Integrated analysis of ferroptosis-related gene signature for overall survival prediction in Asian patients with hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the most prevalent types of cancers in Asia. Accumulating evidence suggests that ferroptosis is a non-apoptotic form of cell death, and has played an important role in cancer biology. Based on the manually curated ferroptosis-related gene set and TCGA-LIHC dataset of Asian patients, we used DESeq2, Kaplan-Meier analysis, and univariate Cox regression to identify differentially expressed ferroptosis-related genes with significantly prognostic capacity. A risk signature was constructed based on the selected genes for predicting the survival of HCC patients in Asia. The survival prediction accuracy was confirmed by the time-dependent receiver operating characteristic (ROC) curve analysis. Gene set variation analysis (GSVA) was used to explore the functional associations of the signature. Ferroptosis potential index (FPI) and xCell algorithm was applied to quantify ferroptosis and immune cell infiltration, respectively. Two independent datasets from the GEO and the ICGC database were used for external validation. The ferroptosis-related signature could accurately predict the survival outcomes of HCC patients in Asian (p value < 0.0001). We showed that the signature was an independent factor and was beneficial in elevating risk stratification of current clinicopathologic features, such as the amount of alpha-fetoprotein (AFP) and residual tumor classification. Functional characterization showed that critical processes in tumorigenesis belonged to the high-risk groups, for example inflammatory response, which may be the main driver of HCC. The high-risk group had higher FPIs and infiltrations of macrophages and T-helper cells than the low-risk group. Furthermore, two independent cohorts confirmed the prognostic value of our signature. Overall, our results demonstrated potential application of ferroptosis-related genes as independent biomarkers in Asian HCC patients. Targeting ferroptosis may be clinically useful beyond known clinicopathological factors and provide benefit in immunotherapy.


Distribution of adenosine A1 receptors in primary visual cortex of developing and adult monkeys.
Adenosine is an endogenous neuromodulator, whose actions in the brain are mediated by several, highly specific receptor systems. This study examined the distribution of adenosine A1 receptors in the primary visual cortex of developing and adult monkeys by way of radioligand-binding autoradiography. Receptor density was found to be highest in layers 2/3 and 5 of adult striate cortex and lowest in layer 4. A similar pattern was found in infant monkeys that were in the critical period of development. Furthermore, removal of visual stimulation appeared to have no effect on receptor density in any of the layers. These results show that levels of adenosine A1 receptors are not affected within ocular dominance columns after removal of visual input and that the geniculorecipient layer is less likely to be influenced by endogenous adenosine than other layers during early development and in the adult.


Menstrual and reproductive risk factors and risk for gastric adenocarcinoma in women: findings from the canadian national enhanced cancer surveillance system.
The role of menstrual and reproductive risk factors for gastric cancer has not been well studied. This population-based case-control study included 326 women aged 20 to 74 years with gastric adenocarcinoma. Controls were 326 women frequency matched on age. Data for reproductive and/or hormonal exposure and gastric cancer risk factors were captured through self-administered questionnaire. Later age at menarche was associated with increased risk for adenocarcinoma compared with menarche onset at younger than 13 years of age (13 to 14 years: odds ratio [OR], 1.45; 95% confidence interval [CI], 1.00-2.10; > or =15 years: OR, 1.93; 95% CI, 1.19-3.13). Compared with premenopause, natural menopause was associated with increased risk for adenocarcinoma (OR, 1.99; 95% CI, 0.98-4.05). Compared with nulliparity, 4 or more births were associated with decreased risk for gastric cancer, as was being pregnant for 5 months or longer if the first pregnancy occurred at younger than 24 years (OR, 0.55; 95% CI, 0.31-0.96) or 25 years or older (OR, 0.67; 95% CI, 0.38-1.18). Oral contraceptives and hormone replacement therapy were associated with a non-statistically significant decreased risk. These findings suggest that hormonal factors associated with greater exposure to estrogen and/or progesterone may be associated with decreased risk for gastric cancer.


Echocardiographic diagnosis of thrombus originating from the ductus arteriosus.
Initial functional closure of the ductus arteriosus normally occurs within hours after birth, with permanent closure taking several weeks. The mechanism for ductal closure has been well studied and has not been shown to include thrombus formation. We describe a normal infant found to have a thrombus originating in the ductus arteriosus that occluded the ductus and subsequently extended into the left pulmonary artery, threatening to occlude it as well. This case illustrates the importance of echocardiography in making this rare diagnosis. It also emphasizes the role of echocardiography as an effective means of following the progression or regression of such a thrombus.


The guidance of attention by templates for rejection during visual search.
The hypothesis that foreknowledge of nontarget features in visual search is represented by negative search templates ("templates for rejection") that facilitate attentional guidance remains disputed. In five experiments, we investigated this proposal by measuring search performance and electrophysiological markers of target selection (N2pc components) and nontarget suppression (PD components). We compared search tasks where positive or negative cues signaled the color of targets or nontargets, respectively, and tasks with neutral non-informative cues. Positive cues elicited performance benefits relative to neutral cues. Negative cues produced behavioral and electrophysiological costs for target selection, and some evidence for the inhibition of negatively cued nontargets, but there was no support for the proposal that these items initially attract attention. Performance costs for negative cues dissipated after practice with the same negatively cued nontargets for approximately 25-50 trials, and eventually turned into benefits after several hundreds of trials. However, the emergence of negative cue benefits was not accompanied by electrophysiological evidence for faster or more efficient inhibition of nontargets, indicating that they are not produced by learned suppression mechanisms mediated by negative search templates. We conclude that templates for rejection do not facilitate search but normally interfere with target selection. Although negative cue benefits can be observed after extended exposure to the same nontarget features, these benefits do not reflect active attentional guidance, and are likely to be the result of passive habituation processes.


Prescription tracking and public health.
Monitoring and modifying physicians' prescribing behavior through prescription tracking is integral to pharmaceutical marketing. Health information organizations (HIOs) combine prescription information purchased from pharmacies with anonymized patient medical records purchased from health insurance companies to determine which drugs individual physicians prefer for specific diagnoses and patient populations. This information is used to tailor marketing strategies to individual physicians and to assess the effect of promotions on prescribing behavior. The American Medical Association (AMA) created the Prescription Data Restriction Plan in an attempt to address both the privacy concerns of physicians and industry concerns that legislation could compromise the availability of prescribing data. However, the PDRP only prohibits sales representatives and their immediate supervisors from accessing the most detailed reports. Less than 2% of US physicians have registered for the PDRP, and those who have signed up are not the physicians who are targeted for marketing. Although it has been argued that prescription tracking benefits public health, data gathered by HIOs is designed for marketing drugs. These data are sequestered by industry and are not generally available for genuine public health purposes.


Intermodal transportation hub location optimization with governments subsidies under the Belt and Road Initiative.
Driven by globalization, the COVID-19 outbreak has severely impacted global transport and logistics systems. To better cope with this globalization crisis, the Belt and Road Initiative (BRI)-based on the concept of cooperation-is more important than ever in the post-pandemic era. Taking the BRI as the background, we design an intermodal hub-and-spoke network to provide reference for governments along BRI routes to improve their cross-border transportation system and promote economic recovery. In the context of the BRI, local governments at different nodes have incentives to subsidize hub construction and/or rail transportation to boost economic development. We consider co-opetition behavior among different levels of government caused by subsidies in this intermodal hub location problem, which we call the intermodal hub location problem based on government subsidies. We establish a two-stage mixed-integer programming model. In the first stage, local governments provide subsidies, then the central government decides the number and location of hubs. In the second stage, freight carriers choose the optimal route to transport the goods. To solve the model, we design an optimization method combining a population-based algorithm using contest theory. The results show that rail subsidies are positively correlated with construction subsidies but are not necessarily related to the choice of hubs. Compared with monomodal transportation, intermodal transportation can reduce costs more effectively when there are not too many hubs and the cost of different modes of transportation varies greatly. The influences of local government competition and hub construction investment on network design and government subsidies are further examined.


Que Zui tea ameliorates hepatic lipid accumulation and oxidative stress in high fat diet induced nonalcoholic fatty liver disease.
In this study, the protective effects of hot water (QW) and aqueous-ethanol extracts (QA) from Que Zui tea on non-alcoholic fatty liver disease (NAFLD) were investigated. Quantitative and qualitative analysis revealed that QW and QA were rich in polyphenols, especially 6'-O-caffeoylarbutin. Both QW and QA significantly reduced body weight and liver index, increased serum levels of high density lipoprotein cholesterol (HDL-C), and decreased the levels of total cholesterol (TC), triglyceride (TG), nonesterified free fatty acids (NEFA) and low density lipoprotein cholesterol (LDL-C) in NAFLD rats induced high fat diet. Furthermore, the contents of TC, TG, NEFA, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the liver tissues were inhibited after QW and QA administration. Histopathological examination showed that QW and QA significantly reduced liver lipid accumulation of NAFLD rats. In addition, QW and QA could enhance increase the activity of antioxidant (glutathione, superoxide dismutase and catalase) in the liver by regulation Nrf2 signaling pathway, thereby alleviating liver damage caused by lipid peroxidation. QW and QA activated AMPK/PPAR-α signaling pathway by increasing the expression of adiponectin and its receptor AdipoR2, thereby reducing fat production and enhancing fatty acid β oxidation. These data suggested that QW and QA had the potential to in the prevention and treatment of NAFLD.


The VO2 response to exhaustive square wave exercise: influence of exercise intensity and mode.
We investigated the oxygen uptake ( VO(2)) response to exhaustive square wave exercise of approximately 2, 5 and 8 min duration in cycling and running. Nine males completed a ramp test and three square wave tests on a motorised treadmill and the same four tests on a cycle ergometer, throughout which gas exchange was assessed (Douglas bag method). The peak VO(2) from the ramp test was higher for running than for cycling [mean (SD): 58.4 (2.8) vs. 55.9 (3.7) ml.kg(-1).min(-1); P=0.04]. However VO(2max) (defined as the highest VO(2) achieved in any of the four tests) did not differ between running and cycling [60.0 (2.9) vs. 58.5 (3.3) ml.kg(-1).min(-1); P=0.15]. The peak VO(2) was similar ( P>0.1) for the 5 and 8 min square wave tests [98.5 (1.8) and 99.2 (2.3) % VO(2max) for running; 97.0 (4.2) and 97.5 (2.0) % VO(2max) for cycling] but lower ( P<0.001) for the 2-min test [91.8 (2.5) and 89.9 (5.5) % VO(2max) for running and cycling respectively]. VO(2) increased over the final two 30-s collection periods of the 2-min test for cycling [Delta VO(2)=0.18 (0.15) l.min(-1); P<0.01] but not running [Delta VO(2)=0.00 (0.09) l.min(-1); P=0.98]. We conclude that in the aerobically fit the peak VO(2) for square wave running or cycling at an intensity severe enough to result in exhaustion in approximately 2 min is below VO(2max). In running, VO(2) plateaus at this sub-maximal rate.


Effectiveness of attract-and-kill systems using methyl eugenol incorporated with neonicotinoid insecticides against the oriental fruit fly (Diptera: Tephritidae).
Laboratory bioassays and field trials were conducted to evaluate an "attract-and-kill" system using methyl eugenol (ME) with neonicotinoid insecticides against male oriental fruit fly, Bactrocera dorsalis (Hendel) (Diptera: Tephritidae). In laboratory bioassays, mortality of male flies resulting from the conventional toxicant, naled was 98.3-100% at 24 through 72 h after treatment, whereas the neonicotinoid insecticides imidacloprid and acetamiprid caused only approximately 60-80% at 24 through 72 h after treatment. In the assays of residual effect, naled was persistent up to 96 wk, whereas imidacloprid or acetamiprid was persistent up to 150 wk, resulting in 38.9 or 61.2% male mortality, respectively. Imidacloprid, in particular, caused a delayed lethal effect on flies. In another experiment, male mortality within 28 wk from clothianidin, another neonicotinoid insecticide, was approximately 80% after exposure for 24 h, suggesting a delayed lethal effect similar to those treated with imidacloprid, and mortality was up to 91.8%, if observed, 72 h after treatment. In field trials, attractiveness was similar between ME alone and ME incorporated with naled or neonicotinoids, indicating that addition of these insecticides to ME in traps is not repellent to B. dorsalis males. Using an improved wick-typed trap with longer attractiveness for simulating field application, addition of imidacloprid or acetamiprid maintained 40.1 or 64.3% male mortality, respectively, when assayed once every 2 wk from traps placed in orchards for 42 wk without changing the poison, whereas incorporation with naled resulted in as high as 98.1% after 34 wk and approximately 80% at 42 wk, indicating that persistence is increased compared with sugarcane fiberboard blocks for carrying poison attractants. This study also suggests that neonicotinoid insecticides could be used as an alternative for broad-spectrum insecticides as toxicants in fly traps.


Hypertrophic and antihypertrophic microRNA levels in peripheral blood mononuclear cells and their relationship to left ventricular hypertrophy in patients with essential hypertension.
MicroRNAs regulate several aspects of physiological and pathologic cardiac hypertrophy, and they represent promising therapeutic targets in cardiovascular disease. We assessed the expression levels of the microRNAs miR-1, miR-133a, miR-26b, miR-208b, miR-499, and miR-21, in 102 patients with essential hypertension and 30 healthy individuals. All patients underwent two-dimensional echocardiography. MicroRNA expression levels in peripheral blood mononuclear cells were quantified by real-time reverse transcription polymerase chain reaction. Hypertensive patients showed significantly lower miR-133a (5.06 ± 0.50 vs. 13.20 ± 2.15, P < .001) and miR-26b (6.76 ± 0.53 vs. 9.36 ± 1.40, P = .037) and higher miR-1 (25.99 ± 3.07 vs. 12.28 ± 2.06, P = .019), miR-208b (22.29 ± 2.96 vs. 8.73 ± 1.59, P = .016), miR-499 (10.06 ± 1.05 vs. 5.70 ± 0.91, P = .033), and miR-21 (2.75 ± 0.15 vs. 1.82 ± 0.20, P = .002) expression levels compared with healthy controls. In hypertensive patients, we observed significant negative correlations of miR-1 (r = -0.374, P < .001) and miR-133a (r = -0.431, P < .001) and significant positive correlations of miR-26b (r = 0.302, P = .002), miR-208b (r = 0.426, P < .001), miR-499 (r = 0.433, P < .001) and miR-21 (r = 0.498, P < .001) expression levels with left ventricular mass index. Our data reveal that miR-1, miR-133a, miR-26b, miR-208b, miR-499, and miR-21 show distinct expression profiles in hypertensive patients relative to healthy individuals and they are associated with clinical indices of left ventricular hypertrophy in hypertensive patients. Thus, they may be related to heart hypertrophy in hypertensive patients and are possibly candidate therapeutic targets in hypertensive heart disease.


Use of low dose e-beam irradiation to reduce E. coli O157:H7, non-O157 (VTEC) E. coli and Salmonella viability on meat surfaces.
This study determined the extent that irradiation of fresh beef surfaces with an absorbed dose of 1 kGy electron (e-) beam irradiation might reduce the viability of mixtures of O157 and non-O157 verotoxigenic Escherichia coli (VTEC) and Salmonella. These were grouped together based on similar resistances to irradiation and inoculated on beef surfaces (outside flat and inside round, top and bottom muscle cuts), and then e-beam irradiated. Salmonella serovars were most resistant to 1 kGy treatment, showing a reduction of ≤1.9 log CFU/g. This treatment reduced the viability of two groups of non-O157 E. coli mixtures by ≤4.5 and ≤3.9 log CFU/g. Log reductions of ≤4.0 log CFU/g were observed for E. coli O157:H7 cocktails. Since under normal processing conditions the levels of these pathogens on beef carcasses would be lower than the lethality caused by the treatment used, irradiation at 1 kGy would be expected to eliminate the hazard represented by VTEC E. coli.


Multifunctional hydrogel with reactive oxygen species scavenging and photothermal antibacterial activity accelerates infected diabetic wound healing.
Management of diabetic wound has long been a clinical challenge due to pathological microenvironment of excessive inflammation, persistent hyperglycemia, and biofilm infection caused by overdue reactive oxygen species (ROS) production and defective blood vessels. Herein, a multifunctional hydrogel with ROS scavenging and photothermal antibacterial activity based on oxidized dextran (Odex), gallic acid-grafted gelatin (GAG) and Ferric ion, named OGF, was developed for treatment of infected wound in a diabetic mouse. This hydrogel was double-crosslinked by the dynamically Schiff-base bonds formed between aldehyde groups in Odex and amino groups in GAG and the metal coordination bonds formed between Ferric ion and polyphenol groups or carboxyl groups in GAG, which endowed the resulted OGF hydrogel with well injectable, self-healing and adhesive properties. Due to the high-efficiency photothermal effect of Ferric ion/polyphenol chelate, this hydrogel killed Staphylococcus aureus and Escherichia coli rapidly and completely within 3.5 min under near-infrared light radiation. Furthermore, this composed hydrogel presented good antioxidation, hemostasis and biocompatibility. It also remarkably accelerated the complete re‑epithelialization of Staphylococcus aureus‑infected wound in diabetic mice within 18 days by eliminating infection, mitigating oxidative stress and inflammation, and facilitating angiogenesis. Therefore, the proposed multifunctional hydrogel exerts a great potential for translation in the clinical management of diabetic wounds. STATEMENT OF SIGNIFICANCE: High reactive oxygen species (ROS) levels and vascular defects in diabetic wounds can lead to excessive inflammation, persistent hyperglycemia, biofilm infection and other pathological microenvironments, which can further develop to the chronic wounds. In this study, we designed a multifunctional hydrogel with ROS-scavenging ability and photothermal antibacterial activity for the treatment of infected diabetic wound. As expected, this multifunctional hydrogel dressing highly accelerated the complete re‑epithelialization of Staphylococcus aureus‑infected wound in diabetic mouse by eliminating infection, mitigating oxidative stress and inflammation, as well as facilitating angiogenesis. This work provides a promising therapeutic strategy for infected diabetic wound by inhibition of oxidative stress and biofilm infection.


[3D analysis of occlusal surfaces of teeth and their contacts. Part III. Development of a method for assessing the balance of occlusal contacts].
The aim of the study was to develop a technique for 3D analysis of the occlusal balance of teeth. The development was carried out on the basis of the Avantis 3D software («Avantis 3D» LLC, Russia) using teeth scans of 50 subjects with Class I and II (Division 1) malocclusion and different degree of tooth wear. The algorithm and formulas for calculating the balance of symmetry and antero-posterior occlusal balance are presented. The essential features of the technique and the interpretation of the obtained indicators are explained on different clinical cases. Statistical analysis of the results of measuring occlusal balance of patients with different degree of teeth wear and malocclusion is presented. It is determined that the balance of common contacts is more important than the balance of direct contacts. Alignment of teeth without noticeable wear provides a better occlusal balance then before. The occlusal balance of worn teeth after alignment may be not good and require selective grinding or restoration of their occlusal surfaces.


High levels of inherent variability in microbiological assessment of bronchoalveolar lavage samples from children with persistent bacterial bronchitis and healthy controls.
Bronchoalveolar lavage (BAL) is widely regarded as providing "gold standard" samples for infective lower respiratory tract disease. Current approaches have been adopted empirically without robust assessment and hence carry many assumptions that have not been tested. Many of these uncertainties were highlighted in the ATS pediatric bronchoscopy guidelines. This study was designed to explore some of these issues. BAL was undertaken via an endotracheal tube in 13 subjects aged less than 6 years with persistent bacterial bronchitis and five healthy controls. Aliquots of the same pooled BAL sample were sent to two accredited laboratories. one producing semiquantitative results and the other quantitative results. For five patients potentially pathogenic bacteria were grown by one laboratory but not the other, while in three more there were discrepancies in the organisms reported. Despite being symptomatic and off antibiotics, only 3 of 13 patients were reported to have a pathogen at a density of more than 1 × 104 colony forming unit. There was at best a poor correlation between semiquantitative and quantitative data. Potential pathogens were cultured in two of five control samples. The results suggest that the results from conventional microbiological assessment of BAL samples can be highly variable and that the proposal that a discrete cut-off is of value in patients with chronic endobronchial infection is probably invalid.


Ways of knowing: a nurse and a physician discuss clinical decisions, actions, and lessons.
The authors, both experienced clinicians, met to discuss multiple and diverse ways of knowing in the clinical setting. How do we know what we know? Can we tease out the lessons we have learned from our experience in a sufficiently creative way so that we can apply them to new clinical situations and nurture the next generations of nurses and physicians- and our colleagues-with those insights? This article is a record of that discussion.


Vacuum-powered bubble-assisted solvent extraction followed by macroporous resin enrichment for isolation of podophyllotoxin from Sinopodophyllum emodi.
A vacuum-powered bubble-assisted solvent extraction (VBE) technique was used to extract podophyllotoxin from the root of Sinopodophyllum emodi. We optimized the VBE procedure and showed it had the highest efficiency of extraction compared to other conventional extraction techniques. Based upon the results of single-factor experiments, a three-factor, three-level experiment design was developed by application of a Box-Behnken design. The method was validated by stability, repeatability and recovery experiments. The optimal conditions were: solvent, 60% (v/v) ethanol; particle size of the sample, 60-80 mesh; soak time, 2h; liquid/solid ratio, 21L/kg; air flow, 32mL/min; vacuum-powered bubble extraction time, 65min. The VBE method we developed achieved efficient extraction of podophyllotoxin from S. emodi. The podophyllotoxin extracted can be enriched and separated by an HPD300 macroporous resin adsorption and desorption process. The results indicated that VBE is a convenient, rapid and efficient sample preparation technique.


Synthesis of optically pure [60]fullerene e,e,e-tris adducts.
The reaction of readily available optically active Si-tethered tris(malonates) with C60 gave easily separable diastereoisomers differing by the absolute configuration of the inherently chiral addition pattern on the fullerene core. The absolute configuration of the e,e,e addition pattern has been unambiguously determined using X-ray crystal structure analysis.


Prospective observations on stopping prolonged venom immunotherapy.
After a decade spent establishing the safety, efficacy, and optimal techniques for venom immunotherapy, we have begun a series of studies to determine how long venom immunotherapy must be continued. In retrospective surveys, patients who had stopped venom immunotherapy after 1 to 2 years had a substantial risk (25%) of systemic sting reactions, but this was less than 50% of the risk in untreated patients. In this first prospective study, 30 patients elected to stop venom immunotherapy after at least 5 years of therapy. Skin test sensitivity had decreased significantly during therapy in 18/30 patients but remained clearly positive in 23/30 (seven patients became equivocal or negative). Serum venom-specific IgE antibodies were at the lower limit of detection (1 ng/ml) in 11/30 patients. After stopping treatment, the mean serum venom-specific IgG antibody level declined from 5.5 +/- 0.6 micrograms/ml to 2.4 +/- 0.3 micrograms/ml by 9 months, which is the same as the mean venom IgG in untreated patients. After 12 months without therapy, live sting challenge caused no systemic reaction in 29 patients. The mean venom IgG level 1 month after the sting had risen significantly to 4.1 +/- 0.5 micrograms/ml, but there was no significant increase of venom IgE. These results suggest that prolonged venom immunotherapy leads to isotype-specific suppression of the venom IgE antibody response and may provide persistent clinical protection by mechanisms other than IgG blocking antibodies. The observations are to be interpreted very cautiously. Further investigations are needed to extend these observations in additional patients and for longer periods of time, and to examine possible mechanisms for this apparent loss of clinical reactivity.


Preadsorption of boar semen with kaolin: increased efficiency of foot-and-mouth disease virus detection.
The boar semen-associated cytotoxic factor(s), but not the antiviral activity, were removed by adsorption with kaolin. Although foot-and-mouth disease virus was efficiently removed from medium by kaolin or kieselguhr, the virus was not removed from semen-virus mixtures. Because the cytotoxicity induced by boar semen apparently altered the ability of tissue culture cells to support virus replication, preadsorption with kaolin increased the probability of detecting this virus in semen samples.


Successful prioritisation of inguinal herniotomies in children during the COVID-19 pandemic to minimise emergency presentations.
The coronavirus disease 2019 (COVID-19) disrupted the delivery of elective surgery in children. We introduced guidance to mitigate this impact. By reviewing the outcomes for inguinal herniotomies, we aimed to determine if this guidance has enabled us to prevent an increase in the elective surgery wait time and therefore the need for emergency surgery for incarcerated hernias. This report aims to share our learnt lessons about responding to a crisis limiting accessibility to elective surgery. We performed a retrospective review of all elective and emergency herniotomies performed between April 1 and September 30, 2019 (pre-COVID-19) and the same period in 2020 (post-COVID-19). We compared the data on wait time from referral to clinic review/elective surgery and incarceration rates. During the study period in 2019, 76 elective herniotomies were performed compared to 46 in 2020. We did not observe a simultaneous increase in emergency herniotomies in 2020 (27 [2020] vs 25 [2019], OR [95% CI] = 1.53 [0.79-2.9]; p = 0.2). The median time from referral to elective surgery in 2019 compared to 2020 did not differ (56 vs 59 days, respectively; p = 0.61). In 2020, 72% of children that required emergency surgery had not been previously referred to our service and the median age (interquartile range) at which they presented with an incarcerated hernia was 2.8 months (2.1-13.7 months). By adhering to local guidelines for resumption of elective activity, the pandemic did not result in children waiting longer to be seen by a surgeon for a suspected inguinal hernia. As a result, we did not perform more emergency herniotomies. Urgent prioritisation of hernias in infants, from birth up to 3 months old, was a beneficial strategy. Public health education on childhood hernias will improve outcomes. The online version contains supplementary material available at 10.1186/s43159-023-00243-1.


COVID-19 vaccination in Africa: A case of unsatisfied expectation and ill-preparedness.
With a population of 1.3 billion people, of which 56% reside in rural settings, Africa seemed ill-prepared to handle the distribution of a COVID-19 vaccine. In addition, the capacity needed for a successful COVID-19 vaccination campaign in Africa surpassed the available resources in local and state health agencies. As a result, African governments were advised to coordinate resources, health officials, and vaccinators, including local health practitioners, medical technicians, and pharmacists for the largest-ever vaccination campaign in Africa. Although the rolling out of the SARS-COV-2 vaccine was, as expected, slow in many African countries, and not yet enough to cover the entire population in Africa, the mass vaccination campaign in Africa must continue to ensure that priority for vaccination is extended beyond front-liners (healthcare workers) and specific high-risk populations, which has largely been the case in some African countries. This article highlights the overarching areas that we believe need to be prioritized to enhance Africa's effectiveness and coverage in the mass COVID-19 vaccination program.


A new method for measuring antibody using radiolabeled protein A1 in a solid-phase radioimmunoassay.
A micro solid-phase radioimmunoassay was developed which utilizes radiolabeled staphylococcal Protein A ([125I]Protein A) in place of radiolabeled anti-immunoglobulin ([125I]anti-IgG) for the measurement of antibody. For the assay, antigen is adsorbed to the wells of a microtiter plate followed by dilutions of serum and [125I]-Protein A in subsequent steps. We found that this assay can be used to measure antibody (Ab) against a variety of antigens in human and rabbit but not goat immune serum. Binding of [125I]Protein A and [125I]anti-IgG to human and rabbit IgG was comparable. It was possible to quantify this amount of Ab in human serum by reference to immune rabbit serum. The sensitivity of this assay for rabbit antibody was 1 ng/ml.


Detection with the polymerase chain reaction of human papillomavirus DNA in condylomata acuminata treated in vitro with liquid nitrogen, trichloroacetic acid, and podophyllin.
The mechanisms of action for local treatments used against condylomata acuminata are unknown, but most are believed to cause physical destruction of infected tissue. Our purpose was to determine whether liquid nitrogen, trichloroacetic acid (TCA), and podophyllin damage HPV DNA found in condylomata acuminata. Fourteen genital warts were excised from 14 patients and divided. One part was treated with liquid nitrogen, the second and third parts were treated with TCA and podophyllin, respectively, and the remainder served as a control. DNA was then extracted from tissue by proteolytic digestion and amplified by the polymerase chain reaction. Dot blots were performed with the use of radiolabeled consensus and HPV type-specific probes. HPV DNA was amplified and detected in 100% of untreated specimens, in 92% of specimens treated with liquid nitrogen, and in 15% and 7% of specimens treated with podophyllin and TCA, respectively. TCA and podophyllin damage HPV DNA more effectively than does liquid nitrogen.


Association of physical activity and visual attention in older adults.
This study was conducted to examine possible associations between physical activity and visual attention in community-dwelling older adults. Older adults (age 65-95) completed the Useful Field of View (UFOV (R)) test of visual attention, and they also reported current physical activity levels using the Exercise Participation Questionnaire (EPQ) and the Physical Activity Scale for the Elderly (PASE). UFOV (R) performance was significantly correlated with both measures of physical activity, but some of these effects overlapped with the effects of age. The 21 participants (15%) who reported regular participation on the EPQ were found to have significantly better UFOV (R) scores than the more inactive participants both before and after controlling for age, gender, and visual acuity. The preservation of visual attention skills across the life span may be more highly correlated with regular participation in exercise training activities than it is with more general occupational and leisure-related physical activity.


Direct observation of laser generated free radicals from a myocardium target site.
The first direct observation of unstable free radicals generated by laser irradiation of myocardium samples has been performed by EPR at 100 K. Characteristic iron signals are measured for pulsed laser ablation of the sample. The EPR results are discussed in relation to the relative efficiency of the various types of lasers to produce free radicals. A comparison is made of the types of free radicals produced by the action of pulsed vs continuous wave (cw) laser energy.


The reality of cholangiocarcinoma in India- real world data from a tertiary referral centre.
Cholangiocarcinomas (CCA) are rare tumours originating from bile duct. Due to their asymptomatic nature they are usually diagnosed when the disease is advanced. Little data exists with respect to their incidence and treatment outcomes in low and middle income countries. A retrospective analysis of a prospectively maintained database of all patients with perihilar (pCCA) and intrahepatic (iCCA) CCA registered between January 2012 and December 2018 was performed. A total of 760 patients, 427 (56.2%) diagnosed with pCCA and 333 (43.8%) of iCCA were included. Patients with localised, locally advanced and metastatic disease in pCCA were 45.5%, 25.9%, 8.5% and that in iCCA were 22.1%, 10.1% and 67.7% respectively. Only 141 (43.9%, 57 - iCCA, 84 -pCCA) of the total 321 patients started on some definitive cancer directed therapy could complete the intended treatment. The overall curative resection rate for all patients of iCCA was 14.5% whereas for patients of pCCA it was only 10.5%. More than half of CCA patients are not able to complete their intended treatment, being worse for pCCA as compared to iCCA. Early referral and centralisation of treatment for this complex disease might be the way forward to achieve optimal outcomes.


Pleiotropic effect of the gene hairless on hepatotoxicity of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin in mice.
Treatment of mice of the A2G-hr/+ congenic line with 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in the development of hepatic porphyria over a period of 4 weeks. Female mice responded to a lesser extent than did males. The degree of porphyria in haired heterozygotes (hr/+) was less than in the corresponding hairless homozygotes (hr/hr) and the haired mice had lower resting metabolic rates than hairless mice. Adaptation of mice of either genotype to a 32-33 degrees C environment resulted in a decrease in resting metabolic rate and a reduction in hepatic porphyrin levels. Histologically-demonstrated necrotic changes in livers were accompanied by increased activity of alanine aminotransferase and sorbitol dehydrogenase in the plasma; however, there was no clear temporal trend in plasma enzyme levels. Elevated environmental temperature reduced the plasma alanine aminotransferase activity. The study provided evidence for a pleiotropic effect of variation at the hr locus being expressed in TCDD hepatotoxicity. Suggestions for mechanisms whereby the effect can be mediated through alterations in resting metabolic rate are made.


[Development of Arbuscular Mycorrhiza in Highly Responsive and Mycotrophic Host Plant-Black Medick (Medicago lupulina L.)].
The main phases of arbuscular mycorrhiza (AM) development were analyzed in black medick (Medicago lupulina) with Glomus intraradices. Methods of light and transmission electron microscopy were used to investigate AM. The first mycorrhization was identified on the seventh day after sowing. M. lupulina with AM-fungus Glomus intraradices formed Arum type of AM. Roots of black medick at fruiting stage (on the 88th day) were characterized by the development of forceful mycelium. The thickness of mycelium was comparable with the vascular system of root central cylinder. The development of vesicules into intraradical spores was shown. Micelium, arbuscules, and vesicules developed in close vicinity to the division zone of root tip. This might be evidence of an active symbiotic interaction between partners. All stages of fungal development and breeding, including intraradical spores (in inter-cellular matrix of root cortex), were identified in the roots of black medick, which indicated an active utilization of host plant nutrient substrates by the mycosymbiont. Plant cell cytoplasm extension was identified around young arbuscular branches but not for intracellular hyphae. The presence of active symbiosis was confirmed by increased accumulation of phosphorus in M. lupulina root tissues under conditions of G. intraradices inoculation and low phosphorus level in the soil. Thus, black medick cultivar-population can be characterized as an ecologically obligate mycotrophic plant under conditions of low level of available phosphorus in the soil. Specific features of AM development in intensively mycotrophic black medick, starting from the stage of the first true leaf until host plant fruiting, were evaluated. The obtained plant-microbe system is a perspective model object for further ultracytological and molecular genetic studies of the mechanisms controlling arbuscular mycorrhiza symbiotic efficiency, including selection and investigation of new symbiotic plant mutants.


Effect of chronic restraint stress and alpha-lipoic acid on lipid peroxidation and antioxidant enzyme activities in rat peripheral organs.
The aim of this study was to evaluate the effect of chronic restraint stress and alpha-lipoic acid (LA) administration on lipid peroxidation and antioxidant enzyme activities in rat peripheral organs. Forty male wistar rats, aged 3 months were randomized to one of the following groups: control, restraint stress, LA treated and restraint stress+LA treated. Chronic restraint stress was applied for 21 days (1h/day) and LA (100 mg/kg/day) was administered intraperitoneally for the same period. Restraint stress had no statistically significant effect on lipid peroxidation, copper/zinc superoxide dismutase (Cu/Zn SOD), catalase (CAT) and glutathione peroxidase (GPx) activity in rat liver and heart, when compared to the control group. Lipid peroxidation, determined by measuring malondialdehyde (MDA) levels, was found to be increased in the kidney of restraint stress treated rats, compared to controls. Restraint stress-induced lipid peroxidation in the kidney was significantly decreased via LA treatment. Administration of LA also enhanced GPx and decreased Cu/Zn SOD activity in rat kidney, liver and heart, compared to the control group. The presented data shows that LA is a protective agent against restraint stress--the inducer of lipid peroxidation in the kidney. These findings also suggest that LA-induced changes in antioxidant enzyme activities in rat peripheral organs may contribute to their versatile effects observed in vivo.


Integrating evidence-based PTSD treatment into intensive eating disorders treatment: a preliminary investigation.
Given data suggesting common co-occurrence and worse outcomes for individuals with eating disorders (EDs) and post-traumatic stress disorder (PTSD), it is critical to identify integrated treatment approaches for this group of patients. Past work has explored the feasibility and initial efficacy of intervention approaches that draw on evidence-based treatments for both EDs and PTSD; however, this work remains limited in scope. In the current study, we explored the feasibility and naturalistic outcomes of PTSD treatment delivered within the context of intensive ED treatment. Participants were 57 adult men and women with DSM-5 EDs and comorbid PTSD who completed a course of either Prolonged Exposure (PE; n = 22) or Cognitive Processing Therapy (CPT; n = 35) (Msessions = 10.40; SD = 5.13) and weekly validated measurements of clinical symptoms while enrolled in ED programming. Multi-level models for PTSD symptoms indicated a significant linear effect of time, such that participants demonstrated significant decreases over time in PTSD symptoms, regardless of treatment modality. Our preliminary investigation provides support for the feasibility and efficacy of an integrated approach to treating EDs and PTSD. It is critical for future work to undertake randomized tests of this integrated approach using large, heterogeneous samples. Level IV, multiple time series with intervention.


Current aspects of penal surgical liability in Greece.
The surgeon may face in every day practice issues that may render him liable. The legal liability usually emerges due to the negligence exhibited during the preoperative, the operative and the postoperative stage. The surgeon, as any doctor, isn't liable for the result, but he is responsible for the correct diagnosis and therapeutic treatment, always according to the principles of the Medical science and to the possibilities available to him in every specific case (facilities and time). The continuous education about the issues of his speciality, the adaptation of scientifically approved techniques, the correct monitoring of the patient, both preoperatively and postoperatively, and finally the good communication with the patient are necessary for the proper practice of Medicine; but also constitute the "shield" of the surgeon against any possible legal conflict.


Regulation of the preovulatory gonadotropin surge by endogenous steroids.
Estradiol secreted by growing ovarian follicle(s) has been considered classically to be the neural trigger for the preovulatory surge of gonadotropins. The observation that the estradiol-induced gonadotropin surge in ovariectomized rats is of lesser magnitude and duration than that found in the cycling rat at proestrus has resulted in a search for other steroid regulators. Progesterone is a major regulator of the preovulatory gonadotropin surge. It can only act in the presence of an estrogen background, which is necessary for the synthesis of progesterone receptors. In the estrogen-primed ovariectomized rat, progesterone is able to initiate and enhance the gonadotropin surge to the magnitude observed on the day of proestrus and limit it to 1 day. The physiological role of progresterone in the induction of the preovulatory gonadotropin surge has been demonstrated by the attenuation of the progesterone-induced surge and the endogenous proestrus surge by progesterone receptor antagonist RU486 and the progesterone synthesis inhibitor trilostane. The promoter region of the follicle-stimulating hormone (FHS)-beta gene contains multiple progesterone response elements and progesterone brings about FSH release as well. The reduction of progesterone in the 5 alpha-position appears to be important for the regulation of progesterone secretion. Corticosteroids appear to play a significant role in the secondary FSH surge on late proestrus and early estrus.


Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk.
To identify variants for multiple myeloma risk, we conducted a genome-wide association study with validation in additional series totaling 4,692 individuals with multiple myeloma (cases) and 10,990 controls. We identified four risk loci at 3q26.2 (rs10936599, P = 8.70 × 10(-14)), 6p21.33 (rs2285803, PSORS1C2, P = 9.67 × 10(-11)), 17p11.2 (rs4273077, TNFRSF13B, P = 7.67 × 10(-9)) and 22q13.1 (rs877529, CBX7, P = 7.63 × 10(-16)). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy, as well as insight into the biological basis of predisposition.


Transcranial Direct Current Stimulation Ameliorates Behavioral Deficits and Reduces Oxidative Stress in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Mouse Model of Parkinson's Disease.
Oxidative stress is involved in the pathological process of Parkinson's disease (PD). The present study was designed to investigate the effects of transcranial direct current stimulation (tDCS) on the oxidative stress in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The animals were modulated by tDCS. Behavioral alterations were observed after three weeks of tDCS treatment using rotary performance tests. The mice were sacrificed for the measurement of the level of dopamine (DA), enzymatic tyrosine hydroxylase (TH), nonenzymatic malonaldehyde (MDA), an enzymatic superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) in the mouse brain and serum. The mice treated with MPTP had an increased MDA level but a decreased SOD and GSH-Px activity, as well as a behavior impairment. These abnormalities were significantly attenuated by tDCS treatment and by levodopa and benserazide. The study demonstrated that the tDCS could have a potential for the therapeutic usage in the PD.


Fast filtering for RNA homology search.
Homology search for RNAs can use secondary structure information to increase power by modeling base pairs, as in covariance models, but the resulting computational costs are high. Typical acceleration strategies rely on at least one filtering stage using sequence-only search. Here we present the multi-segment CYK (MSCYK) filter, which implements a heuristic of ungapped structural alignment for RNA homology search. Compared to gapped alignment, this approximation has lower computation time requirements (O(N⁴) reduced to O(N³), and space requirements (O(N³) reduced to O(N²). A vector-parallel implementation of this method gives up to 100-fold speed-up; vector-parallel implementations of standard gapped alignment at two levels of precision give 3- and 6-fold speed-ups. These approaches are combined to create a filtering pipeline that scores RNA secondary structure at all stages, with results that are synergistic with existing methods.


Unravelling the nuclear matrix proteome.
The nuclear matrix (NM) model posits the presence of a protein/RNA scaffold that spans the mammalian nucleus. The NM proteins are involved in basic nuclear function and are a promising source of protein biomarkers for cancer. Importantly, the NM proteome is operationally defined as the proteins from cells and tissue that are extracted following a specific biochemical protocol; in brief, the soluble proteins and lipids, cytoskeleton, and chromatin elements are removed in a sequential fashion, leaving behind the proteins that compose the NM. So far, the NM has not been sufficiently verified as a biological entity and only preliminary at the molecular level. Here, we argue for a combined effort of proteomics, immunodetection and microscopy to unravel the composition and structure of the NM.


A two step model for lateral growth of collagen fibrils.
A two step model of lateral growth of type I collagen fibrils is presented which is an extension of a previous model. Step I of lateral growth involves interactions between pairs of opposite charges which form dipoles perpendicular to the molecular axis and results in removal of loosely bound water between collagen molecules in solution. During step II of lateral aggregation, rearrangement of the inner hydration layer occurs as a result of intermolecular interactions between dipoles parallel to the molecular axis, unpaired charges and hydrophobic residues. It is proposed that differences in fibril diameters between types I, II and III collagen reflect differences in the extent of step II lateral aggregation. Type III collagen which forms thinner fibrils than type I, is shown to have fewer theoretical step II charge-charge interactions consistent with the model that fibril diameters are dependent on secondary lateral growth. Based on this model the fibril forming ability of collagen is in part a result of interactions between dipoles oriented perpendicular to the molecular axis whereas the extent of fibril diameter growth reflects secondary charge-charge and hydrophobic interactions.


The generation effect and the modeling of associations in memory.
The search of associative memory (SAM) model of Gillund and Shiffrin (1984) was applied to data of two experiments that examined the generation effect (Slamecka & Graf, 1978). Subjects studied a list of related word pairs, in which they either read both words in the pair or generated the right- hand response term using the left-hand stimulus term plus the response word fragment as generation cues. Experiment 1 manipulated encoding condition within subjects and used an incidental learning procedure. Experiment 2 manipulated encoding condition between subjects and used an intentional learning procedure. Memory was tested with recognition, cued recall, and free recall. A higher order association model gave a better and more parsimonious fit to the results than did an item-level association model. The relationship between various versions of SAM and current accounts of the generation effect are discussed, particulary the two-factor theory of Hirshman and Bjork (1988).


Face-to-face spatial orientation fine-tunes the brain for neurocognitive processing in conversation.
We here demonstrate that face-to-face spatial orientation induces a special 'social mode' for neurocognitive processing during conversation, even in the absence of visibility. Participants conversed face to face, face to face but visually occluded, and back to back to tease apart effects caused by seeing visual communicative signals and by spatial orientation. Using dual EEG, we found that (1) listeners' brains engaged more strongly while conversing face to face than back to back, irrespective of the visibility of communicative signals, (2) listeners attended to speech more strongly in a back-to-back compared to a face-to-face spatial orientation without visibility; visual signals further reduced the attention needed; (3) the brains of interlocutors were more in sync in a face-to-face compared to a back-to-back spatial orientation, even when they could not see each other; visual signals further enhanced this pattern. Communicating in face-to-face spatial orientation is thus sufficient to induce a special 'social mode' which fine-tunes the brain for neurocognitive processing in conversation.


Nonsquamous cancer of the vagina.
This report retrospectively analyzes 48 cases of primary vaginal cancer treated at Walter Reed Army Medical Center and the Naval Hospital, Bethesda, from 1962 through 1983. There was an unusually high number of uncommon histologic types. Nine patients had an adenocarcinoma, 5 had a sarcoma, 3 had a melanoma, 2 had an adenosquamous carcinoma, 1 had a lymphoma, and 1 had a carcinoid tumor. The remaining 27 patients had a squamous cell carcinoma. This represents a 43% prevalence of nonsquamous lesions. Nonsquamous cancer of the vagina occurred in patients at an earlier age than squamous cell carcinoma. Presenting symptoms, the location of the tumor within the vagina, and survival rates were similar for both groups. The clinical characteristics and treatment of the patients with nonsquamous tumors are discussed.


[The fate of fusarium toxins in the course of the synthesis of bioethanol from contaminated grain].
By means of a modelling experiment we followed the fate of deoxynivalenol (DON) and zearalenone (ZEA) in the production of bioethanol from grain.The experiment has been performed at the 'Versuchs- und Lehranstalt für Brauerei in Berlin e.V.' A total of 33 kg. triticale with a concentration of 3.2 mg/kg DON and 0.035 mg/kg ZEA were treated with water and enzymes which yielded the mash. By adding yeasts the mixture was then brought to formentation. Finally, the alcohol was obtained by destillation.The residue was dried by centrifugation to a content of 25% dry matter and put in silage tubes. In each part of the whole process test samples were taken and the content of DON and ZEA was determined. After three month the silage was scraped out from the tubes and analyzed, too. The mycotoxins were analyzed by HPLC with DAD and HPLC with fluorescence detection, corresponding to VDLUFA-methods.The balance of the mycotoxin contents showed no loss of DON in the process. For ZEA, however, a deficit of about 35% was noted. Because of the mass loss during starch fermentation (33 kg grain yield 8 kg draff) the mycotoxin contents were enhanced by a factor of 2 to 4.DON is well dissolved in water and therefore partially washed out by filtration of the mash. As the whole process is performed in practice as a cycle, the filtrate with DON is permanently recycled in the brewery process. Therefore the mycotoxin concentration in the original grain should not exceed the legal EU boundary values of 1.25 mg/kg DON and 0.1 mg/kg ZEA.


High-resolution MR imaging anatomy of the orbit. Correlation with comparative cryosectional anatomy.
High resolution MR imaging of the orbit enables visualization of anatomic details in the orbit, including important blood vessels, muscles, nerves and connective tissue structures. The best resolution of anatomic details currently is obtained by using surface coils and T1-weighted spin echo sequences. Some examples of clinical applications demonstrate that a detailed knowledge of orbital imaging anatomy is a prerequisite for successful interpretation of clinical MR images. Additionally, this noninvasive diagnostic technique may be used for anatomical in vivo studies.


Inherited polyposis syndromes: molecular mechanisms, clinicopathology, and genetic testing.
The inherited polyposis syndromes are a group of conditions in which multiple gastrointestinal polyps occur in the lumen of the gastrointestinal tract, most exhibit an increased risk of colon cancer. Benign and malignant extraintestinal tumors might also be observed. Recent elucidation of the underlying gene mutations has contributed to our understanding of the cell biology and molecular mechanisms associated with gastrointestinal tumorigenesis. Developments have also allowed genetic testing to become an integral component in accurate diagnosis, categorization, and management of inherited polyposis syndromes. In this review, we will focus on familial adenomatous polyposis, mutY human homologue-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis, and Cowden syndrome. It is essential that both physician and patient understand the benefits and limitations of genetic testing before submission of samples to the laboratory. There are many issues accompanying molecular diagnosis of cancer syndromes, and genetic counseling is an essential prelude to genetic testing.


Retracted: Dynamic Mechanism and Decision Analysis of Urban Exhibition Tourism Development Based on High-Performance Computing.
[This retracts the article DOI: 10.1155/2022/3806752.].


Prevalence and severity of asthma among Indian school children aged between 6 and 14 years: associations with parental smoking and traffic pollution.
Phase three of the International Study of Asthma and Allergy in Children (ISAAC) was carried out at various sites in India. The prevalence of asthma symptoms in school children and the effect of environmental tobacco smoke and traffic pollution on the occurrence of asthma were analysed. Two groups of school children, aged 6-7 yr and 13-14 yr, participated according to the ISAAC protocol. Schools were randomly selected and responses to the ISAAC questionnaire were recorded. The prevalence of asthma was 5.35% in the 6-7 yr age group and 6.05% in the 13-14 yr age group. The odds ratios (ORs) for the risk of asthma in children with exposure to mild, moderate and heavy traffic pollution compared with minimal traffic pollution were 1.63 (95% CI: 1.43, 1.85), 1.71 (95% CI: 1.49, 1.96) and 1.53 (95% CI: 1.31, 1.78), respectively, in the younger group. Similarly, in the older group, they were 1.19 (95% CI: 1.04, 1.36), 1.51 (95% CI: 1.31, 1.75) and 1.51 (95% CI: 1.29, 1.76). Asthma was associated with maternal smoking [6-7 yr group: OR = 2.72 (2.05, 3.6); 13-14 yr group: OR = 2.14 (1.72, 2.66)] and paternal smoking [6-7 yr group: OR = 1.9 (1.70, 2.11); 13-14 yr group: OR = 1.21 (1.09, 1.34)]. The prevalence of asthma was lower in the 6-7 than the 13-14 yr age group. Environmental tobacco smoke and traffic pollution were the factors most strongly associated with asthma in Indian children.


Hydrogen bond and other descriptors for thalidomide and its N-alkyl analogs; prediction of physicochemical and biological properties.
Descriptors for thalidomide and its N-alkyl derivatives have been obtained from solubilities reported by Goosen et al. It I shown that thalidomide and the three N-alkylthalidomides are reasonably strong hydrogen bond bases, and that thalidomide is a hydrogen bond acid. From the obtained descriptors, a large number of physicochemical and biochemical properties of the four thalidomides were predicted, including several water-solvent partition coefficients. Predictions of skin permeation of the four thalidomides are in excellent agreement with experiment. Thalidomide is predicted to be only moderately to poorly distributed to the brain, but N-pentylthalidomide, is predicted to be very well distributed to the brain. All four thalidomides have very high predicted % human intestinal absorption.


Relationships between the mitochondrial transmembrane potential, ATP concentration, and cytotoxicity in isolated rat hepatocytes.
The relationships between mitochondrial transmembrane potential, ATP concentration, and cytotoxicity were evaluated after exposure of isolated rat hepatocytes to different mitochondrial poisons. Both the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its fully oxidized metabolite, the 1-methyl-4-phenylpyridinium (MPP+) ion, caused a concentration- and time-dependent depolarization of mitochondrial membranes which followed ATP depletion and preceded cytotoxicity. The effect of MPTP, but not that of MPP+, was prevented by deprenyl, an inhibitor of MPTP conversion to MPP+ via monoamine oxidase type B. Addition of fructose to the hepatocyte incubations treated with either MPTP or MPP+ counteracted the loss of mitochondrial transmembrane potential. Fructose was also effective in protecting against the mitochondrial membrane depolarization as well as ATP depletion and cytotoxicity induced by antimycin. A, carbonyl cyanide p-trifluoromethoxyphenyl hydrazone, and valinomycin. Data confirm the key role played by MPP(+)-induced mitochondrial damage in MPTP toxicity and indicate that (i) ATP produced via the glycolytic pathway can be utilized by hepatocytes to maintain mitochondrial electrochemical gradient, and (ii) a loss of mitochondrial membrane potential may occur only when supplies of ATP are depleted.


Deletion of Six3 in post-proliferative neurons produces weakened SCN circadian output, improved metabolic function, and dwarfism in male mice.
The increasing prevalence of obesity makes it important to increase the understanding of the maturation and function of the neuronal integrators and regulators of metabolic function. Behavioral, molecular, and physiological analyses of transgenic mice with Sine oculis 3 (Six3) deleted in mature neurons using the Synapsincreallele. Conditional deletion of the homeodomain transcription factor Six3 in mature neurons causes dwarfism and weakens circadian wheel-running activity rhythms but increases general activity at night, and improves metabolic function, without impacting pubertal onset or fertility in males. The reduced growth in 6-week-old Six3fl/fl:Synapsincre (Six3syn) males correlates with increased somatostatin (SS) expression in the hypothalamus and reduced growth hormone (GH) in the pituitary. In contrast, 12-week-old Six3syn males have increased GH release, despite an increased number of the inhibitory SS neurons in the periventricular nucleus. GH is important in glucose metabolism, muscle function, and bone health. Interestingly, Six3syn males have improved glucose tolerance at 7, 12, and 18 weeks of age, which, in adulthood, is associated with increased % lean mass and increased metabolic rates. Further, 12-week-old Six3syn males have reduced bone mineralization and a lower bone mineral density, indicating that reduced GH levels during early life cause a long-term reduction in bone mineralization. Our study points to the novel role of Six3 in post-proliferative neurons to regulate metabolic function through SS neuron control of GH release.


Association of Clinicopathological Features With Outcome in Chondrosarcomas of the Head and Neck.
The aim of this study is to assess the association between clinical and radiological features as well as of isocitrate dehydrogenase 1 and 2 (IDH 1,2) mutations with outcome in head and neck chondrosarcomas. Retrospective study. Tertiary referral center. Clinical, histological, and molecular data of patients with head and neck chondrosarcomas treated by surgery were collected. Forty-six patients were included. The mean age at diagnosis was 56 years (range, 17-78). The tumor originated from the skull base (52.2%), facial bones (28.2%), or laryngotracheal area (19.6%). At last follow-up (median 52.5 months), 38 patients were alive, 30 of which were disease free, whereas 8 had died, 4 of disease progression and 4 of other causes. Fourteen (30.4%) had local recurrence and 2 (4.3%) had lung metastasis. All cases were negative for cytokeratin AE1/AE3, brachyury, and IDH1 at immunohistochemistry, while Sanger sequencing identified IDH1/2 point mutations, typically IDH1 R132C, in 9 (37.5%) tumors arising from the skull base. Margin infiltration on the surgical specimen negatively affected the outcome, whereas no correlation was identified with IDH mutation status. An adequate margin positively affects survival. IDH mutation status does not affect patient outcome.


Medicinal leeches used to salvage a traumatic nasal flap.
We report a case in which medicinal leeches (Hirudo medicinalis) were used to rescue a traumatic nasal flap from venous congestion and loss. A healthy 18-year-old had a bicycling accident and, in addition to other facial injuries, presented with a complex full thickness nasal laceration. After he had been resuscitated and the flap sutured, he was treated with two leeches four times a day for 48 h. His recovery was satisfactory and uncomplicated. Oral and maxillofacial surgeons should be familiar with the use of leeches, as they have a small but occasionally important role in the management of both traumatic and reconstructive flaps.


Ecology of SO2 resistance: III. Metabolic changes of C3 and C4 Atriplex species due to SO2 fumigations.
The photosynthetic processes of two ecologically-matched, herbaceous Atriplex species differed in their response to SO2 fumigations. Atriplex triangularis, a C3 species, was more sensitive than the C4 species, A. sabulosa. This difference in sensitivity can be attributed in part to the higher conductance of the C3 species in normal air and saturating light as well as greater stimulation of stomatal opening following exposure to SO2. In addition, photosynthetic mechanisms of the C3 species had higher intrinsic SO2 sensitivity than the C4 species. Differences between photosynthetic responses of these two species may also reflect differences in morphological configuration of mesophyll tissues and greater SO2 sensitivity of the initial photosynthetic carboxlating enzyme of the C3 species. It is likely that certain of the differences in photosynthetic SO2 sensitivity of these contrasting C3 and C4 Atriplex species are characteristic of C3 and C4 plants in general.


Comparison of systemic absorption between ofloxacin ophthalmic in situ gels and ofloxacin conventional ophthalmic solutions administration to rabbit eyes by HPLC-MS/MS.
In recent years, many pharmaceutical scientists have focused on developing the in situ gel-forming systems to overcome the poor bioavailability and therapeutic response exhibited by conventional ophthalmic solutions due to rapid pre-corneal elimination of the drug. The present work was to compare the systemic absorptions of ophthalmic ofloxacin in situ gel with the conventional ofloxacin eye drop after topical instillation to rabbit eyes by HPLC-MS/MS method and also determine the relative contribution of the nasal and the conjunctival mucosae to systemic ofloxacin absorption following topical instillation. The systemic AUC, Cmax, Tmax and Ke for ophthalmic in situ gel and ophthalmic solution after ocular instillation were 202.63±118.85 and 202.25±57.74 ng mL(-1) h, 54.22±28.31 and 48.4±25.97 ng mL(-1), 1.08±0.20 and 1.25±0.88 h, 0.0576±0.0207 and 0.0388±0.0248, respectively. And the values for the ratios of the AUC of anterior chamber of rabbit eye to blood plasma, AUCac/AUCpl, for ofloxacin conventional eye drop and in situ gel were 0.25 and 0.52, respectively. Statistic results showed that there was no significant difference in systemic absorption between the test groups and the reference groups (P>0.05) as both formulations have an AUCsa/AUCpl of 0.35. Therefore, the ophthalmic in situ gel may not decrease the drugs systemic absorption when administered in an equivalent dose as ophthalmic solutions into the rabbit eyes.


The effect of repetition tempo on cardiovascular and metabolic stress when time under tension is matched during lower body exercise.
To investigate the effect of repetition tempo on cardiovascular and metabolic stress when time under tension (TUT) and effort are matched during sessions of lower body resistance training (RT). In a repeated-measures, cross-over design, 11 recreationally trained females (n = 5) and males (n = 6) performed 5 sets of belt squats under the following conditions: slow-repetition tempo (SLOW; 10 reps with 4-s eccentric and 2-s concentric) and traditional-repetition tempo (TRAD; 20 reps with 2-s eccentric and 1-s concentric). TUT (60 s) was matched between conditions and external load was adjusted so that lifters were close to concentric muscular failure at the end of each set. External load, total volume load (TVL), impulse (IMP), blood lactate, ratings of perceived exertion (RPE), HR, and muscle oxygenation were measured. Data indicated that TVL (p < 0.001), blood lactate (p = 0.017), RPE (p = 0.015), and HR (p < 0.001) were significantly greater during TRAD while external load (p = 0.030) and IMP (p = 0.002) were significantly greater during SLOW. Whether it was expressed as minimal values or change scores, muscle oxygenation was not different between protocols. When TUT is matched, TVL, cardiovascular stress, metabolic stress, and perceived exertion are greater when faster repetition tempos are used. In contrast, IMP and external load are greater when slower repetition tempos are used.


Dynamic changes in the osteoclast cytoskeleton in response to growth factors and cell attachment are controlled by beta3 integrin.
The beta3 integrin cytoplasmic domain, and specifically S752, is critical for integrin localization and osteoclast (OC) function. Because growth factors such as macrophage colony-stimulating factor and hepatocyte growth factor affect integrin activation and function via inside-out signaling, a process requiring the beta integrin cytoplasmic tail, we examined the effect of these growth factors on OC precursors. To this end, we retrovirally expressed various beta3 integrins with cytoplasmic tail mutations in beta3-deficient OC precursors. We find that S752 in the beta3 cytoplasmic tail is required for growth factor-induced integrin activation, cytoskeletal reorganization, and membrane protrusion, thereby affecting OC adhesion, migration, and bone resorption. The small GTPases Rho and Rac mediate cytoskeletal reorganization, and activation of each is defective in OC precursors lacking a functional beta3 subunit. Activation of the upstream mediators c-Src and c-Cbl is also dependent on beta3. Interestingly, although the FAK-related kinase Pyk2 interacts with c-Src and c-Cbl, its activation is not disrupted in the absence of functional beta3. Instead, its activation is dependent upon intracellular calcium, and on the beta2 integrin. Thus, the beta3 cytoplasmic domain is responsible for activation of specific intracellular signals leading to cytoskeletal reorganization critical for OC function.


Postoperative Complications and Reoperative Surgery in the Treatment of Patients With Zenker Diverticulum.
The association of the surgical approach, surgical specialty, and other factors with the outcomes of surgical treatment of Zenker diverticulum (ZD) have been debated in the literature. To explore the outcomes of 3 different surgical methods used in the management of ZD and determine the associations between patient characteristics, such as preoperative comorbidities and treatment outcomes. This retrospective, population-based cohort study examined patient records of patients who underwent surgical treatment for ZD from the Care Register for Healthcare database in Finland between January 1996 and December 2015. Data review and analysis were completed in 2021. Surgical treatment for ZD. Complications of surgical procedures used in the management of ZD. In this study, 1044 patients (median [IQR] age, 70.0 [22.0-98.0] years; 416 female individuals [39.8%]) surgically treated for ZD were identified. Most patients (606 [58.0%]) had no preoperative comorbidities. A total of 67 (6.4%) complications were recorded, with a mortality rate of 0.9%. The likelihood of complications was associated with patient age (t [1042] = 2.28; Cohen d, 0.29; 95%, CI 0.04, 0.54), surgical approach (Cramer V = 0.14 [95% CI 0.07-0.21]), and surgical specialty (Cramer V, 0.16; 95% CI, 0.06-0.28). The median (IQR) length of stay in association with the primary surgical intervention was 3.0 (0-85.0) days. Length of stay was associated with patient age (Cramer V, 0.14; 95% CI, 0.06-0.25), especially in patients older than 90 years, surgical approach (F [2, 466.2] = 26.9; ηp2 = 0.08; 95% CI, 0.05-0.11), and surgical specialty (F [4, 22.1] = 11.0; ηp2 = 0.07; 95% CI, 0.04-0.10). Reoperation was associated with the initial surgical approach (Cramer V, 0.18; 95% CI, 0.12-0.23) and surgical specialty (Cramer V, 0.14; 95% CI, 0.09-0.21). The results of this cohort study suggest that the outcomes of surgical management depended on the surgical approach, surgical specialty, and patient age. Overall, surgical treatment may be considered safe and may be considered for all patients with symptomatic ZD.


β-Cyclodextrin hydrogels for the ocular release of antibacterial thiosemicarbazones.
Two types of hydrophilic networks with conjugated beta-cyclodextrin (β-CD) were developed with the aim of engineering useful platforms for the localized release of an antimicrobial 5,6-dimethoxy-1-indanone N4-allyl thiosemicarbazone (TSC) in the eye and its potential application in ophthalmic diseases. Poly(2-hydroxyethyl methacrylate) soft contact lenses (SCLs) displaying β-CD, namely pHEMA-co-β-CD, and super-hydrophilic hydrogels (SHHs) of directly cross-linked hydroxypropyl-β-CD were synthesized and characterized regarding their structure (ATR/FT-IR), drug loading capacity, swelling and in vitro release in artificial lacrimal fluid. Incorporation of TSC to the networks was carried out both during polymerization (DP method) and after synthesis (PP method). The first method led to similar drug loads in all the hydrogels, with minor drug loss during the washing steps to remove unreacted monomers, while the second method evidenced the influence of structural parameters on the loading efficiency (proportion of CD units, mesh size, swelling degree). Both systems provided a controlled TSC release for at least two weeks, TSC concentrations (up to 4000μg/g dry hydrogel) being within an optimal therapeutic window for the antimicrobial ocular treatment. Microbiological tests against P. aeruginosa and S. aureus confirmed the ability of TSC-loaded pHEMA-co-β-CD network to inhibit bacterial growth.


Transportation mode and timing of spinal cord decompression and stabilization in patients with traumatic spinal cord injury in Iran.
Cross-sectional retrospective study. To describe the transportation mode to hospital and timing of spinal cord decompression and stabilization (D&S), length of hospital stay, frequency of pressure injuries, and sepsis during hospitalization. Brain and Spinal Injury Research Center, Tehran, Iran. Eight hundred and thirty patients with traumatic spinal cord injury (TSCI) were enrolled. Mode of transportation and length of time to reach the first hospital, length of hospital stay (LOS), and the time span between hospital arrival and decompression and stabilization (D&S) were recorded. Fifty-nine percent of the enrolled individuals were transported to the first hospital by ambulance, while 41% were transferred by vehicles without medical equipment and personnel. Median length of time to reach the first hospital was 1 h for both ambulance and non-equipped car groups, with no statistically significant difference (p = 0.1). Median LOS, frequencies of pressure injuries, and sepsis based on the injury levels were not significantly different between two transportation modalities. One hundred and seventy-seven individuals had early surgery, and 254 had late surgery. Median LOS was 13 days in the early surgery group and 20 days in the late surgery group (p = 0.002). Frequencies of pressure injuries and sepsis were not significantly different between the late and early surgery groups for various injury levels. About 59% of our patients had been transported to a hospital by non-medical personnel. Those with late surgery had significantly longer LOS. Improving TSCI patients' transportation method and early surgical interventions, if possible, may be considered.


Direct medical costs of disease and gastrointestinal side effects during treatment for arthritis.
We conducted a study to determine the costs of caring for patients with arthritis. Data were obtained from the Medicaid Management Information System (MMIS) of Washington, DC. A retrospective analysis was undertaken of all direct medical costs related to individual Medicaid recipients who obtained treatment for arthritis. First, all data were adjusted for patient compliance with nonsteroidal anti-inflammatory drugs (NSAIDs). Second, we determined the actual expenditure of treating arthritis. Last, the medical costs of treating adverse gastrointestinal side effects were examined. There was a linear relationship between compliance and pharmaceutical dose schedule per diem. Treatment costs per quarter were $145; 54 percent of the cost was for NSAIDs with the remainder equally divided between physician and hospital costs. Approximately 25 percent of the population experienced NSAID-related gastrointestinal side effects that required further medical care. The per-quarter mean cost of treating these adverse gastrointestinal drug reactions was $66 per person, which added nearly 46 percent to the per-quarter mean cost of treatment. The total cost of treating patients with arthritis therefore averaged $211 per quarter. Nearly one third of overall cost went to provide medical care to the 25 percent of the population who experienced adverse reactions, and slightly more than two thirds went towards treating the disease itself. Overall costs of treating adverse drug reactions were accounted for by pharmaceuticals (about 42 percent), usually the histamine (H2)-receptor antagonist cimetidine, rare but expensive inpatient hospital care (about 38 percent) and physician visits (about 20 percent).


Social vulnerability, exposure to environmental risk factors, and accessibility of healthcare services: Evidence from 2,000+ informal settlements in Argentina.
Globally, the question of how to improve the living standards of the inhabitants of informal settlements is a key political concern. These neighborhoods are characterized by economic vulnerability, social marginalization, and inaccessibility of basic services. The aim of this study is to provide evidence about the environmental risk factors faced by these populations in Argentina, and to identify whether their greater exposure to risk factors is associated with greater accessibility of healthcare services. We analyzed an original database that provides information about basic characteristics of the neighborhood, environmental risk factors (proximity to garbage dumps, industrial waste, and high-voltage towers), and accessibility of basic healthcare services on over 2000 informal settlements in Argentina. We calculated descriptive statistics and developed multivariate econometric models to estimate the probability of accessibility of healthcare services. On average, 31% of informal settlements were close to a garbage dump, 19% were close to a high-voltage tower, and 10% were close to industrial waste. In addition, 39% of these neighborhoods do not have a healthcare center nearby, 65% do not have an accessible hospital, and 39% are not consistently served by ambulances in the event of an emergency. The econometric estimates suggest that the accessibility of hospital healthcare service and to an ambulance service is positively associated with the age of the neighborhood, and whether the neighborhood is a slum, but there is no evidence of association with the exposure to environmental risk factors. In short, the populations living in informal settlements in Argentina are exposed to harmful environmental risk factors. Access to basic healthcare services is limited and does not reflect the elevated exposure to environmental risks. Health, environmental, and economic dimensions should be considered when designing and implementing public policies for vulnerable populations.


Presence of 21-Hydroxylase Antibodies in a Boy with X-Linked Adrenal Hypoplasia Congenita.
X-linked adrenal hypoplasia congenita is a rare cause of primary adrenal insufficiency (PAI) in children due to mutations in NR0B1/DAX1 (nuclear receptor subfamily 0, group B, member 1/dosage-sensitive sex reversal-adrenal hypoplasia congenita at the critical region of the X chromosome, gene 1). Another rare cause of PAI in children is autoimmune adrenal disease (AAD) which could be either isolated or as part of autoimmune polyglandular syndrome. Antibody to major auto-antigen, 21-hydroxylase, is highly specific for AAD. We report a now 19-month-old male with PAI due to NR0B1 gene mutation and positive adrenal antibodies. Initially, he presented at 15 days of life with isolated hypoaldosteronism which later unfolded into complete PAI. Data analysis was done via retrospective chart review. Genetic analysis of the NR0B1 gene revealed a known hemizygous mutation in c.1069C>T; p.Gln357X. Simultaneously, he was noted to have positive 21-hydroxylase antibodies. According to our knowledge, this is the first case in the literature with NR0B1 mutation causing adrenal insufficiency with coexistent positive adrenal antibodies. In addition to his already compromised adrenal function due to NR0B1 mutation, he is now at risk for the development of associated autoimmune conditions requiring close follow-up.


[Similarities between Metchnikowia and Salmonella 0 6,7 antigens].
The antigenic similarity between Metschnikowia and Salmonella cholerae suis 0 6,7 antigen is reviewed and discussed briefly.


E-cadherin/α-catenin deregulated co-expression in thyroid carcinoma based on tissue microarray digital image analysis.
Deregulation of cell-to-cell adhesion molecules is a common and also critical genetic event in epithelial malignancies leading to an increasing metastatic potential. Among them, e-cadherin and catenins--especially α and β--, act as oncogenes during the carcinogenetic process affecting specific signaling transduction pathways (i.e. Wnt/ b-catenin). Concerning thyroid carcinoma, decreased or loss of expression in these proteins seems to affect the biological behavior of the neoplasm increasing its aggressiveness. The aim of this study was to investigate the deregulation of e-cadherin/α-catenin complex in thyroid carcinomas. Thirty-five paraffin-embedded tissue samples including thyroid carcinomas (N=20) and also 15 cases of benign follicular nodules were cored at 1 mm diameter and transferred to a microarray block. Immunohistochemistry (IHC) was performed using anti-e-cadherin/α-catenin antibodies. Digital image analysis was also implemented for measuring the corresponding protein expression levels. E-cadherin/α-catenin protein expression demonstrated a significant progressive decrease regarding benign and malignant lesions (p=0.001). Simultaneous e-cadherin/α-catenin reduced or loss of expression was observed in 10/20 (50%) cancer cases correlated to advanced stage (especially nodal metastasis) of the examined tumours (p=0.02). Concerning the histological type, combined loss of e-cadherin/α-catenin expression was predominantly associated with follicular and anaplastic histology (p=0.001). Interestingly, α-catenin protein expression pattern was significantly correlated with the grade of differentiation of the examined malignancies (p=0.01). Progressive loss of e-cadherin mainly and also α-catenin expression is associated with an aggressive phenotype (low differentiation, increased metastatic activity/advanced stage) in thyroid carcinomas. Based on their aberrant protein expression, novel agents have been developed for restoring their normal function.


The minimally invasive endoscopic technique for the treatment of symptomatic benign bone lesions: Preliminary results from a retrospective study.
The present study aimed to evaluate the short-term clinical feasibility and efficacy of the minimally invasive endoscopic technique (MIET) for the treatment of symptomatic benign bone lesions. This single-institution retrospective study investigated 34 patients with symptomatic benign bone lesions from December 2015 to June 2017. Patients involved in this study presented with definite indications for surgical intervention. All procedures were performed under endoscopic guidance for direct visualization followed by complete curettage of tumor tissue. There were 19 males and 15 females, with a mean age of 33.3 ± 12.7 years (range, 17-68 years). The lesions were located in the upper extremities (20, 58.8%), lower extremities (9, 26.5%) and pelvis (5, 14.7%). Primary outcomes were measured before and after intervention using the visual analog scale (VAS), the Musculoskeletal Tumor Society (MSTS) stage and the 36-item Short-Form Health Survey (SF-36) scoring system. Of the 34 patients included in this study, all completed follow-up examinations, with a mean follow-up duration of 22.4 ± 7.6 months (range, 13-35 months). Significantly improved VAS, MSTS and SF-36 scores were observed at 3 months after the initial treatment (P < 0.001), suggesting enhanced pain relief and improved functional recovery and quality of life following surgery. All procedures were technically successful, with the exception of 3 cases (8.8%) manifesting access site numbness; these patients recovered within the follow-up period through symptomatic treatment alone. Only 2 patients (5.9%; one osteoblastoma and one enchondroma) experienced local recurrence and underwent standard open curettage within the follow-up period. All patients showed functional stability without any major complications. The MIET is an effective and safe alternative treatment for symptomatic benign bone lesions. The short-term efficacy of MIET was favorable and associated with improved pain palliation, quality of life and functional recovery.


A randomized controlled trial to test the efficacy of a diabetes behavioral intervention to prevent memory decline in older blacks/African Americans with diabetes and mild cognitive impairment.
The prevalence of dementia in Blacks/African Americans (AAs) is almost twice that of Whites. Inequities in access to health care, socioeconomic conditions, and diabetes contribute to this disparity. Poorly controlled diabetes, which is more prevalent in Blacks/AAs, causes microvascular disease and neurodegeneration and increases dementia risk. Improving glycemic control, therefore, may prevent cognitive decline. To address this issue, we developed Diabetes Regulation for Eyesight and Memory (DREAM), a community health worker (CHW)-led behavioral intervention to improve diabetes self-management and thereby prevent cognitive decline. DREAM consists of home-based diabetes education, goal setting, and telehealth visits with a diabetes nurse educator. Exploratory aims will investigate whether APOE genotype moderates and retinal biomarkers mediate treatment effects. This report describes the trial's rationale, methodology, and study procedures. (clinicaltrials.gov identifier NCT04259047). This randomized controlled trial will test the efficacy of DREAM to prevent decline in memory (primary outcome) in Blacks/AAs aged 65+ with poorly controlled diabetes and Mild Cognitive Impairment (MCI). Two hundred participants will be randomized to DREAM or an attention control condition, and will receive 11 in-home treatment sessions over two years. Outcome data are collected at 6, 12, 18, and 24 months. The primary outcome is verbal learning as measured by Hopkins Verbal Learning Test (HVLT) Total Recall scores. Participants will have retinal imaging at baseline, 12, and 24 months. This research aims to prevent cognitive decline in older Blacks/AAs with diabetes and MCI. If successful, this research will preserve health in an underserved population and reduce racial health disparities.


Nuclear Receptor NR1H3 in Familial Multiple Sclerosis.
Multiple sclerosis (MS) is an inflammatory disease characterized by myelin loss and neuronal dysfunction. Despite the aggregation observed in some families, pathogenic mutations have remained elusive. In this study, we describe the identification of NR1H3 p.Arg415Gln in seven MS patients from two multi-incident families presenting severe and progressive disease, with an average age at onset of 34 years. Additionally, association analysis of common variants in NR1H3 identified rs2279238 conferring a 1.35-fold increased risk of developing progressive MS. The p.Arg415Gln position is highly conserved in orthologs and paralogs, and disrupts NR1H3 heterodimerization and transcriptional activation of target genes. Protein expression analysis revealed that mutant NR1H3 (LXRA) alters gene expression profiles, suggesting a disruption in transcriptional regulation as one of the mechanisms underlying MS pathogenesis. Our study indicates that pharmacological activation of LXRA or its targets may lead to effective treatments for the highly debilitating and currently untreatable progressive phase of MS.


A comparison of d, l-fenfluramine and citalopram challenges in healthy adults.
Dimensional personality characteristics (e.g. impulsivity) and related behaviors and psychiatric disorders are linked to abnormalities of central nervous system (CNS) serotonergic functioning. Although neuroendocrine [e.g. plasma prolactin (PRL)] responses to the serotonin agonist, fenfluramine, have been used widely to index CNS serotonergic responsivity, safety concerns constrain continued use of fenfluramine. Citalopram, which inhibits serotonin reuptake, may serve as an alternative pre-synaptic neuropharmacologic challenge agent, due to its high selectivity and absence of intrinsic activity at serotonin or other receptor families. Twenty-two healthy adults who had been administered a fenfluramine challenge before May 1996 completed a 5-h oral citalopram challenge 3-6 years later. PRL responsivity to citalopram correlated significantly with PRL response to fenfluramine for baseline-corrected maximal and area-under-the-curve (AUC) indices ( r's > or =0.49, P's< or =0.02). The magnitude of the correlations is notable given the length of time between challenges. The results support the use of citalopram as an alternate neuroendocrine challenge to index CNS serotonergic responsivity.


Progress towards automated diabetic ocular screening: a review of image analysis and intelligent systems for diabetic retinopathy.
Patients with diabetes require annual screening for effective timing of sight-saving treatment. However, the lack of screening and the shortage of ophthalmologists limit the ocular health care available. This is stimulating research into automated analysis of the reflectance images of the ocular fundus. Publications applicable to the automated screening of diabetic retinopathy are summarised. The review has been structured to mimic some of the processes that an ophthalmologist performs when examining the retina. Thus image processing tasks, such as vessel and lesion location, are reviewed before any intelligent or automated systems. Most research has been undertaken in identification of the retinal vasculature and analysis of early pathological changes. Progress has been made in the identification of the retinal vasculature and the more common pathological features, such as small aneurysms and exudates. Ancillary research into image preprocessing has also been identified. In summary, the advent of digital data sets has made image analysis more accessible, although questions regarding the assessment of individual algorithms and whole systems are only just being addressed.


Actin Sliding Velocities are Influenced by the Driving Forces of Actin-Myosin Binding.
Unloaded shortening speeds, V, of muscle are thought to be limited by actin-bound myosin heads that resist shortening, or V = a·d·τon-1 where τon-1 is the rate at which myosin detaches from actin and d is myosin's step size. The a-term describes the efficiency of force transmission between myosin heads, and has been shown to become less than one at low myosin densities in a motility assay. Molecules such as inorganic phosphate, Pi, and blebbistatin inhibit both V and actin-myosin strong binding kinetics suggesting a link between V and attachment kinetics. To determine whether these small molecules slow V by increasing resistance to actin sliding or by decreasing the efficiency of force transmission, a, we determine how inhibition of V by Pi and blebbistatin changes the force exerted on actin filaments during an in vitro sliding assay, measured from changes in the rate, τbreak-1, at which actin filaments break. Upon addition of 30 mM Pi to a low (30 μM) [ATP] motility buffer V decreased from 1.8 to 1.3 μm·sec-1 and τbreak-1 from 0.029 to 0.018 sec-1. Upon addition of 50 μM blebbistatin to a low [ATP] motility buffer, V decreased from 1.0 to 0.7 μm·sec-1 and τbreak-1 from 0.059 to 0.022 sec-1. These results imply that blebbistatin and Pi slow V by decreasing force transmission, a, not by increasing resistive forces, implying that actin-myosin attachment kinetics influence V.


[Patient Questionnaire for Assessment of Rehabilitation Motivation (PAREMO-20) - psychometric evaluation and validation in a sample of cancer patients with different tumour sites].
A significant body of research suggests that patient motivation is related to better rehabilitation outcome with regard to psychosocial and physical well-being. Thus, patient motivation gains increasing attention with regard to the course of treatment and individual treatment planning in the practice and research in medical rehabilitation. This study aims to validate the PAREMO-20, a measure of rehabilitation motivation in a sample of cancer patients with different tumour sites. 1193 cancer patients participated in a prospective study evaluating the medical and psychosocial effects of inpatient cancer rehabilitation. A set of various questionnaires was completed at the beginning and at the end of the rehabilitation measure as well as at one year follow-up (participation rate at follow-up: 78%). The PAREMO-20 was psychometrically examined on this sample. Validity was examined using a cancer-specific questionnaire for individual therapy goals, as well as the HADS-D and the SF-8. The original six factors were replicated. The factor solution emerging through PCA was tested with a confirmatory factor analysis. Maximum likelihood estimation of this model produced good fit statistics. Internal consistencies were high to satisfactory with Cronbach's Alpha=0.88 to Alpha=0.59. Psychological distress and physical impairments were positively associated with anxiety and depression, as well as with therapy goal dimensions. Moderate to high (negative) correlations were observed with health related quality of life, in particular with the mental-health dimension (r=-0.74, p=0.01). The PAREMO-20 is a reliable, valid and economic instrument, which can be recommended for use in clinical care.


P-cadherin induces anoikis-resistance of matrix-detached breast cancer cells by promoting pentose phosphate pathway and decreasing oxidative stress.
Successful metastatic spreading relies on cancer cells with stem-like properties, glycolytic metabolism and increased antioxidant protection, allowing them to escape anoikis and to survive in circulation. The expression of P-cadherin, a poor prognostic factor in breast cancer, is associated with hypoxic, glycolytic and acidosis biomarkers. In agreement, P-cadherin-enriched breast cancer cell populations presents a glycolytic and an acid-resistance phenotype. Our aim was to evaluate whether P-cadherin expression controls the glycolytic and oxidative phosphorylation fluxes of matrix-detached breast cancer cells, acting as an antioxidant and enhancing their survival in anchorage-independent conditions. By using matrix-detached breast cancer cells, we concluded that P-cadherin increases glucose-6-phosphate dehydrogenase expression, up-regulating the carbon flux through the pentose phosphate pathway, while inhibiting pyruvate oxidation to acetyl-coA via pyruvate dehydrogenase kinase-4 (PDK-4) activation. Accordingly, P-cadherin expression conferred increased sensitivity to dichloroacetate (DCA), a PDK inhibitor. P-cadherin expression also regulates oxidative stress in matrix-detached breast cancer cells, through the control of antioxidant systems, such as catalase and superoxide dismutases (SOD)1 and 2, providing these cells with an increased resistance to doxorubicin-induced anoikis. Importantly, this association was validated in primary invasive breast carcinomas, where an enrichment of SOD2 was found in P-cadherin-overexpressing breast carcinomas. In conclusion, we propose that P-cadherin up-regulates carbon flux through the pentose phosphate pathway and decreases oxidative stress in matrix-detached breast cancer cells. These metabolic remodeling and antioxidant roles of P-cadherin can promote the survival of breast cancer cells in circulation and in metastatic sites, being a possible player in breast cancer therapeutic resistance to pro-oxidant-based interventions.


Are medical postgraduate certification processes valid? A systematic review of the published evidence.
To collate the published works on validation of assessments used in postgraduate medical certification. Systematic review of original papers on reliability and validity of assessments used in medical postgraduate certification. Medical and education research databases. Fifty-five papers were identified from 1985 to 2000. A wide range of approaches to validation were employed. Inter-rater reliability and internal consistency were the most reported foci for validation. There were just two papers on consequential validity, and only a few on construct validity. These two forms of validity are considered central in recent general education writing. The majority of papers were from general and family practice. There was a noticeable lack of papers from the UK Royal Colleges (except the Royal College of General Practitioners), despite 5 years of the new unified grade and the renewed emphasis on the role of the Royal Colleges in setting assessment criteria. There is a relative scarcity of published papers on validation of assessment for postgraduate medical certification considering the influence these high stakes processes have on doctors career progression and employment opportunities. General and family practice institutions in a number of English speaking countries have set an example to others, by showing that rigour and transparency in assessment development and implementation can be reflected in publication.