, the prevalence of PFO in PACI and POCI decreased significantly along with age, whereas there was no change in TACI. If any relationship exists between stroke and PFO, this is more likely in PACI and POCI at a younger age. Our results are consistent with recent findings that underline PFO alone must not be considered a significant independent predictor for stroke; so the presence of PFO alone doesn't permit rushed causal correlations or 'therapeutic aggressiveness'.


Should stable UNOS Status 2 patients be transplanted?
Improved outcomes with contemporary medical therapy in patients with advanced heart failure brings into question the survival advantage of transplantation for patients in stable United Network for Organ Sharing (UNOS) Status 2. Between January 1999 and June 2001, a total of 7,539 adult patients were listed for heart transplantation. Of those, 4,255 (56.4%) patients were listed as UNOS Status 2. Using a competing risk method, we computed probabilities of events while on the waiting list. Additionally, we used a time-dependent proportional hazards model to determine predictors of death before and after transplantation. Demographics included age >60 (72%), female sex (23%), ischemic causes for transplantation (49%), white race (85%), and median time on the waiting list (544 days). Laboratory and hemodynamic values included mean serum albumin of 3.9 g/dl, serum creatinine of 1.4 mg/dl, mean pulmonary artery pressure of 28 mm Hg, mean pulmonary capillary wedge pressure of 19 mm Hg, and mean cardiac output of 4.5 liter/min. Final outcomes on the waiting list for patients initially listed as UNOS Status 2 were transplantation (48%), removal from the list (11.5%), death (11.4%), and continued listing (29%). At 30 months after transplantation, survival was 81% for patients undergoing transplantation as Status 1A, 77% as Status 1B, and 83% as Status 2, and showed no difference among groups. At 365 days, survival analysis showed no difference for patients listed and undergoing transplantation as UNOS Status 2 compared with those still waiting as Status 2. In the current era of advances in medical and surgical therapies for heart failure, we found no survival benefit of cardiac transplantation at 1 year for patients initially listed as UNOS Status 2.


Distinct physical condition and social behavior phenotypes of CD157 and CD38 knockout mice during aging.
The ability of CD38 and CD157 to utilize nicotinamide adenine dinucleotide (NAD) has received much attention because the aging-induced elevation of CD38 expression plays a role in the senescence-related decline in NAD levels. Therefore, it is of interest to examine and compare the effects of age-associated changes on the general health and brain function impairment of Cd157 and Cd38 knockout (CD157 KO and CD38 KO) mice. The body weight and behaviors were measured in 8-week-old (young adult) or 12-month-old (middle-aged) male mice of both KO strains. The locomotor activity, anxiety-like behavior, and social behavior of the mice were measured in the open field and three-chamber tests. The middle-aged CD157 KO male mice gained more body weight than young adult KO mice, while little or no body weight gain was observed in the middle-aged CD38 KO mice. Middle-aged CD157 KO mice displayed increased anxiety-like behavior and decreased sociability and interaction compared with young adult KO mice. Middle-aged CD38 KO mice showed less anxiety and hyperactivity than CD157 KO mice, similar to young adult CD38 KO mice. The results reveal marked age-dependent changes in male CD157 KO mice but not in male CD38 KO mice. We discuss the distinct differences in aging effects from the perspective of inhibition of NAD metabolism in CD157 and CD38 KO mice, which may contribute to differential behavioral changes during aging.


Investigations of calcium homeostasis mechanisms in nerve cells and their alterations during brain pathology.
The paper summarises new data about the molecular mechanisms of calcium homeostasis maintenance in nerve cells and generation of intracellular calcium transients--the most general secondary messenger triggering or modulating all steps of neuronal life cycle and its main functions. It describes the low- and high-voltage activated plasmalemmal ion channels injecting Ca2+ into the cell, cytosolic buffering systems which rapidly bind the main part of injected ions, properties of intracellular stores accumulating Ca2+ ions due to the activity of CERCA-pumps and releasing them back into the cytosol via the CICR mechanism, possible participation of mitochondria in this process, extrusion of Ca2+ from the cell by PMCA-pumps. By introducing new techniques, quantitative characteristics are obtained of these mechanisms and of their participation in determining the amplitude and kinetics of calcium signals in different neurons, as well as their changes during ageing and some forms of brain pathology.


Genomics in multiple myeloma: biology and clinical implications.
The advent of new techniques, such as interphase fluorescence in situ hybridization, and, more recently, global array-based gene expression profiling, has accelerated genomic research in myeloma. Distinct biologic subtypes, characterized by unique genetic abnormalities with differing clinical outcomes, have been identified. The identification of these primary genetic defects, and the deregulated oncogenes and pathways in myeloma, has allowed for the development of more targeted therapies. This has led to the discovery of an increased number of active agents in the treatment of myeloma. Genetics also have prognostic importance in myeloma. Recent studies have elucidated a genetic prognostic hierarchy, and have enabled improved definition of the prognostic significance of their interactions. The current challenges are to: improve the dissection of the genetic heterogeneity of the disease; better define progression events; improve the risk stratification of patients; more accurately select patients who will respond well to a particular treatment; and develop more rational combinations of treatment. Genomics will have an important role to play in all of these goals.


Reliability and validity of the Dutch adaptation of the Quebec Back Pain Disability Scale.
The purposes of this study were to determine whether a Dutch translation of the Quebec Back Pain Disability Scale (QBPDS) retains the high levels of reliability and validity of the original English version and to determine whether it is therefore more practical to translate this scale, and possibly other scales, than to generate language- and culture-specific instruments. Subjects were 120 individuals with chronic low back pain. The QBPDS was filled out at the beginning of the study, after 1 week, and after 4 months. Reliability was determined by calculating Pearson correlation coefficients and intraclass correlation coefficients in addition to Cronbach's alpha and item-total correlation at the beginning of the study and after 4 months. Validity was examined by correlating the QBPDS scores to external criteria scores at a single point in time (cross-sectional) and over a period of time (longitudinal). Pearson and intraclass correlation coefficients for test-retest reliability were .90. Cronbach's alpha was .95. The cross-sectional construct validity coefficients were .80 (RDQ) and .70 (pain severity). The longitudinal construct validity coefficients were .60 (RDQ), .53 (pain severity), and .35 (course of the complaint). Our results support previous findings of the English and French versions of the QBPDS. Whether this instrument can be used as an evaluative instrument remains unknown.


Lysine methylation signaling in skeletal muscle biology: from myogenesis to clinical insights.
Lysine methylation signaling is well studied for its key roles in the regulation of transcription states through modifications on histone proteins. While histone lysine methylation has been extensively studied, recent discoveries of lysine methylation on thousands of non-histone proteins has broadened our appreciation for this small chemical modification in the regulation of protein function. In this review, we highlight the significance of histone and non-histone lysine methylation signaling in skeletal muscle biology, spanning development, maintenance, regeneration, and disease progression. Furthermore, we discuss potential future implications for its roles in skeletal muscle biology as well as clinical applications for the treatment of skeletal muscle-related diseases.


Long-term (52-78 weeks) treatment with colesevelam HCl added to metformin therapy in type 2 diabetes mellitus patients.
To evaluate the long-term safety, tolerability, and efficacy of colesevelam HCl (colesevelam) in type 2 diabetes mellitus patients receiving metformin monotherapy or metformin combination therapy. This post-hoc subgroup analysis examined data from type 2 diabetes mellitus patients aged 18 to 75 years with a hemoglobin A(1c) of 7.5% to 9.5%, who received metformin as part of their treatment via their participation in one of three randomized, double-blind base studies wherein colesevelam (3.75 g/day) or a placebo was added to existing metformin-, insulin-, or sulfonylurea-based treatment. After completing the base studies, the subjects who initially received blinded colesevelam (n = 196) or the placebo (n = 166) entered a 52-week extension study wherein they received open-label colesevelam (3.75 g/day). This analysis describes the 362 patients receiving background metformin therapy who also received open-label colesevelam (3.75 g/day) during a 1-year extension study. From a safety perspective, hypoglycemia was reported by 11 patients (3.0%; none severe). Drug-related adverse events (AEs) occurred in 38 patients (10.5%). At least one serious AE occurred in 35 patients (9.7%), with only one being assessed by investigators as drug related (exacerbation of diverticulitis). Twenty-four patients (6.6%) discontinued open-label treatment because of an AE (10 due to a drug-related AE). Compared with baseline values obtained prior to the start of both the base and extension studies, colesevelam improved and maintained improvement in hemoglobin A(1c) and various lipid parameters. This analysis found colesevelam to be generally safe and effective for long-term therapy in type 2 diabetes mellitus patients with inadequately controlled glucose while treated with metformin monotherapy or metformin combination therapy.


Successful linkage between formal and informal care systems: the mobilization of outside help by caregivers of persons with Alzheimer's disease.
Health interventions are currently being revamped to address the specific needs of chronic illness and population aging. In this context, focus has increasingly turned to Alzheimer-type dementia, an illness that is considered to mobilize a large number of social actors into long-term involvement of varying intensity. Linkage problems between families and professional systems have been well documented, yet the reasons for this remain relatively unexplored. In this article, we outline how we used social network data and narrative methods to better understand the linkage processes between formal and informal care systems. We present the trajectories of four caregivers of people suffering from Alzheimer's disease who were able to establish relationships with resources outside the family. In each of the cases, the dimensions of trust and recognition were central to establishing and maintaining supportive relationships, and must therefore be understood in light of social network dynamics and the broader environment. Although preliminary, this study contributes to the state of knowledge on linkage problems by proposing "bottom-up" solutions that are client centered.


Fisetin activates Hippo pathway and JNK/ERK/AP-1 signaling to inhibit proliferation and induce apoptosis of human osteosarcoma cells via ZAK overexpression.
Osteosarcoma (OS) is a tumor entity that can cause a large number of cancer-related deaths. Although chemotherapy can decrease proliferation and increase apoptosis of human OS cells, the clinical prognosis remains poor. Fisetin is a flavonol found in fruits and vegetables and is reported to inhibit cell growth in numerous cancers. But the molecular mechanism underlying fisetin in human OS cells is not clear. It is known that sterile-alpha motif and leucine zipper containing kinase (ZAK), a kinase in the MAP3K family, is involved in various cell processes, including proliferation and apoptosis. In our lab, we have demonstrated that overexpression of ZAK can induce apoptosis in human OS cells. In the previous studies, MAP4K, the upstream of MAP3K, can act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway. Turning on the Hippo pathway can decrease proliferation and otherwise cause cell apoptosis in cancer cells. In this study, we found that fisetin can upregulate ZAK expression to induce the Hippo pathway and mediate the activation of JNK/ERK, the downstream of ZAK, to trigger cell apoptosis via AP-1 dependent manner in human OS cells. These findings reveal a novel molecular mechanism underlying fisetin effect on human OS cells.


Proteomic analysis of proteins selectively associated with hydroxyapatite, brushite, and uric acid crystals precipitated from human urine.
The aim of this study was to compare the intracrystalline protein profiles of hydroxyapatite (HA), brushite (BR), and uric acid (UA) crystals precipitated from the same urine samples. HA, BR, and UA crystals were precipitated on two different occasions from the same pooled healthy urine. Crystals were washed to remove surface-bound proteins, and their composition was confirmed using Fourier transform infrared spectroscopy (FTIR) and field emission scanning electron microscopy (FESEM) coupled with energy dispersive X-ray analysis (EDAX). SDS-PAGE was used for visual comparison of the protein content of the demineralised crystal extracts, which were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). HA comprised nanosized particles interspersed with organic material, which was absent from the BR and UA crystals. The number and type of individual proteins differed between the 3 minerals: 45 proteins were detected in the HA crystal extracts and 77 in the BR crystals, including a number of keratins, which were regarded as methodological contaminants. After excluding the keratins, 21 proteins were common to both HA and BR crystals. Seven nonkeratin proteins were identified in the UA extracts. Several proteins consistently detected in the HA and BR crystal extracts have been previously implicated in kidney stone disease, including osteopontin, prothrombin, protein S100A9 (calgranulin B), inter-α-inhibitor, α1-microglobulin bikunin (AMBP), heparan sulfate proteoglycan, and Tamm-Horsfall glycoprotein, all of which are strong calcium binders. We concluded that the association of proteins with HA, BR, and UA crystals formed in healthy urine is selective and that only a few of the numerous proteins present in healthy urine are likely to play any significant role in preventing stone pathogenesis.


Appropriateness of requests for human serum albumin at the University Hospital of Palermo, Italy: a prospective study.
First, to assess the appropriateness of requests for albumin using current guidelines; second, to evaluate physicians' compliance with this protocol. Descriptive, prospective study. 'Paolo Giaccone' University Hospital in Palermo (Italy). The six departments with the highest orders for albumin. An experimental, pharmacist-driven process for daily orders of albumin was activated over a period of 1 month. Pharmacy personnel handed out order forms on six different wards. Physicians were required to select one of a number of intended uses listed on the form. Data on albumin and serum protein levels; number of vials and grams of albumin requested/day; number of vials and grams of albumin/day needed to normalize serum albumin levels; informed consent; indications and appropriateness of use. A total of 126 forms were collected. Mean serum albumin and protein levels of patients in the different wards were close to normal (2.5 and 5 g/dl, respectively). The albumin doses requested by the various wards were 2 to 7 times higher than expected. 37.3% of the requests were for appropriate indications, 40.5% were for occasionally appropriate indications and 18.2% were inappropriate. According to current guidelines, 83.3% of requests were appropriate. 45% of orders from the Intensive Care ward were for inappropriate indications. The introduction of a well-defined, flexible pharmacist-driven ordering process for albumin could reduce omissions in albumin indications and aid request assessment. It would allow pharmacists to collaborate with physicians in verifying whether requests are appropriate and whether prescriptions comply with current guidelines.


Kinetic gas-water transfer and gas accumulation in porous media during pulsed oxygen sparging.
Gas-water mass transfer and the transport of dissolved gases in variably saturated porous media are key processes for in-situ remediation by pulsed gas sparging. In this context, gas dissolution tests were conducted during pulsed oxygen gas injection into sand columns. The columns were recharged with anoxic water, effluents were analyzed for dissolved O2, and tracer tests were performed to detect accumulation of trapped gas. In a second series oxygen gas was blended with sulfur hexafluoride (SF6), and O2 and SF6 breakthrough curves were recorded. To interpret experimental results, a numerical model was applied that simulates multi-species kinetic mass transfer during gas dissolution. The model predicted breakthrough curves of dissolved gas species and delivered spatially resolved values for gas phase accumulation and composition, which are not directly accessible experimentally. It was shown how dissolved nitrogen accumulates increasingly in trapped gas phase and inhibits its complete dissolution, in case the pulsed gas injections were operated based on O2 breakthrough only. Accumulation of nitrogen also retarded dissolved oxygen transport and thus oxygen breakthrough. Experiments plus modeling demonstrated that SF6 measurements are highly sensitive to the gas dissolution processes, and provide a more sensitive criterion for determining gas injection frequencies during pulsed biosparging.


The clinical importance of articulations of the fibula.
Abnormal articular surfaces of the tibiofibular joint may result in painful knees. Aberrations in the tibiofibular joint may be secondary to old fractures of the bones of the ankle or the bones of the ipsilateral leg. Similarly, neuromuscular disease with growth abnormalities or primary osteoarthritis of the tibiofemoral joint may initiate secondarily abnormalities in the joint in question. There is a definite close relationship between mobility of the bones of the ankle and the status of the upper tibiofibular joint. For that reason, this articulation should be included in the routine examination of the knee joint.


Modes of transmission of influenza B virus in households.
While influenza A and B viruses can be transmitted via respiratory droplets, the importance of small droplet nuclei "aerosols" in transmission is controversial. In Hong Kong and Bangkok, in 2008-11, subjects were recruited from outpatient clinics if they had recent onset of acute respiratory illness and none of their household contacts were ill. Following a positive rapid influenza diagnostic test result, subjects were randomly allocated to one of three household-based interventions: hand hygiene, hand hygiene plus face masks, and a control group. Index cases plus their household contacts were followed for 7-10 days to identify secondary infections by reverse transcription polymerase chain reaction (RT-PCR) testing of respiratory specimens. Index cases with RT-PCR-confirmed influenza B were included in the present analyses. We used a mathematical model to make inferences on the modes of transmission, facilitated by apparent differences in clinical presentation of secondary infections resulting from aerosol transmission. We estimated that approximately 37% and 26% of influenza B virus transmission was via the aerosol mode in households in Hong Kong and Bangkok, respectively. In the fitted model, influenza B virus infections were associated with a 56%-72% risk of fever plus cough if infected via aerosol route, and a 23%-31% risk of fever plus cough if infected via the other two modes of transmission. Aerosol transmission may be an important mode of spread of influenza B virus. The point estimates of aerosol transmission were slightly lower for influenza B virus compared to previously published estimates for influenza A virus in both Hong Kong and Bangkok. Caution should be taken in interpreting these findings because of the multiple assumptions inherent in the model, including that there is limited biological evidence to date supporting a difference in the clinical features of influenza B virus infection by different modes.


[Treatment of differentiated thyroid cancer].
The prevalence of thyroid cancer is steadily rising and the fortuitous discovery of a thyroid nodule is a frequent situation for the clinician. The clinical importance is the need to exclude thyroid cancer. In this article we present the initial work up and treatment options for differentiated thyroid cancer. Initial diagnosis is done with a dosage of thyroid stimulating hormone and a fine needle aspiration guided by ultrasonography, which permits classification of the lesion and guides the choice of treatment.


Highly active oxide photocathode for photoelectrochemical water reduction.
A clean and efficient way to overcome the limited supply of fossil fuels and the greenhouse effect is the production of hydrogen fuel from sunlight and water through the semiconductor/water junction of a photoelectrochemical cell, where energy collection and water electrolysis are combined into a single semiconductor electrode. We present a highly active photocathode for solar H(2) production, consisting of electrodeposited cuprous oxide, which was protected against photocathodic decomposition in water by nanolayers of Al-doped zinc oxide and titanium oxide and activated for hydrogen evolution with electrodeposited Pt nanoparticles. The roles of the different surface protection components were investigated, and in the best case electrodes showed photocurrents of up to -7.6 mA cm(-2) at a potential of 0 V versus the reversible hydrogen electrode at mild pH. The electrodes remained active after 1 h of testing, cuprous oxide was found to be stable during the water reduction reaction and the Faradaic efficiency was estimated to be close to 100%.


Association of intradialysis blood sodium level, blood pressure variability, and hydration status with hemodialysis-related headache: a prospective cohort study.
To identify primary factors contributing to hemodialysis-related headache (HRH) in maintenance hemodialysis (MHD) patients. Adult outpatients receiving MHD were prospectively enrolled from a hemodialysis (HD) center of a tertiary hospital in China. Twelve dialysis sessions were successively monitored for each patient. HRH is defined as having at least three headache episodes that begin during HD and resolve within 72 h of HD session completion. Blood gas analysis during headache episodes and body composition analysis after dialysis were conducted. Hour-to-hour vital sign variability during dialysis was assessed using the metric of average real variability (ARV). Multivariable logistic regression analysis was conducted to explore the factors triggering HRH. A total of 95 Chinese MHD patients were enrolled, with 92 patients (60.9% were males) included in the final analysis. The mean age of the 92 patients was 59.3 ± 17.5 years, and the median dialysis vintage was 27.1 (12-46.2) months. Among them, 12 patients (13%) complained of 42 headache attacks, and eight (8.7%) were diagnosed with HRH. For eight patients with HRH, headache occurred 100.3 ± 69.5 min after the start of dialysis, with a mean VAS score of 4.3 ± 1 points. The quality of headaches was dull (six patients), pulsating (one patient), or stabbing pain (one patient); all the headaches were bilateral, with one having concomitant vomiting. The intradialysis headache duration and the whole headache duration were 98.8 ± 68.1 and 120 (65-217.5) minutes, respectively. Younger age (OR = 0.844, 95% CI 0.719-0.991, p = 0.039), decreased blood sodium level (OR = 0.309 in the range of 133-142 mmol/L, 95% CI 0.111-0.856, p = 0.024), increased ARV of intradialysis systolic blood pressure (OR = 3.067, 95% CI 1.006-9.348, p = 0.049) and ratio of overhydration to dry weight (OR = 1.990, 95% CI 1.033-3.832, p = 0.040) were found to be independent risk factors for HRH. This study suggested a significant attribution of blood sodium, hydration status and blood pressure variability to HRH.


Cytoplasmic pressure maintains epithelial integrity and inhibits cell motility.
Cytoplasmic pressure, a function of actomyosin contractility and water flow, can regulate cellular morphology and dynamics. In mesenchymal cells, cytoplasmic pressure powers cell protrusion through physiological three-dimensional extracellular matrices. However, the role of intracellular pressure in epithelial cells is relatively unclear. Here we find that high cytoplasmic pressure is necessary to maintain barrier function, one of the hallmarks of epithelial homeostasis. Further, our data show that decreased cytoplasmic pressure facilitates lamellipodia formation during the epithelial to mesenchymal transition (EMT). Critically, activation of the actin nucleating protein Arp2/3 is required for the reduction in cytoplasmic pressure and lamellipodia formation in response to treatment with hepatocyte growth factor (HGF) to induce EMT. Thus, elevated cytoplasmic pressure functions to maintain epithelial tissue integrity, while reduced cytoplasmic pressure triggers lamellipodia formation and motility during HGF-dependent EMT.


Nonmineralized and Mineralized Collagen Scaffolds Induce Differential Osteogenic Signaling Pathways in Human Mesenchymal Stem Cells.
The instructive capabilities of extracellular matrix components in progenitor cell differentiation have recently generated significant interest in the development of bioinspired materials for regenerative applications. Previously, a correlation was described between the osteogenic capabilities of nanoparticulate mineralized collagen glycosaminoglycan scaffolds (MC-GAG) and an autogenous activation of small mothers against decapentaplegic ( Smad1/5) in the canonical bone morphogenetic protein receptor (BMPR) pathway with a diminished extracellular signal regulated kinase 1/2 (ERK1/2) activation when compared to nonmineralized collagen glycosaminoglycan scaffolds (Col-GAG). This work utilizes a canonical BMPR inhibitor (dorsomorphin homologue 1, DMH1) and an inhibitor of the mitogen activated protein kinase/ERK kinase (MEK)/(ERK) cascade (PD98059) to characterize the necessity of each pathway for osteogenesis. While DMH1 inhibits runt-related transcription factor 2 (Runx2) and bone sialoprotein II (BSPII) gene expression of primary human mesenchymal stem cells (hMSCs) on MC-GAG, PD98059 inhibits BSPII expression on Col-GAG independent of Runx2 expression. DMH1 inhibits mineralization on both Col-GAG and MC-GAG, however, PD98059 only inhibits mineralization on Col-GAG. DMH1 inhibits both Smad1/5 phosphorylation and Runx2 protein expression, whereas PD98059 inhibits ERK1/2 and c-Jun amino-terminal kinase 1/2 (JNK1/2) phosphorylation without affecting Runx2. Thus, activation of the canonical BMPR signaling is necessary for osteogenic differentiation and mineralization of hMSCs on Col-GAG or MC-GAG. The MEK/ERK cascade, intimately tied to JNK activation, is necessary for Runx2-independent osteogenesis on Col-GAG, while completely dispensable in osteogenesis on MC-GAG.


A Case of Fulminant Myocarditis With Preceding Repeated Episodes of Congestive Heart Failure.
We report a rare case of fulminant myocarditis that was considered to have smoldered for a few months before it finally exteriorized. An 80-year-old man had had two episodes of mild congestive heart failure with preserved ejection function (HFPEF) within 3 months before he was finally admitted for the treatment of rapidly progressive heart failure. Cardiac function deteriorated remarkably on the final admission. Extracorporeal cardiopulmonary support was used because of pump failure and conduction disability, however, the patient died on the 16th day. Endomyocardial biopsy revealed numerous inflammatory infiltrates in myocardium compatible with fulminant myocarditis. However, advanced fibrosis and increased number of B lymphocytes and plasma cells found in the present case were not typical for fulminant myocarditis. Considering several distinctive findings in clinical and laboratory findings together, two preceding HFPEF episodes were highly likely to be associated with myocarditis.


Green to deep-red emissive carbon dot formation by C+ ion implantation on nitrogen beam created self-masked nano-template.
We report the formation of green to red emissive arrays of carbon dot on silicon-nitride nano-templates by successive implantation of nitrogen and carbon broad ion beams. The patterned nano-templates are formed by 14 keV N2+ ion-bombardment at grazing incident (700) on Si. Subsequently, 5 keV C+ ions are implanted at the selective sites of the pyramidal nano-template by taking advantage of the self-masking effect. The nano-pyramidal pattern and the implanted carbon dots at the specific sites are confirmed by Atomic Force Microscopy and cross sectional Transmission Electron Microscopy measurements. The developed carbon dots are mostly amorphous and consists of SiC and graphitic nitrogen (CN). G-band and D-band carbons are identified by Raman spectroscopy, while the presence of SiC and CN are detected by XPS measurements. A change of band-gap is observed for C-implanted templates by the UV-Vis spectroscopy. Excitation wavelength-dependent photoemission from the dots is found in the green to red region. Maximum intense PL is observed in the green-orange region for excitation wavelength of 425 nm and a redshift of PL with decreasing intensity is observed with the increase of excitation wavelength. The observed photoluminescence is described in terms of the combined effects of quantum confinement, graphitic nitrogen and defect induced additional states formation in the carbon dots. The potential applications of CDs are also addressed.&#xD.


Induction of L-form-like cell shape change of Bacillus subtilis under microculture conditions.
A remarkable cell shape change was observed in Bacillus subtilis strain 168 under microculture conditions on CI agar medium (Spizizen's minimal medium supplemented with a trace amount of yeast extract and Casamino acids). Cells cultured under a cover glass changed in form from rod-shaped to spherical, large and irregular shapes that closely resembled L-form cells. The cell shape change was observed only with CI medium, not with Spizizen's minimum medium alone or other rich media. The whole-cell protein profile of cells grown under cover glass and cells grown on CI agar plates differed in several respects. Tandem mass analysis of nine gel bands which differed in protein expression between the two conditions showed that proteins related to nitrate respiration and fermentation were expressed in the shape-changed cells grown under cover glass. The cell shape change of CI cultures was repressed when excess KNO3 was added to the medium. Whole-cell protein analysis of the normal rod-shaped cells grown with 0.1% KNO3 and the shape-changed cells grown without KNO3 revealed that the expression of the branched-chain alpha-keto acid dehydrogenase complex (coded by the bfmB gene locus) was elevated in the shape-changed cells. Inactivation of the bfmB locus resulted in the repression of cell shape change, and cells in which bfmB expression was induced by IPTG did show changes in shape. Transmission electron microscopy of ultrathin sections demonstrated that the shape-changed cells had thin walls, and plasmolysis of cells fixed with a solution including 0.1 M sucrose was observed. Clarifying the mechanism of thinning of the cell wall may lead to the development of a new type of cell wall biosynthetic inhibitor.


Modulation of nitrergic pathway by sesamol prevents cognitive deficits and associated biochemical alterations in intracerebroventricular streptozotocin administered rats.
Alzheimer's disease is a neurodegenerative disorder characterized by progressive cognitive decline and widespread loss of neurons and their synapses in the cerebral cortex and hippocampus. Increasing evidence indicates that factors such as oxidative-nitrergic stress, glutathione depletion, impaired protein metabolism and cholinergic deficit can interact in a vicious cycle, which is central to Alzheimer's disease pathogenesis. Intracerebroventricular (i.c.v.) streptozotocin induced-cognitive impairment has been widely used as an experimental paradigm to study Alzheimer's disease. In the present study, i.c.v. streptozotocin produced significant cognitive deficits as measured in Morris water maze and elevated plus maze task coupled with increased serum TNF-α levels and marked rise in brain acetylcholinesterase and oxidative-nitrergic stress in female Wistar rats. Sesamol (5-hydroxy-1,3-benzodioxole or 3,4-methylenedioxyphenol), a potent anti-oxidant and anti-inflammatory molecule markedly improved cognitive impairment, reduced acetylcholinesterase activity, TNF-α levels and attenuated oxidative-nitrergic stress in brain of i.c.v.-streptozotocin treated rats. Administration of L-arginine (125 mg/kg i.p), a nitric oxide donor, alone to i.c.v.-streptozotocin treated rats accentuated behavioral and biochemical deficits and also abolished the protective effect of sesamol (8 mg/kg). L-NAME (10 mg/kgi.p.), a non-specific NOS inhibitor significantly restored all the behavioral and biochemical indices in i.c.v.-streptozotocin rats. Moreover, combination of L-NAME with sub-effective dose of sesamol (4 mg/kg) potentiated its protective effect. Our findings demonstrate the effectiveness of sesamol in preventing intracerebroventricular streptozotocin-induced cognitive deficits by modulating nitrergic signaling and oxido-inflammatory cascade.


Association rule mining based study for identification of clinical parameters akin to occurrence of brain tumor.
Healthcare sector is generating a large amount of information corresponding to diagnosis, disease identification and treatment of an individual. Mining knowledge and providing scientific decision-making for the diagnosis & treatment of disease from the clinical dataset is therefore increasingly becoming necessary. Aim of this study was to assess the applicability of knowledge discovery in brain tumor data warehouse, applying data mining techniques for investigation of clinical parameters that can be associated with occurrence of brain tumor. In this study, a brain tumor warehouse was developed comprising of clinical data for 550 patients. Apriori association rule algorithm was applied to discover associative rules among the clinical parameters. The rules discovered in the study suggests - high values of Creatinine, Blood Urea Nitrogen (BUN), SGOT & SGPT to be directly associated with tumor occurrence for patients in the primary stage with atleast 85% confidence and more than 50% support. A normalized regression model is proposed based on these parameters along with Haemoglobin content, Alkaline Phosphatase and Serum Bilirubin for prediction of occurrence of STATE (brain tumor) as 0 (absent) or 1 (present). The results indicate that the methodology followed will be of good value for the diagnostic procedure of brain tumor, especially when large data volumes are involved and screening based on discovered parameters would allow clinicians to detect tumors at an early stage of development.


Pathogenic bacteria experience pervasive RNA polymerase backtracking during infection.
Eukaryotic hosts have defense mechanisms that may disrupt molecular transactions along the pathogen's chromosome through excessive DNA damage. Given that DNA damage stalls RNA polymerase (RNAP) thereby increasing mutagenesis, investigating how host defense mechanisms impact the movement of the transcription machinery on the pathogen chromosome is crucial. Using a new methodology we developed, we elucidated the dynamics of RNAP movement and association with the chromosome in the pathogenic bacterium Salmonella enterica during infection. We found that dynamics of RNAP movement on the chromosome change significantly during infection genome-wide, including at regions that encode for key virulence genes. In particular, we found that there is pervasive RNAP backtracking on the bacterial chromosome during infections and that anti-backtracking factors are critical for pathogenesis. Altogether, our results suggest that, interestingly, the host environment can promote the development of antimicrobial resistance and hypervirulence as stalled RNAPs can accelerate evolution through increased mutagenesis.


[Effect of age on carcinogenesis in female rats induced by methyl (acetoxymethyl) nitrosamine].
A single intraperitoneal injection of methyl-acetoxymethyl-nitrosamine produced tumors in 85.7% of 3 month-old female rats and in 62.5% of 14 month-old ones matched by 26.5% in controls. Intestinal tumors developed most frequently. Also, tumors of the pituitary, thyroid, breast, uterus as well as leukemia were detected. Multiple intestinal tumors were more frequent in the young age group (1.43 and 1.00), tumor-free interval in older animals being 217 days longer. Studies on DNA alkylation and repair were carried out using intraperitoneal injections of 14C-methyl-acetoxymethyl-nitrosamine. Young animals showed higher levels of methylpurines in organ tissues other than those of small intestine 3 hrs after treatment. The rate of methylpurine excretion in young rats was higher, too. However, liver tissue of old rats showed a higher rate of O6-methylguanine repair than that in younger ones.


Cyclin-dependent kinase 16/PCTAIRE kinase 1 is activated by cyclin Y and is essential for spermatogenesis.
Cyclin-dependent kinase 16 (CDK16, PCTK1) is a poorly characterized protein kinase, highly expressed in the testis and the brain. Here, we report that CDK16 is activated by membrane-associated cyclin Y (CCNY). Treatment of transfected human cells with the protein kinase A (PKA) activator forskolin blocked, while kinase inhibition promoted, CCNY-dependent targeting of CDK16-green fluorescent protein (GFP) to the cell membrane. CCNY binding to CDK16 required a region upstream of the kinase domain and was found to be inhibited by phosphorylation of serine 153, a potential PKA phosphorylation site. Thus, in contrast to other CDKs, CDK16 is regulated by phosphorylation-controlled cyclin binding. CDK16 isolated from murine testis was unphosphorylated, interacted with CCNY, and exhibited kinase activity. To investigate the function of CDK16 in vivo, we established a conditional knockout allele. Mice lacking CDK16 developed normally, but male mice were infertile. Spermatozoa isolated from their epididymis displayed thinning and elongation of the annulus region, adopted a bent shape, and showed impaired motility. Moreover, CDK16-deficient spermatozoa had malformed heads and excess residual cytoplasm, suggesting a role of CDK16 in spermiation. Thus, CDK16 is a membrane-targeted CDK essential for spermatogenesis.


Hydrothermal impacts on trace element and isotope ocean biogeochemistry.
Hydrothermal activity occurs in all ocean basins, releasing high concentrations of key trace elements and isotopes (TEIs) into the oceans. Importantly, the calculated rate of entrainment of the entire ocean volume through turbulently mixing buoyant hydrothermal plumes is so vigorous as to be comparable to that of deep-ocean thermohaline circulation. Consequently, biogeochemical processes active within deep-ocean hydrothermal plumes have long been known to have the potential to impact global-scale biogeochemical cycles. More recently, new results from GEOTRACES have revealed that plumes rich in dissolved Fe, an important micronutrient that is limiting to productivity in some areas, are widespread above mid-ocean ridges and extend out into the deep-ocean interior. While Fe is only one element among the full suite of TEIs of interest to GEOTRACES, these preliminary results are important because they illustrate how inputs from seafloor venting might impact the global biogeochemical budgets of many other TEIs. To determine the global impact of seafloor venting, however, requires two key questions to be addressed: (i) What processes are active close to vent sites that regulate the initial high-temperature hydrothermal fluxes for the full suite of TEIs that are dispersed through non-buoyant hydrothermal plumes? (ii) How do those processes vary, globally, in response to changing geologic settings at the seafloor and/or the geochemistry of the overlying ocean water? In this paper, we review key findings from recent work in this realm, highlight a series of key hypotheses arising from that research and propose a series of new GEOTRACES modelling, section and process studies that could be implemented, nationally and internationally, to address these issues.This article is part of the themed issue 'Biological and climatic impacts of ocean trace element chemistry'.


Vasopressin stimulates prostaglandin and thromboxane synthesis in toad bladder epithelial cells.
The effects of arginine vasopressin (AVP) and its nonpressor analogue desamino-8-arginine vasopressin (dDAVP) on immunoreactive prostaglandin E and thromboxane B2 synthesis from endogenous arachidonic acid by epithelial cells isolated from toad urinary bladders were investigated. In epithelial cell suspensions prepared using a collagenase treatment, AVP (5 mU/ml) stimulated prostaglandin E synthesis from 0.27 +/- 0.05 to 0.53 +/- 0.09 pmol . min-1 . mg protein-1 (P less than 0.01, n = 6) and stimulated thromboxane A2 synthesis, as assessed by measurement of its stable metabolite thromboxane B2, from 0.032 +/- 0.004 to 0.054 +/- 0.009 pmol . min-1 . mg protein-1 (P less than 0.02, n = 6). dDAVP (130 nM) also stimulated immunoreactive prostaglandin E and thromboxane B2 synthesis (P less than 0.05, n = 6). In cells prepared by EDTA treatment or scraping, aVP did not alter prostaglandin or thromboxane synthesis. This study demonstrates that AVP and dDAVP stimulate both prostaglandin and thromboxane synthesis in epithelial cells from the toad urinary bladder and suggests that the antidiuretic activity of these peptides is associated with this effect. The results are consistent with previous observations that the synthesis of prostaglandin E and thromboxane by epithelial cells results in a negative and positive modulation, respectively, of the action of AVP on water transport.


Availability of eIF4E regulates skeletal muscle protein synthesis during recovery from exercise.
We examined the association of the mRNA cap binding protein eIF4E with the translational inhibitor 4E-BP1 in the acute modulation of skeletal muscle protein synthesis during recovery from exercise. Fasting male rats were run on a treadmill for 2 h at 26 m/min and were realimented immediately after exercise with either saline, a carbohydrate-only meal, or a nutritionally complete meal (54.5% carbohydrate, 14% protein, and 31.5% fat). Exercised animals and nonexercised controls were studied 1 h postexercise. Muscle protein synthesis decreased 26% after exercise and was associated with a fourfold increase in the amount of eIF4E present in the inactive eIF4E.4E-BP1 complex and a concomitant 71% decrease in the association of eIF4E with eIF4G. Refeeding the complete meal, but not the carbohydrate meal, increased muscle protein synthesis equal to controls, despite similar plasma concentrations of insulin. Additionally, eIF4E.4E-BP1 association was inversely related and eIF4E.eIF4G association was positively correlated to muscle protein synthesis. This study demonstrates that recovery of muscle protein synthesis after exercise is related to the availability of eIF4E for 48S ribosomal complex formation, and postexercise meal composition influences recovery via modulation of translation initiation.


Dual-Mode and Label-Free Detection of Exosomes from Plasma Using an Electrochemical Quartz Crystal Microbalance with Dissipation Monitoring.
The biomolecular contents of extracellular vesicles, such as exosomes, have been shown to be crucial in intercellular communication and disease propagation. As a result, there has been a recent surge in the exploration of novel biosensing platforms that can sensitively and specifically detect exosomal content such as proteins and nucleic acids, with a view toward application in diagnostic assays. Here, we demonstrate dual-mode and label-free detection of plasma exosomes using an electrochemical quartz crystal microbalance with dissipation monitoring (EQCM-D). The platform adopts a direct immunosensing approach to effectively capture exosomes via their surface protein expression of CD63. By combining QCM-D with a tandem in situ electrochemical impedance spectroscopy measurement, we are able to demonstrate relationships between mass, viscoelasticity and impedance inducing properties of each functional layer and analyte. In addition to lowering the limit of detection (by a factor of 2-4) to 6.71 × 107 exosome-sized particles (ESP) per mL in 25% v/v serum, the synergy between dissipation and impedance response introduces improved sensing specificity by offering further distinction between soft and rigid analytes, thereby promoting EQCM-D as an important technique for exosome analysis.


Increased expression of inducible nitric oxide synthase and peroxynitrite in Helicobacter pylori gastric ulcer.
The role of nitric oxide in ulcer formation remains unknown. Accordingly, we assessed local expression of inducible nitric oxide synthase (NOS) and nitration of tyrosine as an indicator of peroxynitrite formation in patients with Helicobacter pylori (HP)-associated gastric ulcers compared with HP-negative ulcers. Biopsy specimens were taken from the ulcer margin and from an area remote from the ulcer portion. Inducible NOS, nitrotyrosine, and macrophage immunoreactivity were assessed immunohistochemically using a labeled streptavidin-biotin method. In HP-positive gastric ulcers, inducible NOS and nitrotyrosine immunoreactivity was frequently observed at active ulcer margins, sometimes in surface epithelial cells as well as in the lamina propria. Occasionally, inducible NOS and nitrotyrosine reactivity were found in areas remote from the lesion in cases of HP-positive ulcer and HP-related gastritis. Macrophages accumulated significantly in the margin of HP-positive ulcers. In HP-negative gastric ulcers, inducible NOS and nitrotyrosine immunoreactivity also were frequent at the ulcer margin, but no significant immunoreactivity was observed at a distance. HP eradication caused significant attenuation in inducible NOS and macrophage immunoreactivity. In conclusion, nitric oxide and peroxynitrite formation is increased in HP-infected gastric mucosa, suggesting that HP promotes nitric oxide stress.


Improvement of the soy formate dehydrogenase properties by rational design.
Previous experiments on substitution of the residue Phe290 to Asp, Asn and Ser in NAD(+)-dependent formate dehydrogenase from soya Glycine max (SoyFDH) showed important role of the residue in enzyme thermal stability and catalytic properties (Alekseeva et al. Prot. Eng. Des. Sel., 2012a; 25: :781-88). In this work, we continued site-directed mutagenesis experiments of the Phe290 and the residue was changed to Ala, Thr, Tyr, Glu and Gln. All amino acid changes resulted in increase of catalytic constant from 2.9 to 3.5-4.7 s(-1). The substitution Phe290Ala led to KM (NAD+) decrease from 13.3 to 8.6 μM, and substitutions Phe290Tyr and Phe290Glu resulted in decrease and increase of KM (HCOO-) from 1.5 to 0.9 and -2.9 mM, respectively. The highest improvement of catalytic properties was observed for SoyFDH Phe290Ala which showed 2-fold higher catalytic efficiency with both substrates. Stability of mutants was examined by study of thermal inactivation kinetics and differential scanning calorimetry (DSC). All five amino acids provided increase of thermal stability of mutant SoyFDH in comparison with wild-type enzyme. Mutant SoyFDH Phe290Glu showed the highest improvement-the stabilization effect was 43 at 56°C. The DSC data agree with results of thermal inactivation kinetics. Substitutions Phe290Tyr, Phe290Thr, Phe290Gln and Phe290Glu provided Tm value increase 0.6°-6.6°. SoyFDH Phe290Glu and previously prepared SoyFDH Phe290Asp show similar thermal stability as enzymes from Candida boidinii and Mycobacterium vaccae N10 and have higher catalytic efficiency with NAD(+) compared with all described FDHs. Therefore, these mutants are very perspective enzymes for coenzyme regeneration in processes of chiral synthesis with dehydrogenases.


Exercise without weight loss does not reduce C-reactive protein: the INFLAME study.
Numerous cross-sectional studies have observed an inverse association between C-reactive protein (CRP) and physical activity. Exercise training trials have produced conflicting results, but none of these studies was specifically designed to examine CRP. The objective of the Inflammation and Exercise (INFLAME) study was to examine whether aerobic exercise training without dietary intervention can reduce CRP in individuals with elevated CRP. The study was a randomized controlled trial of 162 sedentary men and women with elevated CRP (> or = 2.0 mg·L(-1)). Participants were randomized into a nonexercise control group or an exercise group that trained for 4 months. The primary outcome was change in CRP. The study participants had a mean (SD) age of 49.7 (10.9) yr and a mean body mass index of 31.8 (4.0) kg·m(-2). The median (interquartile range (IQR)) and mean baseline CRP levels were 4.1 (2.5-6.1) and 4.8 (3.4) mg·L(-1), respectively. In the exercise group, median exercise compliance was 99.9%. There were no differences in median (IQR) change in CRP between the control and exercise groups (0.0 (-0.5 to 0.9) vs 0.0 (-0.8 to 0.7) mg·L(-1), P = 0.4). The mean (95% confidence interval) change in CRP adjusted for gender and baseline weight was similar in the control and exercise groups, with no significant difference between groups (0.5 (-0.4 to 1.3) vs 0.4 (-0.5 to 1.2) mg·L(-1), P = 0.9). Change in weight was correlated with change in CRP. Exercise training without weight loss is not associated with a reduction in CRP.


Jiao tai wan attenuates hepatic lipid accumulation in type 2 diabetes mellitus.
Jiao Tai Wan (JTW), a Chinese herbal formula containing Rhizoma Coptidis and Cortex Cinnamomi, has been used for diabetic treatment for many years. The aim of this study was to determine the main components in JTW and to investigate the effects of JTW on hepatic lipid accumulation in diabetic rats and humans. JTW extract was prepared and the main components were assayed by HPLC. An animal model of diabetes mellitus was established and JTW was administered intragastrically. In the clinical study, diabetic patients with poor glycemic control were treated with JTW. Blood glucose and lipid parameters, liver histology, hepatic triglyceride content and lipogenic gene expression were examined. Our data demonstrated that JTW significantly improved hyperglycemia, hyperlipidemia and hepatic lipid accumulation in diabetic rats. This was accompanied by the down-regulation of acetyl coenzyme A carboxylase (ACC) and fatty acid synthase (FAS) protein expressions, and the up-regulation of AMP-activated protein kinase (AMPK) and phosphorylated-ACC (pACC) protein expressions in the liver tissues. Diabetic patients also exhibited decreases in their hepatic triglyceride content. The results suggest that JTW attenuates hepatic lipid accumulation in diabetic rats and humans. These beneficial effects are possibly associated with the inhibition of lipogenic gene expression in the liver.


Designed ferromagnetic, ferroelectric Bi(2)NiMnO(6).
A newly designed ferromagnetic, ferroelectric compound, Bi(2)NiMnO(6), was prepared by high-pressure synthesis at 6 GPa. The crystal structure, as determined by synchrotron X-ray powder diffraction, is a heavily distorted double perovskite with Ni(2+) and Mn(4+) ions ordered in a rock-salt configuration. The presence of 6s(2) lone pairs of Bi(3+) ions and the covalent Bi-O bonds give ferroelectric properties with T(CE) of 485 K, while -Ni(2+)-O-Mn(4+)-O-Ni(2+)- magnetic paths lead to a ferromagnetism with T(CM) of 140 K. This simple material design to distribute two magnetic elements with and without e(g) electrons on B sites of Bi- and Pb-based perovkites can be applied to other Bi(2)M(2+)M'(4+)O(6) and Pb(2)M(3+)M'(5+)O(6) systems to search for newer ferromagnetic ferroelectrics.


Correlates of Executive Functions in Multiple Sclerosis Based on Structural and Functional MR Imaging: Insights from a Multicenter Study.
Purpose To study the concomitant use of structural and functional magnetic resonance (MR) imaging correlates to explain information processing speed (IPS) and executive function (EF) in multiple sclerosis (MS). Materials and Methods Local ethics committee approval was obtained at all sites for this prospective, multicenter study. All subjects provided written informed consent. Twenty-six patients with relapsing-remitting MS and 32 healthy control subjects from four centers underwent structural and functional MR imaging, including a go/no-go task and neuropsychological assessment. Subtests of the Brief Repeatable Battery of Neuropsychological Tests, the Wisconsin Card Sorting Test, and the performance with the functional MR imaging paradigm were used as estimates of IPS and EF. Activation of the thalamus and the inferior frontal gyrus (pars triangularis), thalamic volume, T2 lesion load, and age were used to explain IPS and EF in regression models. Results Compared with control subjects, patients showed increased activation in a frontoparietal network, including both thalami, during the execution of the go/no-go task. Patients had decreased thalamic volume (P < .001). Among tested variables, thalamic volume (β = 0.606, P = .001), together with thalamic activation (β = -0.410, P = .022), were the best predictors of IPS and EF and helped explain 52.7% of the variance in IPS and EF. Conclusion This study highlights the potential of the combined use of functional and morphologic parameters to explain IPS and EF in patients with relapsing-remitting MS and confirms the central role of the thalamus as a relay station in executive functioning. (©) RSNA, 2016.


Empirical analysis of cost-effective and equitable solid waste management systems: Environmental and economic perspectives.
The solid waste management (SWM) system is in a transitional phase in developing economies, and local municipalities and waste management companies are stepping toward integrating a waste treatment approach in the scheme of waste handling. However, there is an urgent need to explore cost-effective techniques, models, and potential revenue streams to sustain the state-run waste sector self-sufficiently. The proposed SWM model aims to support the local waste sector in Islamabad, the capital city of Pakistan, with 100% service area coverage to attain environmental and economic sustainability by defining dedicated waste collection streams to ensure quality material recovery under a cost-effective approach and modality. The innovative approach is applied to allocate the tonnage to various streams as per the city's current land use plan. The estimated/cost of the cleanliness services will be USD13.1 million per annum with an estimated per ton cost of USD 23. The establishment of the proposed material recovery facility (MRF) will process about 500 t/d of waste to produce 45 t/d compost and recover 130 t/d of recyclables. The environmentally friendly model saves 2.4 million tons of CO2‒eq/month from composting and recycling. The average economic potential from MRF and debris-crushing plants, including environmental benefit value, is calculated as USD 3.97 million annually. Recovery of services fee (70%) for various collection streams based on city land use and socio-economic conditions will generate revenue of USD 7.33 million annually. The total revenue will be USD 11.31 million (86% of total annual expenditures) to track the sector's self-sufficiency. To successfully reach the Sustainable Development Goals (SDGs) and Nationally Determined Contributions (NDCs), engaging the private sector from environmentally advanced economies to collaborate in the waste sector to enhance local technical capabilities is recommended.


[Significance of ST segment depression in the precordial leads during the acute phase of inferior myocardial infarction].
Reciprocal changes of the ST segment in the acute phase of inferior myocardial infarction are common but their significance remain controversial. We studied this problem by comparing the ECG on admission of 83 patients with acute inferior myocardial infarction, with the clinical outcome and haemodynamic and angiographic data obtained on average 3 weeks after the onset of symptoms. Fifty nine patients (Group I) had ST depression greater than or equal to 1 mm in at least one of the leads V1 to V4; 24 patients (Group II) had no ST depression in this territory. The patients in Group I were older (59.6 +/- 6.4 vs 54 +/- 5.3 years, p less than 0.01), had higher total CPK (1 835 +/- 940 vs 875 +/- 305, p less than 0.01) and MB fractions (269 +/- 102 vs 95 +/- 35), more complications during the hospital period (80%, mainly haemodynamic vs 38%, p less than 0.01) and more severe left ventricular dysfunction: ejection fraction 52.2 +/- 6% vs 59.2 +/- 7%, p less than 0.05; cardiac index 2.75 +/- 0.4 l/min/m2 vs 3.25 +/- 0.3 l/min/m2, p less than 0.005). There was no difference in left ventricular wall motion between the groups on biplane angiography. However, coronary angiography showed left coronary disease to be more common in Group I (84%) than in Group II (37%), p less than 0.005. Left anterior descending and left circumflex disease was equally common. Patients with persistent ST depression after 48 hours had lower ejection fractions than those in whom it regressed within 48 hours.(ABSTRACT TRUNCATED AT 250 WORDS)


Pediatric Chest Radiographic and CT Findings of Electronic Cigarette or Vaping Product Use-associated Lung Injury (EVALI).
Background Electronic cigarette or vaping product use-associated lung injury (EVALI) is a serious public health concern with substantial morbidity and mortality, particularly in young individuals. Purpose To evaluate chest radiographic and chest CT findings of EVALI in the pediatric population. Materials and Methods This was a retrospective study of children who presented to a tertiary pediatric hospital from December 2018 to December 2019. Patients fulfilled the Centers for Disease Control and Prevention criteria for EVALI and had chest radiographs and CT images available at initial presentation. Two pediatric radiologists independently reviewed imaging for pattern, distribution, and extent of pulmonary abnormalities, as well as for extrapulmonary abnormalities. Clinical information, management, and outcomes were reviewed. Interobserver agreement was measured with Cohen κ coefficient. Results Seven male patients (50%) and seven female patients (50%) (mean age, 16 years; range, 13-18 years) were evaluated. All patients underwent chest radiography and CT within 4 days of presentation (range, 0-4 days). Chest radiographic findings included ground-glass opacity in 14 of 14 (100%) and consolidation in eight of 14 (57%). CT findings included ground-glass opacity in 14 of 14 (100%), consolidation in nine of 14 (64%), and interlobular septal thickening in two of 14 (14%). At CT, subpleural sparing was seen in 11 of 14 (79%) and a reversed halo sign was seen in five of 14 (36%). Chest radiographic and CT abnormalities were predominately bilateral in 14 of 14 (100%) and symmetric in 13 of 14 (93%), with lower lobe predominance in seven of 14 (50%). Extent of abnormality was predominately diffuse at both chest radiography and CT. There was almost perfect interobserver agreement between two reviewers for detecting abnormalities on chest radiographs (κ = 0.99; 95% confidence interval: 0.97, 1.00) and CT (κ = 0.99; 95% confidence interval: 0.98, 1.00). Conclusion In pediatric patients, electronic cigarette or vaping product use-associated lung injury is characterized by bilateral symmetric ground-glass opacities, consolidation, and a lower lobe predominance at CT. © RSNA, 2020.


Prevalence and pattern of alternative medicine use: the results of a household survey.
Alternative medicine (AM) encompasses all forms of therapies that fall outside the mainstream of medical practice. Its popularity is on the increase. Because previous surveys were limited and not generalizable, we estimated the prevalence, pattern and factors associated with use of AM in the community. A multistage cluster cross-sectional household survey was conducted among Saudi residents of the Riyadh region. Data were collected in 2003 by trained interviewers from primary health care centers using a specially designed questionnaire. Of 1408 individuals participating in the study, 39% were men. The mean (+/-SD) age for the study population was 35.5 (+/-13.9) years. Sixty-eight percent of the respondents had used AM during the last 12 months. The Holy Quran as a therapy was the most frequently used AM (50.3%), followed by honey (40.1%), black seed (39.2%) and myrrh (35.4%). The health belief model was found to be the most important determinant of AM use. Factors independently associated with AM use included perceived failure of medical treatment, the perceived success of AM, a preference for natural materials, and long appointment intervals to see physicians. There is a high prevalence of AM use in the Riyadh region and the most important determinant of AM use was the perceived failure of medical treatment. The study results call for intensive health education campaigns in the media addressing wrong beliefs regarding AM and modern medicine. The popularity of AM in this community should alert decision makers to look at the difficult accessibility to the health system.


Modest wine drinking and decreased prevalence of suspected nonalcoholic fatty liver disease.
People at risk for coronary heart disease are often at risk for nonalcoholic fatty liver disease (NAFLD). The association of modest wine consumption with NAFLD has not been studied and the recommendation of wine for patients at risk for both diseases is controversial. The aim is to test the hypothesis that modest wine consumption is associated with decreased prevalence of NAFLD. We included Third National Health and Nutrition Examination Survey participants who either reported no alcohol consumption or preferentially drinking wine with total alcohol consumption up to 10 g per day. Suspected NAFLD was based on unexplained serum alanine aminotransferase (ALT) elevation over the cut point of the reference laboratory (ALT > 43) and the cut point based on the 95th percentile of healthy subjects (ALT > 30 for men; ALT > 19 for women). Multivariate analysis was adjusted for age, gender, race, neighborhood, income, education, caffeine intake, and physical activity. A total of 7,211 nondrinkers and 945 modest wine drinkers comprised the study sample. Based on the reference laboratory cut point, suspected NAFLD was observed in 3.2% of nondrinkers and 0.4% of modest wine drinkers. The adjusted odds ratio was 0.15 (95% confidence interval, 0.05-0.49). Using the healthy subject cut point, suspected NAFLD was observed in 14.3% of nondrinkers and 8.6% of wine drinkers. The adjusted odds ratio was 0.51 (95% confidence interval, 0.33-0.79). Modest wine consumption is associated with reduced prevalence of suspected NAFLD. The current study supports the safety of one glass of wine per day for cardioprotection in patients at risk for both coronary heart disease and NAFLD.


Anterior "W" Tongue Reduction for Macroglossia in Beckwith-Wiedemann Syndrome.
Macroglossia occurs in 80% to 99% of patients with Beckwith-Wiedemann syndrome (BWS) and a variety of surgical techniques for tongue reduction are offered by surgeons. The purpose of this study is to evaluate the postoperative outcomes of the anterior "W" tongue reduction technique in patients with BWS. A retrospective review was conducted of all patients diagnosed with BWS that underwent an anterior "W" tongue reduction for macroglossia in the past 7 years, performed by 2 surgeons. Demographics, procedural characteristics, perioperative outcomes, and complications were assessed. A total of 19 patients met inclusion criteria consisting of 8 male and 11 female patients. The mean age at the time of surgery was 405 days, mean surgeon operating time was 1.06 h, and mean length of follow-up was 467 days. Postoperative oral competence was observed in 100% of patients. There was no reported history of sleep apnea or airway compromise. Speech delay was seen in 4 patients pre- and postoperatively. Feeding issues decreased from 7 patients preoperatively to 1 patient postoperatively. Preoperative prevalence of class III malocclusion (53%) and isolated anterior open bite (26%) decreased postoperatively to 37% and 16%, respectively. The only reported complications were superficial tip wound dehiscence in 3 patients treated with nystatin antifungal therapy. None of the patients required revisional surgery. Patients treated with the anterior "W" tongue reduction technique had low rates of perioperative complications and significant improvements in oral competence. Anterior "W" tongue reduction is safe and effective for the correction of macroglossia in patients with BWS.


Tirzepatide ameliorates spatial learning and memory impairment through modulation of aberrant insulin resistance and inflammation response in diabetic rats.
Background: One of the typical symptoms of diabetes mellitus patients was memory impairment, which was followed by gradual cognitive deterioration and for which there is no efficient treatment. The anti-diabetic incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were demonstrated to have highly neuroprotective benefits in animal models of AD. We wanted to find out how the GLP-1/GIP dual agonist tirzepatide affected diabetes's impairment of spatial learning memory. Methods: High fat diet and streptozotocin injection-induced diabetic rats were injected intraperitoneally with Tirzepatide (1.35 mg/kg) once a week. The protective effects were assessed using the Morris water maze test, immunofluorescence, and Western blot analysis. Golgi staining was adopted for quantified dendritic spines. Results: Tirzepatide significantly improved impaired glucose tolerance, fasting blood glucose level, and insulin level in diabetic rats. Then, tirzepatide dramatically alleviated spatial learning and memory impairment, inhibited Aβ accumulation, prevented structural damage, boosted the synthesis of synaptic proteins and increased dendritic spines formation in diabetic hippocampus. Furthermore, some aberrant changes in signal molecules concerning inflammation signaling pathways were normalized after tirzepatide treatment in diabetic rats. Finally, PI3K/Akt/GSK3β signaling pathway was restored by tirzepatide. Conclusion: Tirzepatide obviously exerts a protective effect against spatial learning and memory impairment, potentially through regulating abnormal insulin resistance and inflammatory responses.


Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells.
The mevalonate (MEV) cascade is responsible for cholesterol biosynthesis and the formation of the intermediate metabolites geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate (FPP) used in the prenylation of proteins. Here we show that the MEV cascade inhibitor simvastatin induced significant cell death in a wide range of human tumor cell lines, including glioblastoma, astrocytoma, neuroblastoma, lung adenocarcinoma, and breast cancer. Simvastatin induced apoptotic cell death via the intrinsic apoptotic pathway. In all cancer cell types tested, simvastatin-induced cell death was not rescued by cholesterol, but was dependent on GGPP- and FPP-depletion. We confirmed that simvastatin caused the translocation of the small Rho GTPases RhoA, Cdc42, and Rac1/2/3 from cell membranes to the cytosol in U251 (glioblastoma), A549 (lung adenocarcinoma) and MDA-MB-231(breast cancer). Simvastatin-induced Rho-GTP loading significantly increased in U251 cells which were reversed with MEV, FPP, GGPP. In contrast, simvastatin did not change Rho-GTP loading in A549 and MDA-MB-231. Inhibition of geranylgeranyltransferase I by GGTi-298, but not farnesyltransferase by FTi-277, induced significant cell death in U251, A549, and MDA-MB-231. These results indicate that MEV cascade inhibition by simvastatin induced the intrinsic apoptosis pathway via inhibition of Rho family prenylation and depletion of GGPP, in a variety of different human cancer cell lines.


Efficacy of a hip protector to prevent hip fracture in nursing home residents: the HIP PRO randomized controlled trial.
Past studies of the efficacy of hip protectors to prevent hip fracture in nursing home residents have had conflicting results, possibly due to potential biases from clustered randomization designs and modest adherence to intervention. To determine whether an energy-absorbing and energy-dispersing hip protector would reduce the risk of hip fracture when worn by nursing home residents. Multicenter, randomized controlled clinical trial in which 37 nursing homes were randomly assigned to having residents wear a 1-sided hip protector on the left or right hip. Participants were 1042 nursing home residents (mean [SD] aged 85 [7] years; 79% women) who consented and adhered to the hip protector use during a 2-week run-in period and were enrolled. Participating facilities were in greater Boston, Massachusetts, St Louis, Missouri, and Baltimore, Maryland from October 2002 to October 2004. Mean duration of participation for nursing home residents was 7.8 months. None were withdrawn because of adverse effects. Undergarments with a 1-sided hip protector made of a 0.32-cm outer layer of polyethylene (2.7 kg/m3) backed by a hard high-density polyethylene shield (0.95 cm) that was backed by 0.9 kg/m3 of 1.27-kg ethylene vinyl acetate foam. Each facility was visited 3 times per week to assess adherence and provide staff support. Adjudicated hip fracture occurrences on padded vs unpadded hips. After a 20-month follow-up (676 person-years of observation), the study was terminated due to a lack of efficacy. The incidence rate of hip fracture on protected vs unprotected hips did not differ (3.1%; 95% confidence interval [CI], 1.8%-4.4% vs 2.5%; 95% CI, 1.3%-3.7%; P = .70). For the 334 nursing home residents with greater than 80% adherence to hip protector use, the incidence rate of hip fracture on protected vs unprotected hips did not differ (5.3%; 95% CI, 2.6%-8.8% vs 3.5%; 95% CI, 1.3%-5.7%; P = .42). Overall adherence was 73.8%. In this clinical trial of an energy-absorbing/shunting hip protector conducted in US nursing homes, we were unable to detect a protective effect on the risk of hip fracture, despite good adherence to protocol. These results add to the increasing body of evidence that hip protectors, as currently designed, are not effective for preventing hip fracture among nursing home residents. clinicaltrials.gov Identifier: NCT00058864.


Continuous intraocular pressure monitoring in patients with obstructive sleep apnea syndrome using a contact lens sensor.
To analyse nocturnal intraocular pressure (IOP) fluctuations in patients with obstructive sleep apnea syndrome (OSAS) using a contact lens sensor (CLS) and to identify associations between the OSAS parameters determined by polysomnographic study (PSG) and IOP changes. Prospective, observational study. Twenty participants suspected of having OSAS were recruited. During PSG study, IOP was monitored using a CLS placed in the eye of the patient. The patients were classified according to the apnea-hypopnea index (AHI) in two categories, severe (>30) or mild/moderate (<30) OSAS. We evaluated several parameters determined by the IOP curves, including nocturnal elevations (acrophase) and plateau times in acrophase (PTs) defined by mathematical and visual methods. The IOP curves exhibited a nocturnal acrophase followed by PTs of varying extents at which the IOP remained higher than daytime measurement with small variations. We found significant differences in the length of the PTs in patients with severe OSAS compared to those with mild/moderate disease (P = 0.032/P = 0.028). We found a positive correlation between PTs and OSAS severity measured by the total number of apneic events (r = 0.681/0.751 P = 0.004/0.001) and AHI (r = 0.674/0.710, P = 0.004/0.002). Respiratory-related arousal and oxygen saturation also were associated significantly with the IOP PT length. Periods of nocturnal IOP elevation lasted longer in severe OSAS patients than those with mild/moderate OSAS and correlate with the severity of the disease. The length of the nocturnal PT is also associated to respiratory parameters altered in patients with OSAS.


Coping Processes, Self-Efficacy, and CPAP Use in Adults With Obstructive Sleep Apnea.
Background: Coping strategies are predictive of 1 week CPAP use. Coping strategies may predict longer-term CPAP use among adults with obstructive sleep apnea (OSA). Objectives: To investigate the influence of two coping styles (active and passive) and individual coping processes on CPAP use at 1 week and 1 month; and explore the association between self-efficacy and coping on CPAP use. Participants: CPAP-naïve adults (52.3% male, 90.9% White) newly diagnosed with OSA (AHI ≥ 5 events/hr) from two U.S. clinical sleep centers (n = 66). Methods: A post-hoc analysis from a prospective, longitudinal study that examined influential factors on CPAP use among CPAP-naïve patients with newly diagnosed OSA. The Ways of Coping Questionnaire and the Self-Efficacy Measure for Sleep Apnea were completed immediately after CPAP titration polysomnography. Objective 1 week and 1 month CPAP use (mean hr/night) were the primary outcomes. Descriptive analyses and stepwise multiple linear regression analyses modeling for CPAP use (mean hr/night). Results: Active coping was significantly associated with greater CPAP use (mean hr/night) at 1 week, but not at 1 month (p = 0.0397; p = 0.0556, respectively). Higher Planful Problem Solving was significantly associated with greater average CPAP use at 1 week and 1 month (p = 0.0117, p = 0.0378, respectively). Self-efficacy was significantly associated with greater average CPAP use at 1 week (p = 0.0056) and 1 month (p = 0.0056). Conclusions: Self-efficacy and Planful Problem Solving coping are promising behavioral intervention targets to promote CPAP use in newly diagnosed OSA.