Methylation of protocadherin 10, a novel tumor suppressor, is associated with poor prognosis in patients with gastric cancer.
By using methylation-sensitive representational difference analysis, we identified protocadherin 10 (PCDH10), a gene that encodes a protocadherin and is silenced in a tumor-specific manner. We analyzed its epigenetic inactivation, biological effects, and prognostic significance in gastric cancer. Methylation status was evaluated by combined bisulfite restriction analysis and bisulfite sequencing. The effects of PCDH10 re-expression were determined in growth, apoptosis, proliferation, and invasion assays. PCDH10 target genes were identified by complementary DNA microarray analysis. PCDH10 was silenced or down-regulated in 94% (16 of 17) of gastric cancer cell lines; expression levels were restored by exposure to demethylating agents. Re-expression of PCDH10 in MKN45 gastric cancer cells reduced colony formation in vitro and tumor growth in mice; it also inhibited cell proliferation (P < .01), induced cell apoptosis (P < .001), and repressed cell invasion (P < .05), up-regulating the pro-apoptosis genes Fas, Caspase 8, Jun, and CDKN1A; the antiproliferation gene FGFR; and the anti-invasion gene HTATIP2. PCDH10 methylation was detected in 82% (85 of 104) of gastric tumors compared with 37% (38 of 104) of paired nontumor tissues (P < .0001). In the latter, PCDH10 methylation was higher in precancerous lesions (27 of 45; 60%) than in chronic gastritis samples (11 of 59; 19%) (P < .0001). After a median follow-up period of 16.8 months, multivariate analysis revealed that patients with PCDH10 methylation in adjacent nontumor areas had a significant decrease in overall survival. Kaplan-Meier survival curves showed that PCDH10 methylation was associated significantly with shortened survival in stage I-III gastric cancer patients. PCDH10 is a gastric tumor suppressor; its methylation at early stages of gastric carcinogenesis is an independent prognostic factor.


Paclitaxel delivery from cobalt-chromium alloy surfaces using self-assembled monolayers.
Polymer-based platforms in drug-eluting stents (DESs) can cause adverse reactions in patients. Hence, the development of a polymer-free drug delivery platform may reduce adverse reactions to DES. In this study, the use of a polymer-free platform, self-assembled monolayers (SAMs), is explored for delivering an antiproliferative drug [paclitaxel (PAT)] from a stent material [cobalt-chromium ((Co-Cr) alloy]. Initially, carboxylic acid terminated phosphonic acid SAMs were coated on Co-Cr alloy. Two different doses (25 and 100 μg/cm²) of PAT were coated on SAM coated Co-Cr surfaces using a microdrop deposition method. Also, control experiments were carried out to coat PAT directly on Co-Cr surfaces with no SAM modification. The PAT coated specimens were characterized using the Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and atomic force microscopy (AFM). FTIR spectra showed the successful deposition of PAT on SAM coated and control-Co-Cr surfaces. SEM images showed islands of high density PAT crystals on SAM coated surfaces, while low density PAT crystals were observed on control-Co-Cr alloy. AFM images showed molecular distribution of PAT on SAM coated as well as control-Co-Cr alloy surfaces. In vitro drug release studies showed that PAT was released from SAM coated Co-Cr surfaces in a biphasic manner (an initial burst release in first 7 days was followed by a slow release for up to 35 days), while the PAT was burst released from control-Co-Cr surfaces within 1-3 days. Thus, this study demonstrated the use of SAMs for delivering PAT from Co-Cr alloy surfaces for potential use in drug-eluting stents.


Dermatological problems of onchocerciasis in Nebbi District, Uganda.
A cross-sectional survey of 770 subjects in onchocerciasis hyperendemic villages and 223 subjects from a control community in Nebbi District in the West Nile region of Uganda revealed a high prevalence of onchocercal skin disease of 48% in endemic villages. The most common skin problem was troublesome itching (40%); and the prevalent skin lesions were chronic papular onchodermatitis (16%), depigmentation (4%), lichenified onchodermatitis (2%) and acute papular onchodermatitis (1%). Other typical varieties of onchocercal skin diseases such as, hanging groin, lymphoedema and marked lymphadenopathy were infrequent, and considered rare. Pityriasis vergicolor was the most common non-onchocercal skin lesion in both control and endemic communities, accounting for 37% of all non-onchocercal skin lesions. These skin lesions were associated with a variety of psycho-social and economic impact; and there was a positive correlation between the prevalence of troublesome itching and the prevalence of modules (correlation coefficient r = 0.62, p = 0.00). Given the prospects of onchocerciasis control based on mass ivermectin distribution in communities where blindness is common, we recommend that treatment be extended to communities where blindness is less common, but skin disease known to be predominant.


The Impact of High-Level Isolation Units Beyond High-Consequence Pathogen Preparedness.
In response to the 2014 Ebola outbreak, the Office of the Assistant Secretary for Preparedness and Response (ASPR) funded the creation of 10 Regional Ebola and Other Special Pathogen Treatment Centers (RESPTCs) across the United States. These high-level isolation units are designed to provide care for patients infected with high-consequence pathogens, such as viral hemorrhagic fevers, in an environment that is safe for patients, staff, the hospital, and surrounding communities. This commentary describes the impact on infection prevention and preparedness that the Johns Hopkins biocontainment unit has on the hospital and health system beyond the unit itself. Training, research projects, and collaborative partnerships conducted by a high-level isolation unit team while the unit is not activated for patient care can enhance infection prevention, multidisciplinary training and innovation, personal protective equipment design and testing, clinical skills, and infection prevention beyond the isolation setting.


Identification of SHANK2 Pathogenic Variants in a Chinese Uygur Population with Schizophrenia.
Genomic studies on schizophrenia (SCZ) have revealed several candidate genes involved in excitatory synapse function and plasticity associated with its etiology. SHANK2 is a postsynaptic scaffolding protein, which anchors a protein complex connecting NMDAR, AMPAR, and mGluR receptors at excitatory neuronal synapses. Mutations in the SHANK2 gene have been reported to be associated with human autism spectrum disorders (ASDs) and SCZ. To identify variants in the SHANK2 gene and determine the association of SHANK2 with SCZ in the Chinese Uygur population, we conducted targeted sequencing of whole exon regions and exon-intron boundaries of SHANK2 in 1574 SCZ patients and 1481 healthy controls. A total of 149 variants were identified, including six common variants and 143 rare variants. For common variants, rs62622853 and rs3924047 showed allelic significance with SCZ before correction, but the association was eliminated after Bonferroni correction. Seven rare nonsynonymous variants, p.Arg739Trp, p.Pro807Leu, p.Ile854Phe, p.Thr1322Ser, p.Leu1434Arg, p.Val1486Ile, and p.Thr1674Met, occurred only in the patients but not in any of the healthy controls. In silico analysis predicted that p.Arg739Trp, p.Leu1434Arg, and p.Val1486Ile variants are likely to be damaging. The present study suggests that individuals with two novel rare nonsynonymous variants (p.Arg739Trp, p.Leu1434Arg) and p.Val1486Ile variants of SHANK2 might increase the susceptibility to developing SCZ disorder.


Severe intravascular hemolysis after triple valve replacement: cure by replacement of aortic and mitral valves with porcine xenografts.
A case report of a patient with a triple cardiac valve replacement complicated by severe postoperative intravascular hemolysis is presented. The patient had neither prosthetic valvular dysfunction nor paravalvular leak and had an excellent hemodynamic response to the operation. Despite intensive medical management, the patient required transfusions of 500 ml of blood every 3 weeks. Replacement of the aortic and mitral prostheses with porcine xenografts alleviated the problem. When a patient requires triple valve replacement, the use of homograft or heterograft valves should be seriously considered as a means of minimizing this potential complication.


Floor and Ceiling Effects, Time to Completion, and Question Burden of PROMIS CAT Domains Among Shoulder and Knee Patients Undergoing Nonoperative and Operative Treatment.
The Patient-Reported Outcomes Measurement Information System (PROMIS) computer adaptive tests (CATs) have emerged as an efficient technique for measuring patient-reported outcomes among orthopaedic patients. The purpose of this study was to investigate the floor and ceiling (F/C) effects, time to completion (TTC), and question burden of PROMIS CATs administered to patients presenting to a shoulder and sports medicine orthopaedic clinic. Patients prospectively completed PROMIS CATs including the physical function (PROMIS-PF) or upper-extremity function (PROMIS-UE), pain interference (PROMIS-PI), and depression (PROMIS-D) domains at their initial encounter and were retrospectively included in this study. Adult patients indicating a single problem involving either the shoulder or knee were included. Patients were also grouped as either preoperative or nonoperative. F/C effects were defined as the proportion of respondents scoring the highest (ceiling) or lowest (floor) possible score across a given domain. Included were 2,952 patients (average age, 51.0 ± 16.9 years). The PROMIS-UE, PROMIS-PF, and PROMIS-PI demonstrated negligible F/C effects across all shoulder and knee patients (<2%). The PROMIS-D displayed moderate to significant floor effects (13.9% to 18.9%) and a 0% ceiling effect in all main patient groups. The mean TTC and mean question burden of the PROMIS-UE, PROMIS-PF, and PROMIS-PI ranged from 45.3 to 54.4 seconds and 4.1 to 4.9 questions for all patient groups, while the PROMIS-D exhibited a TTC ranging from 20.9 to 38.6 seconds for all groups and a question burden that ranged from 6.2 to 6.7 questions. The PROMIS-PF, PROMIS-UE, and PROMIS-PI demonstrated favorable F/C effects, TTC, and question burden among both nonoperative and preoperative patients. These findings justify consideration of the PROMIS-PF, PROMIS-UE, and PROMIS-PI for clinical and research applications involving shoulder and knee sports medicine patients. Additionally, we found moderate to significant floor effects for the PROMIS-D in all patient groups, which may be multifactorial in nature and may not be unexpected in patients with an isolated joint concern. This study highlights the psychometric properties of PROMIS CAT forms for knee and shoulder patients. Understanding these basic properties is important in considering the adoption of PROMIS CAT forms for patients with musculoskeletal conditions.


Gut Microbiota Profile and Changes in Body Weight in Elderly Subjects with Overweight/Obesity and Metabolic Syndrome.
Gut microbiota is essential for the development of obesity and related comorbidities. However, studies describing the association between specific bacteria and obesity or weight loss reported discordant results. The present observational study, conducted within the frame of the PREDIMED-Plus clinical trial, aims to assess the association between fecal microbiota, body composition and weight loss, in response to a 12-month lifestyle intervention in a subsample of 372 individuals (age 55-75) with overweight/obesity and metabolic syndrome. Participants were stratified by tertiles of baseline body mass index (BMI) and changes in body weight after 12-month intervention. General assessments, anthropometry and biochemical measurements, and stool samples were collected. 16S amplicon sequencing was performed on bacterial DNA extracted from stool samples and microbiota analyzed. Differential abundance analysis showed an enrichment of Prevotella 9, Lachnospiraceae UCG-001 and Bacteroides, associated with a higher weight loss after 12-month of follow-up, whereas in the cross-sectional analysis, Prevotella 2 and Bacteroides were enriched in the lowest tertile of baseline BMI. Our findings suggest that fecal microbiota plays an important role in the control of body weight, supporting specific genera as potential target in personalized nutrition for obesity management. A more in-depth taxonomic identification method and the need of metabolic information encourages to further investigation.


Ethanol effects in an anxiety/defense test battery.
Two tests, components of an Anxiety/Defense Test Battery, have been designed to measure risk assessment, inhibition of nondefensive behaviors, and movement arrest, all of which occur in the natural defense patterns of rats to threatening stimuli. In these tests, which used a nonpainful threat stimulus (a cat), ethanol (0.6 and 1.2 g/kg) increased two risk assessment behaviors on an initial test day, and produced a wider pattern of changes in all three patterns on a retest (no cat) day, 5 days later. The pattern of results obtained is compatible with a view that defensive behaviors occur in a fixed sequence with the decreasing intensity of threat an important factor in the transition from one defensive behavior to the next, and with ethanol at these doses producing a mild and relatively nonspecific anxiolytic effect. Comparison of male and female subjects on these tasks also suggested that females are more defensive than males, a finding which agrees with a variety of human anxiety studies but is at variance with previous rodent literature.


Biosynthesis of long-chain alcohols by developing and regenerating rat sciatic nerve.
Cell-free preparations of rat sciatic nerve were found to catalyze the reduction of fatty acid to alcohol in the presence of NADPH as reducing cofactor. The reductase was membrane-bound and associated primarily with the microsomal fraction. When fatty acid was the substrate, ATP, coenzyme A (CoA), and Mg2+ were required, indicating the formation of acyl CoA prior to reduction. When acyl CoA was used as substrate, the presence of albumin was required to inhibit acyl CoA hydrolase activity. Fatty acid reductase activity was highest with palmitic and stearic acids, and somewhat lower with lauric and myristic acids. It was inhibited by sulfhydryl reagents, indicating the participation of thiol groups in the reduction. Only traces of long-chain aldehyde could be detected or trapped as semicarbazone. Fatty acid reductase activity in rat sciatic nerve was highest between the second and tenth days after birth and decreased substantially thereafter. Microsomal preparations of sciatic nerve from 10-day-old rats exhibited about four times higher fatty acid reductase activity than brain or spinal cord microsomes from the same animals. Wallerian degeneration and regeneration of adult rat sciatic nerve resulted in enhanced fatty acid reductase activity, which reached a maximum at about 12 days after crush injury.


Poliovirus crystals within the endoplasmic reticulum of endothelial and mononuclear cells in the monkey spinal cord.
The lumbar motor columns of a cynomolgus monkey that had become tetraplegic after experimental infection with a highly virulent strain of type 3 poliovirus were examined by electron microscopy. Crystalline aggregates of poliovirus occurred within the endoplasmic reticulum of endothelial cells as well as of mononuclear inflammatory cells. This finding suggests that the endoplasmic reticulum might be much more involved in poliovirus multiplication than has been previously supposed.


Problems and pointers in osteochondrosis: Twenty years on.
Twenty years ago a supplement of Equine Veterinary Journal was devoted to equine osteochondrosis (OC) and recognised the importance of this developmental disease to the equine industry. In the accompanying editorial several controversial issues were identified and a number of areas for further research were highlighted. Today, equine OC is still a major clinical problem, but the on-going research has resulted in much improved knowledge and understanding of this highly complicated disease. There is still conflicting evidence on the prevalence of OC due to the dynamic character of the condition, widely varying definitions in the literature, and the range of joints affected. Nevertheless there is now convincing evidence that early vascular damage, leading to chondronecrosis, is the major mechanism of onset. The aetiological factors that determine whether a horse will develop clinical signs of OC remain obscure and the complex nature of OC and its multi-factorial character has been clearly demonstrated by genetic studies. These have shown a multitude of loci on a variety of chromosomes linked to osteochondrotic phenotypes, depending on the type of manifestation of OC, the joint involved and the breed. The controversy surrounding the possible key role of copper in the pathogenesis of OC in the early 1990s has evolved into a more limited contribution to repair thus making it just one of the many environmental factors that may have an effect on the occurrence of OC, but not a decisive one. The semantic debate concerning the most appropriate nomenclature seems to have crystallised into a consensus on terminology at three levels: OC or osteochondritis dissecans (OCD) for the disturbance in the process of endochondral ossification, juvenile ostechondral conditions (JOCC) for all joint and growth plate related disorders, and developmental orthopaedic diseases (DOD) for the full range of skeletal conditions in young horses. Future progress in improved management of OC can be expected from more research on cellular and molecular processes and the influences that determine the process of endochondral ossification, the process of articular cartilage maturation, and from epidemiological studies quantifying the long-term effects of OC on health and performance.


Solvent-promoted catalyst-free regioselective N-incorporation multicomponent domino reaction: rapid assembly of π-functionalized [60]fullerene-fused dihydrocarbolines.
Described here is the first example of solvent-promoted catalyst-free N-incorporation multicomponent domino reaction for the direct construction of novel π-extension [60]fullerene-fused dihydrocarbolines from simple hydrocarbons. This unprecedented transformation is proposed to proceed by a sequential N-incorporation/[4+2] cycloaddition/elimination process, involving multiple types of bond cleavage and formation in a single chemical operation. Mechanistic studies uncover that solvent is crucial for the success of the transformation, and multiple solvent-aided deprotonation and proton transfer are involved as key steps.


Three dimensional vestibular ocular reflex testing using a six degrees of freedom motion platform.
The vestibular organ is a sensor that measures angular and linear accelerations with six degrees of freedom (6DF). Complete or partial defects in the vestibular organ results in mild to severe equilibrium problems, such as vertigo, dizziness, oscillopsia, gait unsteadiness nausea and/or vomiting. A good and frequently used measure to quantify gaze stabilization is the gain, which is defined as the magnitude of compensatory eye movements with respect to imposed head movements. To test vestibular function more fully one has to realize that 3D VOR ideally generates compensatory ocular rotations not only with a magnitude (gain) equal and opposite to the head rotation but also about an axis that is co-linear with the head rotation axis (alignment). Abnormal vestibular function thus results in changes in gain and changes in alignment of the 3D VOR response. Here we describe a method to measure 3D VOR using whole body rotation on a 6DF motion platform. Although the method also allows testing translation VOR responses (1), we limit ourselves to a discussion of the method to measure 3D angular VOR. In addition, we restrict ourselves here to description of data collected in healthy subjects in response to angular sinusoidal and impulse stimulation. Subjects are sitting upright and receive whole-body small amplitude sinusoidal and constant acceleration impulses. Sinusoidal stimuli (f = 1 Hz, A = 4°) were delivered about the vertical axis and about axes in the horizontal plane varying between roll and pitch at increments of 22.5° in azimuth. Impulses were delivered in yaw, roll and pitch and in the vertical canal planes. Eye movements were measured using the scleral search coil technique (2). Search coil signals were sampled at a frequency of 1 kHz. The input-output ratio (gain) and misalignment (co-linearity) of the 3D VOR were calculated from the eye coil signals (3). Gain and co-linearity of 3D VOR depended on the orientation of the stimulus axis. Systematic deviations were found in particular during horizontal axis stimulation. In the light the eye rotation axis was properly aligned with the stimulus axis at orientations 0° and 90° azimuth, but gradually deviated more and more towards 45° azimuth. The systematic deviations in misalignment for intermediate axes can be explained by a low gain for torsion (X-axis or roll-axis rotation) and a high gain for vertical eye movements (Y-axis or pitch-axis rotation (see Figure 2). Because intermediate axis stimulation leads a compensatory response based on vector summation of the individual eye rotation components, the net response axis will deviate because the gain for X- and Y-axis are different. In darkness the gain of all eye rotation components had lower values. The result was that the misalignment in darkness and for impulses had different peaks and troughs than in the light: its minimum value was reached for pitch axis stimulation and its maximum for roll axis stimulation. Nine subjects participated in the experiment. All subjects gave their informed consent. The experimental procedure was approved by the Medical Ethics Committee of Erasmus University Medical Center and adhered to the Declaration of Helsinki for research involving human subjects. Six subjects served as controls. Three subjects had a unilateral vestibular impairment due to a vestibular schwannoma. The age of control subjects (six males and three females) ranged from 22 to 55 years. None of the controls had visual or vestibular complaints due to neurological, cardio vascular and ophthalmic disorders. The age of the patients with schwannoma varied between 44 and 64 years (two males and one female). All schwannoma subjects were under medical surveillance and/or had received treatment by a multidisciplinary team consisting of an othorhinolaryngologist and a neurosurgeon of the Erasmus University Medical Center. Tested patients all had a right side vestibular schwannoma and underwent a wait and watch policy (Table 1; subjects N1-N3) after being diagnosed with vestibular schwannoma. Their tumors had been stabile for over 8-10 years on magnetic resonance imaging.


Silicon supply modifies C:N:P stoichiometry and growth of Phragmites australis.
Silicon is a non-essential element for plant growth. Nevertheless, it affects plant stress resistance and in some plants, such as grasses, it may substitute carbon (C) compounds in cell walls, thereby influencing C allocation patterns and biomass production. How variation in silicon supply over a narrow range affects nitrogen (N) and phosphorus (P) uptake by plants has also been investigated in some detail. However, little is known about effects on the stoichiometric relationships between C, N and P when silicon supply varies over a broader range. Here, we assessed the effect of silicon on aboveground biomass production and C:N:P stoichiometry of common reed, Phragmites australis, in a pot experiment in which three widely differing levels of silicon were supplied. Scanning electron microscopy (SEM) showed that elevated silicon supply promoted silica deposition in the epidermis of Phragmites leaves. This resulted in altered N:P ratios, whereas C:N ratios changed only slightly. Plant growth was slightly (but not significantly) enhanced at intermediate silicon supply levels but significantly decreased at high levels. These findings point to the potential of silicon to impact plant growth and elemental stoichiometry and, by extension, to affect biogeochemical cycles in ecosystems dominated by Phragmites and other grasses and sedges.


Raynaud's Phenomenon after COVID-19 Vaccination: Causative Association, Temporal Connection, or Mere Bystander?
Herein, we report a case of a new-onset Raynaud's phenomenon (RP), which occurred in an otherwise healthy 31-year-old Caucasian woman, who lacked any known risk factors and associations with possible causes for secondary RP. However, 2 weeks prior to the development of RP, the patient had received her first injection of the COVID-19 vaccine containing ChAdOx1-SARS-COV-2. The patient presented with well-demarcated, white-pale, cold areas involving the middle fingers of both hands and the ring finger of the right hand, which were triggered by exposure to cold environment and accompanied by a sensation of numbness. Infrared thermography revealed notable temperature differences of up to 10.9°C between affected and nonaffected fingers. Coagulation and immunological parameters, including cryoglobulins and pathological autoantibodies, were within the normal range and antibodies to the heparin/platelet factor 4 complex not detectable. It remains unclear if the development of RP in our patient is causally related to antecedent COVID-19 vaccination; however, the temporal connection to the vaccination, the complete absence of RP in her past medical history, and the lack of any risk factors and triggers raise the suspicion of a yet unknown association with the vaccine. Whether a clear association between the development of RP and COVID-19 vaccination exists or whether RP represents a bystander effect needs to be awaited in case observational reports on RP accumulate. Given the steadily rising numbers of people receiving COVID-19 vaccinations, physicians may remain alert to still unrecognized side effects.


[Analysis of the nutritional state of school children in different districts of the province of Granada (Spain)].
In Spain the prevalence of obesity shows a north-south distribution. In the province of Granada its distribution is unknown. (1) To study the prevalence of overweight and obesity in a sample population of school children and adolescents from different districts in the province of Granada. (2) To verify whether there are significant differences, depending on the district where the students reside. (3) To find a possible correlation between the nutritional state of the students and that of their parents. The population sample was composed of 977 school children and adolescents from 9 to 17 years of age, attending 13 public elementary schools and high schools in the city and province of Granada (Spain). In this analytical and multicentric study, the nutritional state of the subjects was evaluated by means of anthropometric measurements. Furthermore, data were collected by means of questionnaire to discover whether the respondents had a family history of overweight or obesity. We found a high prevalence of overweight and obesity among the studied population. In girls, the greater prevalence of both overweight and obesity ranged from 12 to 14 years of age. In boys, there was an increase in the prevalence of overweight at twelve years of age. Regarding obesity, their rates were significantly lower than those described among girls. There were statistically significant differences for weight (F = 4,154; p = 0,003) but not for height (F = 1,928; p =0,105). But for the variable BMI was statistically significant difference (F = 5.037; P < 0.001) between the studied geographical areas. The results showed that the nutritional state of students with a family history of obesity was significantly worse (p < 0.01). A high prevalence of obesity was found in the sample, especially among the girls. There exists a geographical distribution pattern, possibly derived from the socioeconomic characteristics of each area in the province. The existence of a family history of obesity is an important factor that can determine whether the child will also become obese in the future.


Serum levels of leptin as marker for patients at high risk of gastric cancer.
Serological screening for gastric cancer (GC) may reduce mortality. However, optimal serum markers for advanced gastric precursor lesions are lacking. To evaluate in a case-control study whether serum leptin levels correlate with intestinal metaplasia (IM) and can serve as a tool to identify patients at high risk for GC. Cases were patients with a previous diagnosis of IM or dysplasia, controls were patients without such a diagnosis. All patients underwent endoscopy. Fasting serum was collected for the measurement of leptin, pepsinogens I/II, gastrin, and Helicobacter pylori. Receiver operating characteristic (ROC) curves and their area under the curve (AUC) were provided to compare serum leptin levels with other serological markers. One hundred nineteen cases and 98 controls were included. In cases, the median leptin levels were 116.6 pg/mL versus 81.9 pg/mL in controls (p = .01). After adjustment for age, sex and BMI, leptin levels remained higher in cases than in controls (p < .005). In multivariate analysis, male sex (p = .002), age (<0.001), low pepsinogen levels (p = .004) and high leptin levels (p = .04) were independent markers for the presence of IM. In addition, a ROC curve including age, sex and pepsinogen I levels had an AUC of 0.79 (95% CI (0.73-0.85)). Adding serum leptin levels increased the AUC to 0.81 (95% CI (0.75-0.86)). High leptin levels are associated with an increased risk of IM. Moreover, serum leptin levels are a significant independent marker for the presence of IM. However, in combination with the serological test for pepsinogen I the additional value of serum leptin levels is rather limited.


A Preliminary Experience of Integration of an Electronic Witness System, its Validation, Efficacy on Lab Performance, and Staff Satisfaction Assessment in a Busy Indian in vitro Fertilization Laboratory.
Electronic witness system (EWS) is one of the recent advancements in the field of in vitro fertilization (IVF) that uses radiofrequency identification (RFID) technology to monitor all critical work carried out in each stage of IVF procedures cycle. The main objective of the study was validation and integration of electronic witnessing system, assessment of its efficacy on lab performance, and staff satisfaction in a busy tertiary IVF center. The study data included analysis of 187 consecutive cycles for installation and validation of EWS. The laboratory outcomes were analyzed for development of good-quality embryos followed up for the pregnancy outcome. A total of 751 RFIG tags were involved with 77 patient-assigned barcodes for the all the analyzed cycles. During validation of EWS, a total of 02 (0.46%) red flags were highlighted by EWS from pre-allocated tags within the frequency range of the reader. The maturation rate (83.1%), fertilization rate (74.3%), cleavage rate (93.5%), day 3 grade-A embryo development rate (64.6%), good grade blastocyst development rate (26.4%) were observed in EWS group that was comparable to other groups with no significant difference (P > 0.005). Frozen embryo transfer of EWS cases observed a clinical pregnancy rate (50.0%) that was higher than other groups though statistically not significant as sample size was small. Our preliminary study suggests that EWS does not affect the gametes, embryos, and pregnancy rate, however a larger randomized clinical trials should be undertaken to evaluate the safety and efficacy of EWS.


Cardiovascular surgery during the first wave of COVID-19 pandemic.
In this study, we aimed to evaluate primary outcomes and main characteristics of emergency and elective/urgent cardiovascular surgeries which were performed in the first three months of the novel coronavirus disease 2019 (COVID-19) pandemic in our center. Between March 11th, 2020 and June 11th, 2020, a total of 209 patients (44 males, 165 females; mean age: 57.3±12.8 years; range, 20 to 80 years) who underwent emergency or elective/urgent surgery with cardiovascular pathologies were retrospectively analyzed. The patients were classified as emergency and elective/urgent according to the level of necessity of the surgical procedure at the time of hospital admission. Pre-, intra-, and postoperative data of the patients were recorded. During the study period, 156 elective/urgent and 74 emergency cardiovascular surgeries were performed. Six COVID-19 (+) patients were operated emergently. The number of acute aortic dissection and peripheral vascular surgery was higher in the emergency group (p<0.05). Two patients who were COVID-19 (-) preoperatively became COVID-19 (+) in the postoperative period. In these patients, acute respiratory distress syndrome developed, and extracorporeal membrane oxygenation support was needed. Four patients who needed post-cardiotomy extracorporeal membrane oxygenation support due to low cardiac output were COVID-19 (-) both in the pre- and postoperative periods. The overall in-hospital mortality rate was 9.1%. Even during pandemic such as COVID-19, referral centers with experienced personnel can provide non-pandemic healthcare with a quality close to the daily routine.


LASP-1: a nuclear hub for the UHRF1-DNMT1-G9a-Snail1 complex.
Nuclear LASP-1 (LIM and SH3 protein-1) has a direct correlation with overall survival of breast cancer patients. In this study, immunohistochemical analysis of a human breast TMA showed that LASP-1 is absent in normal human breast epithelium but the expression increases with malignancy and is highly nuclear in aggressive breast cancer. We investigated whether the chemokines and growth factors present in the tumor microenvironment could trigger nuclear translocation of LASP-1.Treatment of human breast cancer cells with CXCL12, EGF and HRG, and HMEC-CXCR2 cells with CXCL8 facilitated nuclear shuttling of LASP-1. Data from the biochemical analysis of the nuclear and cytosolic fractions further confirmed the nuclear translocation of LASP-1 upon chemokine and growth factor treatment. CXCL12-dependent nuclear import of LASP-1 could be blocked by CXCR4 antagonist, AMD-3100. Knock down of LASP-1 resulted in alterations in gene expression leading to an increased level of cell-junction and extracellular matrix proteins and an altered cytokine secretory profile. Three-dimensional cultures of human breast cancer cells on Matrigel revealed an altered colony growth, morphology and arborization pattern in LASP-1 knockdown cells. Functional analysis of the LASP-1 knockdown cells revealed increased adhesion to collagen IV and decreased invasion through the Matrigel. Proteomic analysis of immunoprecipitates of LASP-1 and subsequent validation approaches revealed that LASP-1 associated with the epigenetic machinery especially UHRF1, DNMT1, G9a and the transcription factor Snail1. Interestingly, LASP-1 associated with UHRF1, G9a, Snail1 and di- and tri-methylated histoneH3 in a CXCL12-dependent manner based on immunoprecipitation and proximity ligation assays. LASP-1 also directly bound to Snail1 which may stabilize Snail1. Thus, nuclear LASP-1 appears to functionally serve as a hub for the epigenetic machinery.


Divergent and Synergistic Photocatalysis: Hydro- and Oxoalkylation of Vinyl Arenes for the Stereoselective Synthesis of Cyclopentanols via a Formal [4+1]-Annulation of 1,3-Dicarbonyls.
The controllable divergent reactivity of 1,3-dicarbonyls is described, which enables the efficient hydro- and oxoalkylation of vinyl arenes. Both reaction pathways are initiated through the formation of polarity-reversed C-centered-radical intermediates at the active methylene center of 1,3-dicarbonyls via direct photocatalytic C-H bond transformations. The oxoalkylation of alkenes is achieved under aerobic conditions via a Cu(II)-photomediated rebound mechanism, while the corresponding hydroalkylation becomes possible under a nitrogen atmosphere by the combination of 4CzIPN and a Brønsted base. The breadth of these divergent protocols is demonstrated in the late-stage modification of drugs and natural products and by the transformation of the products to a variety of heterocycles such as pyridines, pyrroles, or furans. Moreover, the two catalytic modes can be combined synergistically for the stereoselective construction of cyclopentanol derivatives in a formal [4+1]-annulation process.


Designing a cultural competency curriculum: asking the stakeholders.
The design of a cultural competency curriculum can be challenging. The 2002 Institute of Medicine report, Unequal Treatment, challenged medical schools to integrate cross-cultural education into the training of all current and future health professionals. However, there is no current consensus on how to do this. The Department of Native Hawaiian Health at the John A. Burns School of Medicine formed a Cultural Competency Curriculum Development team that was charged with developing a curriculum for the medical school to address Native Hawaiian health disparities. By addressing cultural competency training of physicians, the team is hoping to help decrease the health disparities found in Native Hawaiians. Prior attempts to address culture at the time consisted of conferences sponsored by the Native Hawaiian Center of Excellence for faculty and clinicians and Problem Based Learning cases that have imbedded cultural issues. Gather ideas from focus groups of Native Hawaiian stake- holders. The stakeholders consisted of Native Hawaiian medical students, patients and physicians. Information from the focus groups would be incorporated into a medical school curriculum addressing Native Hawaiian health and cultural competency training. Focus groups were held with Native Hawaiian medical students, patients and physicians in the summer and fall of 2006. Institutional Review Board approval was obtained from the University of Hawaii as well as the Native Hawaiian Health Care Systems. Qualitative analysis of tape recorded data was performed by looking for recurrent themes. Primary themes and secondary themes were ascertained based on the number of participants mentioning the topic. Amongst all three groups, cultural sensitivity training was either a primary theme or secondary theme. Primary themes were mentioned by all students, by 80% of the physicians and were mentioned in all 4 patient groups. Secondary themes were mentioned by 75% of students, 50% of the physicians and by 75% of patient group. All groups wanted medical students to receive cultural sensitivity training, and all wanted traditional healing to be included in the training. The content of the training differed slightly between groups. Students wanted a diversity of teaching modalities as well as cultural issues in exams in order to emphasize their importance. They also felt that faculty needed cultural competency training. Patients wanted students to learn about the host culture and its values. Physicians felt that personal transformation was an important and effective tool in cultural sensitivity training. Cultural immersion is a potential teaching tool but physicians were concerned about student stages of readiness and adequate preparation for cultural competency training modalities such as cultural immersion. Cultural competency or sensitivity training was important to patients, students and physicians. The focus group data is being used to help guide the development of the Department of Native Hawaiian Health's cultural competency curriculum.


Highly Efficient Photoelectrochemical Water Splitting with an Immobilized Molecular Co4 O4 Cubane Catalyst.
Molecular Co4 O4 cubane water oxidation catalysts were combined with BiVO4 electrodes for photoelectrochemical (PEC) water splitting. The results show that tuning the substituent groups on cobalt cubane allows the PEC properties of the final molecular catalyst/BiVO4 hybrid photoanodes to be tailored. Upon loading a new cubane complex featuring alkoxy carboxylato bridging ligands (1 h) on BiVO4 , an AM 1.5G photocurrent density of 5 mA cm-2 at 1.23 V vs. RHE for water oxidation was obtained, the highest photocurrent for undoped BiVO4 photoanodes. A high solar-energy conversion efficiency of 1.84 % was obtained for the integrated photoanode, a sixfold enhancement over that of unmodified BiVO4 . These results and the high surface charge separation efficiency support the role of surface-modified molecular catalysts in improving PEC performance and demonstrate the potential of molecule/semiconductor hybrids for efficient artificial photosynthesis.


Single-Fraction Spine Stereotactic Body Radiation Therapy for the Treatment of Chordoma.
Chordoma is a radioresistant tumor that presents a therapeutic challenge with spine involvement, as high doses of radiation are needed for local control while limiting dose to the spinal cord. The purpose of this study is to determine the efficacy and safety of single-fraction spine stereotactic body radiation therapy for the treatment of spine chordoma. A retrospective review of our institutional database from 2006 to 2013 identified 8 patients (12 cases) with chordoma of the spine who were treated with spine stereotactic body radiation therapy. Surgical resection was performed in 7 of the 12 cases. The treatment volume was defined by the bony vertebral level of the tumor along with soft tissue extension appreciated on magnetic resonance imaging fusion. Medical records and imaging were assessed for pain relief and local control. Treatment toxicity was evaluated using Common Terminology Criteria for Adverse Events version 4.0. Median age was 59 years (range, 17-91). Median target volume was 48 cm3 (1-304), and median prescription dose was 16 Gy (11-16). Median conformality index was 1.44 (1.14-3.21), and homogeneity index was 1.12 (1.05-1.19). With a median follow-up time of 9.7 months (.5-84), local control was achieved in 75% of the cases treated. One patient developed limited grade 2 spinal cord myelopathy that resolved with steroids. There were no other treatment toxicities from spine stereotactic body radiation therapy. Single-fraction spine stereotactic body radiation therapy can be safely delivered to treat chordoma of the spine with the potential to improve pain symptoms. Although the early data are suggestive, long-term follow-up with more patients is necessary to determine the efficacy of spine stereotactic body radiation therapy in the treatment of chordoma of the spine.


Outstanding impact of soil tillage on the abundance of soil hydrolases revealed by a metagenomic approach.
The soil represents the main source of novel biocatalysts and biomolecules of industrial relevance. We searched for hydrolases in silico in four shotgun metagenomes (4,079,223 sequences) obtained in a 13-year field trial carried out in southern Brazil, under the no-tillage (NT), or conventional tillage (CT) managements, with crop succession (CS, soybean/wheat), or crop rotation (CR, soybean/maize/wheat/lupine/oat). We identified 42,631 hydrolases belonging to five classes by comparing with the KEGG database, and 44,928 sequences by comparing with the NCBI-NR database. The abundance followed the order: lipases>laccases>cellulases>proteases>amylases>pectinases. Statistically significant differences were attributed to the tillage system, with the NT showing about five times more hydrolases than the CT system. The outstanding differences can be attributed to the management of crop residues, left on the soil surface in the NT, and mechanically broken and incorporated into the soil in the CT. Differences between the CS and the CR were slighter, 10% higher for the CS, but not statistically different. Most of the sequences belonged to fungi (Verticillium, and Colletotrichum for lipases and laccases, and Aspergillus for proteases), and to the archaea Sulfolobus acidocaldarius for amylases. Our results indicate that agricultural soils under conservative managements may represent a hotspot for bioprospection of hydrolases.


Loss of allosteric control but retention of the bifunctional catalytic competence of a fusion protein formed by excision of 260 base pairs from the 3' terminus of pheA from Erwinia herbicola.
A bifunctional protein denoted as the P protein and encoded by pheA is widely present in purple gram-negative bacteria. This P protein carries catalytic domains that specify chorismate mutase (CM-P) and prephenate dehydratase. The instability of a recombinant plasmid carrying a pheA insert cloned from Erwinia herbicola resulted in a loss of 260 bp plus the TAA stop codon from the 3' terminus of pheA. The plasmid carrying the truncated pheA gene (denoted pheA*) was able to complement an Escherichia coli pheA auxotroph. pheA* was shown to be a chimera composed of the residual 5' part of pheA (901 bp) and a 5-bp fragment from the pUC18 vector. The new fusion protein (PheA*) retained both chorismate mutase and prephenate dehydratase activities. PheA* had a calculated subunit molecular weight of 33,574, in comparison to the 43,182-molecular-weight subunit size of PheA. The deletion did not affect the ability of PheA* to assume the native dimeric configuration of PheA. Both the CM-P and prephenate dehydratase components of PheA* were insensitive to L-phenylalanine inhibition, in contrast to the corresponding components of PheA. L-Phenylalanine protected both catalytic activities of PheA from thermal inactivation, and this protective effect of L-phenylalanine upon the PheA* activities was lost. PheA* was more stable than PheA to thermal inactivation; this was more pronounced for prephenate dehydratase than for CM-P. In the presence of dithiothreitol, the differential resistance of PheA* prephenate dehydratase to thermal inactivation was particularly striking.(ABSTRACT TRUNCATED AT 250 WORDS)


Key factors for residency interview selection from the National Resident Matching Program: analysis of residency Program Director surveys, 2016-2020.
As the number of medical school graduates continues to outpace the available residency training positions, applying for residency in the United States has become a highly competitive process, often associated with a low rate of selection and invitation for interview. The National Resident Matching Program (NRMP) Program Director survey provides data assessing factors considered by Program Directors (PD) in selecting and inviting candidates for interview. Assessing the evolution of these factors over time is efficacious to inform and guide prospective applicants toward improving preparation for residency application. We aim to synthesize NRMP data showing factors that PDs reported and rated as important in their decision to select and invite applicants for interview. Data from residency PD surveys from 2008 to 2021 were accessed, but after applying inclusion/exclusion criteria, only the data from 2016 to 2020 were reviewed and analyzed. The NRMP survey reports provided two metrics that characterized PDs' evaluation of the residency factors for interview, namely, "percent citing factor" and "average rating" on a 0 to 5 Likert-type scale. These two metrics were combined into an aggregate measure of importance (AI), and another measure of relative importance (RI) was constructed from normalizing the AI of each individual factor to the sum of the AI within each survey year. The top ranked factors were United States Medical Licensing Examination (USMLE) Step 1/Comprehensive Osteopathic Medical Licensing Examination (COMLEX) Level 1, Letter of Recommendation (LOR) in the specialty, Medical Student Performance Evaluation (MSPE/Dean's Letter), and USMLE Step 2 Clinical Knowledge (CK)/COMLEX Level 2 Cognitive Exam (CE) score, any failed attempt in USMLE/COMLEX, and perceived commitment to specialty. Factors rising in importance were Audition Elective/Rotation Within Your Department, Personal Statement (PS), Perceived Commitment to Specialty, Perceived Interest in Program, LOR in the Specialty, Other Life Experience, and Personal Prior Knowledge of the Applicant. Factors with declining importance were Interest in Academic Career, Awards or Special Honors in Basic Sciences, Graduate of Highly Regarded US Medical School, Awards or Special Honors in Clinical Clerkships, Lack of Gaps in Medical Education, Awards or Special Honors in Clerkship in Desired Specialty, and Consistency of Grades. Compared to the 2021 PD survey, our findings show continued predictive consistency, particularly related to specialty and program commitment. The factors identified for the selection of medical school graduates for interview into a residency program reveal that PDs move toward a more integrated approach. Specifically, PDs are placing increasing emphasis on factors that border on subjective qualities more so than the more traditional, quantitative, and objective metrics. Medical students and educators need to continually apprise themselves of the NRMP data to inform students' preparation endeavors throughout medical school to strengthen their application portfolios and enhance their competitiveness for the matching process.


Common phenotypic and genotypic antimicrobial resistance patterns found in a case study of multiresistant E. coli from cohabitant pets, humans, and household surfaces.
The objective of the study described in this article was to characterize the antimicrobial resistance profiles among E. coli strains isolated from cohabitant pets and humans, evaluating the concurrent colonization of pets, owners, and home surfaces by bacteria carrying the same antimicrobial-resistant genes. The authors also intended to assess whether household surfaces and objects could contribute to the within-household antimicrobial-resistant gene diffusion between human and animal cohabitants. A total of 124 E. coli strains were isolated displaying 24 different phenotypic patterns with a remarkable percentage of multiresistant ones. The same resistance patterns were isolated from the dog's urine, mouth, the laundry floor, the refrigerator door, and the dog's food bowl. Some other multiresistant phenotypes, as long as resistant genes, were found repeatedly in different inhabitants and surfaces of the house. Direct, close contact between all the cohabitants and the touch of contaminated household surfaces and objects could be an explanation for these observations.


Lower mannose-binding lectin contributes to deleterious H1N1 2009 infection in children.
Mannose-binding lectin (MBL) has broad range of activity against viruses through the mechanisms of neutralization, opsonization, and complement activation. Prior studies have demonstrated that MBL inactivated the season's influenza virus. Due to the fact that children have no neutralizing antibody against H1N1 2009 virus, innate immunity may be crucial in the defense against influenza. Therefore, we studied whether MBL levels played a role in H1N1 2009 infection in children. In a prospective survey, we revealed that MBL levels in ICU influenza cases were significantly lower than in children with influenza from infection disease ward. MBL may be involved in innate immune responses to H1N1 2009 infection in children.


Nonhuman primate models of Alzheimer-like cerebral proteopathy.
Nonhuman primates are useful for the study of age-associated changes in the brain and behavior in a model that is biologically proximal to humans. The Aβ and tau proteins, two key players in the pathogenesis of Alzheimer's disease (AD), are highly homologous among primates. With age, all nonhuman primates analyzed to date develop senile (Aβ) plaques and cerebral β-amyloid angiopathy. In contrast, significant tauopathy is unusual in simians, and only humans manifest the profound tauopathy, neuronal degeneration and cognitive impairment that characterize Alzheimer's disease. Primates thus are somewhat paradoxical models of AD-like pathology; on the one hand, they are excellent models of normal aging and naturally occurring Aβ lesions, and they can be useful for testing diagnostic and therapeutic agents targeting aggregated forms of Aβ. On the other hand, the resistance of monkeys and apes to tauopathy and AD-related neurodegeneration, in the presence of substantial cerebral Aβ deposition, suggests that a comparative analysis of human and nonhuman primates could yield informative clues to the uniquely human predisposition to Alzheimer's disease.


A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them.
The basic route and mechanisms for leukocyte migration across the endothelium remain poorly defined. We provide definitive evidence for transcellular (i.e., through individual endothelial cells) diapedesis in vitro and demonstrate that virtually all, both para- and transcellular, diapedesis occurs in the context of a novel "cuplike" transmigratory structure. This endothelial structure was comprised of highly intercellular adhesion molecule-1- and vascular cell adhesion molecule-1-enriched vertical microvilli-like projections that surrounded transmigrating leukocytes and drove redistribution of their integrins into linear tracks oriented parallel to the direction of diapedesis. Disruption of projections was highly correlated with inhibition of transmigration. These findings suggest a novel mechanism, the "transmigratory cup", by which the endothelium provides directional guidance to leukocytes for extravasation.


Retention of high tactile acuity throughout the life span in blindness.
Previous studies of tactile acuity on the fingertip, using passive touch, have demonstrated an age-related decline in spatial resolution for both sighted and blind subjects. We have reexamined this age dependence with two newly designed tactile-acuity charts that require active exploration of the test symbols. One chart used dot patterns similar to braille, and the other used embossed Landolt rings. Groups of blind braille readers and sighted subjects ranging from 12 to 85 years old were tested in two experiments. We replicated previous findings for sighted subjects by showing an age-related decrease in tactile acuity by nearly 1% per year. Surprisingly, the blind subjects retained high acuity into old age, showing no age-related decline. For the blind subjects, tactile acuity did not correlate with braille reading speed, the amount of daily reading, or the age at which braille was learned. We conclude that when measured with active touch, blind subjects retain high tactile acuity into old age, unlike their aging sighted peers. We propose that blind people's use of active touch in daily activities, not specifically braille reading, results in preservation of tactile acuity across the life span.


Piperaquine: a resurgent antimalarial drug.
Piperaquine is a bisquinoline antimalarial drug that was first synthesised in the 1960s, and used extensively in China and Indochina as prophylaxis and treatment during the next 20 years. A number of Chinese research groups documented that it was at least as effective as, and better tolerated than, chloroquine against falciparum and vivax malaria, but no pharmacokinetic characterisation was undertaken. With the development of piperaquine-resistant strains of Plasmodium falciparum and the emergence of the artemisinin derivatives, its use declined during the 1980s. However, during the next decade, piperaquine was rediscovered by Chinese scientists as one of a number of compounds suitable for combination with an artemisinin derivative. The rationale for such artemisinin combination therapies (ACTs) was to provide an inexpensive, short-course treatment regimen with a high cure rate and good tolerability that would reduce transmission and protect against the development of parasite resistance. This approach has now been endorsed by the WHO. Piperaquine-based ACT began as China-Vietnam 4 (CV4): dihydroartemisinin [DHA], trimethoprim, piperaquine phosphate and primaquine phosphate), which was followed by CV8 (the same components as CV4 but in increased quantities), Artecom (in which primaquine was omitted) and Artekin or Duo-Cotecxin (DHA and piperaquine phosphate only). Recent Indochinese studies have confirmed the excellent clinical efficacy of piperaquine-DHA combinations (28-day cure rates >95%), and have demonstrated that currently recommended regimens are not associated with significant cardiotoxicity or other adverse effects. The pharmacokinetic properties of piperaquine have also been characterised recently, revealing that it is a highly lipid-soluble drug with a large volume of distribution at steady state/bioavailability, long elimination half-life and a clearance that is markedly higher in children than in adults. The tolerability, efficacy, pharmacokinetic profile and low cost of piperaquine make it a promising partner drug for use as part of an ACT.


Experimental relocation of the mitochondrial ATP9 gene to the nucleus reveals forces underlying mitochondrial genome evolution.
Only a few genes remain in the mitochondrial genome retained by every eukaryotic organism that carry out essential functions and are implicated in severe diseases. Experimentally relocating these few genes to the nucleus therefore has both therapeutic and evolutionary implications. Numerous unproductive attempts have been made to do so, with a total of only 5 successes across all organisms. We have taken a novel approach to relocating mitochondrial genes that utilizes naturally nuclear versions from other organisms. We demonstrate this approach on subunit 9/c of ATP synthase, successfully relocating this gene for the first time in any organism by expressing the ATP9 genes from Podospora anserina in Saccharomyces cerevisiae. This study substantiates the role of protein structure in mitochondrial gene transfer: expression of chimeric constructs reveals that the P. anserina proteins can be correctly imported into mitochondria due to reduced hydrophobicity of the first transmembrane segment. Nuclear expression of ATP9, while permitting almost fully functional oxidative phosphorylation, perturbs many cellular properties, including cellular morphology, and activates the heat shock response. Altogether, our study establishes a novel strategy for allotopic expression of mitochondrial genes, demonstrates the complex adaptations required to relocate ATP9, and indicates a reason that this gene was only transferred to the nucleus during the evolution of multicellular organisms.


[The effect of cryopreservation on the cytogenetic characteristics of a cell subline of skin fibroblasts from the Indian muntjac].
After thawing cells, previously cryopreserved in the presence of dimethyl sulfoxide (DMSO), a decrease in their viability and increase in unscheduled DNA synthesis was observed. In 7 days, these parameters restored to the control level. Cryopreservation without DMSO resulted in the decrease in both cell viability and replicative and unscheduled DNA synthesis. In 14 days, these characteristics were seen to return to the normal level. Cryopreservation of cells without DMSO and their preservation in liquid nitrogen induced the frequency of chromosomal aberrations, mostly chromosomal breaks. The frequency of chromosomal aberrations increased with the duration of cell preservation in liquid nitrogen. The normal level was achieved following 7 days after cell thawing. Cells treated with DMSO only (without cryopreservation) display an increased number of chromosomal and chromatid breaks and translocations. Nonrandom distribution of chromosomal aberrations was observed, with particular chromosomes being involved in the appearance of dicentrics and translocations. The data obtained indicate that cryoprotective activity of DMSO is probably associated with the cell repair systems. The detected antimutagenic and mutagenic activity of DMSO may presumably reflect various conditions for its interaction with cells (with or without cryopreservation), as well as it may be specific for the muntjac cell line used in the present work.


Stimulation of Cell Elongation by Tetraploidy in Hypocotyls of Dark-Grown Arabidopsis Seedlings.
Plant size is largely determined by the size of individual cells. A number of studies showed a link between ploidy and cell size in land plants, but this link remains controversial. In this study, post-germination growth, which occurs entirely by cell elongation, was examined in diploid and autotetraploid hypocotyls of Arabidopsis thaliana (L.) Heynh. Final hypocotyl length was longer in tetraploid plants than in diploid plants, particularly when seedlings were grown in the dark. The longer hypocotyl in the tetraploid seedlings developed as a result of enhanced cell elongation rather than by an increase in cell number. DNA microarray analysis showed that genes involved in the transport of cuticle precursors were downregulated in a defined region of the tetraploid hypocotyl when compared to the diploid hypocotyl. Cuticle permeability, as assessed by toluidine-blue staining, and cuticular structure, as visualized by electron microscopy, were altered in tetraploid plants. Taken together, these data indicate that promotion of cell elongation is responsible for ploidy-dependent size determination in the Arabidopsis hypocotyl, and that this process is directly or indirectly related to cuticular function.


Invasive aspergillosis: adjunctive combination therapy.
Invasive aspergillosis remains a serious opportunistic fungal infection particularly in patients with a reduced immune defense such as those with hematological malignancies or transplant recipients. The mortality of invasive infections due to Aspergillus spp. is still high. The main reasons for this are the difficulty in diagnosing of these infections and the limited efficacy of antifungal agents. There is no optimal therapy for invasive aspergillosis, and therefore many clinicians have attempted to utilize a combination approach to improve outcomes. The current antifungal classes of drugs targeting the cell wall and cell membrane may need adjunctive agents focused on separate cellular pathways that can be used in combination therapy to maximize the efficacy, a valuable alternative to the monotherapy. The endeavor of this article is to review the literature on combination therapy by using adjunctive agents against Aspergillus spp and assess its eventual usability in the treatment of invasive aspergillosis.


Ischiopagus tripus conjoined twins.
A conjoined twin is one of the rare congenital defects. Ischiopagus variety is even rarer. We present a case of ischiopagus-tripus conjoined twins. They were fused at the lower halves of the bodies. One of the twins was apparently normal looking, active and pink. The other twin was small, ill looking, sluggish and cyanosed. There were two well formed separate lower limbs on one side and a fused limb at the other side. The twins had an imperforate anus and two small orifices draining urine with incompletely developed external genitalia. Pre-operative workup was in progress when the twins passed away.


Outcomes of tympanoplasty in children with down syndrome.
The prevalence of chronic otitis media with effusion (COME), and Eustachian tube dysfunction (ETD) is high in Down syndrome (DS) patients. This often necessitates multiple tympanostomy tube (TT) placements resulting in a higher rate of persistent tympanic membrane (TM) perforation requiring tympanoplasty for repair. To assess risk factors for persistent perforation and outcomes of tympanoplasty in DS patients. Retrospective case series of 91 ears in 69 DS patients with TM perforations, who were either observed or underwent tympanoplasty. Clinical features, surgical outcomes, and hearing outcomes were assessed. 91 ears were evaluated. Sixty perforations were observed, and 31 perforations were repaired. The closure rate was 54.8% for primary surgery, and 70.9% after secondary surgical interventions in the Tympanoplasty Group, compared to 33.0% spontaneous closure rate in the Observation Group (p < 0.001). The only risk factor for failed tympanoplasty repair was persistent COME/ETD (OR 27.2, p = 0.001). In the Observation Group perforations diagnosed at an older age, with >3 TT insertions, and with persistent COME/ETD were less likely to close spontaneously. Patients undergoing tympanoplasty had worse preoperative pure tone averages than those being observed, but significant improvement in air-bone gaps were noted in the Tympanoplasty Group (p = 0.02) post-operatively. Patients were often rehabilitated with hearing aids regardless of intervention (53.3% Observation Group, 48.4% Tympanoplasty Group). Persistent TM perforation in children with Down syndrome was associated with a history of COME/ETD, and multiple prior TT insertions. Tympanoplasty was successful for repair in most patients who underwent surgical intervention, but residual hearing loss was common.


[Modifying effect of deep hypoxia on neutron-irradiated mice].
Deep hypoxia was shown to influence the survival of animals, the state of the small intestine mucosa and the haemopoietic system. DMF (LD50/30) was 2.49 and 1.66 with X- and neutron radiation, respectively. As to haemopoietic stem cells X-irradiated in vivo, D0 was 0.96 +/- 0.04 Gy (control) and 2.82 +/- 0.14 Gy (anoxia). With neutron irradiation, D0 was 0.44 +/- 0.01 Gy and 0.8 +/- 0.03 for the control and experimental animals respectively.


Assessing the implementation of performance management of health care workers in Uganda.
The performance management concept is relatively new to the Ugandan health sector. Uganda has been implementing health sector reforms for nearly two decades. The reforms included the introduction of the results-oriented management in the public sector and the decentralisation of the management of health care workers from central to local governments. This study examined the implementation of performance management of health care workers in order to propose strategies for improvement. The study was a descriptive survey carried out in the Kumi, Mbale, Sironko and Tororo districts and utilising mixed research methodology. A self-administered questionnaire was used to collect quantitative data from the health care workers. A semi-structured interview guide was used to collect qualitative data from the health service managers. The sample for the quantitative method was selected using stratified random sampling. Purposive sampling was used to select health service managers. Quantitative data were analysed using Statistical Package for Social Sciences (version 18.0). Qualitative data were categorised according to the themes and analysed manually. The findings show that to some extent performance management is implemented in the health sector; however, there were loopholes in its implementation. There were inadequacies in setting performance targets and performance management planning was hardly done. Although many health care workers had job descriptions, the performance indicators and standards were not clearly defined and known to all workers and managers. Additionally the schedules for performance assessments were not always adhered to. There were limited prospects for career progression, inadequate performance feedback and poor rewarding mechanisms. Performance management of health care workers is inadequately done in the districts. Performance management is a key component of attempts to improve health sector outcomes. As a result of this study, suggestions to enhance health sector performance management in the districts have been put forward. The authors are optimistic that if these suggestions are implemented, the performance of health care workers is likely to improve.


Factors Affecting Health Care Utilization in OEF/OIF Veterans: The Impact of PTSD and Pain.
Returning Operation Enduring Freedom and Operation Iraqi Freedom veterans are at a high risk for physical and mental health symptoms including pain (90%) and post-traumatic stress disorder (PTSD) (58%). These often present concurrently and result in many health problems, functional impairments, and overall poor rehabilitation. To address postdeployment health, effective and efficient allocation of health care resources is needed. Retrospective study of 144 veterans who completed a second-level screening in the Polytrauma clinic. Veterans completed the PTSD Checklist-Civilian Version. Their pain rating and health care utilization (sum of visits during 12 months, categorized as medical or mental health) was extracted through chart review. The majority of veterans reported significant PTSD (72%) and pain (87%) symptoms; 45% received adequate mental health treatment, defined as ≥8 sessions in 12 months. PTSD and the interaction with pain predicted medical utilization; at high pain levels veterans' PTSD severity predicted utilization. PTSD alone predicted mental health utilization. The results show the increased influence of PTSD symptoms on medical health care services when pain ratings are high and suggest the need for interdisciplinary pain clinics that are able to address the overlapping symptoms of pain and common mental health conditions. Implication of results for VA planning are discussed.


Voltage-tunable elastomer composites that use shape instabilities for rapid structural color changes.
Structurally colored materials can switch colors in response to external stimuli, which makes them potentially useful as colorimetric sensors, dynamic displays, and camouflage. However, their applications are limited by the angular dependence, slow response, and absence of synchronous control in time and space. In addition, out-of-plane deformation from shape instability easily occurs in photonic films, leading to inhomogeneous colors in photonic-crystal materials. To address these challenges, we combine structurally colored photonic glasses and dielectric elastomer actuators. We use an external voltage signal to tune color changes quickly (much less than 0.1 s). The photonic glassses produce colors with low angular dependence, so that their colors are homogeneous even when they become curved due to voltage-triggered instabilities (buckling or wrinkling). As proof of concept, we present a pixelated display in which segments can be independently and rapidly turned on and off. This wide-angle, instability-tolerant, color-changing platform could be used in next-generation soft and curved color displays, camouflage with both shape and color changes, and multifunctional sensors.


Correlated responses of carcass and reproductive traits to selection for rate of lean growth in swine.
Mass selection for an index of increased postweaning average daily gain and decreased backfat thickness was practiced for five generations. Litter size and weight for 221 gilt litters, birth weight and nipple number for 2,242 piglets and weaning weight at 42 d of age for 2,111 pigs were recorded. Carcass measurements were taken on 331 pigs. Differences between means of the lines (select control) were regressed on cumulative selection differential of the index. These regression coefficients were negative (P greater than .10) for total number born, number born alive, number weaned per litter, nipple number and carcass backfat thickness. Coefficients were positive (P greater than .10) for individual pig and litter weights at birth and weaning and for the carcass traits of length, longissimus muscle area and percentage of ham and loin. Absolute values of realized genetic correlations of index with traits evaluated were all .35 or less except the correlation with carcass backfat, which was -.84. None of these was significant; therefore, index selection for lean growth should have little effect on litter size and weight but may have a beneficial effect on carcass backfat.


Thalamic WNT3 Secretion Spatiotemporally Regulates the Neocortical Ribosome Signature and mRNA Translation to Specify Neocortical Cell Subtypes.
Neocortical development requires tightly controlled spatiotemporal gene expression. However, the mechanisms regulating ribosomal complexes and the timed specificity of neocortical mRNA translation are poorly understood. We show that active mRNA translation complexes (polysomes) contain ribosomal protein subsets that undergo dynamic spatiotemporal rearrangements during mouse neocortical development. Ribosomal protein specificity within polysome complexes is regulated by the arrival of in-growing thalamic axons, which secrete the morphogen Wingless-related MMTV (mouse mammary tumor virus) integration site 3 (WNT3). Thalamic WNT3 release during midneurogenesis promotes a change in the levels of Ribosomal protein L7 in polysomes, thereby regulating neocortical translation machinery specificity. Furthermore, we present an RNA sequencing dataset analyzing mRNAs that dynamically associate with polysome complexes as neocortical development progresses, and thus may be regulated spatiotemporally at the level of translation. Thalamic WNT3 regulates neocortical translation of two such mRNAs, Foxp2 and Apc, to promote FOXP2 expression while inhibiting APC expression, thereby driving neocortical neuronal differentiation and suppressing oligodendrocyte maturation, respectively. This mechanism may enable targeted and rapid spatiotemporal control of ribosome composition and selective mRNA translation in complex developing systems like the neocortex. The neocortex is a highly complex circuit generating the most evolutionarily advanced complex cognitive and sensorimotor functions. An intricate progression of molecular and cellular steps during neocortical development determines its structure and function. Our goal is to study the steps regulating spatiotemporal specificity of mRNA translation that govern neocortical development. In this work, we show that the timed secretion of Wingless-related MMTV (mouse mammary tumor virus) integration site 3 (WNT3) by ingrowing axons from the thalamus regulates the combinatorial composition of ribosomal proteins in developing neocortex, which we term the "neocortical ribosome signature." Thalamic WNT3 further regulates the specificity of mRNA translation and development of neurons and oligodendrocytes in the neocortex. This study advances our overall understanding of WNT signaling and the spatiotemporal regulation of mRNA translation in highly complex developing systems.


A pulse-radiolysis study of the manganese-containing superoxide dismutase from Bacillus stearothermophilus.
In the preceding paper the mechanism of catalysis of the manganese-containing superoxide dismutase from Bacillus stearothermophilus was shown to involve a 'fast cycle' and a 'slow cycle' [McAdam, Fox, Lavelle & Fielden, 1977 (Biochem. J. 165, 71-79)]. Further properties of the enzyme was considered in the present paper. Pulse-radiolysis studies, under conditions of low substrate concentration to (i.e. when the fast cycle predominates), showed that enzyme activity decreases as pH increases (6.5-10.2). Activity was unaffected by the addition of H2O2 or NaN3 but slightly decreased by KCN. Both H2O2 and the reducing radical anion CO2-- caused a decrease in A480 of the native enzyme. The rate of the fast catalytic cycle was independent of temperature (5-55 degrees C), and as temperature increases the slow cycle becomes relatively more important. Arrhenius parameters of the rate contants were estimated. The possible identity of the various forms of the enzyme is considered.


Model development for determining the efficacy of a combination coating for the prevention of perioperative device related infections: a pilot study.
Antibiotic resistant bacterial infections are a growing problem in patient care. These infections are difficult to treat and severely affect the patient's quality of life. The goal of this translational experiment was to investigate the antimicrobial potential of cationic steroidal antimicrobial-13 (CSA-13) for the prevention of perioperative device-related infections in vivo. It was hypothesized that when incorporated into a polymeric device coating, the release of CSA-13 could prevent perioperative device-related infection without inhibiting skeletal attachment. To test this hypothesis, 12 skeletally mature sheep received a porous coated titanium implant in the right femoral condyle. Group 1 received the titanium implant and an inoculum of 5 × 10(8) CFU of methicillin-resistant Staphylococcus aureus (MRSA). Group 2 received a CSA-13 coated implant and the MRSA inoculum. Group 3 received only the CSA-13 coated implant and Group 4 received only the implant-without the CSA-13 coating or MRSA inoculum. In conclusion, the CSA-13 combination coating demonstrated bactericidal potential without adversely affecting skeletal attachment. The CSA-13 containing groups exhibited no evidence of bacterial infection at the conclusion of the 12 week study and established skeletal attachment consistent with Group 4. In contrast, all of the Group 1 animals became infected and required euthanasia within 6-10 days. The significance of this finding is that this combination coating could be applied to implanted devices to prevent perioperative device-related infections. This method may facilitate significantly reduced incidences of device-related infections as well as a new method to treat and prevent resistant strain bacterial infections.


Phenotypic and Genomic Comparison of Klebsiella pneumoniae Lytic Phages: vB_KpnM-VAC66 and vB_KpnM-VAC13.
Klebsiella pneumoniae is a human pathogen that worsens the prognosis of many immunocompromised patients. Here, we annotated and compared the genomes of two lytic phages that infect clinical strains of K. pneumoniae (vB_KpnM-VAC13 and vB_KpnM-VAC66) and phenotypically characterized vB_KpnM-VAC66 (time of adsorption of 12 min, burst size of 31.49 ± 0.61 PFU/infected cell, and a host range of 20.8% of the tested strains). Transmission electronic microscopy showed that vB_KpnM-VAC66 belongs to the Myoviridae family. The genomic analysis of the phage vB_KpnM-VAC66 revealed that its genome encoded 289 proteins. When compared to the genome of vB_KpnM-VAC13, they showed a nucleotide similarity of 97.56%, with a 93% of query cover, and the phylogenetic study performed with other Tevenvirinae phages showed a close common ancestor. However, there were 21 coding sequences which differed. Interestingly, the main differences were that vB_KpnM-VAC66 encoded 10 more homing endonucleases than vB_KpnM-VAC13, and that the nucleotidic and amino-acid sequences of the L-shaped tail fiber protein were highly dissimilar, leading to different three-dimensional protein predictions. Both phages differed significantly in their host range. These viruses may be useful in the development of alternative therapies to antibiotics or as a co-therapy increasing its antimicrobial potential, especially when addressing multidrug resistant (MDR) pathogens.


Near-field mediated plexcitonic coupling and giant Rabi splitting in individual metallic dimers.
Strong coupling between resonantly matched localized surface plasmons and molecular excitons results in the formation of new hybridized energy states called plexcitons. Understanding the nature and tunability of these hybrid nanostructures is important for both fundamental studies and the development of new applications. We investigate the interactions between J-aggregate excitons and single plasmonic dimers and report for the first time a unique strong coupling regime in individual plexcitonic nanostructures. Dark-field scattering measurements and finite-difference time-domain simulations of the hybrid nanostructures show strong plexcitonic coupling mediated by the near-field inside each dimer gap, which can be actively controlled by rotating the polarization of the optical excitation. The plexciton dispersion curves, obtained from coupled harmonic oscillator models, show anticrossing behavior at the exciton transition energy and giant Rabi splitting ranging between 230 and 400 meV. These energies are, to the best of our knowledge, the largest obtained on individual hybrid nanostructures.


Technical challenges regarding the use of formalin-fixed paraffin embedded (FFPE) tissue specimens for the detection of bacterial alterations in colorectal cancer.
Formalin-fixed paraffin embedded (FFPE) tissues may provide an exciting resource to study microbial associations in human disease, but the use of these low biomass specimens remains challenging. We aimed to reduce unintentional bacterial interference in molecular analysis of FFPE tissues and investigated the feasibility of conducting quantitative polymerase chain reaction (qPCR) and 16S rRNA amplicon sequencing using 14 colorectal cancer, 14 normal adjacent and 13 healthy control tissues. Bacterial contaminants from the laboratory environment and the co-extraction of human DNA can affect bacterial analysis. The application of undiluted template improves bacterial DNA amplification, allowing the detection of specific bacterial markers (Escherichia coli and Faecalibacterium prausnitzii) by qPCR. Nested and non-nested PCR-based 16S rRNA amplicon sequencing approaches were employed, showing that bacterial communities of tissues and paired paraffin controls cluster separately at genus level on weighted Unifrac in both non-nested (R2 = 0.045; Pr(> F) = 0.053) and nested (R2 = 0.299; Pr(> F) = 0.001) PCR datasets. Nevertheless, considerable overlap of bacterial genera within tissues was seen with paraffin, DNA extraction negatives (non-nested PCR) or PCR negatives (nested PCR). Following mathematical decontamination, no differences in α- and β diversity were found between tumor, normal adjacent and control tissues. Bacterial marker analysis by qPCR seems feasible using non-normalized template, but 16S rRNA amplicon sequencing remains challenging. Critical evaluation of laboratory procedures and incorporation of positive and negative controls for bacterial analysis of FFPE tissues are essential for quality control and to account for bacterial contaminants.


Dynamical signatures from competing, nonadiabatic fragmentation pathways of S-nitrosothiophenol.
S-Nitrosothiols (RSNOs) are derived from the combination of sulfur and nitric oxide (NO) radicals in the Earth's atmosphere and fragment to products following photolysis. Extensive theoretical studies have focused on the thermodynamic and, to a lesser extent, photochemical properties of RSNOs. However, experimental studies of these compounds have been limited due to the inherent instability of RSNOs at room temperature. Using velocity map imaging (VMI), we explore the photodissociation dynamics of jet-cooled S-nitrosothiophenol (PhSNO) from 355 nm photolysis. We report the translational and internal energy distributions of the NO and thiophenoxy (PhS) co-fragments, which are determined by spatial detection of the ionized NO photofragments using 1+1 resonance-enhanced multiphoton ionization (REMPI). The velocity distributions indicate competing PhSNO nonadiabatic dissociation pathways, in which PhS is formed in the ground and first excited electronic states when probing high- and low-energy NO (X2Π1/2, v'', J'') rovibrational states, respectively. The results of multireference electronic structure calculations suggest that direct dissociation on the bright S2 state results in PhS formed in its excited electronic state, whereas intersystem crossing into the triplet manifold leads to population of PhS in its electronic ground state. The dynamical signatures from the dissociation processes are imprinted on the fragments' quantum states and relative translation, which we explore in rigorous detail using state-resolved imaging and high-level theoretical calculations.


Control of ultrafast laser-induced bulk nanogratings in fused silica via pulse time envelopes.
Employing a method of in-situ control we propose an approach for the optimization of self-arranged nanogratings in bulk fused silica under the action of ultrashort laser pulses with programmable time envelopes. A parametric study of the influence of the pulse duration and temporal form asymmetries is given. Using the diffraction properties of the laser-triggered subwavelength patterns we monitor and regulate the period and the quality of the periodic nanoscale arrangement via the effective nonlinear excitation dose. Periodicity tuning on tens of nanometers can be achieved by pulse temporal variations, with a minimum around 0.7 ps at the chosen powers. Equally, strong sensitivity to pulse asymmetries is observed. The driving factor is related to increasing carrier densities due to nonlinear confinement and the development of extended nanoroughness domains upon multiple exposure, creating a pulse-dependent effective accumulation dose via a morpho-dimensional effect. The result may impact the associated optical functions.


Grape Seed Proanthocyanidins Induce Autophagy and Modulate Survivin in HepG2 Cells and Inhibit Xenograft Tumor Growth in Vivo.
Liver cancer is one of the leading causes of death worldwide. Although radiotherapy and chemotherapy are effective in general, they present various side effects, significantly limiting the curative effect. Increasing evidence has shown that the dietary intake of phytochemicals plays an essential role in the chemoprevention or chemotherapy of tumors. In this work, HepG2 cells and nude mice with HepG2-derived xenografts were treated with grape seed proanthocyanidins (GSPs). The results showed that GSPs induced autophagy, and inhibition of autophagy increased apoptosis in HepG2 cells. In addition, GSPs also reduced the expression of survivin. Moreover, survivin was involved in GSPs-induced apoptosis. GSPs at 100 mg/kg and 200 mg/kg significantly inhibited the growth of HepG2 cells in nude mice without causing observable toxicity and autophagy, while inducing the phosphorylation of mitogen-activated protein kinase (MAPK) pathway-associated proteins, p-JNK, p-ERK and p-p38 MAPK and reducing the expression of survivin. These results suggested that GSPs might be promising phytochemicals against liver cancer.


Working with team midwifery: health visitors' views of one team midwifery scheme.
The fragmented nature of maternity services in the UK has led to the introduction of various forms of team midwifery scheme. The aim of such schemes is usually to increase continuity through the provision of antenatal, intrapartum and postnatal care to women by a small team of midwives. Few published studies of this organization of midwifery care exist, and even fewer consider the impact of such schemes on related health professionals. This paper presents the results of an independent survey of health visitors working alongside one team midwifery scheme in the south-east of England. Eighty per cent of the health visitors thought that team midwifery was a good idea in theory; however, just 27% thought it was working well locally and 70% reported that they would like to go back to working in the way they did before the introduction of team midwifery. The survey highlighted the health visitors' concerns in relation to team midwifery locally. Two issues were paramount: firstly a reported deterioration in interdisciplinary communications, and secondly a perceived loss of continuity for the women. Thus team midwifery, as implemented in this locality, may not attain the goals aimed at by the organization of care in this way.


Increased Risk of Falls, Fall-related Injuries and Fractures in People with Type 1 and Type 2 Diabetes - A Nationwide Cohort Study.
People with diabetes could have an increased risk of falls as they show more complications, morbidity and use of medication compared to the general population. This study aimed to estimate the risk of falls and to identify risk factors associated with falls in people with diabetes. The second aim was to estimate fall-related injuries, such as lesions and fractures, including their anatomic localization in people with diabetes compared with the general population. From the Danish National Patient Register, we identified people with Type 1 Diabetes (T1D) (n=12,975) Type 2 Diabetes (T2D) (n=407,009). The cohort was divided into two groups, with respective control groups matched on age and sex (1:1). All episodes of people hospitalized with a first fall from 1996 to 2017 were analyzed using a Cox proportional-hazards model. Risk factors such as age, sex, diabetic complications, a history of alcohol abuse and the use of medication were included in an adjusted analysis. The incidence rate, incidence rate difference and incidence rate ratio (IRR) of falls and the anatomic localization of fall-related injuries as lesions and fractures were identified. The cumulative incidence, of falls requiring hospital treatment, was 13.3% in T1D, 11.9% in T2D. In the adjusted analysis, T1D and T2D were associated with a higher risk of falls [T1D, Hazard Ratio (HR): 1.33 (95% CI: 1.25 - 1.43), T2D, HR: 1.19 (95% CI:1.16 - 1.22), respectively]. Women [group 1, HR 1.21 (CI:95%:1.13 - 1.29), group 2, HR 1.61 (CI:95%:1.58-1.64)], aged >65 years [groups 1, HR 1.52 (CI:95%:1.39 - 1.61), group 2, HR 1.32 (CI:95%:1.58-1.64)], use of selective serotonin receptor inhibitors (SSRI) [group 1, HR 1.35 (CI:95%:1.1.30 - 1.40), group 2, HR 1.32 (CI:95%:1.27-1.38)], opioids [group 1, HR 1.15 (CI:95%:1.12 - 1.19), group 2, HR 1.09 (CI:95%:1.05-1.12)] and a history of alcohol abuse [group 1, HR 1.77 (CI:95%:1.17 - 2.15), group 2, HR 1.88 (CI:95%:1.65-2.15)] were significantly associated with an increased risk of falls in both groups. The IRR of fall-related injuries as hip, radius, humerus and skull/facial fractures were higher in people with T2D than controls [IRR 1.02 (CI:95%:1.01-1.04), IRR 1.39 (CI:95%: 1.18-1.61), IRR 1.24 (CI:95%: 1.12-1.37) and IRR 1.15 (CI:95%:1.07-1.24)]. People with T1D had a higher IRR of hip fractures than controls [IRR: 1.11 (CI:95%:1.02 - 1.23)]. People with diabetes have an increased risk of first fall and a higher incidence of fall- related injuries, including fractures. Advanced aging and sex are non-modifiable risk factors, whereas diabetes, the use of SSRIs and opioids and alcohol abuse could be potentially modifiable risk factors for falls. Gaining information on risk factors for falls could guide the management of diabetes treatment, i.e., choice of drugs, which enables us to improve treatment, particularly in people with a high risk of falls and fractures associated with high mortality.


Tissue distribution of quercetin in rats and pigs.
Quercetin is a dietary polyphenolic compound with potentially beneficial effects on health. Claims that quercetin has biological effects are based mainly on in vitro studies with quercetin aglycone. However, quercetin is rapidly metabolized, and we have little knowledge of its availability to tissues. To assess the long-term tissue distribution of quercetin, 2 groups of rats were given a 0.1 or 1% quercetin diet [approximately 50 or 500 mg/kg body weight (wt)] for 11 wk. In addition, a 3-d study was done with pigs fed a diet containing 500 mg quercetin/kg body wt. Tissue concentrations of quercetin and quercetin metabolites were analyzed with an optimized extraction method. Quercetin and quercetin metabolites were widely distributed in rat tissues, with the highest concentrations in lungs (3.98 and 15.3 nmol/g tissue for the 0.1 and 1% quercetin diet, respectively) and the lowest in brain, white fat, and spleen. In the short-term pig study, liver (5.87 nmol/g tissue) and kidney (2.51 nmol/g tissue) contained high concentrations of quercetin and quercetin metabolites, whereas brain, heart, and spleen had low concentrations. These studies have for the first time identified target tissues of quercetin, which may help to understand its mechanisms of action in vivo.


Ten-year experience with sevelamer and calcium salts as phosphate binders.
Most patients with chronic kidney disease experience abnormalities in serum calcium, phosphorus, parathyroid hormone, and vitamin D metabolism. These can lead to vascular calcification (VC), which has been associated with increased risk for cardiovascular disease and mortality. Although hyperphosphatemia is believed to be a risk factor for mortality and VC, no randomized trial was ever designed to demonstrate that lowering phosphate reduces mortality. Nonetheless, binders have been used extensively, and the preponderance of evidence shows that sevelamer slows the development of VC whereas calcium salts do not. Four studies have demonstrated a slower progression of VC with sevelamer than with calcium-containing binders, although a fifth study showed nonsuperiority. Conversely, the results on mortality with sevelamer have been variable, and data on calcium-based binders are nonexistent. Improved survival with sevelamer was demonstrated in a small randomized clinical trial, whereas a larger randomized trial failed to show a benefit. In addition, preclinical models of renal failure and preliminary clinical data on hemodialysis patients suggest a potential benefit for bone with sevelamer. Meanwhile, several randomized and observational studies suggested no improvement in bone density and fracture rate, and a few noted an increase in total and cardiovascular mortality in the general population given calcium supplements. Although additional studies are needed, there are at least indications that sevelamer may improve vascular and bone health and, perhaps, mortality in hemodialysis patients, whereas data on calcium-based binders are lacking.


Increased CEST specificity for amide and fast-exchanging amine protons using exchange-dependent relaxation rate.
Chemical exchange saturation transfer (CEST) imaging of amides at 3.5 ppm and fast-exchanging amines at 3 ppm provides a unique means to enhance the sensitivity of detection of, for example, proteins/peptides and neurotransmitters, respectively, and hence can provide important information on molecular composition. However, despite the high sensitivity relative to conventional magnetic resonance spectroscopy (MRS), in practice, CEST often has relatively poor specificity. For example, CEST signals are typically influenced by several confounding effects, including direct water saturation (DS), semi-solid non-specific magnetization transfer (MT), the influence of water relaxation times (T1w ) and nearby overlapping CEST signals. Although several editing techniques have been developed to increase the specificity by removing DS, semi-solid MT and T1w influences, it is still challenging to remove overlapping CEST signals from different exchanging sites. For instance, the amide proton transfer (APT) signal could be contaminated by CEST effects from fast-exchanging amines at 3 ppm and intermediate-exchanging amines at 2 ppm. The current work applies an exchange-dependent relaxation rate (Rex ) to address this problem. Simulations demonstrate that: (1) slowly exchanging amides and fast-exchanging amines have distinct dependences on irradiation powers; and (2) Rex serves as a resonance frequency high-pass filter to selectively reduce CEST signals with resonance frequencies closer to water. These characteristics of Rex provide a means to isolate the APT signal from amines. In addition, previous studies have shown that CEST signals from fast-exchanging amines have no distinct features around their resonance frequencies. However, Rex gives Lorentzian lineshapes centered at their resonance frequencies for fast-exchanging amines and thus can significantly increase the specificity of CEST imaging for amides and fast-exchanging amines.


Effects of amino acids administered to a perfused area of the skin in Angora goats.
The effect of infusion of supplemental amino acids on growth of mohair by Angora goats was investigated using a skin perfusion model. Four Angora wethers (average BW 32 +/- 2 kg) were implanted bilaterally with silicon catheters into the superficial branches of the deep circumflex iliac artery and vein. For the first 14 d of the experiment, goats were arterially infused with either a mixture of amino acids (one side) or saline (contralateral side). The hourly infusion rates of amino acids were .36 mg of methionine, .36 mg of lysine, and .72 mg of leucine. The area of skin supplied by the deep circumflex iliac artery was approximately 300 cm2; a tattoo 10 cm x 15 cm was made in the middle of the perfused region for quantifying mohair production and characteristics. Two weeks after cessation of infusions goats were shorn and the mohair from the tattooed regions was examined. Greasy and clean mohair production from the tattooed region were increased by amino acid infusion compared with the contralateral side infused with saline (3.51 vs 3.16 g, P < .04 and 3.13 vs 2.70 g, P < .07, respectively). Although mohair length and diameter were not significantly altered, venous concentrations of valine, threonine, arginine, glycine, and histidine were decreased by infusion of the amino acids (P < .05), no differences in T3, T4, or insulin concentrations in venous blood were detected, but plasma cortisol concentration was reduced (1.38 vs 2.61 micrograms/dL, P < .05) with amino acid infusion.(ABSTRACT TRUNCATED AT 250 WORDS)


Genipin cross-linked fibrin hydrogels for in vitro human articular cartilage tissue-engineered regeneration.
Our objective was to examine the potential of a genipin cross-linked human fibrin hydrogel system as a scaffold for articular cartilage tissue engineering. Human articular chondrocytes were incorporated into modified human fibrin gels and evaluated for mechanical properties, cell viability, gene expression, extracellular matrix production and subcutaneous biodegradation. Genipin, a naturally occurring compound used in the treatment of inflammation, was used as a cross-linker. Genipin cross-linking did not significantly affect cell viability, but significantly increased the dynamic compression and shear moduli of the hydrogel. The ratio of the change in collagen II versus collagen I expression increased more than 8-fold over 5 weeks as detected with real-time RT-PCR. Accumulation of collagen II and aggrecan in hydrogel extracellular matrix was observed after 5 weeks in cell culture. Overall, our results indicate that genipin appeared to inhibit the inflammatory reaction observed 3 weeks after subcutaneous implantation of the fibrin into rats. Therefore, genipin cross-linked fibrin hydrogels can be used as cell-compatible tissue engineering scaffolds for articular cartilage regeneration, for utility in autologous treatments that eliminate the risk of tissue rejection and viral infection.