Brain networks underlying the clinical effects of long-term subthalamic stimulation for Parkinson's disease: a 4-year follow-up study with rCBF SPECT.
The motor improvement derived from high-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) is maintained over time after surgery. The aim of the present prospective follow-up study was to assess regional cerebral blood flow (rCBF) changes related to such improvement in the long term. Ten PD patients with STN-DBS underwent 3 rCBF SPECT studies at rest-once preoperatively in the off-drug condition and the other 2 postoperatively in the off-drug/on-stimulation conditions at 5 +/- 2 and 42 +/- 7 mo. Patients were administered with Unified Parkinson Disease Rating Scale (UPDRS), Hoehn and Yahr (H&Y) scale, and Schwab and England (S&E) scale. Statistical parametric mapping was used to investigate rCBF changes during long-term STN stimulation in comparison with preoperative rCBF and the relationship between rCBF and UPDRS scores was used as a covariate of interest. All patients showed a maximum clinical improvement during the first months after surgery and remained rather stable during further follow-up. The effect of STN-DBS from the pre- to the postoperative condition at 5 mo was to produce rCBF increases in the presupplementary motor area (pre-SMA), premotor (PMC), and dorsolateral prefrontal cortices. From the postoperative condition at 5 mo to that at 42 mo, the STN stimulation produced further rCBF increases in these frontal areas, and also in the primary motor/sensory cortices, globus pallidi, ventral lateral thalamic nuclei, cerebellum, pons, and midbrain entailing the substantia nigra (P < 0.0001). A correlation was detected between the improvement in motor scores and the rCBF increase in the pre-SMA and PMC (P < 0.0001). No correlation was present between the daily consumption of levodopa and the rCBF. Our study suggests that the long-term STN stimulation leads to improvement in neural activity in the frontal motor/associative areas. After an rCBF increase during the first months of stimulation, these regions showed a further increment in the later phase, which was accompanied by an increased activity in subcortical structures. The correlation between motor improvement and rCBF increase in higher order motor cortical areas suggests that even in the long term, as well as in the short term, the STN-DBS achieves its therapeutic benefit by restoring the activity within these cortical regions.


Histological, immunohistochemical and clinical considerations on amniotic membrane transplant for ocular surface reconstruction.
Amniotic membrane (AM) transplantation has been used successfully worldwide in ophthalmology plastic surgery for over 100 years. This review presents the histological and the immunohistochemical features of AM compared to those of the conjunctiva and discusses the techniques of processing and preservation, its mechanism of action in ocular reconstruction, its clinical ophthalmic indications, but also advantages and limitations of grafting with this biomaterial.


Psychosocial factors associated with suicidal ideation in clinical patients with depression.
Depression is a major risk factor for suicide, but few studies have examined psychosocial risk factors for suicide in clinical patients with depression. The purpose of this study was to investigate psychosocial factors which could be associated with suicidal ideation in clinical patients with depression including: sick-leave, help-seeking behavior, and reluctance to admit mental health problems. A multi-center cross-sectional survey using self-report questionnaire was conducted at 54 outpatient psychiatric clinics in Tokyo in 2012. Adult outpatients who were diagnosed by psychiatrists as mood disorders (F30-F39) in the International Classification of Diseases-10 (ICD-10) were included in the study. Those who met the criteria for current hypomanic or manic episode were excluded from the study. A total of 189 patients with depression participated in the survey. Multivariable logistic regression analysis showed that taking sick-leave and having sought help from family were associated with decreased odds of current suicidal ideation. Moderate or more severe depression was associated with increased odds of suicidal ideation, and reluctance to admit own mental health problem tended to increase odds of suicidal ideation. Living status and suicidal ideation before consultation with psychiatrist were not investigated. Severity of suicidal ideation and comorbid psychiatric disorders were not assessed. Importance of treatment of more severe depression for suicide prevention was confirmed. Industrial health staffs should consider the possibility of positive effect of taking sick-leave when they see employees with depression. Promoting help-seeking for family and reducing stigma of mental illness may be effective for suicide prevention.


RGM and its receptor neogenin regulate neuronal survival.
Repulsive guidance molecule (RGM) is an axon guidance protein that repels retinal axons upon activation of the neogenin receptor. To understand the functions of RGM-neogenin complexes in vivo, we used gene transfer technology to perturb their expression in the developing neural tube of chick embryos. Surprisingly, neogenin over-expression or RGM down-expression in the neural tube induces apoptosis. Neogenin pro-apoptotic activity in immortalized neuronal cells and in the neural tube is associated with the cleavage of its cytoplasmic domain by caspases. Thus neogenin is a dependence receptor inducing cell death in the absence of RGM, whereas the presence of RGM inhibits this effect.


Phytochemical and biological activities of some Iranian medicinal plants.
Due to adverse effects of synthetic compounds, there is a growing interest in utilization of plant-derived natural products in the pharmaceutical and food industries. Iranian endemic medicinal plants widely used in traditional practice have attracted much attention as antibacterial and antioxidant agents. This review attempts to compile the accessible scientific research pertained to phytochemical compounds, antibacterial and antioxidant effects of essential oils obtained from some of the most widely used and distributed medicinal plants in Iran. This review has been compiled using references via reliable databases (Google Scholar, SID and Science Direct) from 2010 to 2020. This literature review was limited to references published in English and Persian languages. Based on studies heretofore carried out, essential oils isolated from mentioned medicinal plants exhibited strong antioxidant activity which is attributed to their main phytochemical compounds; thymol, carvacrol, p-cymene and γ-terpinene. In addition, the antibacterial activities of essential oils of most plant species from Apiaceae and Asteraceae families were more susceptible against Gram-positive bacteria; Staphylococcus aureus and Bacillus cereus than Gram-negative bacteria; however, essential oils of other studied plant species manifested similar behaviours against both Gram-positive and -negative bacteria. As there is rich ethnobotanical knowledge behind Iranian endemic medicinal plants, further scientific research is required to prove their safety and efficacy. This review revealed that there are numerous valuable medicinal plants adoptable in food and pharmaceutical industries in the near future.


[Hypertrophy due to left cardiac insufficiency: role of the neurohumoral system].
Left ventricular hypertrophy in patients with hypertensive heart disease is associated with impaired relaxation and myocardial interstitial fibrosis leading to enhanced filling pressure, referred to as left ventricular diastolic dysfunction. Impairment of systolic function, characterized by reduced ejection fraction occurs at a later stage. Activation of the renin-angiotensin-aldosterone system contributes to progression to heart failure by at least two mechanisms: (1) increased left ventricular loading conditions due to vasoconstriction and retention of sodium; (2) direct effects on the myocardium resulting in myocyte hypertrophy and interstitial fibrosis.


[A specific property of bacteria in the genus Klebsiella--a color reaction with 5-aminosalicylic acid in the nutrient medium].
For the first time bacteria of the genus Klebsiella have been found to possess a specific property, characteristic of this genus only, i.e. the capacity of giving color reaction with 5-aminosalicylic acid. This reaction can be observed in all Klebsiella species under study: K. pneumoniae (94.4 +/- 2.3%), K. ozaenae (93.3 +/- 4.5%), K. rhinoscleromatis (100%), K. oxytoca (88.0 +/- 4.9%), K. mobilis (92-5 +/- 4.3% of the strains). In all other bacteria under study (40 species, 22 genera and 7 families) the reaction is negative. The test for the color reaction with 5-aminosalicylic acid confirms the belonging of K. mobilis (Enterobacter aerogenes) to the genus Klebsiella, thus making it possible to simplify and accelerate the identification of Klebsiella.


[Recent advances in the application of TAT, TM, t-PAIC and PIC in thromboembolism].
Thromboembolism is a crucial part of the global disease burden. It has high incidence, high mortality and disability rates, and the mechanism of occurrence and development is extremely complex. It is difficult to detect the disease in the early stage so that we have trouble with clinical prevention and treatment in general. At present, four items of blood coagulation and D-dimer have been widely used in the evaluation and auxiliary diagnosis of thromboembolism, the monitoring of effect for antithrombotic drugs and other fields. The thrombus biomarkers including thrombin-antithrombin complex (TAT), thrombomodulin (TM), tissue plasminogen activator-inhibitor complex (t-PAIC) and α2-plasmin inhibitor-plasmin complex (PIC) fill the gap of laboratory diagnosis before clinical symptoms appear in some degree. This article aims to explain the current application status of TAT, TM, t-PAIC and PIC in thromboembolism and explore their potential application value, so as to provide a reference for selecting appropriate early monitoring indicators for high-risk population of thromboembolism.


The management and mismanagement of a suicidal patient.
The author begins with the premise that the actions of therapists and hospital staff can contribute to the likelihood that a suicidal patient will eventually take his life. He recounts a case history of a depressed 51-year-old man who was hospitalized following a suicide attempt and delineates eight "mistakes" that contributed to the patient's eventual suicide and that are common occurrences in dealing with a suicidal patient. He believes that if more therapists and mental health professionals share mistakes and experiences of this kind with each other, such errors might be minimized or even prevented.


Marine mammals as sentinel species for oceans and human health.
The long-term consequences of climate change and potential environmental degradation are likely to include aspects of disease emergence in marine plants and animals. In turn, these emerging diseases may have epizootic potential, zoonotic implications, and a complex pathogenesis involving other cofactors such as anthropogenic contaminant burden, genetics, and immunologic dysfunction. The concept of marine sentinel organisms provides one approach to evaluating aquatic ecosystem health. Such sentinels are barometers for current or potential negative impacts on individual- and population-level animal health. In turn, using marine sentinels permits better characterization and management of impacts that ultimately affect animal and human health associated with the oceans. Marine mammals are prime sentinel species because many species have long life spans, are long-term coastal residents, feed at a high trophic level, and have unique fat stores that can serve as depots for anthropogenic toxins. Marine mammals may be exposed to environmental stressors such as chemical pollutants, harmful algal biotoxins, and emerging or resurging pathogens. Since many marine mammal species share the coastal environment with humans and consume the same food, they also may serve as effective sentinels for public health problems. Finally, marine mammals are charismatic megafauna that typically stimulate an exaggerated human behavioral response and are thus more likely to be observed.


Enantioselective Claisen rearrangements with a hydrogen-bond donor catalyst.
N,N'-Diphenylguanidinium ion associated with the noncoordinating BArF counterion is shown to be an effective catalyst for the [3,3]-sigmatropic rearrangement of a variety of substituted allyl vinyl ethers. Highly enantioselective catalytic Claisen rearrangements of ester-substituted allyl vinyl ethers are then documented using a new C2-symmetric guanidinium ion derivative.


[Two serious eye injuries after tampering with fireworks].
In this article we describe two separate cases of serious eye injuries that were the result of two teenagers´ attempts to make home-made explosives out of fireworks. They had tampered with the same brand of fireworks, Víti, that appears to be popular for this purpose and instructions are available on the internet. One boy got an intraocular glass splinter and underwent vitrectomy for removal. The other boy suffered burns on his corneas that were treated with amniotic membranes. In both cases the outcome was better than expected at first. The objective of this article is to draw attention to the danger of tampering with fireworks and the necessity of preventive measures to minimize the risk of serious eye injuries.


Analysis of polychlorodibenzo-p-dioxins and polychlorodibenzofurans in stationary source emissions in GC-MS/MS using hydrogen as the carrier gas.
The European and American methods for the determination of polychlorodibenzo-p-dioxins and polychlorodibenzofurans in stationary source emissions require a high-resolution mass spectrometer detector. At the same time, all of the 17 toxic 2,3,7,8-chlorine-substituted isomers have to be separated by an appropriate chromatographic method. The resulting analysis has long runtimes and sometimes a double-column run is needed, which results in a huge waste of time, money and manual labor. To obtain a fast and cost-effective but still reliable analytical system, a single-column gas chromatography with hydrogen as carrier gas and tandem mass spectrometry detection is proposed. The use of hydrogen as the carrier gas is a good choice to shorten runtimes and improve the chromatographic resolution, while tandem mass spectrometry is a well-known alternative for this analysis. All the chromatographic and mass spectrometric parameters fill the requirements of the reference methods with a 35% reduction of runtimes. The accuracy is tested with three fly ash samples of a proficiency interlaboratory test. A good correlation between the results is obtained (R2 = 0.992, slope = 0.9675), and no coelutions are noted. The system robustness is tested during 5 years of constant use and the maximal relative standard deviation of the relative response factor is 18.8%.


Regulatory T cells maintain long-term tolerance to myelin basic protein by inducing a novel, dynamic state of T cell tolerance.
The pathogenesis of multiple sclerosis involves a breakdown in T cell tolerance to myelin proteins like myelin basic protein (MBP). Most MBP-specific T cells are eliminated by central tolerance in adult mice, however, the developmentally regulated expression of MBP allows MBP-specific thymocytes in young mice to escape negative selection. It is not known how these T cells that encounter MBP for the first time in the periphery are regulated. We show that naive MBP-specific T cells transferred into T cell-deficient mice induce severe autoimmunity. Regulatory T cells prevent disease, however, suppression of the newly transferred MBP-specific T cells is abrogated by activating APCs in vivo. Without APC activation, MBP-specific T cells persist in the periphery of protected mice but do not become anergic, raising the question of how long-term tolerance can be maintained if APCs presenting endogenous MBP become activated. Our results demonstrate that regulatory T cells induce naive MBP-specific T cells responding to nonactivated APCs to differentiate into a unique, tolerized state with the ability to produce IL-10 and TGF-beta1 in response to activated, but not nonactivated, APCs presenting MBP. This tolerant response depends on continuous activity of regulatory T cells because, in their absence, these uniquely tolerized MBP-specific T cells can again induce autoimmunity.


Artificial intelligence in clinical workflow processes in vascular surgery and beyond.
In the past decade, artificial intelligence (AI)-based applications have exploded in health care. In cardiovascular disease, and vascular surgery specifically, AI tools such as machine learning, natural language processing, and deep neural networks have been applied to automatically detect underdiagnosed diseases, such as peripheral artery disease, abdominal aortic aneurysms, and atherosclerotic cardiovascular disease. In addition to disease detection and risk stratification, AI has been used to identify guideline-concordant statin therapy use and reasons for nonuse, which has important implications for population-based cardiovascular disease health. Although many studies highlight the potential applications of AI, few address true clinical workflow implementation of available AI-based tools. Specific examples, such as determination of optimal statin treatment based on individual patient risk factors and enhancement of intraoperative fluoroscopy and ultrasound imaging, demonstrate the potential promise of AI integration into clinical workflow. Many challenges to AI implementation in health care remain, including data interoperability, model bias and generalizability, prospective evaluation, privacy and security, and regulation. Multidisciplinary and multi-institutional collaboration, as well as adopting a framework for integration, will be critical for the successful implementation of AI tools into clinical practice.


[Submucosal Partial-turbinectomy (SPT) Preceding an Endoscopic Sinus Surgery (ESS) Procedure].
Preceding a endoscopic sinus surgery (ESS), we have proposed performing a submucosal partial-turbinectomy (SPT) which removes a part of the inferior nasal concha bone attached to maxillary sinus with an antrostomy. By this method, we could not only make a large antrostomy but also obtain good maneuverability by opening the middle nasal meatus in ESS. We performed SPT preceding ESS in 140 cases (261 sides) between January 2012 and June 2014. The stenosis rates of the middle nasal meatus were 14.2% (37 sides from 261 sides) in one month, 7.4% (18 sides from 243 sides) in three months and 3.7% (6 sides from 163 sides) in 6 months after surgery. The closing rates of the antrostomy were 1.5% (4 sides from 261 sides) in one month, 2.9% (7 sides from 243 sides) in three months and 6.7% (11 sides from 163 sides) in 6 months after surgery. We considered that the SPT method would contribute to secure sufficient ventilation routes for wound healing of sinusitis following surgery on the mucous membrane. In addition, the SPT method has merit from the point of deceasing risks of atrophic rhinitis and empty nose syndrome by preserving most of the inferior nasal concha.


Hemodynamic changes in patients developing effective hypovolemia after total paracentesis.
In many centers paracentesis is considered the treatment of choice for tense ascites. However, the mechanism of effective hypovolemia after paracentesis, the main complication associated with this procedure, remains unknown. In the current study, systemic hemodynamics was sequentially studied before and after total paracentesis in 46 patients with cirrhosis and tense ascites. The aim of the study was to assess the mechanism of effective hypovolemia after paracentesis. Plasma renin activity and aldosterone, mean arterial pressure, cardiac output (ECO-Doppler) and systemic vascular resistance were measured before, and 3 h, 6 h and 6 days after total paracentesis associated with plasma volume expansion. Effective hypovolemia after paracentesis (defined as 50% increase in plasma renin activity up to a level over 4 ng x m(-1) x h(-1) at the 6th day after paracentesis) occurred in 20 cases [plasma renin activity increased from 8+/-17 to 19+/-2.7 ng x m(-1) x h(-1)]. In the remaining 26 cases no changes in plasma renin activity [8.5+/-2.4 vs. 8.7+/-2.2 ng x m(-1) x h(-1)] were observed. The amounts of ascitic fluid volume removed were similar. Effective hypovolemia after paracentesis was associated with a significant decrease in mean arterial pressure (89+/-2 vs. 81+/-3 mmHg) and systemic vascular resistance [1263+/-67 vs. 1014+/-80 dyn x s(-1) x cm(-5)] 6 days after treatment. In contrast, no significant changes in these parameters were observed in patients not developing this complication. In the whole group of patients a significant inverse relation was observed between changes in plasma renin activity and in systemic vascular resistance (r=0.74;p< 0.001). These results indicate that effective hypovolemia after paracentesis in cirrhosis is predominantly due to an accentuation of the arteriolar vasodilation already present in these patients.


Preventive effects of trimethoprim/sulphamethoxazole on experimental staphylococcic pyelonephritis in rats.
108 white rats weighing 170-250 G were given trimethoprim, sulphamethoxazole and the combination trimethoprim 1/sulphamethoxazole orally and parenterally in order to test the preventive effect of these substances on experimental hematogenous pyelonephritis due to Staphylococcus aureus. Oral applications of 48 mg/kg/24h of trimethoprim/sulphamethoxazole prevented abscess formation. Intraperitoneal applications of 48mg/24h of the combination did not seem as effective as the oral applications. On the other hand, there was no difference between the effects of oral and parenteral applications when the doses were 96 mg/kg/24h. The preventive effects of trimethoprim and sulphamethoxazole alone were much less than those observed when the combination trimethoprim/sulphamethoxazole was given. No peritoneal or other tissue damage was observed after intraperitoneal injections of trimethoprim/sulphamethoxazole in rats.


Parental and peer influences on the risk of adolescent drug use.
Using a probability sample of 4,230 adolescents from grades 7-12, we used negative binomial regression to estimate the effects of peer and six family variables on the risk of adolescent drug use. Peer drug use had relatively strong effects of adolescent drug use. Parental drug attitudes, sibling drug use, and adult drug use had significant direct effects net of peer influences. In addition, they had significant indirect effects that were mediated by peer drug use. The influences of parental monitoring, attachment to mother, and attachment to father were statistically significant but relatively small. The findings applied to alcohol, binge drinking, cigarettes, marijuana, and other illicit drugs. Editors' Strategic Implications: The authors interpret their findings as being more consistent with social learning than social control theory. This research, although cross-sectional and limited to adolescents' self-reports, contributes to a growing literature on the direct and indirect influences of parents on their teens' substance use rates. It speaks to the need for school- and community-based prevention efforts to focus on families as well as peers.


Epigenetic regulation by long noncoding RNAs in osteo-/adipogenic differentiation of mesenchymal stromal cells and degenerative bone diseases.
Bone is a complex tissue that undergoes constant remodeling to maintain homeostasis, which requires coordinated multilineage differentiation and proper proliferation of mesenchymal stromal cells (MSCs). Mounting evidence indicates that a disturbance of bone homeostasis can trigger degenerative bone diseases, including osteoporosis and osteoarthritis. In addition to conventional genetic modifications, epigenetic modifications (i.e., DNA methylation, histone modifications, and the expression of noncoding RNAs) are considered to be contributing factors that affect bone homeostasis. Long noncoding RNAs (lncRNAs) were previously regarded as 'transcriptional noise' with no biological functions. However, substantial evidence suggests that lncRNAs have roles in the epigenetic regulation of biological processes in MSCs and related diseases. In this review, we summarized the interactions between lncRNAs and epigenetic modifiers associated with osteo-/adipogenic differentiation of MSCs and the pathogenesis of degenerative bone diseases and highlighted promising lncRNA-based diagnostic and therapeutic targets for bone diseases.


Torsemide for Prevention of Persistent Postpartum Hypertension in Women With Preeclampsia: A Randomized Controlled Trial.
To evaluate whether torsemide reduces the rate of persistent postpartum hypertension in women with preeclampsia. We conducted a randomized, double-blind, placebo-controlled trial of women with preeclampsia at a tertiary center from August 2016 to September 2017. Those with gestational hypertension or renal or cardiopulmonary failure were excluded. Within 24 hours of delivery, women were randomized one to one to oral torsemide, 20 mg/d, or placebo, for 5 days. Our primary outcome was blood pressure greater than or equal to 150 mm Hg systolic or 100 mm Hg diastolic (or both) on two occasions at least 4 hours apart by postpartum day 5 or by the time of hospital discharge. Assuming a 50% rate of persistent hypertension in women with preeclampsia, 118 participants were required to detect a 50% rate reduction. Analyses were by intention to treat. From August 2016 to September 2017, 118 women were randomized: 59 were allocated to torsemide and 59 to placebo. Overall, 43 (73%) women in the torsemide and 45 (76%) in the placebo group had either preeclampsia with severe features or preeclampsia superimposed on chronic hypertension. The rate of persistent postpartum hypertension was 44% in the torsemide and 58% in the placebo group (relative risk 0.76, 95% CI 0.5-1.1). No differences were seen in rate of hypertension 7-10 days or 6 weeks postpartum, severe hypertension, length of postpartum hospital stay, readmission for hypertension, or adverse events. There were no cases of severe composite morbidity or deaths. In this trial of women with preeclampsia, a 5-day course of postpartum torsemide did not have a significant effect on the rate of postpartum hypertension. ClinicalTrials.gov, NCT02813551.


[The role of dietitian in cardiac rehabilitation and prevention].
Rehabilitation and secondary prevention programs are recognized as an essential part of the overall care of patients with cardiovascular disease. They consist of multidisciplinary strategies aiming at the reduction of modifiable risk factors for cardiovascular disease. Cardiac rehabilitation includes non-pharmacological interventions as: Patients' evaluation. Nutritional counseling. Risk factors management (serum lipids, blood pressure, weight, diabetes, smoking). Psychosocial interventions. Physical activity and cardiovascular physical training counseling. Their effectiveness in the reduction of mortality through the decrease of risk factors has been proven in the last twenty years. Guidelines on appropriate and well-framed interventions have been released and nutritional interventions have a ringside seat in all programs. During 2007, the Italian Association of Dietitians, ANDID, created a working group of expert dietitians, with the goals of making a review of available scientific literature and of elaborating a Professional Position Papers on the role of Dietitian in cardiac rehabilitation and prevention. This Position Paper retrieves and remarks the available evidence that are important for the dietitians, according to their professional role and their contribution in the management of the topic.


Long-term efficacy and safety of azathioprine in ulcerative colitis.
Azathioprine (AZA) is an established treatment for ulcerative colitis (UC).However, controversy exists regarding its efficacy in inducing and maintaining clinical remission, and long-term data are lacking. We studied the effectiveness of AZA in a large cohort of UC patients treated in a single center. All UC patients treated with AZA were identified from a prospective electronic database. We assessed response to therapy at 4 months and sustained clinical benefit at the last point of follow-up. We also examined predictors of response and sustained clinical benefit, as well as outcomes in those treated with AZA for >5 years. The study included 255 patients. At 4 months, 207 (81.2%) of 255 patients were still on AZA and 163 (63.9%) had responded to therapy. At the last point of follow-up 164 (64.3%) patients were still receiving AZA, of whom 154 (60.4%) achieved sustained clinical benefit. This effect was durable among 71 patients who received AZA for >5 years, with 61 (85.9%) considered to have achieved sustained clinical benefit. Twenty-six patients required admission to hospital for an exacerbation during AZA treatment, 20 patients ultimately required biologic therapy, and 21 underwent colectomy. Only two (2.8%) of 71 patients receiving AZA for >5 years needed to escalate to a biologic therapy, and only one (1.4%) required a colectomy. AZA is a safe and effective therapy in UC patients who fail 5-aminosalisylates in both the short and long term. Escalation to a biologic therapy or colectomy was unlikely among patients who were able to continue AZA therapy beyond 5 years.


Relationship between clinical toxicities and ERCC1 rs3212986 and XRCC3 rs861539 polymorphisms in cervical cancer patients.
Several studies have suggested that there are single nucleotide polymorphisms (SNPs) that can be considered potential biomarkers in the prognosis and therapeutic response of cancer patients. The present study investigated the association between ERCC1 rs3212986 and XRCC3 rs861539 polymorphisms and clinical toxicities induced by chemoradiotherapy (CRT) in cervical cancer. This hospital-based retrospective cohort study included 260 patients with cervical cancer, FIGO stages Ib2-IVa, who underwent CRT (cisplatin). Genetic polymorphisms analysis was performed by allelic discrimination with real-time polymerase chain reaction (RT-PCR). Our results indicated a link between ERCC1 rs3212986 and the onset of late gastrointestinal toxicity (p = 0.038). Furthermore, using a recessive model (AA vs. CC/CA), we found that patients carrying AA homozygous genotype presented a fourfold increased risk of developing late gastrointestinal toxicity when compared with patients with the C allele (odds ratio = 3.727, 95% confidence interval, 1.199-11.588; p = 0.017). No association was found regarding the XRCC3 rs861539 polymorphism and any clinical toxicity event. This is the first study evaluating the relationship between these polymorphisms and clinical toxicities in cervical cancer patients submitted to CRT with cisplatin. These results may contribute toward a better understanding of the influence of genetic polymorphisms in genes associated with DNA repair in the clinical response to CRT of patients with cervical cancer.


Ozone control and methanol fuel use.
Methanol fuel use in motor vehicles and stationary combustion has the potential to improve air quality. A modeling study of methanol fuel use in Los Angeles, California, shows that the low chemical reactivity of methanol vapor slows ozone formation and would lead to lower ozone concentrations. Predicted peak ozone levels decreased up to 16 percent, and exposure to levels above the federal standard dropped by up to 22 percent, when pure (M100) methanol fuel use was simulated for the year 2000. Similar results were obtained for 2010. Use of a gasoline-methanol blend (M85) resulted in smaller reductions. Predicted formaldehyde levels and exposure were not increased severely, and in some cases declined, in the simulations of methanol use.


Coordinated Control of Networked Multiagent Systems via Distributed Cloud Computing Using Multistep State Predictors.
This article studies the coordinated control problem of networked multiagent systems via distributed cloud computing. A distributed cloud predictive control scheme is proposed to achieve desired coordination control performance and compensate actively for communication delays between the cloud computing nodes and between the agents. This scheme includes the design of a multistep state predictor and optimization of control coordination. The multistep state predictor provides a novel way of predicting future immeasurable states of agents in a large horizontal length. The optimization of control coordination minimizes the distributed cost functions which are presented to measure the coordination between the agents so that the optimal design of the coordination controllers is simple with little computational increase for large-scale-networked multiagent systems. Further analysis derives the conditions of simultaneous stability and consensus of the closed-loop-networked multiagent systems using the distributed cloud predictive control scheme. The effectiveness of the proposed scheme is illustrated by an example.


Quality of Care and Its Impact on One-Year Mortality: The Georgia Coverdell Acute Stroke Registry.
Although performance measures help monitor the process change in quality improvement, their utility in measuring long-term outcomes is uncertain. This study assessed the 1-year mortality of acute ischemic stroke patients treated by hospitals participating in the Georgia Coverdell Acute Stroke Registry. Using 10 nationally approved performance measures, quality of care was defined both as an all-or-none measure (defect-free care) and as a composite index. A generalized estimating equation was applied to assess the effect of quality of care on 1-year mortality. Defect-free care did not serve the purpose; however, the composite measure showed that patients who received the lowest and intermediate quality care, respectively, had a 3.94 (95% confidence interval: 3.27, 4.75; P < .0001) and a 1.38 (95% confidence interval: 1.12, 1.62; P = .002) times higher odds of dying in 1 year compared to those who got the best-quality stroke care. Therefore, hospitals should be encouraged to implement quality improvement activities for better long-term patient outcome.


Hearing loss before and after cisplatin-based chemotherapy in testicular cancer survivors: a longitudinal study.
Hearing loss is a well-known long-term effect after cisplatin-based chemotherapy (CBCT) in testicular cancer survivors (TCS), but longitudinal data are sparse. We evaluate hearing loss and the impact of age in TCS treated with CBCT in this longitudinal study. Forty-six TCS treated with CBCT 1980-1994 with audiograms (0.25-8 kHz) pre-chemotherapy (PRE) and at a follow-up survey (SURV) after median 10 years were included (cases). Audiograms at SURV from 46 age-matched TCS without CBCT were included as controls. Linear regression was performed to evaluate predictors for change in the hearing threshold level (HTL) from PRE to SURV. Two definitions of a audiogram-defined hearing loss was applied if: (1) mean HTL for both ears exceeded 20 dB at any frequency 0.25-8 kHz (American Speech-Language-Hearing Association (ASHA) definition) and (2) average HTL for the frequencies 0.5, 1, 2 and 4 kHz exceeded 20 dB (WHO-M4 definition). Self-reported hearing impairment (SURV) was assessed by a questionnaire. Age and cisplatin dose was significantly associated with a greater change in HTL for the frequencies 2-8 kHz. For the 8 kHz frequency, each 100 mg increase in cumulative cisplatin dose was associated with a deterioration of 3.6 dB (95% CI 1.8-5.3, p < .001). The prevalence of hearing loss (ASHA) among cases was 33% PRE, 70% at SURV and 65% among controls at SURV (cases vs. controls, p = .66). According to M4, the prevalence of hearing loss among cases was 6.5% PRE, 13% at SURV and 2.2% among controls at SURV (cases vs. controls, p = .049). Twenty-nine percent of cases, and 33% of controls (p = .70) reported hearing impairment at SURV. Cisplatin is associated with a hearing loss particularly at higher frequencies. Age appear to be an important factor for hearing loss regardless of treatment. The ASHA definition overestimates the hearing problem.


Increased Visit-to-Visit Liver Enzyme Variability Is Associated with Incident Diabetes: A Community-Based 12-Year Prospective Cohort Study.
Fatty liver and/or increased liver enzyme values have been reported to be associated with incident diabetes. We sought to determine whether increased visit-to-visit liver enzyme variability is associated with incident diabetes. Study participants were recruited from the Korean Genome and Epidemiologic Study (KoGES). A total of 4,151 people aged 40 to 69 years was recruited and tested every 2 years for up to 12 years. Visit-to-visit aspartate aminotransferase (AST) and alanine aminotransferase (ALT) variability was evaluated in first the 6-year period through the use of various variability measurements: standard deviation (SD), average successive variability, coefficient of variation (CV), and variation independent of mean (VIM). Oral glucose tolerance test was performed at every visit. During the 6-year follow-up appointments, 13.0% (538/4,151) of people developed incident diabetes. Visit-to-visit AST variability was associated with an increased risk of diabetes independent of conventional risk factors for diabetes (hazard ratio per 1-SD increment [95% confidence interval]: 1.06 [1.00 to 1.11], 1.12 [1.04 to 1.21], and 1.13 [1.04 to 1.22] for SD, CV, and VIM, respectively; all P<0.05); however, no such associations were observed in the visit-to-visit ALT variability. According to alcohol consumption status, both AST and ALT variability were independent predictors for incident diabetes in subjects with heavy alcohol consumption; however, neither AST nor ALT variability was associated with diabetes risk in subjects who did not drink alcohol heavily. Visit-to-visit liver enzyme variability is an independent predictor of incident diabetes. Such association was more evident in those who consumed significant amounts of alcohol.


Targeting Hippo-Dependent and Hippo-Independent YAP1 Signaling for the Treatment of Childhood Rhabdomyosarcoma.
Rhabdomyosarcoma is the most common childhood soft-tissue sarcoma, yet patients with metastatic or recurrent disease continue to do poorly, indicating a need for new treatments. The SRC family tyrosine kinase YES1 is upregulated in rhabdomyosarcoma and is necessary for growth, but clinical trials using single agent dasatinib, a SRC family kinase inhibitor, have failed in sarcomas. YAP1 (YES-associated protein) is highly expressed in rhabdomyosarcoma, driving growth and survival when the upstream Hippo tumor suppressor pathway is silenced, but efforts to pharmacologically inhibit YAP1 have been unsuccessful. Here we demonstrate that treatment of rhabdomyosarcoma with DNA methyltransferase inhibitor (DNMTi) upregulates Hippo activators RASSF1 and RASSF5 by promoter demethylation, activating canonical Hippo signaling and increasing inactivation of YAP1 by phosphorylation. Treatment with DNMTi decreased rhabdomyosarcoma cell growth and increased apoptosis and differentiation, an effect partially rescued by expression of constitutively active YAP (S127A), suggesting the effects of DNMTi treatment are, in part, due to Hippo-dependent inhibition of YAP1. In addition, YES1 and YAP1 interacted in the nucleus of rhabdomyosarcoma cells, and genetic or pharmacologic suppression of YES1 resulted in cytoplasmic retention of YAP1 and decreased YAP1 target gene expression, suggesting YES1 regulates YAP1 in a Hippo-independent manner. Combined treatment with DNMTi and dasatinib targeted both Hippo-dependent and Hippo-independent regulation of YAP1, ablating rhabdomyosarcoma cell growth in vitro and trending toward decreased tumor growth in vivo. These results show that the mechanisms regulating YAP1 in rhabdomyosarcoma can be inhibited by combinatorial therapy of DNMTi and dasatinib, laying the groundwork for future clinical investigations. SIGNIFICANCE: This study elucidates the signaling pathways that regulate the oncogenic protein YAP1 and identifies a combination therapy to target these pathways in the childhood tumor rhabdomyosarcoma.


The safety and efficacy of KAI-1678- an inhibitor of epsilon protein kinase C (εPKC)-versus lidocaine and placebo for the treatment of postherpetic neuralgia: a crossover study design.
Postherpetic neuralgia (PHN) occurs in approximately 10-20% of patients with herpes zoster, and the risk increases with age. In this clinical trial, we evaluated the analgesic properties of KAI-1678-an inhibitor of epsilon protein kinase C-in the treatment of neuropathic pain in patients with PHN. The study was a three-treatment period, double-blind, randomized, placebo and active comparator crossover trial evaluating subcutaneous infusions of KAI-1678 (25 mg), placebo, and lidocaine hydrochloride (700 mg; active comparator). A total of 17 men and 6 women (N = 23) were enrolled after fulfilling diagnosis of PHN with pain persisting for ≥3 months after a segmental herpes zoster eruption. Patients had to have a mean average pain score of ≥4 points on an 11-point numerical rating scale (NRS; ranging from 0 to 10) based on at least three daily entries prior to participation in the subsequent treatment period. Overall, administration of KAI-1678 was generally safe and well tolerated. However, compared with placebo, KAI-1678 did not improve clinical pain scores as recorded using the NRS (0-10). In contrast, subcutaneous infusions of lidocaine were associated with a significant reduction in pain intensity at the end of the infusion. We conclude that KAI-1678 is not efficacious as an acute analgesic for chronic neuropathic pain because of PHN. However, for the first time, the results demonstrate that subcutaneous infusions of lidocaine are effective in treating neuropathic pain. The results of lidocaine treatment also indicate that the crossover study design was adequate to detect a clinically meaningful response in this analgesia study.


The disposition of carboplatin in ovarian cancer patients.
Carboplatin was given as a 30-min infusion to 11 ovarian cancer patients at doses of 170-500 mg/m2. The ages, weights, and creatinine clearances (Clcr) ranged from 44 to 75 years, from 44 to 74 kg, and from 32 to 101 ml/min, respectively. Plasma, plasma ultrafiltrate (PU), and urine samples were obtained at appropriate times for 96 h and were analyzed for platinum. The PU and urine were also analyzed for the parent compound by HPLC. In patients with a Clcr of about 60 ml/min or greater, carboplatin decayed biexponentially with a mean t1/2 alpha of 1.6 h and a t1/2 beta of 3.0 h. The mean (+/- SD) residence time, total body clearance, and apparent volume of distribution were 3.5 +/- 0.4 h, 4.4 +/- 0.85 l/h, and 16 +/- 3 l, respectively. Cmax and AUCinf values increased linearly with dose, and the latter values correlated better with the dose in mg than in mg/m2. No significant quantities of free, ultrafilterable, platinum-containing species other than the parent compound were found in plasma, but platinum from carboplatin became protein-bound and was slowly eliminated with a minimal t1/2 of 5 days. The major route of elimination was excretion via the kidneys. Patients with a Clcr of 60 ml/min or greater excreted 70% of the dose as the parent compound in the urine, with most of this occurring within 12-16 h. All of the platinum in 24-h urine was carboplatin, and only 2%-3% of the dosed platinum was excreted from 48 to 96 h. Patients with a Clcr of less than about 60 ml/min exhibited dose-disproportional increases in AUCinf and MRT values. The latter were inversely related to Clcr (r = -0.98). Over a dose range of 300-500 mg/m2, carboplatin exhibited linear, dose-independent pharmacokinetics in patients with a Clcr of about 60 ml/min or greater, but dose reductions are necessary for patients with mild renal failure.


Is there need for a transformational change to overcome the current problems with postgraduate medical education in India?
In spite of the existence of a dual system of postgraduation, one under the Medical Council of India (MCI) and the other on a parallel track under the National Board of Examinations, postgraduate medical education in India is beset with several problems. For example, the curriculum has not been revised comprehensively for several decades. The diploma course under the MCI has become unpopular and is largely a temporary refuge for those who do not get admission to degree courses. The level of skills of the outgoing graduate is falling and the increase in the number of seats is taking place in a haphazard manner, without reference to the needs. In spite of increase in seats, there is a shortage of specialists at the secondary and tertiary care levels, especially in medical colleges, to share teaching responsibilities. Further, the distribution of specialists is skewed, with some states having far more than others. To remedy these ills and fulfil the requirements of the country over the next two decades, a working group appointed by the erstwhile governors of the MCI was asked to suggest suitable modifications to the existing postgraduate system. After an extensive review of the lacunae in the present system, the needs at various levels and the pattern of postgraduate education in other countries, it was felt that a competency-based model of a 2-year postgraduate course across all specialties, the use of offsite facilities for training and a criterion-based evaluation system entailing continuous monitoring would go a long way to correct some of the deficiencies of the existing system. The details of the proposal and its merits are outlined for wider discussion and to serve as a feedback to the regulatory agencies engaged in the task of improving the medical education system in India. We feel that the adoption of the proposed system would go a long way in improving career options, increasing the availability of teachers and dissemination of specialists to the secondary and primary levels, and improving the quality of outgoing postgraduates.


Structural investigation of proteasome inhibition.
The novel proteolytic mechanism of the 20S proteasome from T. acidophilum has been investigated by X-ray crystallography using small-molecule inhibitors and substrate analogues. The 20S proteasome degrades unfolded substrates into small peptides of a defined length. Calpain inhibitor II, chymostatin and lactacystin all bind in the previously identified active site pocket near Thr1 of all fourteen beta-subunits. The chromogenic substrate analogue Suc-LLVY-AMC binds in the same pocket of the proteolytically inactive T1A mutant of the beta-subunit, but with a significantly altered geometry. The heavy-atom cluster Ta6Br12(2+) used in X-ray structure determination occupies seven sites in the inner compartment of the proteasome and exhibits inhibition of the chymotrypsin-like activity. Other effectors of proteasome activity showed no significant difference in electron density.


Zika virus-related neurotropic flaviviruses infect human placental explants and cause fetal demise in mice.
Although Zika virus (ZIKV) infection in pregnant women can cause placental damage, intrauterine growth restriction, microcephaly, and fetal demise, these disease manifestations only became apparent in the context of a large epidemic in the Americas. We hypothesized that ZIKV is not unique among arboviruses in its ability to cause congenital infection. To evaluate this, we tested the capacity of four emerging arboviruses [West Nile virus (WNV), Powassan virus (POWV), chikungunya virus (CHIKV), and Mayaro virus (MAYV)] from related (flavivirus) and unrelated (alphavirus) genera to infect the placenta and fetus in immunocompetent, wild-type mice. Although all four viruses caused placental infection, only infection with the neurotropic flaviviruses (WNV and POWV) resulted in fetal demise. WNV and POWV also replicated efficiently in second-trimester human maternal (decidua) and fetal (chorionic villi and fetal membrane) explants, whereas CHIKV and MAYV replicated less efficiently. In mice, RNA in situ hybridization and histopathological analysis revealed that WNV infected the placenta and fetal central nervous system, causing injury to the developing brain. In comparison, CHIKV and MAYV did not cause substantive placental or fetal damage despite evidence of vertical transmission. On the basis of the susceptibility of human maternal and fetal tissue explants and pathogenesis experiments in immunocompetent mice, other emerging neurotropic flaviviruses may share with ZIKV the capacity for transplacental transmission, as well as subsequent infection and injury to the developing fetus.


[Latissimus arc of the upper arm].
We observed 2 different kinds of an arcus axillaris which might have caused neurovascular symptoms at the forearm and hand. According to our observations it seems that an arcus axillaris , which is an anomaly of the m. latissimus dorsi, occurs more often than is commonly reported in text-books of anatomy.


Idiotype-specific tolerance: preferential alteration of idiotype expression after neonatal exposure to tolerogen.
The development of HOPC-8 idiotype-positive and HOPC-8 idiotype-negative B cell subpopulations involved in the immune response to a single PC antigen, has been monitored during normal differentiation and in situations where neonatal tolerance had been induced. It was found that H8 id+ and H8 id- anti-PC antibody-secreting cells appeared at approximately the same time in ontogeny and these late maturing subsets constituted equal fractions of the immune response in CBA/CaJ X BALB/c F1 (JBF1) mice. However, when JBF1 mice were injected at birth with graded doses of PC-FGG, responses obtained in 4-week-old mice were predominantly of the H8 id. This PC-specific, idiotype-restricted, unresponsive state was stable upon adoptive transfer. Specific depletion of Thy-1.2-positive cells and in vitro "mixing" experiments involving combined ratios of tolerant and nontolerant spleen cells suggest that the unresponsive state measured 4 weeks after tolerogen administration does not involve suppressor cells. It would appear that intrinsic differences between these idiotypically defined B cell subsets account for the observed differential susceptibility to tolerance induction among PC-responsive B cells.


High performance step-down AR coatings for high refractive-index IR materials.
A numerical thin film synthesis program has been used to design high performance antireflection coatings of the step-down type for a number of IR window materials. In the calculations, the dispersion of the optical constants of all the materials is accounted for. Various trade offs between the width of the AR region and the maximum reflection within that width are possible. For example, an AR coating for germanium has been found in which the reflectance is <0.1% over a 1.4:1 range of wavelengths. Similar designs have been developed for silicon, cadmium telluride, zinc selenide, and zinc sulfide substrates. The experimentally measured performance of several coatings will be given.


Ageing and hearing loss.
Although many adults retain good hearing as they age, hearing loss associated with ageing is common among elderly persons. There are a number of pathophysiolological processes underlying age-related changes to functional components in the inner ear. Genetic factors determine the ageing process but are under the influence of intrinsic and environmental factors. It is difficult to distinguish changes of normal ageing from those of other contributing factors. The effects of age-related deafness can have significant physical, functional and mental health consequences. Although a deficit in hearing can be corrected to some degree by a hearing aid or other appropriate amplification devices, hearing-related rehabilitative needs are much more than simply amplifying external sound. Only by better understanding the process of ageing and its effect on the auditory function can we better accommodate elderly people in our day-to-day interactions. We review here the structure and function of the inner ear, pathophysiology associated with age-related hearing loss (ARHL), heritability, allelism and modifier genes of ARHL, and evaluate the genetic analyses for identification of genetic factors that are involved.


Expression of E-cadherin, beta-catenin, cathepsin D, gelatinases and their inhibitors in invasive ductal breast carcinomas.
E-cadherin, beta-catenin, cathepsin D, matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 are all invasion-related proteins. The expression patterns of these proteins in invasive ductal breast carcinomas, and their associations with known clinicopathological parameters, tumor recurrence and expressions of estrogen receptor (ER), progesterone receptor (PR), PS2 and c-erbB2 were not well studied in Chinese patients. In a set of 94 invasive ductal breast carcinomas, protein expressions of these molecular markers were investigated by immunohistochemistry, and their associations with known clinicopathological parameters, tumor recurrence and expressions of ER, PR, PS2 and c-erbB2 were also examined. In addition, the interrelationship between the expressions of these proteins were studied. Preserved membrane E-cadherin expression was associated with late tumor stage and tumor recurrence, whereas the reduced junctional beta-catenin associated with positive lymph node status and c-erbB2 overexpression. Positive staining of cathepsin D in tumor stromal cells displayed a significant association with late tumor stage. High expression of MMP-2 in cancer cells was associated with large tumor size and PR positive expression. TIMP-2 expression was positively associated with tumor recurrence. In addition, inter-relationship between the expressions of these biomarkers was also assessed. Cathepsin D staining in cancer cells was inversely correlated with its staining in stromal cells, and also inversely correlated with MMP-2 staining in tumor stromal cells. MMP-2 expression in stromal cells displayed an inverse correlation with TIMP-2 expression. MMP-9 expression displayed parallel associations with TIMP-1 and TIMP-2 expression. Evaluation of E-cadherin, beta-catenin, cathepsin D, MMP-2 and TIMP-2 expression may be of some help in more accurately predicting the prognosis of invasive ductal breast carcinomas.


Factors associated with acute respiratory infection in children under the age of 5 years: evidence from the 2011 Ethiopia Demographic and Health Survey.
Acute respiratory tract infection (ARI) remains the major cause of child mortality in Sub-Saharan Africa. Various factors are associated with its occurrence and vary by context. However, available large-scale, population-based data are not fully exploited to identify locally relevant risk factors. The objective of this study was to identify factors associated with ARI in children under the age of 5 years in Ethiopia. Further analysis of the 2011 Ethiopia Demographic and Health Survey was carried out involving 11,645 children under the age of 5 years and their mothers. Information relevant to the current study was extracted from the main data set and a working data set was prepared. A complex survey logistic regression analysis was applied. Acute ARI in this study was associated with severe malnutrition. Children who were severely wasted were highly likely to develop ARI (adjusted odds ratio [AOR] 1.7; 95% confidence interval [CI] 1.1-2.5). ARI was less likely to occur in children from families with an educated father and professional mother (AOR 0.4; 95% CI 0.2-0.6 and AOR 0.1; 95% CI 0.01-0.6, respectively). Malnourished children from a lower socioeconomic category are more likely to suffer from ARI. Targeting disadvantaged children for effective interventions can help reduce the burden of morbidity and death due to ARI.


Accuracy of MRI in comparison with clinical and arthroscopic findings in ligamentous and meniscal injuries of the knee.
Rapidly progressing medical technology sometimes obscures the importance of history and physical examination. This study was designed to assess the value of MRI and clinical examination in the diagnosis of ligamentous and meniscal knee injuries in comparison with arthroscopic findings. In the year 2003-2004, we conducted a prospective, single blind study to assess ligamentous and meniscal injuries of the knee in patients with acute knee trauma. The mean age was 27.9 years. The sex distribution was 81.4% male and 18.6% female; 42.9% of injuries affected the right knee and 57.1% the left knee. All the included patients were ordered a MRI, executed in five separate centres. All patients underwent arthroscopy by the author. Arthroscopic findings were the diagnostic reference. Clinical examination was accurate in 91.4%, and MRI in 88.5% of anterior cruciate ligament injuries. For posterior cruciate ligament injuries, clinical accuracy was 100% and MRI 94.6%. Clinical examination was accurate in 96.9% and MRI in 85.9% of medial meniscal injuries. For lateral meniscus injuries, clinical accuracy was 85.4% and MRI 73.8%. MRI findings showed the lowest correlation with arthroscopic findings in lateral meniscus injuries (r = 0/47). Clinical diagnostic performance was poorest in case of combined cruciate ligament and meniscal injuries. We found an excellent correlation between MRI and clinical findings. However, when MRI is normal, high clinical suspicion and a skilled clinical examination are more reliable.


[Laser applications in condylomata acuminata].
Condylomata acuminata are benign epidermal proliferations caused by human papillomavirus (HPV). Recent epidemiological data have shown that HPV infection is the most common sexually transmitted disease. Some HPV types are considered to be potentially oncogenic. Therefore, effective examinations and treatment of both sexual partners are important in all cases. The CO2 laser and the Nd:-YAG laser have gained widespread acceptance in the treatment of HPV efflorescences. CO2 lasers are characterized by surface absorption; the Nd:-YAG laser effect depends on volume absorption; depth of coagulation can be controlled by laser power, spot size and exposure time. Both of these fundamentally different laser effects lead to excellent cosmetic results and high cure rates. Our follow-up examinations revealed recurrences in 22%.


46 XY gonadal dysgenesis in adulthood 'pitfalls of late diagnosis'.
Disorders of sex development (DSD) include congenital conditions where developments of chromosomal, gonadal or anatomical sex are atypical. Ostrer in 2000, reported a prevalence of 1:20 000 for 46 XY DSD and complete gonadal dysgenesis. A 21-year-old patient consulted for sexual ambiguity at the out-patient department of the Philippine general hospital. At birth, the perceived female external genitalia and clitoromegaly, led the parents to register and eventually rear the patient as a female. At puberty, he developed masculine features and growth of phallus. Patient was more interested in male activities and began to identify himself as male in the community. The discrepancy between his birth certificate and his male gender jeopardised his ambition to become a policeman; this led him to seek medical consult. On physical examination, he was phenotypically male. The external genitalia showed the phallus length of 3.5 cm and perineoscrotal hypospadias. Chromosomal sex was normal 46 XY with neither numerical nor structural aberrations in all cell lines, serum testosterone was low and gonadotrophins were elevated. Whole abdominal CT scan showed bilaterally undescended testes and a 4.5 cm blind vaginal pouch seen on genitogram. Bilateral orchidectomy with first stage repair of hypospadias was performed. On histopathology, the right testis was fibrotic and the left testis showed minimal testicular tissue with absent spermatids. The clinical, endocrine, cytogenetic and histopathologic data are consistent with gonadal dysgenesis syndrome.


Self-assembled phytosterol-fructose-chitosan nanoparticles as a carrier of anticancer drug.
Self-assembled nanoparticles were synthesized from water-soluble fructose-chitosan, substituted by succinyl linkages with phytosterols as hydrophobic moieties for self-assembly. The physicochemical properties of the prepared self-assembled nanoparticles were characterized by Fourier transform infrared spectroscopy, fluorescence spectroscopy, and transmission electron microscopy. Doxorubicin (DOX), as a model anticancer drug, was physically entrapped inside prepared self-assembled nanoparticles by the dialysis method. With increasing initial levels of the drug, the drug loading content increased, but the encapsulation efficiency decreased. The release profiles in vitro demonstrated that the DOX showed slow sustained released over 48 h, and the release rate in phosphate buffered saline (PBS) solution (pH 7.4) was much slower than in PBS solution (pH 5.5 and pH 6.5), indicating the prepared self-assembled nanoparticles had the potential to be used as a carrier for targeted delivery of hydrophobic anticancer drugs with declined cytotoxicity to normal tissues.


Is amyloid beta-protein glycated in Alzheimer's disease?
Recent data suggest that protein glycation is involved in the process of amyloid formation in Alzheimer's disease (AD). To further investigate this issue, we analyzed the presence of advanced glycation end products (AGE) in soluble and insoluble forms of amyloid beta-protein (A beta) as well as in apolipoprotein E (apoE), a protein bound to amyloid deposits. Both proteins were extracted from cerebral cortex obtained from patients with AD and probed by immunoblotting with two antibodies specific for different AGE, already known to immunocytochemically label amyloid plaques. All the AGE antibodies failed to recognize either A beta or apoE, whereas they reacted with synthetic A beta glycated in vitro. These findings indicate that other proteins associated with amyloid deposits are candidates to be modified with AGE in Alzheimer's cerebral tissue.


High-level Expression and One-step Purification of Chimeric Antigen Containing HTLV-I-II Diagnostic Epitopes in Escherichia coli.
Purification and preparation of three diagnostic antigens used for the detection of human T-lymphotropic virus (HTLV)-I/-II infection in E.coli are different parts of a multi-step method. In this study, our aim was to design a chimeric protein for the simultaneous detection of HTLV-I and HTLV-II antibodies. Immunodominant B cell linear epitopes of envelope and capsid proteins of HTLV-I/-II were selected and linked together; using a suitable amino acid linker and a chimeric antigen (CA). The codon-optimized synthetic DNA encoding the CA was subcloned into the pGS21aexpression vector and CA expressed as His-GST fused protein in E. coli BL21 (DE3) cells. Then the recombinant CA was purified, using the Ni-NTA (Nickle Nitrilotriacetic acid) affinity chromatography under native conditions. The Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and densitometric scanning results showed that CA accounted for 15% of the total cellular proteins and approximately 50% of the expressed histidine-glutathione s-transferase-chimeric antigen (His-GST-CA) proteins were soluble. The CA was successfully purified in one step with a purity of greater than 90%, which is suitable for antigenicity evaluations. Enzyme-linked immunosorbent assay (ELISA) results showed that the GST fused CA reacted in a concentration-dependent manner with HTLV-I/-II infected sera and was able to distinguish normal serum from HTLV-I/-II infected one with a proper sensitivity. With further validation, CA, as described in the present study could be introduced as a novel reliable, cost-effective and easy alternative for the three separate HTLV-I/-II diagnostic peptide antigens, which is prepared as a fusion with GST.


The effect of voice rest on the outcome of phonosurgery for benign laryngeal lesions: preliminary results of a prospective randomized study.
According to the literature, voice rest following phonosurgery, as recommended in clinical practice, varies between 3 and 7 days. However, up until now, no randomized trials have been published comparing voice rest of short versus long duration. This is an ongoing prospective randomized study, comparing strict voice rest of 5 versus 10 days on the voice following phonosurgery. Thirty-one elective patients operated on for benign laryngeal lesions were randomized. They completed pre- and postoperative assessments, including perceptual voice quality (Grade, Roughness, Breathiness, Asthenia, Strain, Instability scale), Voice Handicap Index total score, and voice analysis with both acoustic and aerodynamic measurements. Additional factors such as smoking, vocal abuse, reflux, and preoperative speech therapy were also taken into account. Sixteen patients were randomized to follow 5 days' voice rest and 15 patients were randomized to 10 days' voice rest. Statistical analysis showed no significant differences in pre- or postoperative measurements between the 2 groups. However, multilinear regression analysis for the effect of voice rest duration on postoperative values showed a significant improvement in maximum phonation time (MPT) with 10 days' voice rest. Preliminary results show a benefit of prolonged voice rest (10 days' duration) on MPT.


Combination of malaria vector control interventions in pyrethroid resistance area in Benin: a cluster randomised controlled trial.
Malaria control efforts and elimination in Africa are being challenged by the development of resistance of parasites to antimalarial drugs and vectors to insecticides. We investigated whether the combination of long-lasting insecticidal mosquito nets (LLINs) with indoor residual spraying (IRS) or carbamate-treated plastic sheeting (CTPS) conferred enhanced protection against malaria and better management of pyrethroid-resistance in vectors than did LLINs alone. We did a cluster randomised controlled trial in 28 villages in southern Benin, west Africa. Inclusion criteria of the villages were moderate level of pyrethroid resistance in malaria vectors and minimum distance between villages of 2 km. We assessed four malaria vector control interventions: LLIN targeted coverage to pregnant women and children younger than 6 years (TLLIN, reference group), LLIN universal coverage of all sleeping units (ULLIN), TLLIN plus full coverage of carbamate-IRS applied every 8 months (TLLIN+IRS), and ULLIN plus full coverage of CTPS lined up to the upper part of the household walls (ULLIN+CTPS). The interventions were allocated to villages by a block randomisation on the basis of preliminary surveys and children of each village were randomly selected to participate with computer-generated numbers. The primary endpoint was the incidence density rate of Plasmodium falciparum clinical malaria in children younger than 6 years as was analysed by Poisson regression taking into account the effect of age and the sampling design with a generalised estimating equation approach. Clinical and parasitological information were obtained by active case detection of malaria episodes during 12 periods of 6 consecutive days scheduled at six weekly intervals and by cross-sectional surveys of asymptomatic plasmodial infections. Children or study investigators were not masked to study group. This study is registered with Current Controlled Trials, number ISRCTN07404145. Of 58 villages assessed, 28 were randomly assigned to intervention groups. 413-429 children were followed up in each intervention group for 18 months. The clinical incidence density of malaria was not reduced in the children from the ULLIN group (incidence density rate 0·95, 95% CI 0·67-1·36, p=0·79), nor in those from the TLLIN+IRS group (1·32, 0·90-1·93, p=0·15) or from the ULLIN+CTPS group (1·05, 0·75-1·48, p=0·77) compared with the reference group (TLLIN). The same trend was observed with the prevalence and parasite density of asymptomatic infections (non significant regression coefficients). No significant benefit for reducing malaria morbidity, infection, and transmission was reported when combining LLIN+IRS or LLIN+CTPS compared with a background of LLIN coverage. These findings are important for national malaria control programmes and should help the design of more cost-effective strategies for malaria control and elimination. Ministère Français des Affaires Etrangères et Européennes (FSP project 2006-22), Institut de Recherche pour le Développement, President's Malaria Initiative (PMI) of US Governement.


BmCPV-Derived Circular DNA vcDNA-S7 Mediated by Bombyx mori Reverse Transcriptase (RT) Regulates BmCPV Infection.
Circular DNAs derived from single-stranded RNA viruses play important roles in counteracting viral infection. However, whether double-stranded RNA viruses generate functional circular DNAs is still unknown. Using circDNA sequencing, divergent PCR, DNA in situ hybridization and rolling circular amplification, we presently confirmed that in silkworm, Bombyx mori cytoplasmic polyhedrosis virus (BmCPV), a double-stranded RNA virus belonging to cypovirus, is prone to produce a BmCPV-derived circular DNA termed as vcDNA-S7. We have also found that vcDNA-S7 formation is mediated by endogenous reverse transcriptase (RT), and the proliferation of BmCPV can be inhibited by vcDNA-S7 in vitro and in vivo. Moreover, we have discovered that the silkworm RNAi immune pathway is activated by vcDNA-S7, while viral small interfering RNAs (vsiRNAs) derived from transcribed RNA by vcDNA-S7 can be detected by small RNA deep sequencing. These results suggest that BmCPV-derived vcDNA-S7, mediated by RT, can serve as a template for the biogenesis of antiviral siRNAs, which may lead to the repression of BmCPV infection. To our knowledge, this is the first demonstration that a circular DNA, produced by double stranded RNA viruses, is capable of regulating virus infection.


Microcytosis as a risk marker of cancer in primary care: a cohort study using electronic patient records.
Microcytosis (smaller than normal red blood cells) has previously been identified as a possible early risk marker for some cancers. However, the role of microcytosis across all cancers has not been fully investigated. To examine cancer incidence in a cohort of patients with microcytosis, with and without accompanying anaemia. Cohort study of patients aged ≥40 years using UK primary care electronic patient records. The 1-year cancer incidence was compared between cohorts of patients with a mean red cell volume of <85 femtolitres (fL) (low) or 85-101 fL (normal). Further analyses examined sex, age group, cancer site, and haemoglobin values. Of 12 289 patients with microcytosis, 497 had a new cancer diagnosis within 1 year (4.0%, 95% confidence interval [CI] = 3.7 to 4.4), compared with 1465 of 73 150 without microcytosis (2.0%, CI = 1.9 to 2.1). In males, 298 out of 4800 with microcytosis were diagnosed with cancer (6.2%, CI = 5.5 to 6.9), compared with 940 out of 34 653 without (2.7%, CI = 2.5 to 2.9). In females with microcytosis, 199 out of 7489 were diagnosed with cancer (2.7%, CI = 2.3 to 3.1), compared with 525 out of 38 497 without (1.4%, CI = 1.3 to 1.5). In patients with microcytosis but normal haemoglobin, 86 out of 2637 males (3.3%, CI = 2.6 to 4.0) and 101 out of 5055 females (2.0%, CI = 1.6 to 2.4) were diagnosed with cancer. Microcytosis is a predictor of underlying cancer even if haemoglobin is normal. Although a benign explanation is more likely, clinicians in primary care should consider simple testing for cancer on encountering unexplained microcytosis, particularly in males.


Medical school culture and generalist education: perceptions of a medical school faculty.
As part of an initiative to promote the education of generalist physicians at the University of North Carolina, a series of meetings were held over a 12-month period between generalist senior faculty and faculty from a range of departments in the School of Medicine and other health professions schools. Through open discussion about generalist initiatives, we hoped to understand their issues, attitudes, and opinions regarding generalists and generalist education. The major themes arising from these dialogues were 1) uncertainty about the definition of the generalist physician, 2) beliefs about the poor clinical reputations of generalists, 3) lack of a scientific basis for generalist practice, and 4) beliefs that few new resources are needed to undertake and expand generalist education. We comment on the validity and possible reasons for these perceptions and suggest strategies that can enhance generalist culture in the medical school.


Effects of masticatory muscle function affected by BTX on maxillofacial bone growth through the sutural modification.
To evaluate the effect of botulinum toxin type A (BTX)-induced masticatory muscle hypofunction on the maxillofacial suture bone growth of growing rats. Department of Orthodontics at Taipei Medical University. Forty-eight male 4-week-old Wistar rats were divided into four groups. The N group received injections of normal saline into each of the masseter and temporalis muscles. The M group received injections of normal saline into each of the temporalis muscle and injections of BTX into each of the masseter muscle. The T group received injections of normal saline into each of the masseter muscle and injections of BTX into each of the temporalis muscle. The MT group received injections of BTX into each of the masseter and temporalis muscles. Rats were sacrificed after 42 days of growth. Changes in body and muscle weight were measured. Anthropometric measurements of the maxillary arch, sutural bone mineral density and sutural bone deposition distances were recorded. Statistical comparisons were performed using analysis of variance. No significant change in body weight was found across groups. However, significant decreases were observed in muscle weight, anthropometric measurements, sutural bone mineral density and bone apposition distance in the BTX-injected group. Reduced masticatory muscle function in growing rats can affect maxillofacial suture bone growth.


Reliable Road Scene Interpretation Based on ITOM with the Integrated Fusion of Vehicle and Lane Tracker in Dense Traffic Situation.
Lane detection and tracking in a complex road environment is one of the most important research areas in highly automated driving systems. Studies on lane detection cover a variety of difficulties, such as shadowy situations, dimmed lane painting, and obstacles that prohibit lane feature detection. There are several hard cases in which lane candidate features are not easily extracted from image frames captured by a driving vehicle. We have carefully selected typical scenarios in which the extraction of lane candidate features can be easily corrupted by road vehicles and road markers that lead to degradations in the understanding of road scenes, resulting in difficult decision making. We have introduced two main contributions to the interpretation of road scenes in dense traffic environments. First, to obtain robust road scene understanding, we have designed a novel framework combining a lane tracker method integrated with a camera and a radar forward vehicle tracker system, which is especially useful in dense traffic situations. We have introduced an image template occupancy matching method with the integrated vehicle tracker that makes it possible to avoid extracting irrelevant lane features caused by forward target vehicles and road markers. Second, we present a robust multi-lane detection by a tracking algorithm that incudes adjacent lanes as well as ego lanes. We verify a comprehensive experimental evaluation with a real dataset comprised of problematic road scenarios. Experimental result shows that the proposed method is very reliable for multi-lane detection at the presented difficult situations.


Occupational safety and health: a method to test the collection of 'grey data' by line managers.
This paper describes and discusses a method for collecting data relating to the potential for illness or injury to occur in an organization. The reason for using the term 'grey' is explained and the underpinning philosophy of fuzzy thinking is also discussed. The method used was an audit which attempted to measure the degree to which certain types of failure were present in one organization. The audit used a term approach in design and execution and was found to be a useful and useable tool for collecting information relating potential causes of injury or illness.


[Plasma cell leukemia].
Plasma cell leukemia (PCL) is a rare disorder which develops spontaneously (primary PCL) or evolves in patients with multiple myeloma (secondary PCL). It is defined by the presence of 2 × 10(9)/L peripheral blood plasma cells or plasmacytosis accounting for more than 20 % of the differential white cell count. PCL presents more often extramedullary involvement, anemia, thrombocytopenia, hypercalcemia, as well as impaired renal function. Cytogenetic abnormalities and mutations observed in PCL lead to escape from immune surveillance and independence from the bone marrow microenvironment with changes in expression of adhesion molecules or chemokines receptors. The outcome of PCL has improved with combination approaches with novel agents (including bortezomib and immunomodulatory drugs, such as lenalidomide) and with autologous stem cell transplantation. Allogeneic hematopoietic stem cell transplantation is currently available for young patients. This article is an overview of this rare and severe disease and the different therapeutics options that are recommended.


Release behavior and bioefficacy of imazethapyr formulations based on biopolymeric hydrogels.
Controlled release formulations of imazethapyr herbicide have been developed employing guar gum-g-cl-polyacrylate/bentonite clay hydrogel composite (GG-HG) and guar gum-g-cl-PNIPAm nano hydrogel (GG-NHG) as carriers, to assess the suitability of biopolymeric hydrogels as controlled herbicide release devices. The kinetics of imazethapyr release from the developed formulations was studied in water and it revealed that the developed formulations of imazethapyr behaved as slow release formulations as compared to commercial formulation. The calculated diffusion exponent (n) values showed that Fickian diffusion was the predominant mechanism of imazethapyr release from the developed formulations. Time for release of half of the loaded imazethapyr (t1/2) ranged between 0.06 and 4.8 days in case of GG-NHG and 4.4 and 12.6 days for the GG-HG formulations. Weed control index (WCI) of GG-HG and GG-NHG formulations was similar to that of the commercial formulation and the herbicidal effect was observed for relatively longer period. Guar gum-based biopolymeric hydrogels in both macro and nano particle size range can serve as potential carriers in developing slow release herbicide formulations.


Genomic characterization of TT viruses (TTVs) in pigs, cats and dogs and their relatedness with species-specific TTVs in primates and tupaias.
Using PCR with primers derived from a non-coding region of the human TT virus (TTV) genome, the TTV sequence in serum samples obtained from pigs (Sus domesticus), dogs (Canis familiaris) and cats (Felis catus) was identified and the entire genomic sequence was determined for each representative isolate. Three TTV isolates (Sd-TTV31 from a pig, Cf-TTV10 from a dog and Fc-TTV4 from a cat) comprising 2878, 2797 and 2064 nucleotides, respectively, each had three open reading frames (ORFs) encoding 436-635 (ORF1), 73-105 (ORF2) and 224-243 (ORF3) aa but lacked ORF4, similar to tupaia TTV. ORF3 was presumed to arise from a splicing of TTV mRNA, similar to human prototype TTV. Although the nucleotide sequence of Sd-TTV31, Cf-TTV10 and Fc-TTV4 differed by more than 50% from each other and from previously reported TTVs of 3.4-3.9 kb and TTV-like mini viruses (TLMVs) of 2.8-3.0 kb isolated from humans and non-human primates as well as tupaia TTVs of 2.2 kb, they resembled known TTVs and TLMVs with regard to genomic organization and presumed transcriptional profile rather than animal circoviruses of 1.7-2.3 kb. Phylogenetic analysis revealed that Sd-TTV31, Cf-TTV10 and Fc-TTV4 were closer to TTVs from lower-order primates and tupaias than to TTVs from higher-order primates and TLMVs. These results indicate that domestic pigs, cats and dogs are naturally infected with species-specific TTVs with small genomic size and suggest a wide distribution of TTVs with extremely divergent genomic sequence and length in animals.


Front of Pack Labels Enhance Attention to Nutrition Information in Novel & Commercial Brands.
1) To assess whether Front-of-Pack (FOP) nutrition labels garner attention more readily than more complete, mandated nutrition information (the Nutrition Facts Panel (NFP), required in the US), and 2) To determine whether label design characteristics, specifically, color coding and/or coding with facial icons, increase attention to the FOP label. In two experiments, we tracked the allocation of attention while participants (n=125) viewed novel and commercial packages with varied FOP designs using a change detection methodology. We found empirical evidence that FOP labels are attended more often, and earlier, than the currently mandated NFP, and that this benefit is due both to its placement on the front of the package and to the design characteristics of the FOP. Specifically, the use of color in FOPs increased attention to the label, but there was no evidence that coding information via facial icons impacted attention. Our work supports a growing body of evidence supporting the use of FOP labels to attract attention to nutritional information. Findings may be relevant to inform policy decisions on labeling standards.


Influence of dental materials used for sealing caries lesions on laser fluorescence measurements.
The aim of this study was to determine the influence of thickness and aging on the intrinsic fluorescence of sealing materials and their ability to block fluorescence from the underlying surface as assessed using a laser fluorescence device. Cavities of 0.5 mm and 1 mm depth were drilled into acrylic boards which were placed over two surfaces with different fluorescence properties: a low-fluorescence surface, to assess the intrinsic fluorescence of the sealing materials, and a high-fluorescence surface, to assess the fluorescence-blocking ability of the sealing materials. Ten cavities of each depth were filled with different sealing materials: Adper Scotchbond Multi-Purpose, Adper Single Bond 2, FluroShield, Conseal f and UltraSeal XT Plus. Fluorescence was measured with a DIAGNOdent pen at five different time points: empty cavity, after polymerization, and 1 day, 1 week and 1 month after filling. The individual values after polymerization, as well as the area under the curve for the different periods were submitted to ANOVA and the Tukey test (p < 0.05). At 0.5 mm, Scotchbond, FluroShield and UltraSeal showed insignificant changes in intrinsic fluorescence with aging and lower fluorescence after polymerization than Single Bond and Conseal. At 1 mm, Scotchbond and FluroShield showed the lowest intrinsic fluorescence, but only Scotchbond showed no chagnes in fluorescence with aging. At both depths, Scotchbond blocked significantly less fluorescence. All sealing materials blocked more fluorescence when applied to a depth of 1 mm. At 0.5 mm, fissure sealants blocked more fluorescence than adhesives, and did not show significant changes with aging. Scotchbond had the least affect on the fluorescence from the underlying surface and would probably have the least affect on the monitoring of sealed dental caries by laser fluorescence.


Production of extracellular slime by coryneforms colonizing hydrocephalus shunts.
Corynebacterium spp. are responsible for an important minority of cases of colonization of cerebrospinal fluid shunts used for the treatment of hydrocephalus. In common with coagulase-negative staphylococci, they present a serious therapeutic problem because they are often resistant to multiple antibiotics. We studied the morphologies of coryneforms in colonized hydrocephalus shunts removed from patients and observed extracellular slime similar in appearance to that seen in coagulase-negative staphylococci. We also studied a series of such isolates from other cases of hydrocephalus shunt colonization using an established laboratory model and consistently observed slime production in these shunts as well. We propose that this might be a further reason for failure to eradicate these organisms without shunt removal as well as a factor in their pathogenesis in device-related infections.


An analysis of the influence of impurities on fast particle attenuation and on fast ion spectral shape in LHD.
Neutral particle fluxes measured by neutral particle analyzers can provide information about the ion temperature as well as the non-Maxwellian anisotropic ion distribution tails from neutral beam injection and ion cyclotron radio frequency heating. In the case of multidirectional diagnostics employing high resolution atomic energy spectrometers, the neutral atomic flux source is not localized in contrast to pellet charge exchange or diagnostic neutral beam methods. The correct interpretation of such measurements from plasma in a complex toroidally asymmetric geometry, like that of LHD, requires careful numerical modeling of the neutral flux formation. Previously a measured neutral flux calculation scheme was developed and was used for the LHD geometry and a suitable analytic expression for ionization cross sections sigma(s)(z)(E,n(e),T(e),Z(eff)) of impurities was formulated by Janev et al. [Nucl. Fusion 29, 2125 (1989)]. In this paper, the attenuation of fast particles by impurities is incorporated into the neutral flux calculation scheme and the influence of impurities on the calculated neutral flux spectra is shown. Finally, the behavior of the calculated and experimental suprathermal particle distributions is compared for pure hydrogen and for argon impurity seeded plasmas.


Total synthesis of herbimycin A.
[structure: see text] Hsp90 has recently emerged as a promising biological target for treatment of cancer. Herbimycin A and other members of the benzoquinoid ansamycin class of natural products are known to inhibit Hsp90 activity. The total synthesis of herbimycin A was achieved from the commercially available Roche ester 1 by using allylmetals to control the stereogenic centers at C6, C7, C10, C11, and C12 and a ring-closing metathesis to control the (Z)-double bond of the (E,Z)-dienic moiety.


Preoperative stoma site marking reduces postoperative stoma-related complications in emergency surgery: A single center retrospective cohort study.
Stoma site marking is an important factor in reducing stoma-related complications, thereby influencing the long-term quality of life in the elective setting. The impact of preoperative stoma site marking in emergency stoma creation is largely unknown. We aimed to determine whether preoperative stoma site marking in emergency stoma creation reduces stoma-related complications. Patients who underwent emergency stoma creation at our hospital between 2009 and 2022 were examined by reviewing our prospective database and retrospective chart review. Subjects were classified into the "marking (+)" or "marking (-)" group according to stoma site marking (194 and 151 patients, respectively). The changes in the frequency of stoma marking over time and the effects of stoma marking on stoma-related complications were analyzed. The overall frequency of grade 2 or higher stoma-related complications was lower in the marking (+) group than in the marking (-) group (24% versus 36%, p = 0.010). Stoma site marking was associated with fewer soma site bleeding (2% versus 10%, p < 0.001), and the frequency of peristomal dermatitis was also lower (10%) in the marking (+) group (versus 18%, p = 0.042). Moreover, the lack of stoma site marking was an independent risk factor for overall stoma-related complications (adjusted odds ratio: 1.69, p = 0.034). Preoperative stoma site marking was associated with stoma-related complications in emergency surgery. The clinical significance of our attempt is worth validating with prospective studies.


The Bad guy cooperates with good cop p53: Bad is transcriptionally up-regulated by p53 and forms a Bad/p53 complex at the mitochondria to induce apoptosis.
Although the regulation of several Bcl-2 family molecules, including Puma, Noxa, Bax, and Bid, by p53 has been studied intensively, the interplay between Bad (Bcl-2 antagonist of cell death) and p53 has not yet been reported thus far. Here, we report that p53 activates Bad transcription and expression through binding to a short conserved sequence located approximately 6.6 kb upstream of the translation start point. We also demonstrate that Bad physically interacts with cytoplasmic p53, thereby preventing p53 from entering the nucleus and resulting in reduced transcription of Bad. Moreover, Bad is able to direct p53 to the mitochondria and forms a p53/Bad complex at the mitochondria. Two lines of evidences support this hypothesis: first, when mitochondria purified from p53-deficient H1299 cells are incubated with p53 and either wild-type (wt) Bad or mutant Bad (this mutant binds p53 yet is unable to migrate to mitochondria), p53 can be detected only in mitochondria incubated with wt Bad and not in those incubated with mutant Bad; second, knockdown of Bad expression reduces mitochondrial localization of p53. The mitochondrial p53/Bad complex promotes apoptosis via activation and oligomerization of Bak. Elimination of Bad expression by RNA interference notably attenuates apoptosis induced by etoposide. Hence, our collective data provide the first evidence that Bad plays dual roles in both p53 transcription-dependent and -independent pathways.


Acute and chronic effects of traditional and high-speed resistance training on blood pressure in older adults: A crossover study and systematic review and meta-analysis.
The present study included two related investigations that explored the acute and chronic effects of high-speed resistance training (HSRT) on blood pressure (BP) in older adults. The first study involved a randomized crossover study that compared the acute effects of traditional resistance exercise (TRT) and high-speed resistance training (HSRT) on hemodynamic parameters in frail older adults. Sixteen institutionalized frail older adults were recruited. BP was recorded before, over 1 h, and 24 h after the end of the experimental session. Participants performed 4 resistance exercises involving 4-8 sets with 4-10 repetitions at moderate intensity. The second study was a systematic review and meta-analysis of experimental studies that investigated the acute and chronic effects of HSRT on BP in older adults. Crossover, quasi-experimental, and randomized controlled trials that examined the effects of HSRT on BP in people aged 60+ years as a primary or secondary outcome were included. Studies were retrieved from MEDLINE, SPORTDiscuss, CINAHL, SCOPUS and AgeLine databases from inception through December 31, 2021. The risk of bias was evaluated using the Newcastle - Ottawa Quality Assessment Scale (NOS). A pooled effect size was calculated based on standard mean differences (SMD). In study 1, we observed that both TRT and HSRT caused post-exercise hypotension (PEH). However, systolic BP (SBP) was significantly lowered for up to 60 min after TRT, while it was only reduced 30 and 50 min after HSRT. There was no difference in SBP between resistance exercise protocols. A reduction in mean arterial pressure was only observed after TRT. In study 2, 1114 articles were identified, and 8 were included in the meta-analysis. Pooled analyses indicated that HSRT did not cause significant PEH. However, a significant reduction in SBP was observed after HSRT programs in comparison to controls (SMD = 0.61, P = 0.009) and baseline values (SMD = 2.03, P = 0.04). In study one, we observed that both TRT and HSRT caused systolic PEH in comparison to baseline in frail older adults. However, specific patterns were observed according to each type of RT. Indeed, a longer PEH in comparison to baseline was observed after TRT, whereas HSRT had greater reductions in comparison to CS. In addition, TRT had exclusive reductions in MAP. These results were not supported by our meta-analysis, given that no significant effects of an acute session of HSRT on office and ambulatorial BP were observed. On the other hand, our findings suggest that HSRT might significantly reduce SBP in older adults.


ROS mediated selection for increased NADPH availability in Escherichia coli.
The economical production of chemicals and fuels by microbial processes remains an intense area of interest in biotechnology. A key limitation in such efforts concerns the availability of key co-factors, in this case NADPH, required for target pathways. Many of the strategies pursued for increasing NADPH availability in Escherichia coli involve manipulations to the central metabolism, which can create redox imbalances and overall growth defects. In this study we used a reactive oxygen species based selection to search for novel methods of increasing NADPH availability. We report a loss of function mutation in the gene hdfR appears to increase NADPH availability in E. coli. Additionally, we show this excess NADPH can be used to improve the production of 3HP in E. coli.


Effect of the Premature Infant Oral Motor Intervention on Sucking Capacity in Preterm Infants in Turkey: A Randomized Controlled Trial.
Preterm infants have oral feeding difficulty that often delays discharge, indicating a need for evidence-based interventions for oral-motor development. To test the Premature Infant Oral Motor Intervention (PIOMI) on the development of oral-motor function, feeding, and anthropometric outcomes using sucking manometry. A single-blind randomized experimental design was conducted with a sample of 60 preterm infants from 2 neonatal intensive care units between May 2019 and March 2020. The experimental group received PIOMI for 5 min/d for 14 consecutive days. Sucking capacity, anthropometrics (weight and head circumference), bottle feeding, breast/chest feeding initiation, and length of hospital stay were measured. The Yakut Sucking Manometer (PCT/TR2019/050678) was developed specifically for this study and tested for the first time. The experimental group had a statistically significant percent increase over controls in sucking power (69%), continuous sucking before releasing the bottle (16%), sucking time (13%), and sucking amount (12%) with partial η 2 values of interaction between the groups of 0.692, 0.164, 0.136, and 0.121, respectively. The experimental group had a higher increase in weight (89%) and head circumference (81%) over controls ( F = 485.130, P < .001; F = 254.754, P < .001, respectively). The experimental group transitioned to oral feeding 9.9 days earlier than controls ( t = -2.822; P = .007), started breast/chest feeding 10.8 days earlier ( t = 3.016; P = .004), and were discharged 3.0 days earlier. The PIOMI had a significant positive effect on anthropometrics, sucking capacity, readiness to initiate bottle and breast/chest feeding, and a 3-day reduction in length of hospital stay.


Sex initiates adaptive evolution by recombination between beneficial loci.
Current theory proposes that sex can increase genetic variation and produce high fitness genotypes if genetic associations between alleles at different loci are non-random. In case beneficial and deleterious alleles at different loci are in linkage disequilibrium, sex may i) recombine beneficial alleles of different loci, ii) liberate beneficial alleles from genetic backgrounds of low fitness, or iii) recombine deleterious mutations for more effective elimination. In our study, we found that the first mechanism dominated the initial phase of adaptive evolution in Brachionus calyciflorus rotifers during a natural selection experiment. We used populations that had been locally adapted to two environments previously, creating a linkage disequilibrium between beneficial and deleterious alleles at different loci in a combined environment. We observed the highest fitness increase when several beneficial alleles of different loci could be recombined, while the other mechanisms were ineffective. Our study thus provides evidence for the hypothesis that sex can speed up adaptation by recombination between beneficial alleles of different loci, in particular during early stages of adaptive evolution in our system. We also suggest that the benefits of sex might change over time and state of adaptive progress.


Total Synthesis of Divergolides E and H.
This manuscript describes the first total syntheses of divergolides E and H. The route employs a telescoped hetero-Diels-Alder and oxidative carbon-hydrogen bond cleavage as an entry into the central bridged bicyclic acetal unit. Additional key steps of the highly convergent route include a desymmetrizing epoxidation, a chelation-controlled alkenylzinc addition, an amide formation between a hindered aniline and an acylating agent that is prone to ketene formation, and a challenging macrolactonization.


Systematic weakly nonlinear analysis of radial viscous fingering.
We present a weakly nonlinear analysis of the interface dynamics in a radial Hele-Shaw cell driven by both injection and rotation. We extend the systematic expansion introduced in [E. Alvarez-Lacalle et al., Phys. Rev. E 64, 016302 (2001)] to the radial geometry, and compute explicitly the first nonlinear contributions. We also find the necessary and sufficient condition for the uniform convergence of the nonlinear expansion. Within this region of convergence, the analytical predictions at low orders are compared satisfactorily to exact solutions and numerical integration of the problem. This is particularly remarkable in configurations (with no counterpart in the channel geometry) for which the interplay between injection and rotation allows that condition to be satisfied at all times. In the case of the purely centrifugal forcing we demonstrate that nonlinear couplings make the interface more unstable for lower viscosity contrast between the fluids.