cAMP assays in GPCR drug discovery.
GPCRs are a major family of cell surface receptors and the most druggable protein targets in modern medicine. Recent elucidation of crystal structures of a vast number of GPCRs eludes to the finer details of biased agonism or functional selectivity of many of these receptors and warrants a better understanding of their biological effects as well as therapeutic potential. Receptor function is measured in terms desensitization/resensitization, which provides insights on receptor activation and differential coupling to various G proteins. This review article presents thoughts on the potential of GPCR desensitization assay/cAMP assay, a highly sensitive and versatile platform for high-throughput assays for elucidating novel functions of many orphan GPCRs. Besides, these assays also are very sensitive to screen for agonists, partial agonists, or antagonists and provide a simplified system for novel drug discovery for Gs-coupled GPCRs and understanding their physiological implications.


Efficacy of maternal vaccination during pregnancy against infant respiratory viruses.
Maternal vaccinations were effective in preventing RSV-associated lower respiratory tract infection and influenza in infants. The protection for infants against influenza was highest at 2 months and gradually declined up to 6 months of age. https://bit.ly/3ry3DAH.


A comparison of subject-dependent and subject-independent channel selection strategies for single-trial P300 brain computer interfaces.
Brain computer interfaces (BCI) represent an alternative for patients whose cognitive functions are preserved, but are unable to communicate via conventional means. A commonly used BCI paradigm is based on the detection of event-related potentials, particularly the P300, immersed in the electroencephalogram (EEG). In order to transfer laboratory-tested BCIs into systems that can be used by at homes, it is relevant to investigate if it is possible to select a limited set of EEG channels that work for most subjects and across different sessions without a significant decrease in performance. In this work, two strategies for channel selection for a single-trial P300 brain computer interface were evaluated and compared. The first strategy was tailored specifically for each subject, whereas the second strategy aimed at finding a subject-independent set of channels. In both strategies, genetic algorithms (GAs) and recursive feature elimination algorithms were used. The classification stage was performed using a linear discriminant. A dataset of EEG recordings from 18 healthy subjects was used test the proposed configurations. Performance indexes were calculated to evaluate the system. Results showed that a fixed subset of four subject-independent EEG channels selected using GA provided the best compromise between BCI setup and single-trial system performance.


[Hemodynamic monitoring in intensive care and emergency medicine : Integration of clinical signs and ultrasound findings].
Hemodynamic monitoring is required in critically ill patients presenting with circulatory shock. Besides the clinical evaluation, noninvasive technologies can be used. Guidelines on volume resuscitation and cardiogenic shock already recommend bedside ultrasound as a diagnostic tool. To differentiate the cause of circulatory shock and monitor the effects of therapies, hemodynamic monitoring is necessary. This review discusses possibilities of the different invasive and noninvasive monitoring tools with a focus on the integration of clinical and sonographic parameters.


Problem gambling in a federal prison population: results from the South Oaks Gambling Screen.
Three hundred and sixty three medium security federal prison inmates were interviewed with the South Oaks Gambling Screen (SOGS) with 5.2% of the sample achieving SOGS scores greater than 4 and another 7.4% attaining scores of 3 or 4, traditional markers of pathological gambling and problem gambling, respectively. Attempts were made to evaluate the relative accuracy of the continuum and dichotomy models of problem gambling by contrasting three groups of subjects (SOGS<3, SOGS=3 or 4, SOGS>4) on a series of gambling-related measures and comparing the relative ability of the SOGS and a dichotomized version of the SOGS to account for residual variance in these same gambling-related measures. Results were consistent with the view that problem gambling embodies features of both a continuum and dichotomy. Nearly half the subjects had desisted from problem gambling on their own, although self-remitters displayed less severe and extensive patterns of problem gambling than non-remitting subjects.


Examining Nurse and Patient Factors Before and After Implementing an Oncology Acuity Tool: A Mixed Methods Study.
Background and Purpose: To evaluate the nurse documentation compliance, pressure injury compliance, and fall prevention compliance before and after implementing an oncology acuity tool (OAT) at a specialized cancer center in Jordan. Methods: A mixed methods design was used. A qualitative approach was employed using a semistructured interview with 15 nurses selected by purposive sampling. In contrast, the quantitative approach included pre- and post-data obtained to identify the role of adopting the OAT in improving nursing documentation and applying fall and pressure injury-prevention precaution measures. Results: The thematic analysis developed seven themes, including oncology acuity score (OAS) and assignment processes, OAS and patient outcomes, OAS and nurse outcomes, limitations of the OAT, driving forces, restraining forces, and recommendations or suggestions. The results showed significant improvements in nursing documentation (p =.0385), application of pressure injury (p ≤ .00001), and falling precaution measures (p ≤ .00001). Conclusion: Nurse assignment, nursing compliance, and patients' and nurses' outcomes improved after utilizing the OAT.


Long-Term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in Children Aged ⩾6 Years with Cystic Fibrosis and at Least One F508del Allele: A Phase 3, Open-Label Clinical Trial.
Rationale: A 24-week, phase 3, open-label study showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in children aged 6-11 years with cystic fibrosis (CF) and one or more F508del-CFTR alleles. Objectives: To assess long-term safety and efficacy of ELX/TEZ/IVA in children who completed the pivotal 24-week phase 3 trial. Methods: In this phase 3, two-part (part A and part B), open-label extension study, children aged ⩾6 years with CF heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) or homozygous for F508del (F/F genotype) who completed the 24-week parent study received ELX/TEZ/IVA based on weight. Children weighing <30 kg received ELX 100 mg once daily/TEZ 50 mg once daily/IVA 75 mg every 12 hours, whereas children weighing ⩾30 kg received ELX 200 mg once daily/TEZ 100 mg once daily/IVA 150 mg every 12 hours (adult dose). The 96-week analysis of part A of this extension study is reported here. Measurements and Main Results: Sixty-four children (F/MF genotypes, n = 36; F/F genotype, n = 28) were enrolled and received one or more doses of ELX/TEZ/IVA. Mean (SD) period of exposure to ELX/TEZ/IVA was 93.9 (11.1) weeks. The primary endpoint was safety and tolerability. Adverse events and serious adverse events were consistent with common manifestations of CF disease. Overall, exposure-adjusted rates of adverse events and serious adverse events (407.74 and 4.72 events per 100 patient-years) were lower than in the parent study (987.04 and 8.68 events per 100 patient-years). One child (1.6%) had an adverse event of aggression that was moderate in severity and resolved after study drug discontinuation. From parent study baseline at Week 96 of this extension study, the mean percent predicted FEV1 increased (11.2 [95% confidence interval (CI), 8.3 to 14.2] percentage points), sweat chloride concentration decreased (-62.3 [95% CI, -65.9 to -58.8] mmol/L), Cystic Fibrosis Questionnaire-Revised respiratory domain score increased (13.3 [95% CI, 11.4 to 15.1] points), and lung clearance index 2.5 decreased (-2.00 [95% CI, -2.45 to -1.55] units). Increases in growth parameters were also observed. The estimated pulmonary exacerbation rate per 48 weeks was 0.04. The annualized rate of change in percent predicted FEV1 was 0.51 (95% CI, -0.73 to 1.75) percentage points per year. Conclusions: ELX/TEZ/IVA continued to be generally safe and well tolerated in children aged ⩾6 years through an additional 96 weeks of treatment. Improvements in lung function, respiratory symptoms, and CFTR function observed in the parent study were maintained. These results demonstrate the favorable long-term safety profile and durable clinical benefits of ELX/TEZ/IVA in this pediatric population. Clinical trial registered with www.clinicaltrials.gov (NCT04183790).


Rating intervals: an experiment in peer review.
The National Institute of Health (NIH) peer review process for research grant applications is one of the largest and most respected systems of its kind in the world. Recently, however, the distribution of raw priority scores voted by NIH study sections has been skewed, and the rating behavior of individual review groups has been quite variable. These phenomena have made funding decisions more difficult. To achieve greater uniformity of rating behavior and a broader description of scores, an experiment was conducted involving 24 study sections. Standard adjectival descriptors and standard rating scales were used. On a random basis, half of the study sections were instructed to vote in units of 0.1 while the other half used an interval of 0.5. The results of this study have now been translated into standard practice at NIH.


A neuroscientific approach to consciousness.
For a neuroscientist, consciousness currently defies any formal operational definition. However, the phenomenon is distinct from self-consciousness: after all, one can "let oneself go," when experiencing extreme emotion, but still be accessing a sentiment, subjective, conscious state. This raw, basic subjective state does not appear to be an exclusive property of the human brain. There is no obvious qualitative transformation in either the anatomy or the physiology of the central nervous system of human or non-human animals, no phylogenetic Rubicon in the animal kingdom. Similarly, there is no clear ontogenetic line that is crossed as the brain grows in the womb, no single event or change in brain physiology, and certainly not at birth, when consciousness might be generated in an all-or-none fashion. A more plausible, and scientific, view of consciousness might be therefore that it is not a different property of the brain, some magic bullet, but that it is a consequence of a quantitative increase in the complexity of the human brain: consciousness will grow as brains grow. Hence, consciousness is most likely to be a continuously variable property of the brain, in both phylogenetic and ontogenetic terms. Here, we describe how modern techniques may be utilized to determine the physiological basis of consciousness.


Leptin decreases de novo lipogenesis in patients with lipodystrophy.
De novo lipogenesis (DNL) plays a role in the development of hepatic steatosis. In humans with lipodystrophy, reduced adipose tissue causes lower plasma leptin, insulin resistance, dyslipidemia, and ectopic triglyceride (TG) accumulation. We hypothesized that recombinant leptin (metreleptin) for 6 months in 11 patients with lipodystrophy would reduce DNL by decreasing insulin resistance and glycemia, thus reducing circulating TG and hepatic TG. The percentage of TG in TG-rich lipoprotein particle (TRLP-TG) derived from DNL (%DNL) was measured by deuterium incorporation from body water into palmitate. At baseline, DNL was elevated, similar to levels previously shown in obesity-associated nonalcoholic fatty liver disease (NAFLD). After metreleptin, DNL decreased into the normal range. Similarly, absolute DNL (TRLP-TG × %DNL) decreased by 88% to near-normal levels. Metreleptin improved peripheral insulin sensitivity (hyperinsulinemic-euglycemic clamp) and lowered hemoglobin A1c and hepatic TG. Both before and after metreleptin, DNL positively correlated with insulin resistance, insulin doses, and hepatic TG, supporting the hypothesis that hyperinsulinemia stimulates DNL and that elevated DNL is integral to the pathogenesis of lipodystrophy-associated NAFLD. These data suggest that leptin-mediated improvement in insulin sensitivity increases clearance of blood glucose by peripheral tissues, reduces hepatic carbohydrate flux, and lowers insulinemia, resulting in DNL reductions and improvements in hepatic steatosis and dyslipidemia.


Depressive Symptoms in Adolescence: Longitudinal Links with Maternal Empathy and Psychological Control.
Building on self-determination theory (Deci and Ryan in Psychological Inquiry, 11, 227-268. doi: 10.1207/S15327965PLI1104_01 , 2000), the aim of the current study was to examine the role of maternal affective and cognitive empathy in predicting adolescents' depressive symptoms, through mothers' psychological control use. Less empathic mothers may be less sensitive to adolescents' need for psychological autonomy, and thus prone to violating this need using psychological control, which may in turn predict adolescents' depressive symptoms. Moreover, according to interpersonal theory of depression (Coyne in Journal of Abnormal Psychology, 85, 186-193. doi: 10.1037/0021-843x.85.2.186 , 1976), adolescents' depressive symptoms may elicit rejecting responses, such as mothers' psychological control. For six waves, 497 adolescents (57 % boys, M age T1 = 13.03) annually completed questionnaires on depressive symptoms and maternal psychological control, while mothers reported on their empathy. Cross-lagged path analyses showed that throughout adolescence, both mothers' affective and cognitive empathy indirectly predicted boys' and girls' depressive symptoms, through psychological control. Additionally, depressive symptoms predicted psychological control for boys, and early adolescent girls. These results highlight the importance of (1) mothers' affective and cognitive empathy in predicting adolescents' depressive symptoms, and (2) taking gender into account when examining adolescent-effects.


Computer-assisted preoperative planning of reduction of and osteosynthesis of scapular fracture: A case report.
Reports on the use of computer-assisted trauma surgery of comminuted scapula fracture are still quite rare. In this article, we present a case of comminuted scapula fracture, the surgical reconstruction of which was pre-operatively planned using a complex software solution. For surgical planning of the fracture, we used the TraumaTech software facilitating virtual reconstruction (both manual and automatic), surgery planning, design of the implant, planning of screw placement and lengths, and production of a 3D print model of the fracture and the implant. The software also supported ordering such custom-made plate from a plate producer who was capable of fast and precise production of the plate. The surgery using the custom-ordered plate was successful. The actual used screw lengths did not differ from the planned ones by more than 2 mm. One year after the surgery, the patient was capable of more demanding activities and doing sports activities. This approach provides a great way to prevent complications of the surgery and to shorten its duration. To the best of our knowledge, this is the first description of the treatment of a scapula comminuted fracture utilizing computer-assisted preoperative planning.


Pilot trial of paclitaxel-trastuzumab adjuvant therapy for early stage breast cancer: a trial of the ECOG-ACRIN cancer research group (E2198).
Blockade of human epidermal growth factor receptor type 2 (HER2) has dramatically improved outcome for patients with HER2-positive breast cancer. Trastuzumab, an anti-HER2 monoclonal antibody, has previously demonstrated improvement in overall survival (OS) in patients with metastatic and early stage HER2-positive breast cancer. However, trastuzumab can cause congestive heart failure (CHF) with an increased frequency for patients who have also received an anthracycline. The current trial was designed to evaluate the impact of the duration of trastuzumab on CHF. E2198 included 227 eligible women with histologically confirmed stage II or IIIA HER2-positive breast cancer. The patients were randomised to receive 12 weeks of paclitaxel and trastuzumab followed by four cycles of doxorubicin and cyclophosphamide (abbreviated Arm) or the aforementioned treatment with additional 1 year of trastuzumab (conventional Arm). The primary end point was to evaluate the safety of this variable duration of trastuzumab therapy, particularly cardiac toxicity defined as CHF or left ventricular ejection fraction decrease >10%. Secondary end points included disease-free survival (DFS) and OS. Compared with 12-week treatment with trastuzumab, 1 year of trastuzumab-based therapy did not increase the frequency or severity of cardiac toxicity: three patients on the abbreviated Arm and four on the conventional Arm experienced CHF. The 5-year DFS was 76% and 73% for the abbreviated and conventional Arms, respectively, with a hazard ratio (HR) of 1.3 (95% CI: 0.8-2.1; P=0.3). There was also no statistically significance difference in OS (HR, 1.4; P=0.3). Compared with 12 weeks of treatment, 1 year of treatment with trastuzumab did not significantly increase the risk of cardiac toxicity. Although not powered for efficacy comparisons, the longer duration of trastuzumab therapy did not demonstrate a signal for marked superiority.


Pharmacogenetics and cost-effectiveness analysis: a two-way street.
Genetic and proteomic information can be used to identify those patient groups who are most susceptible to a disease and those who are most likely to respond to particular pharmacological treatments. In this review we discuss the impact of cost-effectiveness analysis (CEA) regarding the way pharmacogenetics are adopted by healthcare systems and also, the potential impact of pharmacogenetics on the way CEA is conducted. We conclude that, although CEA can help incentivise the development of appropriate pharmacogenetic tests, when used inappropriately by payers or when ignored by developers, it can act as an obstacle to the adoption of health and efficiency improving technologies.


Increased ubiquitination and reduced plasma membrane trafficking of placental amino acid transporter SNAT-2 in human IUGR.
Placental amino acid transport is decreased in intrauterine growth restriction (IUGR); however, the underlying mechanisms remain largely unknown. We have shown that mechanistic target of rapamycin (mTOR) signalling regulates system A amino acid transport by modulating the ubiquitination and plasma membrane trafficking of sodium-coupled neutral amino acid transporter 2 (SNAT-2) in cultured primary human trophoblast cells. We hypothesize that IUGR is associated with (1) inhibition of placental mTORC1 and mTORC2 signalling pathways, (2) increased amino acid transporter ubiquitination in placental homogenates and (3) decreased protein expression of SNAT-2 in the syncytiotrophoblast microvillous plasma membrane (MVM). To test this hypothesis, we collected placental tissue and isolated MVM from women with pregnancies complicated by IUGR (n=25) and gestational age-matched women with appropriately grown control infants (n=19, birth weights between the twenty-fifth to seventy-fifth percentiles). The activity of mTORC1 and mTORC2 was decreased whereas the protein expression of the ubiquitin ligase NEDD4-2 (neural precursor cell expressed developmentally down-regulated protein 4-2; +72%, P<0.0001) and the ubiquitination of SNAT-2 (+180%, P<0.05) were increased in homogenates of IUGR placentas. Furthermore, IUGR was associated with decreased system A amino acid transport activity (-72%, P<0.0001) and SNAT-1 (-42%, P<0.05) and SNAT-2 (-31%, P<0.05) protein expression in MVM. In summary, these findings are consistent with the possibility that decreased placental mTOR activity causes down-regulation of placental system A activity by shifting SNAT-2 trafficking towards proteasomal degradation, thereby contributing to decreased fetal amino acid availability and restricted fetal growth in IUGR.


Effect of fasting glucose levels on mortality rate in patients with and without diabetes mellitus and coronary artery disease undergoing percutaneous coronary intervention.
Diabetes mellitus (DM) is predictive of increased mortality for patients with coronary artery disease (CAD). To what extent this risk extends below the diabetic threshold (fasting glucose level [FG] <126 mg/dL) is uncertain. The study objective was to determine the risk associated with FG in a prospectively assembled cohort of 1612 patients with CAD who were undergoing percutaneous coronary intervention (PCI) and had a FG measured or a clinical diagnosis of DM (CDM). Patients were grouped as: CDM; no CDM, but FG > or =126 mg/dL (ADA-DM); impaired FG, 110-125 mg/dL (IFG); or normal FG, <110 mg/dL (NFG). Survival was assessed for 2.8 +/- 1.2 years. The average patient age was 62 +/- 12 years; 74% of the patients were men. Diagnostic frequencies were: CDM, 24%; ADA-DM, 18%; IFG, 19%; and NFG, 39%. Mortality rates were greater for patients in the CDM (44/394 [11.2%], P <.0001), ADA-DM (27/283 [9.5%], P <.001), and IFG (20/305 [6.6%], P =.04) groups than patients in the NFG group(12/630 [1.9%]). Independent receiver operating characteristic analysis chose FG > or =109 mg/dL as the best cutoff for increased risk (sensitivity, 81%; specificity, 51%). After adjustment with Cox regression analysis, CDM (hazard ratio [HR] = 5.0; 95% CI, 2.6-9.6; P <.001), ADA-DM (HR, 4.1; 95% CI, 2.1-8.2; P <.001), and IFG status (HR, 3.2; 95% CI, 1.5-6.5; P =.002) remained independent predictors of mortality. Prognostically significant abnormalities of FG are much more prevalent (61%) than expected in patients with CAD who are undergoing PCI. Despite revascularization, the associated mortality risk of even mild elevations in FG is substantial, emphasizing the importance of early detection and treatment of glycemia-related risk.


Radiation Therapy Oncology Group: radiosurgery quality assurance guidelines.
A multidisciplinary Radiation Therapy Oncology Group (RTOG) task force has developed quality assurance guidelines for radiosurgery. The purpose of the guidelines are fourfold: (1) To ensure that participating institutions have the proper equipment and appropriate technique(s) to administer radiosurgery; (2) to outline a standard data set for each treated patient to assess protocol compliance; (3) to define minor and major deviations in protocol treatment; and (4) to set forth clinical data necessary to determine treatment efficacy, including failure patterns, and treatment toxicity. These guidelines are being implemented into active and developing radiosurgery protocols.


Clinical experience and perception of abortion: A cross-sectional survey of gynecologists in Japan.
This study describes aspects of early induced abortion from the experience and perspectives of a sample of gynecologists in Japan. The survey questionnaire data were collected from 343 gynecologists from September to October 2010. Approximately 83% of participants preferred using only dilation and curettage (D&C), and 10.4% used electric vacuum aspiration (EVA). The cost of surgical abortion was not covered by insurance. Most gynecologists used intravenous pain management during abortion. Approximately 50% of the gynecologists were opposed to introducing medical abortion in Japan.


[Not Available].
Feed grain production for on-farm use is widespread in Bavarian agriculture and garants a reliable production of healthy foodstuff. Therefore the quality of feed grain is very important for farmers. In an orientating investigation of the on-farm stored feed grain quality from the harvest years 1991 to 2000 1757 samples were analysed. Based on values for guidance by the German government for DON and ZEA and Commission Regulation EC No 472/2002 for OTA the results show that only 2% of the positive samples have amounts higher then 0,05 mg ZEA/kg grain, 4% of the positive samples contain more then 1 mg DON/kg grain and 2% of the positive samples have amounts higher then 0,003 mg OTA/kg feed grain. These illustrate the good conservation and storage quality on Bavarian farms.


Facial nerve grading systems.
A comprehensive, accurate, and valid system for reporting results of facial nerve surgery and disease is needed. This study describes and statistically analyzes eight currently available systems for reliability, validity, and ease of use. They are divided into three grading categories: gross scales, regional systems, and specific scales. Botman and Jongkees, May, and Peitersen have proposed five-point gross scales. Janssen, Smith, Adour and Swanson, and Yanagihara have devised regional systems. Stennert has proposed a specific criteria scale. Fifteen otologists experienced with facial nerve problems used modifications of the existing scales to evaluate videotapes of 12 patients representing the complete range of facial function. The observers' responses were translated back to the original scales. Observers also ranked patients from least to most severe, to obtain an accurate assessment of facial function for patients in the study. A follow-up questionnaire examined observers' system preferences. Validity is measured by correlating responses to different scales and by comparing responses to each scale with observers' rankings. All scales have good validity except the scales of Stennert and Yanagihara. Consistency of responses is determined by reliability coefficients. Coefficients for all scales are high except for the gross scale, which is moderately reliable, and the Stennert scale, which is unreliable. Results indicate that all scales succeed in evaluating patients with normal function or total paralysis. The regional scales have the highest reliabilities but they also have wide response ranges. Most also assume a level of precision that is unsubstantiated. Gross scales have smaller ranges, which result in greater agreement of responses but lower reliability. Comparisons to more complex scales show that the simpler gross scales convey similar information about patients. The study concludes that a gross scale is the best type of system and proposes a new scale for international acceptance. This system has six categories, includes secondary defects, is designed to clearly differentiate between moderate degrees of dysfunction, and should facilitate interpretation and communication of facial nerve results.


Effect of rivaroxaban and dabigatran on platelet functions: in vitro study.
Clinical benefit-risk balance of direct oral anticoagulants (DOAC) in atherothrombosis prevention differs between anti-Xa and anti-IIa drugs and their specific effect on platelet functions remains controversial. We hence investigated rivaroxaban and dabigatran effect on platelets in identical experimental conditions. Blood of fifteen healthy volunteers was spiked with DOAC which plasma concentrations were measured by specific anti-Xa or anti-IIa assays. Light transmission aggregometry measured in platelet-rich plasma used low doses of agonists: 0.5 mM arachidonic acid, 2.5 μM ADP, 0.5 μM epinephrine, 0.8 μg/ml collagen, 7.5 μM TRAP-6 and 0.5 pM tissue factor in the presence of H-Gly-Pro-Arg-Pro-OH to prevent fibrin polymerization. Platelet adhesion on collagen fibres was evaluated in whole blood under flow. Same experiments were reproduced in the presence of aspirin. Median [95% CI] plasma concentrations were of 28 [23-36], 128 [119-144] and 321 [293-361] ng/ml for rivaroxaban and 39 [34-45], 171 [166-193] and 353 [349-382] ng/ml for dabigatran. DOAC did not modify platelet aggregation or adhesion on collagen fibres at any tested concentrations. However, they delayed platelet aggregation secondary to coagulation activation with a more potent effect with dabigatran (p < 0.001). Aspirin did not modify DOAC effect. Efficacy of combining DOAC and aspirin in atherothrombosis prevention would not stem from a direct antiplatelet effect of the formers but to their additive inhibitory effect on platelet aggregation secondary to coagulation activation. This effect differs according to DOAC molecules and may also result from the pleiotropic roles of the different coagulation factors targeted by DOAC.


DO ANDROGENS PREDICT CARDIOVASCULAR RISK INCLUDING CARDIOTROPHIN-1 LEVELS in PATIENTS WITH OBESE and LEAN POLYCYSTIC OVARY SYNDROME.
We aimed to investigate Cardiotrophin-1 (CT-1) levels along with other markers of cardiovascular disease and the association of androgen levels with these parameters in both lean and overweight or obese PCOS patients. The study included 90 overweight or obese PCOS patients with metabolic syndrome (MS) and 80 lean PCOS patients without MS. The control group consisted of 140 healthy females. Anthropometric measurements, plasma glucose, insulin, lipid and hormone profile, homocysteine, hs-CRP, CT-1 levels and carotid-IMT were evaluated in all study subjects. Fasting insulin, HOMA values were significantly higher in obese PCOS patients. Total testosteron levels were higher in both PCOS groups with respect to both controls. Serum homocysteine, hs-CRP, CT-1 and carotid-IMT values were significantly higher in both PCOS groups compared to controls (p=0.001, pCIMT: 0.005). CT-1 was positively correlated with insulin, HOMA, total testosterone, homocysteine, hs-CRP and carotid IMT. After multiple regression analysis, CT-1 was significantly positively correlated with total testosterone, hs-CRP and carotid IMT. CT-1 was associated with other cardiovascular risk markers and its use as a cardiovascular risk marker might be suggested. Cardiovascular risk was increased even in lean PCOS patients without MS and it might be associated with elevated androgen levels.


Dosimetric consequences of interstitial extravasation following i.v. administration of a radiopharmaceutical.
The worst case radiation dose to tissue due to inadvertent intravenous injection of a radiopharmaceutical was estimated for the most commonly utilised radioisotopes. The probability of radiation injury induction was examined for the various radionuclides considering the maximal specific activity values encountered in diagnostic practice. A possible approach to the management of incidents involving extravasal activity deposition is discussed.


Climate Change and Health in New England: A Review of Training and Policy Initiatives at Health Education Institutions and Professional Societies.
There has been increasing interest in climate change among healthcare professionals, but it is unclear to what extent resources on this topic are available to students and clinicians in New England. Structured review of publicly available information regarding climate change and health activity at schools of medicine, public health, and physician assistant studies and in state medical and physician assistant societies in New England. Of 39 programs reviewed, 18 (46%) had at least one climate-related initiative. Six universities accounted for 87% of climate change and health initiatives in the region. Three out of 12 state professional associations had committees or position statements addressing climate change. There is substantial activity related to climate change and health in New England, but it is concentrated in a small number of locations. Opportunities exist to improve access to education on this topic and increase involvement of health professional associations.


Flexion contracture of the thumb: a malignant etiology.
A patient was first seen with a flexion deformity of the thumb interphalangeal joint that was initially diagnosed and treated as traumatic in origin. A painful forearm soft tissue mass was ultimately discovered; biopsy of the flexor pollicis longus tendon showed metastatic adenocarcinoma. Extensive evaluation failed to locate the origin of the primary tumor. Treatment consisted of local radiation and systemic chemotherapy. After 1 year, the patient is alive and well, has no evidence of disease, and refuses correction of the thumb interphalangeal flexion contracture.


Risk stratification in the elderly patient after coronary artery bypass grafting: the prognostic value of radionuclide cineangiography.
Recent data have shown that assessment of left ventricular function by radionuclide cineangiography (RNCA) predicts survival and cardiac events among non-age-selected patients who have previously undergone coronary artery bypass grafting (CABG). However, the prognostic value of this noninvasive approach is not known for elderly patients who now undergo CABG with progressively increasing frequency and who survive longer because of operation. Such easily applied prognostic indexes may be useful to determine whether survival benefits are likely to be maintained or additional therapy should be considered. To obtain information on factors related to long-term survival and cardiac events among elderly patients after CABG and, specifically, to determine the prognostic implications of left ventricular performance at rest and during exercise for predicting all causes of death, major nonsurgical cardiac events (death or myocardial infarction), and event-free or surgery-free survival, we evaluated the late postoperative course of 41 patients, aged 65 years and older, who had undergone RNCA 1 month or more (mean 2.3 +/- 2.4 years; range 0.1 to 9 years) after CABG. Average follow-up among patients with event-free survival was 8.8 years after index radionuclide assessment. During follow-up 13 patients died with no known intercurrent event, five patients had nonfatal myocardial infarctions, and five underwent late (> or = 3 months after RNCA) repeat CABG or percutaneous transluminal coronary angioplasty. Log-rank comparisons of Kaplan-Meier product limit estimate curves identified only left ventricular ejection fraction at rest as significantly predictive of survival (p < 0.04). Patients with left ventricular ejection fraction at rest of less than 45% had a 7.8% average annual mortality risk, which was more than three times that of patients with normal resting function. Statistical trends also were found between mortality rates and completeness of revascularization (p < 0.06), major nonsurgical cardiac events and extent of anatomic disease (p < 0.08), and event-free or surgery-free survival and our index of completeness of revascularization (p = 0.08) and age at index RNCA (p < 0.07). Assessment of left ventricular ejection fraction at rest is prognostically useful after CABG among elderly patients. The efficacy and timing of this approach should be confirmed in further investigations with larger and more varied patient subgroups.


Cocaine-Induced Endocannabinoid Mobilization in the Ventral Tegmental Area.
Cocaine is a highly addictive drug that acts upon the brain's reward circuitry via the inhibition of monoamine uptake. Endogenous cannabinoids (eCB) are lipid molecules released from midbrain dopamine (DA) neurons that modulate cocaine's effects through poorly understood mechanisms. We find that cocaine stimulates release of the eCB, 2-arachidonoylglycerol (2-AG), in the rat ventral midbrain to suppress GABAergic inhibition of DA neurons, through activation of presynaptic cannabinoid CB1 receptors. Cocaine mobilizes 2-AG via inhibition of norepinephrine uptake and promotion of a cooperative interaction between Gq/11-coupled type-1 metabotropic glutamate and α1-adrenergic receptors to stimulate internal calcium stores and activate phospholipase C. The disinhibition of DA neurons by cocaine-mobilized 2-AG is also functionally relevant because it augments DA release in the nucleus accumbens in vivo. Our results identify a mechanism through which the eCB system can regulate the rewarding and addictive properties of cocaine.


Alginate coated chitosan nanogel for the controlled topical delivery of Silver sulfadiazine.
Burn wounds environment favors the growth of micro-organisms causing delay in wound healing. The traditional treatment with antimicrobial creams offer inaccurate doses. The aim of the present study is to formulate and evaluate different silver sulfadiazine loaded nanogel formulations. A factorial design experiment was used for the identification of critical process parameters and for the optimization of the respective process conditions. The prepared drug loaded nanogels were characterized for their particle size, zeta potential, entrapment efficiency and swelling index in order to demonstrate their physicochemical properties, in addition, FTIR, TEM, SEM and in vitro release were used for characterization. The release profile of all tested nanogels showed an initial burst followed by a slow and continuous release rate. An optimum nanogel formulation was predicted by the JMP® software according to the stated prediction expressions and was composed of 0.4% sodium alginate (ALG) and 0.414% Silver sulfadiazine (SSD). The optimized formulation showed higher therapeutic efficacy in vivo when compared to market product.


Terfezia boudieri and Terfezia claveryi inhibit the LPS/IFN-γ-mediated inflammation in RAW 264.7 macrophages through an Nrf2-independent mechanism.
Desert truffles have been used as traditional treatments for numerous inflammatory disorders. However, the molecular mechanisms underlying their anti-inflammatory effects in RAW 264.7 macrophages have yet to be fully elucidated. The present study investigated the anti-inflammatory activities of two main desert truffles, Terfezia boudieri and T. claveryi, and the underlying mechanisms associated with their anti-inflammatory activities in RAW 264.7 macrophages stimulated with lipopolysaccharide/interferon-gamma (LPS/IFN-γ). Our results demonstrated that treatment with T. boudieri and T. claveryi extracts effectively suppressed the inflammatory response in LPS/IFN-γ-stimulated RAW 264.7 macrophages. Specifically, T. boudieri extract was found to reduce the production of nitric oxide and inhibit the expression of various pro-inflammatory markers, including inducible nitric oxide synthase, cyclooxygenase-2 (COX-2), tumor necrosis factor-α, and interleukin-6 (IL-6) at both the mRNA and protein levels. Similarly, T. claveryi extract exhibited comparable inhibitory effects, except for the expression of IL-6 and COX-2 at the protein level, where no significant effect was observed. Moreover, both studied extracts significantly downregulated the microRNA expression levels of miR-21, miR-146a, and miR-155, suggesting that T. boudieri and T. claveryi suppress the inflammatory response in LPS/IFN-γ-stimulated RAW 264.7 cells through an epigenetic mechanism. Furthermore, our study reveals a new mechanism for the anti-inflammatory properties of desert truffle extracts. We show for the first time that Terfezia extracts do not rely on the nuclear factor erythroid 2-related factor 2 pathway, previously linked to anti-inflammatory responses. This expands our understanding of natural product anti-inflammatory mechanisms and could have important implications for developing new therapies. To account for differences in truffle effects, extracts prepared were subjected to secondary metabolites profiling using UPLC-MS. UPLC-MS led to the annotation of 87 secondary metabolites belonging to various classes, including amino acids, carbohydrates, alkaloids, amides, fatty acids, sterols, and phenolic compounds. Therefore, these results indicate that T. boudieri and T. claveryi exhibit anti-inflammatory activities through suppressing multiple inflammatory mediators and cytokines and may be potential anti-inflammatory agents.


Effect of monomer blend and chlorhexidine-adding on physical, mechanical and biological properties of experimental infiltrants.
The aim of the study was to evaluate antimicrobial inhibition zone, degree of conversion (DC) and Knoop hardness (KH) of experimental infiltrants. Experimental low viscosity monomer blends were prepared and chlorhexidine diacetate salt (CHX) (0.1% or 0.2%) was added comprising the groups: G1) TEGDMA; G2) TEGDMA/0.1CHX; G3) TEGDMA/0.2CHX; G4) TEGDMA/UDMA; G5) TEGDMA/UDMA/0.1CHX; G6) TEGDMA/UDMA/0.2CHX; G7) TEGDMA/BISEMA; G8) TEGDMA/BISEMA/0.1CHX; G9) TEGDMA/BISEMA/0.2CHX. Icon® was used as control group. Specimens of resin blends were made (n=9) to accomplished DC and KH. Pour plate was accomplished to evaluate antimicrobial groups' activity against Streptococcus mutans (SM) and Lactobacillus acidophilus (LA). Data obtained were submitted to two-way ANOVA and Tukey tests for blends comparisons and Dunnett's test for comparisons between experimental infiltrants and Icon® (p<0.05). In relation to antimicrobial effect, uncured blends showed higher antibacterial activity than cured ones for the most of blends. After polymerization, G5 showed the highest inhibition zone against SM and, G3 and G6 against LA. Concerning KH, TEGDMA/UDMA-based blends showed the highest values of KH number and it was influenced by monomeric base, regardless CHX concentration. DC was not affected by monomer blend composition, neither for CHX concentration. The antimicrobial activity was affected by monomeric base, CHX concentration and polymerization. Experimental infiltrants presented similar or higher performance than Icon® for the properties evaluated. White spot lesion infiltration with low viscosity monomer blends (infiltrants) is an alternative to stop initial caries lesions progression. The incorporation of an antimicrobial agent as chlorhexidine diacetate salt in infiltrants composition could enhance the performance of these materials.


Effect of a single treatment with the alkylating carcinogens dimethylnitrosamine and methyl methanesulphonate on liver regenerating after partial hepatectomy. IV. Effect on methylase-mediated methylation of DNA.
The possibility that carcinogens may affect methylase-mediated methylation of replicating DNA was investigated. A system eminently suitable for this purpose is liver regenerating after partial hepatectomy, as one injection of dimethylnitrosamine (DMN) given during the ensuing period of increased DNA synthesis induces hepatocellular carcinoma. Methylation of DNA by DNA methylase normally occurs only in proportion to DNA synthesis. Therefore simultaneous measurements were made of synthesis (incorporation of [14C]adenine into DNA adenine, or of d[5-3H]cytidine into DNA cytosine), and of methylation (incorporation of [methyl-3H]methionine into 5-methylcytosine of DNA) in liver regenerating after partial hepatectomy. After treatment with DMN, the ratio of methylation: synthesis remained within the normal range. Methyl methanesulphonate (MMS), a compound which damages DNA in regenerating liver in a similar but not identical way to DMN and which does not induce tumors in liver even when given after partial hepatectomy, caused an increase in methylation in relation to synthesis. These experiments therefore do not support the view that altered DNA methylase activity is involved in carcinogenesis.


Potential applications of gut microbiota to control human physiology.
The microorganisms living in our gut have been a black box to us for a long time. However, with the recent advances in high throughput DNA sequencing technologies, it is now possible to assess virtually all microorganisms in our gut including non-culturable ones. With the use of powerful bioinformatics tools to deal with multivariate analyses of huge amounts of data from metagenomics, metatranscriptomics, metabolomics, we now start to gain some important insights into these tiny gut inhabitants. Our knowledge is increasing about who they are, to some extent, what they do and how they affect our health. Gut microbiota have a broad spectrum of possible effects on health, from preventing serious diseases, improving immune system and gut health to stimulating the brain centers responsible for appetite and food intake control. Further, we may be on the verge of being capable of manipulating the gut microbiota by diet control to possibly improve our health. Diets consisting of different components that are fermentable by microbiota are substrates for different kinds of microbes in the gut. Thus, diet control can be used to favor the growth of some selected gut inhabitants. Nowadays, the gut microbiota is taken into account as a separate organ in human body and their activities and metabolites in gut have many physiological and neurological effects. In this mini-review, we discuss the diversity of gut microbiota, the technologies used to assess them, factors that affect microbial composition and metabolites that affect human physiology, and their potential applications in satiety control via the gut-brain axis.


Diagnosis of invasive fungal infections: challenges and recent developments.
The global burden of invasive fungal infections (IFIs) has shown an upsurge in recent years due to the higher load of immunocompromised patients suffering from various diseases. The role of early and accurate diagnosis in the aggressive containment of the fungal infection at the initial stages becomes crucial thus, preventing the development of a life-threatening situation. With the changing demands of clinical mycology, the field of fungal diagnostics has evolved and come a long way from traditional methods of microscopy and culturing to more advanced non-culture-based tools. With the advent of more powerful approaches such as novel PCR assays, T2 Candida, microfluidic chip technology, next generation sequencing, new generation biosensors, nanotechnology-based tools, artificial intelligence-based models, the face of fungal diagnostics is constantly changing for the better. All these advances have been reviewed here giving the latest update to our readers in the most orderly flow. A detailed literature survey was conducted by the team followed by data collection, pertinent data extraction, in-depth analysis, and composing the various sub-sections and the final review. The review is unique in its kind as it discusses the advances in molecular methods; advances in serology-based methods; advances in biosensor technology; and advances in machine learning-based models, all under one roof. To the best of our knowledge, there has been no review covering all of these fields (especially biosensor technology and machine learning using artificial intelligence) with relevance to invasive fungal infections. The review will undoubtedly assist in updating the scientific community's understanding of the most recent advancements that are on the horizon and that may be implemented as adjuncts to the traditional diagnostic algorithms.


Starting a national, prospective colorectal cancer registry in a developing country: how to do it, potential limitations and results of a pilot study.
Prospective registries of patients operated on for malignancies at a national scale are not common in developing countries. The aim of this work is to report the process of creation of a prospective national colorectal cancer registry in a middle-income country in Latin America and the main results of a pilot study involving eight centres. The project involved the creation of a national database including all patients operated on for colorectal cancer in Argentina and a 30-year plan to make improvements based on the information provided by the registry. The first phase comprised the prospective registration of all patients treated in eight tertiary referral centres during a 6-month period. Three hundred and seventeen patients were prospectively recruited during the study period, and 244 (77%) were operated on for colon cancer. The completion rate for all variables was >95%. The median age for the group was 66.88 years. Right-sided colon tumours were the most frequent. Colorectal specialists performed 257 (81.07%) of the procedures, and in 273 (87.22%) patients a laparoscopic approach was used with an overall conversion rate of 12.45%. Major complication and anastomotic leakage rates for the group were 18.55% and 8.81%, respectively. The mortality rate was 1.94%. Multivariate analysis showed that young patients and operations performed by general surgeons were the most common factors independently related to worse postoperative outcomes. Note that this manuscript describes an early phase of the project that included only eight tertiary referral centres. Despite its limitations, this study describes the effort made to generate reliable data on which to base future decisions to improve patient care. Furthermore, it might set an example for other developing countries to start their own registries.


Maternal deaths in the Kilimanjaro region of Tanzania.
The maternal deaths in a supra-regional reference hospital between 1971 and 1977 are reviewed and avoidable factors discussed. Improvements in ante-natal care have diminished the number of deaths from obstetric causes and as a result deaths from associated diseases are assuming greater significance. Particular attention is drawn to the enterocolitis group of diseases which account for 15% of the total deaths in this series. The effect of pregnancy on amoebic colitis has not been widely appreciated.


Hyaluronan in skin: aspects of aging and its pharmacologic modulation.
Hyaluronan is a glycosaminoglycan polymer prominent in embryogenesis and in tissues undergoing repair. It is responsible for the water content of skin, where half the hyaluronan of the body is present. As in other tissues, it undergoes rapid turnover. Its biology is vastly different between dermis and epidermis. Levels do not diminish with age but instead become increasingly associated with tissues and resistant to extraction in vitro. Hyaluronan-binding proteins are involved, most of which remain unidentified. Hyaluronan size is critical for its various functions. High molecular size reflects intact tissues and antiangiogenic and immunosuppressive state, whereas smaller polymers are distress signals and potent inducers of inflammation and angiogenesis.


Assessment of Qatar community pharmacists' competence and practices related to renal and gastrointestinal adverse effects of nonprescription NSAIDs.
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently dispensed nonprescription drugs in community pharmacies. However, inappropriate use of NSAIDs by consumers has been associated with development of gastrointestinal (GI) injuries and renal injuries. Community pharmacists' education of consumers on proper use of NSAIDs and their associated adverse effects has been shown to reduce the GI and renal injuries. In Qatar, no studies have been done to assess the community pharmacists' knowledge, attitude, and practices related to renal and GI adverse effects of NSAIDs. Therefore, this study aimed to assess Qatar community pharmacists' knowledge, attitude, and practices on the safe use of nonprescription NSAIDs to reduce the risk of kidney and GI injuries. A cross-sectional web-based survey was conducted among community pharmacists in Qatar. A pre-tested 28-item questionnaire that was developed through a multi-phase iterative process was administered to a convenient sample of community pharmacists in Qatar. Data were analyzed using descriptive and inferential statistics with statistical significance set at p < 0.05. Overall, 114 community pharmacists responded to the online questionnaire (response rate 15.2%). Approximately 90% of the community pharmacists demonstrated from good to excellent knowledge on the renal and GI adverse effects of NSAIDs, with none of their sociodemographic and professional characteristics having a significant effect on their knowledge scores. More than half of the pharmacists reported that they always or usually educated patients on the dosage (98.6%), administration (95.8%), side effects and precautions (78%), and contraindications (71.2%) of NSAIDs during their routine practices. The majority of the pharmacists had positive attitude towards educating patients about adverse effects of NSAIDs, as well as identifying high-risk patients who should avoid nonprescription NSAIDs. However, 45.7% of the pharmacists strongly agreed or agreed that educating patients about NSAIDs can be time consuming. Community pharmacists in Qatar demonstrated good knowledge of the renal and GI adverse effects of NSAIDs with some obvious areas of improvement, and this can be reinforced through continuing professional development. They also showed positive attitudes towards protecting patients against the renal and GI adverse effects of NSAID. However, a significant proportion of the pharmacists admitted that educating patients on NSAIDs was time consuming, which is a cause of concern warranting further investigation. Community pharmacy managers should provide community pharmacists adequate time and support to educate individuals at risk of renal and GI injuries who obtain NSAIDs from their pharmacies. Also, the Ministry of Public Health of Qatar should consider making counseling on high-risk medications (e.g., NSAIDs and insulin) by community pharmacists mandatory so that measures can be put in place in the pharmacies to free the pharmacist for education and counseling.


Neural control of the canine pylorus.
After atropine administration the anesthetized dog exhibits significant spontaneous pyloric contractile activity and an inhibition-relaxation response upon electrical vagal stimulation. This inhibition-relaxation response was completely blocked by tetrodotoxin administration and by transection of the intraabdominal vagal nerves. In addition, tetrodotoxin administration caused a dramatic increase in spontaneous pyloric motor activity. The histaminergic receptor antagonists diphenhydramine and cimetidine did not block the inhibition-relaxation response. The octapeptide of cholecystokinin (CCK-OP) caused a dose-dependent increase in antral and pyloric motor activity which was significantly decreased by atropine administration. Therefore, histamine and CCK do not appear to play a significant role in the vagally mediated inhibition-relaxation response of the canine pylorus or in the atropine-resistant spontaneous pyloric motor activity.


Cooperation between non-essential DNA polymerases contributes to genome stability in Saccharomyces cerevisiae.
DNA polymerases influence genome stability through their involvement in DNA replication, response to DNA damage, and DNA repair processes. Saccharomyces cerevisiae possess four non-essential DNA polymerases, Pol λ, Pol η, Pol ζ, and Rev1, which have varying roles in genome stability. In order to assess the contribution of the non-essential DNA polymerases in genome stability, we analyzed the pol4Δ rev1Δ rev3Δ rad30Δ quadruple mutant in microhomology mediated repair, due to recent studies linking some of these DNA polymerases to this repair pathway. Our results suggest that the length and quality of microhomology influence both the overall efficiency of repair and the involvement of DNA polymerases. Furthermore, the non-essential DNA polymerases demonstrate overlapping and redundant functions when repairing double-strand breaks using short microhomologies containing mismatches. Then, we examined genome-wide mutation accumulation in the pol4Δ rev1Δ rev3Δ rad30Δ quadruple mutant compared to wild type cells. We found a significant decrease in the overall rate of mutation accumulation in the quadruple mutant cells compared to wildtype, but an increase in frameshift mutations and a shift towards transversion base-substitution with a preference for G:C to T:A or C:G. Thus, the non-essential DNA polymerases have an impact on the nature of the mutational spectrum. The sequence and functional homology shared between human and S. cerevisiae non-essential DNA polymerases suggest these DNA polymerases may have a similar role in human cells.


The importance of recognizing a history of sexual abuse in female adolescents.
We have become increasingly aware of sexual abuse in our society, and yet the majority of teens who were sexually abused as children enter adolescence carrying the secret of their abuse. Such hidden abuse may have devastating effects on the development of personal identity, self-esteem, attitudes, behaviors, and interpersonal relationships that may persist and set a pattern for a troubled adulthood. This article details how children cope with a sexually abusive situation, the long-term effects of unresolved sexual abuse, and diagnostic criteria to differentiate a hidden history of sexual abuse from other trauma and conditions. Focus is on recognizing and assessing "legitimate" symptoms that may be conscious or unconscious cries for help by victims of previous sexual abuse. Correct diagnosis is essential to appropriate intervention to lessen possible further psychologic damage during adolescence.


Is the Co-administration of Metformin and Clomiphene Superior to Induce Ovulation in Infertile Patients With Poly Cystic Ovary Syndrome and Confirmed Insulin-Resistance: A Double Blind Randomized Clinical Trial.
This study aimed to compare the effects of clomiphene citrate (CC) combined with metformin or placebo on infertile patients with poly cystic ovary syndrome (PCOS) and insulin resistance (IR). We included 151 infertile women with PCOS and IR in a university hospital from November 2015 to April 2022 in this prospective, double-blind, randomized, placebo-controlled trial. Patients were randomized into two groups; group A: received CC plus metformin (n = 76) and group B: received CC plus placebo (n = 75). The ovulation rate was the main outcome measure. Clinical pregnancy, ongoing pregnancy, live birth and abortion rates were secondary outcome measures. There was no remarkable difference in ovulation rate in two groups. Moreover, no significant changes were observed in clinical pregnancy, ongoing pregnancy, live birth and abortion rates between two groups. A larger proportion of women in group A suffered from side effects of metformin (9.3% versus 1.4%; p=0.064), although this was not significant. In IR infertile women with PCOS, metformin pre-treatment did not increase the ovulation, clinical pregnancy and live birth rates in patients on clomiphene citrate.


Saratin, an inhibitor of collagen-platelet interaction, decreases venous anastomotic intimal hyperplasia in a canine dialysis access model.
Prosthetic dialysis access thrombosis and/or stenosis is the most common cause of graft impairment or loss and is primarily attributed to venous outflow stenosis due to intimal hyperplasia. Intimal hyperplasia is thought to result from interactions between areas of exposed subendothelial collagen in an injured vessel and platelets, resulting in platelet adhesion. Saratin, an inhibitor of the vWF-dependent binding of platelet to collagen interaction, has been shown in vitro to reduce the adhesion of platelets to collagen. In the current study, the authors investigated the effects of topical saratin administration in a canine dialysis access model in regard to intimal hyperplasia development at the venous anastomosis. Fourteen female mongrel dogs underwent placement of a femoral polytetrafluoroethylene (PTFE) dialysis access graft and were placed into 1 of 2 groups: 1) control or 2) experimental with topical saratin application. The experimental group had 600 microg of saratin (1 microg/microL) applied for 5 minutes directly onto the venous anastomosis before restoration of blood flow;control groups received vehicle control. At 4 weeks postoperative, a portion of the graft was removed along with a segment of the outflow vein. Veins were subsequently processed, sectioned, and analyzed along the length of the excised segment and divided into blocks that included the area of the graft toe, midanastomotic region and heel, and blocks A-E. Intimal hyperplasia was assessed by a computer-assisted morphometric analysis. Platelet counts and bleeding times were also measured. Vein segments in the control group (n=7) showed pronounced intimal hyperplasia in blocks B, C, and D as compared to the saratin group (n=6). Distribution of intimal hyperplasia by blocks between control and saratin groups were as follows: block [A] 8.6 +/- 1.9 vs 9.7 +/- 3.0% (p=NS), [B] 32.7 +/- 6.3 vs 10.7 +/- 3.5% (p=0.01), [C] 44.8 +/- 6.2% vs 10.3 +/- 1.5% (p=0.0004), [D] 40.8 +/- 11.0 vs 9.1 +/- 4.2% (p=0.02), [E] 7.5 +/- 5.5 vs 2.7 +/- 0.4% (p=NS). Intimal hyperplasia normalized to vein wall thickness also showed a significant reduction with saratin application. Bleeding times and platelet counts obtained at different time points during the experiment showed no difference between control and saratin groups. In a canine dialysis access model using PTFE grafts, topical application of saratin at the venous anastomosis decreased intimal hyperplasia development by as much as 77% when compared with control animals. Saratin provides for a method of substantially reducing intimal hyperplasia by direct local application without systemic side effects.


The asymptomatic bruit.
A review of 144 carotid endarterectomies performed in 108 patients at the Oklahoma Health Science Center over the past six years showed an acceptable operative morbidity and mortality in group of patients with an asymptomatic midcervical bruit who underwent prophylactic carotid endarterectomy prior to anticipated elective surgery. Long-term follow-up showed these patients to be free of neurologic symptoms of fatalities in 100 per cent of long-term survivors and suggests that carefully selected patients with an asymptomatic bruit may undergo carotid endarterectomy to prevent future neurologic complication.


Self-adjuvanting synthetic antitumor vaccines from MUC1 glycopeptides conjugated to T-cell epitopes from tetanus toxoid.
The T-helper epitope peptide P30 (green in the scheme) from tetanus toxoid was used as the immunostimulant in MUC1 glycopeptide antitumor vaccines and apparently also acts as a built-in adjuvant. P30-conjugated glycopeptide vaccines containing three glycans in the immunodominant motifs PDTRP and GSTAP induced much stronger immune responses and complement dependent cytotoxicity mediated killing of tumor cells when applied in plain PBS solution without complete Freund's adjuvant.


Partial purification and characterization of bovine mammary gland prolactin receptor.
Prolactin (PRL) receptors from the mammary gland of the lactating cow were solubilized with 3-[(3-cholamidopropyl)dimethylamonio]-1-propane sulfonate (CHAPS). Affinite chromatography on human growth hormone (hGH) coupled to Affi-Gel 10 resulted in over 500-fold purification, as compared to microsomal fractions. Scatchard analysis of the binding of hGH indicated an increase in the affinity constant of 2.5-fold after solubilization and of further 2-fold after the affinity purification. The specific binding activity of the affinity-purified fraction was 9000 fmol hGH/mg protein. Complexes of Triton X-100-solubilized receptors with [125I]hGH were analyzed by gel filtration on Sephadex G-150, in the presence of Triton X-100. A minor fraction of the complexes eluted as high molecular weight (Mr) aggregates, whereas a major fraction eluted as a 150 kDa peak. Assuming a contribution of approximately 30% to the Mr by the bound detergent and a hormone: receptor ratio of 1:1 in the complex, a Mr of 80-85 kDa can be calculated for the receptor molecule. Affinity labelling of the receptor with [125I]hGH revealed a Mr of 37 +/- 0.5 kDa (n = 7) for the binding subunit. Specific high Mr aggregates were also observed after crosslinking; however, the size of the labelled species was not affected by reducing agents. Homologous and heterologous competitive binding studies with ovine PRL (oPRL) or hGH revealed a considerably higher affinity for hGH as compared to oPRL. The competitive displacement patterns obtained with oPRL or hGH as tracers were similar, indicating that both hormones bound to the same receptor sites with different affinities. A similar difference in affinity was retained by the affinity-purified receptors.


Serotonin-induced inward current in rat facial motoneurons: evidence for mediation by G proteins but not protein kinase C.
The 5-HT-induced inward current in rat facial motoneurons was rendered irreversible by intracellular GTP gamma S, an hydrolysis-resistant analog of guanosine 5'-triphosphate which sustains G protein activation. Conversely, the 5-HT response was reduced by GDP beta S, an analog of guanosine 5'-diphosphate which interferes with G protein activation. Inhibitors of protein kinase C enhanced the 5-HT-induced inward current. Thus, the slow inward current induced by 5-HT in facial motoneurons appears to be mediated by G proteins but modulated negatively by protein kinase C.


Infrared spectroscopic characterization of the interaction of lipid bilayers with phenol, salicylic acid and o-acetylsalicylic acid.
The interaction of phenol (PHE), salicylic acid (SA) and o-acetylsalicylic acid (ASA) with bilayers of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) was investigated by infrared spectrometry. The temperature of the main gel to liquid crystal phase transition of DPPC is markedly depressed in the presence of the three guest molecules. The temperature depression depends on the nature and concentration of the additives. The temperature of the pretransition is also affected by these guest molecules and the depression in temperature is even more pronounced than that of the main transition temperature. Possible modes of interaction of these guest molecules with the lipid bilayers are discussed.


Pseudohypoparathyroidism type II and anticonvulsant rickets.
A patient treated with anticonvulsants showed hypocalcemia and hyperphosphatemia in association with increased serum parathyroid hormone, reduced serum 25-hydroxy D3, diminished response in phosphorus excretion to exogenous parathyroid hormone and normal response in cyclic AMP excretion. Oral administration of Vitamin D3 resulted in normalization of serum 25-hydroxy D3, calcium, and phosphorus. At this stage, phosphorus excretion after parathyroid hormone returned to normal. These findings suggest that the patient had pseudohypoparathyroidism type II with anti-convulsant medication as a complicating factor.


Ocular injury resulting in eye removal at a large tertiary care center in China.
To investigate the risk factors for eye removal following ocular trauma at a major ophthalmology department in China. A retrospective study of patients who underwent eye removal surgery following ocular trauma was completed. Clinical outcomes were consulted in detail through the hospital's computed medical data system. Patients' information including age, gender, cause of ocular trauma, affected eye, and education level was collected and recorded in a standardized database. Chi-squared test, Student's t-test, Fisher's exact test, and bivariate correlation analysis were used for statistical comparisons. The present study included 1675 removal eyes from 1674 patients over the 20-year period. Patients included 80.5% males and 19.5% females, with mean age of 38y. The majority of the patients (70.7%) were blue-collar workers (physical laborers), and 1098 patients (65.6%) did not receive high school education. Work-related injuries were the most common reason for eye removal (n=739, 44.1%), of which 441 cases (59.7%) were related to metal/nail wounds. The most frequent injury type in males was work-related injuries (49.7%), whereas the most frequent injury type in females was home-related injuries (25.8%). Work-related injuries are a leading cause of severe ocular injury resulting in eye removal. In addition, men and undereducated patients are more likely to undergo eye removal surgery following ocular trauma. This study identified multiple high-risk factors leading to eye removal following ocular trauma, which is of great importance for preventing severe eye injuries.


Purification and properties of two succinate semialdehyde dehydrogenases from human brain.
In human brain there are two major isoenzymes of succinate semialdehyde dehydrogenase (succinate-semialdehyde: NAD+ oxidoreductase, EC 22.214.171.124). They are composed of two apparently identical subunits with a molecular weight of 69 000. The Km (limits) for their substrates NAD+ and succinate semialdehyde are 1.6.10(-5) M and 3.7.10(-6) M, respectively, for one enzyme, and 1.85.10(-5) M and 2.10(-6) M, respectively, for the other. These values, and other kinetic data obtained from the two enzymes are not very different. However the enzymes differ in the following respects: their behavior on ion exchange and 5'-AMP affinity columns, their isoelectric points, their tryptic fingerprints and in their amino acid compositions.


Looking beyond caseload numbers for long-term home-care case managers.
Determining the best use of case managers' time is difficult both because of the great variability in the factors and the lack of outcome studies. In place of the outcome studies, the responses to focus group questions of 89 experienced case managers from across Canada were used to indicate a value for case management functions in the areas of direct care, indirect care management, and program management. The case managers identified greater value for direct care with clients and families who are new to home care or who have complex problems in comparison to clients in more stable or manageable situations. Case managers were frustrated by the lack of agency and community policies and resources to allow case managers to properly support people in their homes. The case managers valued addressing problems on a program or community basis rather than the usual case-by-case. Although preliminary, the approach could be useful in assessing the efficient and effective use of a scarce resource, case managers' time.


Ethanol exposure as inducer of stable voluntary ethanol drinking in the male rat.
The effects of restricted 'Saturday night drinking' on voluntary ethanol intake was tested in male rats. During a treatment period of 57 weeks the animals (group B) could choose between ethanol and water for 24 h each week. After this period of choice they received ethanol (2.0 g/kg) i.v. Total weekly exposure was around 6-7 g/kg. Of two control groups, one was given i.p. injections of saline once a week (group A) and the other, in addition to saline injections, a continuous choice between ethanol (10%) and water as drinking fluid (group C). Weekly ethanol exposure was approximately 14 g/kg in group C. During a testing period of 46 weeks group A and C had continuous access to a choice between ethanol and water. After week 5 of the testing period concentrations of ethanol varied in 3-week intervals. For each tested concentration (5, 15, 20 and 25%) intake was calculated as g/kg per day based on the total period. For the reference concentration (10%) corresponding intake was calculated on 2 weeks prior to and 2 weeks after the tested concentration. In group B there was always a very strong correlation (r = 0.86-0.99) between intake of the different tested concentration and the corresponding reference concentration. This indicates that a strong individual preference for a defined daily dose of ethanol had developed in these rats. The corresponding relation was less developed in group C especially when higher concentrations of ethanol were tested. At the end of the testing period voluntary ethanol intake was slightly higher in group B and C when compared to group A. Analyses of blood ethanol levels at defined times during the testing period indicated an interrupted ethanol intake with occasionally substantial blood levels. Thus intermittent ethanol exposure can induce a voluntary ethanol drinking pattern in male rats which might be used as an animal model of alcoholism.


Proteins of the Bacillus stearothermophilus ribosome. Crystallization of protein L6.
Crystals of ribosomal protein L6 from Bacillus stearothermophilus suitable for high resolution structural studies have been obtained. Crystals are hexagonal with space group P6122 (or the enantiomorph P6522) and cell dimensions a = b = 72.7 A, c = 124.9 A. A search for heavy atom derivatives is in progress.


Comparison of efficacy of supraspinatus tendon tears diagnostic tests: a prospective study on the "full-can," the "empty-can," and the "Whipple" tests.
This study compares the clinical results of the Whipple, empty-can, and full-can tests to detect supraspinatus tendon tears. We determined the sensitivities, specificities, and positive and negative predictive values of each test with respect to the intraoperative supraspinatus tendon lesion confirmation. We examined 61 patients (26 women, 35 men) presenting for arthroscopic surgery with functional disability or persisting shoulder pain. All the patients underwent Whipple, empty-can, and full-can testing. We correlated the clinical results of the tests with the confirmation of a supraspinatus tendon lesion by direct arthroscopic visualization. We examined 34 right and 27 left shoulders. For full and partial supraspinatus tendon tears, the Whipple test showed a sensitivity of 88.6% and a specificity of 29.4%, whereas the empty-can test and the full-can test had sensitivities of 88.6% and 75.0%, and specificities of 58.8% and 47.1%, respectively. Compared with the empty-can test and the full-can test, the Whipple test was less specific, while its sensitivity was equal to that of the empty-can test and higher than that for the full-can test. Because of its low specificity, the Whipple test has a high risk of false-positive results in comparison with the other tests.


Performance and retention mechanisms of corn silk to atmospheric heavy metal lead.
Atmospheric heavy metals are seriously harmful, and porous materials have unique advantages in the control of air pollutants. However, the direct use of plant porous materials to purify atmospheric heavy metals are rare. So agricultural waste corn silk with porous structures was selected to analyze the retention capability and mechanism to the atmospheric lead. The results show that the corn silk can effectively retain atmospheric lead in natural growing state or fixed experimental conditions. The analysis of a total of 765 corn silk samples from 17 different regions in Shandong province, China, shows that atmospheric lead is the main source of lead in the corn silk, and corn silk can be used for biological monitoring of atmospheric lead to some extent. Based on the analysis with different techniques including scanning electron microscope (SEM), energy spectrum dispersive X-ray spectrometer (EDS), Fourier infrared spectrometer (FTIR) and Zeta potential, the effective retention of lead by corn silk is due to a variety of mechanisms, including physical adsorption, electrostatic adsorption, complexation, chelation and ion exchange. So agricultural waste corn silk has great potential in the application of biosorption or preparation of porous materials in purification of atmospheric heavy metals.


PtCuFe alloy nanochains: Synthesis and composition-performance relationship in methanol oxidation and hydrogen evolution reactions.
The controllable synthesis of 1-dimensional (1D) multi-metal Pt-based alloys, with enhanced electro-chemical properties remains a challenge, despite the wide application of Pt-based catalysts in fuel cells and in the hydrogen evolution reaction (HER). Herein, we fabricate PtCuFe alloy nanochains (NCs) that have a tunable composition by flexibly adjusting the molar ratios of the metal precursors. It was found that Cu2+ is key in the formation of 1D NCs, as confirmed by transmission electron microscopy characterizations. In addition, the alloyed Fe can further increase the content of the metallic state of Cu in the PtCuFe NCs. The as-prepared PtCuFe NCs exhibited higher catalytic activity and stability than those of the Pt nanoparticles (NPs), PtFe NPs, and PtCu NCs, for the methanol oxidation reaction (MOR) and HER. Additionally, the composition-performance relationship of PtCuxFey NCs toward the MOR and HER were investigated. The hybrid density functional theory calculation and analysis showed that the 1D PtCuFe NCs have a lower lowest unoccupied molecular orbital (LUMO) than those of the 2- and 3-dimensional PtCuFe, verifying that the 1D PtCuFe NCs exhibit the highest activity for the MOR. This work has established a new method for the controllable synthesis of multi-metal Pt-based NCs/alloy catalysts and their subsequent applications in other electro-catalytic reactions.


Life-Threatening Portal Flow Steal Reappearing Under Increased Intrahepatic Vascular Resistance After Living Donor Liver Transplantation.
Maintenance of adequate portal inflow is crucial for graft regeneration in adult living donor liver transplantation (ALDLT) to allow the recipients to meet their early metabolic demands. A persistent large spontaneous portosystemic shunt can divert portal flow away from the liver graft, leading to impaired or delayed graft regeneration and subsequent graft failure. The importance of obliterating huge portosystemic shunt during liver transplantation is obvious for successful ALDLT. However, in partial liver graft with a relatively small graft-to-recipient weight ratio (GRWR) (compared with deceased donor whole graft liver transplantation), even the persisting small portosystemic shunt may result in repeated portal flow steal when a liver graft faces increased intrahepatic vascular resistance caused by rejection or graft congestion with hepatic venous outflow stenosis. We present 2 complicated cases of reappearing portal flow steal that were derived from the remaining small portosystemic shunt under the increased vascular resistance of the liver graft, even after interruption of a large portosystemic shunt during ALDLT. Because ALDLT is always a partial liver graft, even when GRWR is over 1%, it is much more vulnerable to hemodynamic changes in portal flow by rejection or graft congestion by hepatic venous outflow obstruction. Therefore, a comprehensive understanding of complex portosystemic shunt and complete reinterruption of reappearing portosystemic shunt, even though small and insignificant, during ALDLT is important for graft salvage procedures before irreversible liver graft damage.


Biological mechanisms of immune escape and implications for immunotherapy in head and neck squamous cell carcinoma.
Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with high morbidity and mortality. Despite advances in cytotoxic therapies and surgical techniques, overall survival (OS) has not improved over the past few decades. This emphasises the need for intense investigation into novel therapies with good tumour control and minimal toxicity. Cancer immunotherapy has led this endeavour, attempting to improve tumour recognition and expand immune responses against tumour cells. While various forms of HNSCC immunotherapy are in preclinical trials, the most promising direction thus far has been with monoclonal antibodies (mAbs), targeting growth factor and immune checkpoint receptors. Preclinical and early phase trials have shown unprecedented efficacy with minimal adverse effects. This article will review biological mechanisms of immune escape and implications for immunotherapy in HNSCC.


Anionic clays for sunscreen agent safe use: photoprotection, photostability and prevention of their skin penetration.
The use of sunscreen preparations is recently growing and their efficacy and safety must be taken into account since they are applied on the skin frequently and for many hours. Exposition to sunlight, in fact, can cause sunscreen photodegradation and determine their decrease in UV protection often with the occurrence of allergic and/or toxic degradation products. A high photostability is hence very important for their effectiveness and safety. The aim of this work is to obtain new sunscreen formulations stabilized by intercalating PABA, within the lamellar structures of two kinds of hydrotalcite. PABA was chosen as model sunscreen because of its high photoinstability and photosensitizing properties that nowadays bar its utilization. Both intercalated products showed an increased protection range and, in one case, an improved sunscreen photostability. Sunscreen release from creams containing intercalated or free PABA was evaluated as well. The very low or negligible sunscreen release, obtained from the intercalated product loaded formulations, resulted in a lack of a close contact between skin and filter with the consequence that cutaneous reactions and allergy problems are eliminated. The use of these materials resulted in a good strategic technological approach in order to increase efficacy and safety of solar products.


Identification of novel nuclear localization signal within the ErbB-2 protein.
ErbB2, a member of the receptor tyrosine kinase family, is frequently over-expressed in breast cancer. Proteolysis of the extracellular domain of ErbB2 results in constitutive activation of ErbB2 kinase. Recent study reported that ErbB2 is found in the nucleus. Here, we showed that ErbB2 is imported into the nucleus through a nuclear localization signal (NLS)-mediated mechanism. The NLS sequence KRRQQKIRKYTMRR (aa655-668) contains three clusters of basic amino acids and it is sufficient to target GFP into the nucleus. However, mutation in any basic amino acid cluster of this NLS sequence significantly affects its nuclear localization. Furthermore, it was found that this NLS is essential for the nuclear localization of ErbB2 since the intracellular domain of Erb2 lacking NLS completely abrogates its nuclear translocation. Taken together, our study identified a novel nuclear localization signal and reveals a novel mechanism underlying ErbB2 nuclear trafficking and localization.


Contribution of orthographic knowledge to reading and spelling in Bosnian highly transparent orthography.
The link between orthographic processing skills and reading and spelling abilities has been demonstrated in different studies and languages. However, previous research has not fully clarified this relationship. We examined the relationship between orthographic knowledge and reading and spelling performance in children from the second to the fifth grade of elementary school. We included measures of orthographic knowledge in two scripts (Latin and Cyrillic) for the same language, at both the lexical and sublexical levels. Word-specific orthographic knowledge was assessed by presenting children with pairs of words in which one word followed the orthographic rules of the Bosnian language, while the other was spelled incorrectly. General orthographic knowledge was assessed with an orthographic word-likeness task, where children had to choose the correct pseudoword, which followed legal orthographic patterns, while the incorrect ones did not. Reading and spelling, phonological awareness, and working memory were also included in the research. In Latin, no relationship was found between reading and spelling and orthographic knowledge, independent of the measure of orthographic processing. In Cyrillic, spelling performance predicts progress in general orthographic knowledge. The results of the study suggest that orthographic knowledge does not contribute to reading and spelling between Grades 2 and 3. General orthographic knowledge was an independent predictor of spelling in Grades 4 and 5 for Cyrillic, the second script. The findings suggest that the development of orthographic knowledge should be considered in the context of the specific language, script, and orthography.


Autoimmune autonomic ganglionopathy: Ganglionic acetylcholine receptor autoantibodies.
Autoimmune Autonomic Ganglionopathy (AAG) is a rare immune-mediated disease of the autonomic nervous system. The incidence of AAG is unknown and diagnosis is often difficult due to the multicompartmental nature of the autonomic nervous system - sympathetic, parasympathetic and enteric components - with variable severity and number of components affected. Diagnostic confidence is increased when ganglionic acetylcholine receptor (gnACHR) autoantibodies are detected. Three gnACHR autoantibody diagnostic assays have been described (two binding assays, one receptor immunomodulation assay), but cross-validation between assays is limited. The prevalence of gnACHR autoantibodies in AAG is not known, with application of different clinical and laboratory criteria in the few studies of AAG cohorts and large retrospective laboratory studies of positive gnACHR autoantibodies lacking adequate clinical characterisation. Furthermore, the rate of unexpected gnACHR autoantibody positivity in conditions without overt autonomic dysfunction (false positive results) adds to the complexity of their interpretation. We review the pathophysiology of gnACHR autoantibodies and assays for their detection, with immunomodulation and high titer radioimmunoprecipitation results likely offering better AAG disease identification.


Recombinant tissue-type plasminogen activator followed by heparin compared with heparin alone for refractory unstable angina pectoris.
Patients with unstable angina pectoris who remain symptomatic despite medical treatment are at high risk of death and myocardial infarction. The incidence of refractory unstable angina was examined in a consecutive series of 103 patients who received conventional medical treatment with nitrates, beta blockers, calcium antagonists and aspirin. During 48 hours of continuous electrocardiographic monitoring, 24 patients had greater than or equal to 1 anginal attack, 5 of whom had both painful and painless ischemic episodes. In these 24 patients with unstable angina refractory to conventional medical treatment, the short-term efficacy of recombinant tissue-type plasminogen activator (rt-PA) followed by heparin was assessed and compared with heparin alone in a randomized double-blind trial. Recurrences of ischemic attacks during a 72-hour follow-up period were documented in 9 of the 12 patients given heparin alone. All patients experienced at least 1 symptomatic ischemic episode and 1 patient had both painful and painless ischemia. No patient given rt-PA plus heparin had either symptomatic or asymptomatic ischemic attacks during follow-up. Kaplan-Meier curves analysis demonstrated a significantly higher probability of being ischemia free in the group of patients treated with rt-PA followed by heparin than in the group treated with heparin alone (p less than 0.01). Quantitative coronary arteriography failed to reveal any significant changes of ischemia-related lesions before and after each treatment. This study demonstrates that the combination of rt-PA and heparin has a greater protective effect than heparin alone in treating recurrent ischemic episodes in patients with refractory unstable angina.(ABSTRACT TRUNCATED AT 250 WORDS)


Surgical treatment of large contaminated abdominal wall defects.
Repair of a large, severely contaminated abdominal wall defect is a challenging problem. Most patients are currently treated with a multistaged procedure, which is time consuming, carries a high complication rate, and is often not finalized. In this study, our experience with a one-stage repair of contaminated abdominal wall defects using the Components Separation Method was evaluated with respect to morbidity and recurrence. Medical records of patients with contaminated abdominal wall defects, treated with the Components Separation Method from 1996 to 2000, were studied. Patients were invited to visit the outpatient clinic for a physical examination. Twenty-six patients with a median age of 49 years and a mean defect size of 267 cm2 were treated. Intraoperative contamination, graded according to the National Research Council (NRC), showed 22 National Research Council III patients and 4 National Research Council IV patients. Postoperatively, five superficial wound infections, three cases of pneumonia, three instances of recurrent enterocutaneous fistulation, and two cases of sepsis were observed. One of the patients with sepsis died after anastomotic disruption led to peritonitis and multiple organ failure. Two asymptomatic recurrences were diagnosed (8%) after a median followup of 27 months. Large contaminated abdominal wall hernias can be closed by the Components Separation Method, with a low recurrence rate but considerable morbidity.


Molecular scanning of the human carboxypeptidase E gene for mutations in Chinese subjects with coronary atherosclerosis.
To test the hypothesis that the identification of mutation in the carboxypeptidase E (CPE) gene which leads to marked hyperproinsulinaemia is consistent with a possible role for mutations in CPE in the development of coronary heart disease. The study subjects consisted of 51 consecutive patients (34 males and 17 females) who will undergo coronary angiography for suspected or known coronary atherosclerosis. Coronary heart disease (CHD) was defined as having a luminal diameter stenosis > or =50% in at least one of three major coronary arteries by coronary angiography or based on the Rose Questionnaire. The insulin and proinsulin level were measured using highly sensitive two-site sandwich ELISA methods. Screening for mutations of the eight exons of the CPE gene was performed by polymerase chain reaction followed by bidirectional sequencing. We scanned eight exons and exon-intron junctional region. Overall, we found 12 distinct variants in the intron region and three variants in the exon region. Among the 15 variants, 10 mutations were rare. The further explored study reveal that the above five non-rare variants would not affect the level of glucose, insulin, and proinsulin. However, the results suggest that the prevalence of the coronary heart disease was significant difference between the wild type group and mutant type group according to the A4545G (P = 0.020). The results from the logistic regression reveal that the subjects with the CPE mutation of A4545G, the odds ratio for the coronary heart disease was 0.196 (95% CI: 0.046 to 0.830, P = 0.027). In the present study, the mutation of CPE gene would not affect the level of glucose, insulin, and proinsulin. The hypothesis of a possible role for mutations in CPE in the development of coronary heart disease needs further study.


Iterative procedure for improved computer-generated-hologram reconstruction.
A detour phase hologram is used as the initial binary pattern from which to apply an iterative Fourier method for modifying the hologram and thereby improving the signal-to-noise ratio of the reconstructed wave front. Improvements are shown to be significant with this approach, especially when a binary phase hologram is optimized with this iterative method.


Toward novel antiparasitic formulations: Complexes of Albendazole desmotropes and β-cyclodextrin.
Novel complexes of two different solid forms of Albendazol and β-cyclodextrin were investigated in an attempt to obtain promising candidates for the preparation of alternative matrices used in pharmaceutical oral formulations. The interaction between each form of Albendazol and β-cyclodextrin was studied in solution and solid state, in order to investigate their effect on the solubility and dissolution rate of Albendazol solid forms. The solid supramolecular systems were characterized using a variety of techniques including natural-abundance 13C cross-polarization magic-angle-spinning nuclear magnetic resonance, powder X-ray diffraction, Fourier transform-infrared spectroscopy and scanning electron microscopy. The results obtained showed the highest increment of solubility and dissolution rate, in simulated gastric fluid, for the Albendazole II:β-cyclodextrin systems. Thus, these new complexes constitute an interesting alternative for improving the oral bioavailability of Albendazol.


Clinical and dosimetric factors for symptomatic radiation pneumonitis after stereotactic body radiotherapy for early-stage non-small cell lung cancer.
The present study attempted to identify risk factors for symptomatic radiation pneumonitis (RP) after stereotactic body radiotherapy (SBRT) in patients with early-stage non-small cell lung cancer (NSCLC). We reviewed 244 patients with early-stage NSCLC treated with SBRT. The primary endpoint was the incidence of grade ≥2 RP. Gray's test was performed to examine the relationship between clinical risk factors and grade ≥2 RP, and the Fine-Gray model was used for a multivariate analysis. The effects of each dose parameter on grade ≥2 RP were evaluated with the Fine-Gray model and optimal thresholds were tested using receiver operating characteristic (ROC) curves. With a median follow-up period of 48 months, the 4-year cumulative incidence of grade ≥2 RP was 15.3%. Gray's test revealed that tumor size, a central tumor, interstitial pneumonia, and the biologically effective dose correlated with RP. In the multivariate analysis, a central tumor and interstitial pneumonia remained significant factors (p < 0.001, p = 0.002). Among dose parameters, the total lung volume (%) receiving at least 8 Gy (V8), V10, V20, and the mean lung dose correlated with RP (p = 0.012, 0.011, 0.022, and 0.014, respectively). The results of the Fine-Gray model and ROC curve analyses showed that V10 >16.7% was the best indicator of symptomatic RP among dose parameters. The present results suggest that a central tumor and interstitial pneumonia are independent risk factors for symptomatic RP and lung V10 ≤16.7% is recommended as the threshold in SBRT.


Subcortical aphasia: two clinical-CT scan correlation studies.
Two clinical-CT scan studies were undertaken in order to investigate the frequency and the characteristics of aphasia following strictly subcortical left hemisphere lesions. In Study 1, all patients whose CT scan, carried out within a given period, showed subcortical lesions in both hemispheres, were evaluated for presence and type of aphasia; conversely, in Study 2 the records of all patients referred to our Aphasia Unit for language evaluation within a given period, were examined for presence of subcortical lesions on the CT scan. In Study 1 aphasia was found in two out of six patients. In Study 2 stabilized, strictly subcortical lesions of the left hemisphere were found in six out of 250 patients referred to the Aphasia Unit; 4 out of 6 were aphasics. Closer scrutiny of the type of language disorder in the aphasics from both studies (N = 6) suggests the possibility of differentiating two types of defect: an atypical non fluent aphasia, sometimes associated with anterior capsular-putaminal lesions, and a mild fluent aphasia, sometimes associated with posterior capsular-putaminal lesions.


Preparation of Retinal Explant Cultures.
Organotypic retinal explants are routinely used as alternatives to in vitro cell culture and to replace the use of animals in modelling retinal neurodegenerative diseases. Retinal explants fill the gap between in vivo which are expensive, time consuming, and complex due to inaccessibility of target tissues. However, organotypic retinal explants are less expensive and rapid and retinal cell types in the explant maintain their morphologic interactions with other cells in the retina. Therefore, retinal explants have high potential to be used as tools to assess the pharmacological and other therapies prior to in vivo validation, reducing the use of live animals.


Intradural lipoma presenting in pregnancy.
Progressive peripheral neuropathy is an unusual condition in pregnancy requiring specialist opinion to identify the possible underlying pathology. The case presented is that of a patient with cervical intradural lipoma and worsening neurological symptoms, treated surgically at the time of caesarean section. This rare disease and its management are discussed.


Prognostic value of CXCR4 expression in patients with clear cell renal cell carcinoma.
The expression of CXCR4 is implicated in the metastatic dissemination of different cancers. The information on its prognostic value has been very limited in clear cell renal cell carcinoma (ccRCC). Our objective was to explore the prognostic value of CXCR4 in ccRCC. 104 patients with a ccRCC were studied. There were 69 men and 35 women with an average age of 64.5 years old (range: 34-86 years). The CXCR4 expression was evaluated by immunohistochemistry. The follow-up varied from 12 to 184 months with a mean of 79.5 months. Kaplan-Meier with a log rank test was performed to compare overall survival and cancer-specific survival after surgery. Univariate and multivariate analyses were performed according to the Cox regression model. CXCR4 expression was found in 68/104 (65.4%) of tumor samples. CXCR4 expression was located in the nucleus in 55/68 (80.8%) cases while cytoplasm or membrane location was found in 13/68 (19.2%) cases. High expression was found in 25/68 (36.8%) cases. During follow-up, 39 patients died, of which 26 died of cancer. Kaplan-Meier analysis revealed that a high expression of CXCR4 was associated with a reduced overall survival (p=0.017) and cancer-specific survival (p=0.022). Univariate analysis indicated that a high expression of CXCR4 was a significant factor for a poorer overall survival (p=0.020) and cancer-specific survival (p=0.027). By multivariate analysis, a high expression of CXCR4 appeared to be an independent factor of overall survival (p=0.024) and cancer-specific survival (p=0.028). This study suggested that a high CXCR4 expression was correlated with a worse outcome for ccRCC patients.


Waveform load analysis for fatigue in the printed PLA.
Additive manufacturing is fast becoming a key process to manufacture a customized design with complex geometry and one process usually employed is based on the fused filament fabrication. Up to now this method is typically employed for rapid prototyping, it is therefore their mechanical strength is lower than the components manufactured using conventional casting process. It is well known that most failures are happened under repeated loads; therefore, a functional component mandatory needs to reach endurance strength under cyclic loads. Hence, this study set out to clarify several aspects of filament fused test specimens to determine their effect on accumulated damage to then predict component life under repeated loads. In this study is considered three waveforms such as sinusoidal, triangular and square, where it is observed that the square waveform provides the most severe loads. This study therefore makes a major contribution to research on the fatigue properties of parts manufactured using fused filament by reporting their fatigue behaviour under different fatigue load conditions. It would give a better understanding to improve the mechanical prediction of PLA, thereby it might be used to manufacture a functional component instead of only a prototype or spare part.