Metastatic renal carcinoma: evaluation of antiangiogenic therapy with dynamic contrast-enhanced CT.
To determine whether tumor perfusion parameters assessed by using dynamic contrast material-enhanced computed tomography (CT) could help predict and detect response in patients receiving antiangiogenic therapy for metastatic renal cell carcinoma. Institutional ethics committee approval and informed consent were obtained. In two phase-III trials involving 51 patients with metastatic renal cell carcinoma (38 men, 13 women; age range, 30-80 years) receiving antiangiogenic drugs (sorafenib [n = 10], sunitinib [n = 22]), a placebo (n = 12), or interferon alfa (n = 7), serial dynamic contrast-enhanced CT was performed, during 90 seconds before and after injection of 80 mL of iobitridol. Perfusion parameters of a target metastatic tumor (tumor blood flow [TBF], tumor blood volume [TBV], mean transit time, and vascular permeability-surface area product) were calculated. Values before and after treatment were compared by using a Wilcoxon signed rank test, and relative changes in groups were compared by using the Wilcoxon rank sum test. Results were compared with Response Evaluation Criteria in Solid Tumors response and with progression-free and overall survival by using Kaplan-Meier curves. Among patients receiving antiangiogenic drugs, baseline perfusion parameters were higher in responders than in stable patients (TBF = 245.3 vs 119.5 mL/min/100 mL, P = .04; TBV = 15.5 vs 8.2 mL/100 mL, P = .02) but were not significantly predictive of survival. After the first cycle of treatment, there was a significant decrease in TBF (162.5 vs 76.7 mL/min/100 mL, P = .0002) and TBV (9.1 vs 3.9 mL/100 mL, P < .0001) in patients receiving antiangiogenic treatment. Renal carcinoma perfusion parameters determined with dynamic contrast-enhanced CT can help predict biologic response to antiangiogenic drugs before beginning therapy and help detect an effect after a single cycle of treatment.


Ni-Catalyzed 1,1- and 1,3-Aminoboration of Unactivated Alkenes.
Alkene borylfunctionalization reactions have emerged as useful methods for chemical synthesis. While much progress has been made on 1,2-borylamination reactions, the related 1,1- and 1,3-borylaminations have not been reported. Herein, a Ni-catalyzed 1,1-borylamination of 1,1-disubstituted and monosubstituted alkenes and a 1,3-borylamination of cyclic alkenes are presented. Key to development of these reactions was the identification of an alkyllithium activator in combination with Mg salts. The utility of the products and the mechanistic details are discussed.


Nursing students' experiences of, and socialisation in, dementia care in the acute hospital setting.
An ageing population with a range of co-morbidities means the number of hospital admissions of older people with dementia is increasing. People with dementia can find acute hospital settings unsettling and they need to be cared for by a workforce skilled and knowledgeable in dementia care. To explore nursing students' experiences of, and socialisation in, dementia care in the acute hospital setting in England through a secondary qualitative analysis of data from a phenomenological study of nursing students' cultural beliefs around, and understanding of, dementia. Data from ten focus groups with 81 undergraduate nursing students at two universities in the south of England were subjected to content analysis. This was a secondary qualitative analysis of data retrieved from an earlier study. Two categories emerged: 'exposure to dementia care' and 'socialisation in dementia care'. Participants often felt unprepared to care for patients with dementia and their experiences were negatively affected by staff's views of patients with dementia, who were often considered challenging to manage. Participants also encountered specialist dementia nurses who enabled them to learn more about person-centred dementia care. Optimal dementia care knowledge and skills can contribute to enhanced patient outcomes and positive attitudes towards older people's care. To reduce deficits in dementia care education, nurses need regular continuing professional development in dementia care, higher education institutions need to commit to developing dementia care in their curricula, and students need to be socialised in dementia care earlier during undergraduate nurse education.


Epidemiology of Candida species infections in critically ill non-immunosuppressed patients.
A substantial proportion of patients become colonised with Candida spp during hospital stay, but only few subsequently develop severe infection. Clinical signs of severe infection manifest early but lack specificity until late in the course of the disease, thus representing a particular challenge for diagnosis. Mostly nosocomial, invasive candidiasis occurs in only 1-8% of patients admitted to hospitals, but in around 10% of patients housed in intensive care units where it can represent up to 15% of all nosocomial infections. We review the epidemiology of invasive candidiasis in non-immunocompromised, critically ill patients with special emphasis on disease trends over time, pathophysiology, diagnostic approach, risk factors, and impact. Recent epidemiological data suggesting that the emergence of non-albicans candida strains with reduced susceptibility to azoles, previously linked to the use of new antifungals for empiric and prophylactic therapy in immunocompromised patients, may not have occurred in the critically ill. Management of invasive candidiasis in these patients will be addressed in the December issue of The Lancet Infectious Diseases.


Internal herniation of the small and large intestines in 18 cattle.
Internal intestinal hernia was diagnosed during laparotomy in 18 cattle with a tentative diagnosis of ileus; the diagnosis was made during a second laparotomy in two cases. In 14 cattle, the hernial orifice was in the visceral layer of the greater omentum and the intestines had herniated into the caudal recess of the omental bursa. In two animals both the visceral and parietal layers had an opening; in one, the orifice was in the mesoduodenum, and in the other in the mesojejunum. The length of the hernial orifice ranged from 3 to >25 cm and the length of the herniated intestine ranged from 30 cm to the entire length of the small and large intestines. The omental rents were located near the caudal flexure of the duodenum (n=9), ventrally near the rumen (n=6) or in both of these locations (n=1). Seven cattle were euthanased intraoperatively because of incarceration of the jejunum; three of these had ruptured intestines and localised peritonitis; another animal was euthanased following a second laparotomy because of peritonitis. Ten animals, two of which underwent jejunal resection-anastomosis, recovered and were discharged. Nine of these survived a 6-month-postoperative period (mean ± SD: 27 ± 18 months) and remained free of colic, and one was slaughtered 3 months postoperatively because of rupture of the mammary suspensory ligament.


The effects of dietary and nutrient interventions on arterial stiffness: a systematic review.
Although dietary and nutrient interventions have been extensively studied as a means of improving arterial stiffness, to our knowledge no systematic analysis of the data has been conducted. The aim of the current study was to systematically review the human clinical trial data and qualitatively examine the efficacy of dietary and nutrient interventions in the treatment of arterial stiffness. We systematically searched multiple databases until July 2010 for relevant randomized controlled human clinical trials of common dietary and nutrient interventions in the treatment of arterial stiffness. Located studies were subject to strict inclusion criteria and objectively assessed for scientific quality. Of the 75 relevant studies located, we considered 38 studies to be appropriate for review. Results revealed support for intakes of omega-3 (n-3) fish oils (Cohen's d = 0.21-0.81) and soy isoflavones (Cohen's d = 0.35-0.39) in the treatment of arterial stiffness. There was limited but consistent evidence to suggest that salt restriction (Cohen's d = 0.28-0.37) as well as consumption of fermented-milk products (Cohen's d = 0.15-0.33) that contain bioactive peptides improved arterial stiffness. The evidentiary support for intakes of vitamins, micronutrients, and herbal medicines was insufficient. Limited but consistent evidence suggested that caffeine intake acutely increased arterial stiffness (Cohen's d = 0.34-0.51). Current evidence from several small studies suggests that omega-3 and soy isoflavone supplementation provides an effective means of reducing arterial stiffness. There was little research that explored intakes of herbal medicines or micronutrients in the treatment of arterial stiffness, and this remains an area of potential research.


Dermatitis herpetiformis cured by hormone replacement for panhypopituitarism.
Dermatitis herpetiformis is an autoimmune skin disorder frequently associated with gastrointestinal diseases. We report a 53-year-old male with a four-year history of refractory dermatitis herpetiformis associated with hypopituitarism. Endocrine testing, ophthalmological examination and magnetic resonance imaging revealed hypopituitarism due to a non-functioning pituitary macroadenoma. Following transsphenoidal removal of the pituitary tumor and appropriate hormone replacement, complete remission of the skin disorder was obtained. We discuss the permissive role of panhypopituitarism in the course of dermatitis herpetiformis.


The efficacy of disulfiram for the treatment of alcohol use disorder.
Alcohol use disorders (AUD) involving hazardous, harmful, and addictive misuse of alcohol are widespread in most parts of the world. The aim of this study was to review the effect of disulfiram in the treatment of patients with AUD. The effect of disulfiram was evaluated according to the primary outcome of an intake of alcohol below 30 and 20 g/d for men and women, respectively, as well as secondary outcomes such as days until relapse, alcohol intake, and numbers of drinking days. A systematic review of the literature was conducted using MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL). Eleven randomized controlled trials were included with a total of 1,527 patients. They compared disulfiram treatment with placebo, none or other abstinence-supportive treatments. Overall, 6 studies reported of a significant better effect on abstinence for patients treated with disulfiram. Six of 9 studies measuring secondary outcomes reported that patients treated with disulfiram had significantly more days until relapse and fewer drinking days, respectively. The quality of the included studies was moderate. Heterogeneity was significant in most of the meta-analyses, but valid results were found regarding the effect of disulfiram versus placebo over 12 months and unsupervised disulfiram versus other or no treatment. The vast majority of significant studies were of shorter duration, while only 3 studies of 12 months were significant regarding more days until relapse and/or reduction in drinking days. Supervised treatment with disulfiram has some effect on short-term abstinence and days until relapse as well as number of drinking days when compared with placebo, none, or other treatments for patients with alcohol dependency or abuse. Long-term effect on abstinence has not been evaluated yet. However, there is a need for more homogeneous and high-quality studies in the future regarding the efficacy of disulfiram.


Expression of primary cilia-related genes in developing mouse gonads.
Mechanisms governing differentiation of the bipotential gonad into the testes or ovaries are complex and still vague. The primary cilium is an organelle involved in cell signaling, which controls the development of many organs, but the role of primary cilium in the sex determination and sexual differentiation of gonads is com-pletely unknown. Here we studied the expression of genes involved in primary cilium formation and function-ing in fetal mouse gonads, before, during and after sexual differentiation. We studied the expression of 175 primary cilia-related genes using microarray technique. 144 of these genes were ubiquitously expressed in all studied cell types with no significant differences in expression level. Such a high level of expression of primary cilia-related genes in developing mouse gonads suggests that the primary cilia and/or primary cilia-related genes are important for the development of both somatic and germline component of the gonads. Only 31 genes showed a difference in expression between different cell types, which suggests that they have different functions in the somatic and germ cells. These results justify further studies on the role of primary cilia and the primary cilia-related genes in gonad development.


Hydrogel Bioink Reinforcement for Additive Manufacturing: A Focused Review of Emerging Strategies.
Bioprinting is an emerging approach for fabricating cell-laden 3D scaffolds via robotic deposition of cells and biomaterials into custom shapes and patterns to replicate complex tissue architectures. Bioprinting uses hydrogel solutions called bioinks as both cell carriers and structural components, requiring bioinks to be highly printable while providing a robust and cell-friendly microenvironment. Unfortunately, conventional hydrogel bioinks have not been able to meet these requirements and are mechanically weak due to their heterogeneously crosslinked networks and lack of energy dissipation mechanisms. Advanced bioink designs using various methods of dissipating mechanical energy are aimed at developing next-generation cellularized 3D scaffolds to mimic anatomical size, tissue architecture, and tissue-specific functions. These next-generation bioinks need to have high print fidelity and should provide a biocompatible microenvironment along with improved mechanical properties. To design these advanced bioink formulations, it is important to understand the structure-property-function relationships of hydrogel networks. By specifically leveraging biophysical and biochemical characteristics of hydrogel networks, high performance bioinks can be designed to control and direct cell functions. In this review article, current and emerging approaches in hydrogel design and bioink reinforcement techniques are critically evaluated. This bottom-up perspective provides a materials-centric approach to bioink design for 3D bioprinting.


Reassessing access to intensive care using an estimate of the population incidence of critical illness.
The consistently observed male predominance of patients in intensive care units (ICUs) has raised concerns about gender-based disparities in ICU access. Comparing rates of ICU admission requires choosing a normalizing factor (denominator), and the denominator usually used to compare such rates between subpopulations is the size of those subpopulations. However, the appropriate denominator is the number of people whose medical condition warranted ICU care. We devised an estimate of the number of critically ill people in the general population, and used it to compare rates of ICU admission by gender and income. This population-based, retrospective analysis included all adults in the Canadian province of Manitoba, 2004-2015. We created an estimate for the number of critically ill people who warrant ICU care, and used it as the denominator to generate critical illness-normalized rates of ICU admission. These were compared to the usual population-normalized rates of ICU care. Men outnumbered women in ICUs for all age groups; population-normalized male:female rate ratios significantly exceed 0 for every age group, ranging from 1.15 to 2.10. Using critical-illness normalized rates, this male predominance largely disappeared; critically ill men and women aged 45-74 years were admitted in equivalent proportions (critical-illness normalized rate ratios 0.96-1.01). While population-normalized rates of ICU care were higher in lower income strata (p < 0.001), the gradient for critical illness-based rates was reversed (p < 0.001). Across a 30-year adult age span, the male predominance of ICU patients was accounted for by higher estimated rates of critical illness among men. People in lower income strata had lower critical-illness normalized rates of ICU admission. Our methods highlight that correct inferences about access to healthcare require calculating rates using denominators appropriate for this purpose.


Angiotensin-converting enzyme inhibition alters the fibrinolytic response to cardiopulmonary bypass.
Increased plasminogen activator inhibitor-1 (PAI-1) concentrations after coronary artery bypass grafting (CABG) are associated with increased risk of vein graft occlusion. Because angiotensin II stimulates PAI-1 expression, we tested the hypothesis that preoperative angiotensin-converting enzyme (ACE) inhibition decreases PAI-1 expression after CABG. We measured the effects of cardiopulmonary bypass (CPB) on PAI-1 antigen and tissue-type plasminogen activator (tPA) antigen and activity in 31 patients taking an ACE inhibitor (ACEI) who were randomized to continue ACEI until the morning of surgery (ACEI group, n=19) or to discontinue it 48 hours before surgery (No-ACEI group, n=12). Arterial blood samples were taken at baseline before CPB, twice during CPB, after separation from CPB, and on postoperative day 1 (POD1). CPB caused an early decrease in PAI-1 antigen, followed by an increase in PAI-1 antigen on POD1 (P<0.001 for effect of time). ACE inhibition attenuated the increase in PAI-1 antigen such that both PAI-1 antigen on POD1 (P=0.013) and the change in PAI-1 antigen from baseline to POD1 (P=0.009) were higher in the No-ACEI group (from 17.0+/-5.0 to 48.7+/-8.8 ng/mL) versus the ACEI group (from 19.9+/-3.4 to 33.1+/-6.2 ng/mL). There was no significant difference between the 2 groups in intraoperative tPA activity (P=0.259); however, the increase in tPA activity was significantly greater in the ACEI group than in the No-ACEI group (P=0.030). Preoperative ACEI attenuates the increase in PAI-1 after CABG, suggesting a role for ACE inhibition in reducing the risk of acute graft thrombosis.


[The hidden curriculum in medical teaching].
Medical education must ascribe to a curriculum but clinical teaching poses special difficulties that go beyond any programming attempt. Attitudes and skills learned during tutored clinical practice are called the "hidden curriculum". The figure and personal features of the teacher, his environment and the atmosphere that projects every particular medical school, are essential to shape the characteristics of the student. Paradoxically, it is almost impossible to measure the impact of this hidden curriculum. This article is a reflection on an issue that is acquiring special relevance in medical education.


The diffusion of physicians.
Physicians move from place to place over their careers; this is thought to reflect the economic theory that they seek better opportunities to practice. Using national data, this study tracked physician movement between counties classified by physician-to-population ratio and socioeconomic characteristics. Approximately one-quarter of practicing physicians moved in each of two ten-year periods, 1981-1991 and 1991-2001. The overall tendency of movers was to go to places with lower physician-to-population ratios but higher per capita incomes and lower unemployment. These trends, if they continue, may help decrease access to physician care in rural and urban underserved areas.


Acute complications associated with removal of flexible intramedullary femoral rods placed for pediatric femoral shaft fractures.
The American Academy of Orthopaedic Surgeons position statement on the treatment of pediatric femoral shaft fractures could not comment on the safety of flexible intramedullary (IM) rod removal because of a lack of published evidence. This study reviews the acute complications of flexible IM rod removal from pediatric patients treated for femoral shaft fractures. A retrospective clinical and radiographic analysis at a single institution over a 5-year period. Demographic and radiographic parameters were analyzed to determine their influence on intraoperative and immediate postoperative complications. One hundred sixty-three subjects (133 males, 30 females), mean age of 9.3±2.8 years (range, 2.7 to 14.8 y) and mean weight of 34.4±15.3 kg (range, 14.0 to 139.0 kg), underwent femoral flexible IM rod removal a mean 12.4±10.8 months (range, 2.4 to 63.8 mo) after placement with mean operative time of 51.1±22.3 minutes (range, 10 to 131 min). One hundred fifty-one subjects (92.6%) had stainless-steel Ender rods and the remaining nails were titanium. There were no significant demographic, intraoperative, or radiographic differences comparing subjects with Ender versus titanium rods. Indications for rod removal were pain at insertion site, family request, or surgeon's recommendation. There were 4 (2.5%) minor intraoperative difficulties, including the inability to remove 1 of 2 rods secondary to IM migration (n=1) and complete bone overgrowth at insertion site resulting in prolonged extraction time (n=3). Three of the 4 subjects had the rods placed >60 months before removal. Immediately postoperative (n=134), there were 4 (3.0%) complications, including superficial wound infection (n=3, 2.2%) and knee contracture (n=1, 0.8%). Subjects were released to full activities at a mean 4.7±1.8 weeks postoperatively with no known postoperative fractures. The rate of intraoperative and immediate postoperative complications is low. Neither patient demographics, fracture characteristics, nor operative technique influenced the complication rate. Intraoperative difficulties may be minimized with removal of rods before signs of overgrowth. Level IV, intervention case series.


Effect of dietary zinc source, zinc concentration, and exogenous phytase on intestinal phytate degradation products, bone mineralization, and zinc status of broiler chickens.
This study aimed to determine the effect of Zn source and dietary level on intestinal myo-inositol hexakisphosphate (InsP6) disappearance, intestinal accumulation of lower InsP and myo-inositol (MI), prececal mineral digestibility, bone mineralization, and Zn status of broilers without and with exogenous phytase in the feed. Male Ross 308 broilers were allocated in groups of 10 to 8 treatments with 8 pens each. Experimental diets were fed from d 7 to d 28 and contained 33 mg/kg dry matter plant-intrinsic Zn. Experimental factors were phytase supplementation (0 or 750 FTU/kg) and Zn source (none [0 mg/kg Zn], Zn-sulfate [30 mg/kg Zn], Zn-oxide [30 mg/kg Zn]). Additional treatments with 90 mg/kg Zn as Zn-sulfate or Zn-oxide and phytase were included to test the effect of Zn level. No Zn source or Zn level effects were observed for ADG, feed conversion ratio, prececal P digestibility, intestinal InsP6 disappearance, and bone ash concentration. However, those measurements were increased by exogenous phytase (P < 0.001), except the feed conversion ratio, which was decreased (P < 0.001). Ileal MI concentrations were affected by phytase × Zn source interaction (P < 0.030). Birds receiving exogenous phytase and Zn supplementation had the highest MI concentrations regardless of exogenous Zn source, whereas MI concentrations were intermediate for birds receiving exogenous phytase only. Exogenous phytase and exogenous Zn source increased the Zn concentration in bone and blood of broilers (P < 0.001). In conclusion, measures of exogenous phytase efficacy were not affected by phytase × Zn source interaction. Further studies are needed to rule out an effect from Zn sources other than those tested in this study and to investigate the effect of Zn supplementation on endogenous phosphatases. The missing effect of increasing Zn supplementation from 30 to 90 mg/kg in phytase-supplemented diets gives reason to reconsider the Zn supplementation level used by the industry.


Effect of chronic ethanol feeding on endotoxin-induced hepatic injury: role of adhesion molecules on leukocytes and hepatic sinusoid.
Endotoxin is postulated to be an important aggravating factor for alcoholic liver disease. We have previously reported that rats fed ethanol are more vulnerable to endotoxin-induced liver damage, and hepatic microcirculatory disturbance plays an important role for this liver damage by observation with an intravital microscopy. In this study, we have investigated the role of adhesion molecules in endotoxin-induced microcirculatory disturbance in chronic ethanol-fed rats. Male Wistar rats were pair-fed with ethanol liquid diet (ethanol group) or an isocaloric control diet (control group) for 6 weeks. Leukocyte adherence to the hepatic sinusoid by stimulation with lipopolysaccharides (1 mg/kg of body weight) was observed by an inverted fluorescence microscopy equipped with a silicon-intensified target camera and was found to be enhanced in ethanol-fed rats. Tumor necrosis factor-alpha and GRO/CINC-1 (rat counterpart of interleukin-8) was increased in the blood in these animals. Subsequent expression of adhesion molecules, LFA-1 beta-chain on leukocytes were demonstrated by flow cytometry, which suggests a possible involvement of leukocyte adherence to the hepatic damage in ethanol-fed animals. Preadministration of anti-rat LFA-1 beta-chain monoclonal antibody effectively suppressed leukocyte adherence to the hepatic sinusoid. These results suggest that the enhanced sequestration of neutrophils to the liver with these adhesion molecules may play a significant role in the pathogenesis of alcoholic liver disease.


PASSCLAIM - Synthesis and review of existing processes.
Several approaches to the use of health claims on foods have been made around the world, and the common theme is that any health claim will require scientific validation and substantiation. There is also broad consensus that any regulatory framework should protect the consumer, promote fair trade and encourage innovation in the food industry.This paper is based on a critical evaluation of existing international approaches to the scientific substantiation of health claims, with a view to identifying common new ideas, definitions, best practice and a methodology to underpin current and future developments. There is a clear need to have uniform understanding, terminology and description of types of nutrition and health claims. Two broad categories were defined: Nutrition Claims, i. e. what the product contains, and Health Claims, i. e. relating to health, well-being and/or performance, including well-established nutrient function claims, enhanced function claims and disease risk reduction claims. Such health claims relate to what the food or food components does or do. The categories of health claims are closely and progressively related and are, in practice, part of a continuum. Provision is also made for "generic" or well-established, generally accepted claims and for "innovative" or "product-specific" claims. Special attention was paid to reflect the health-promoting properties of a food or food component in such a way as to facilitate the making of risk reduction claims outside the medical scope of the term prevention. The paper sets out basic principles and guidelines for communication of health claims and principles of nutritional safety. The main body of the work examines the process for the assessment of scientific support for health claims on food and emphasises an evidence-based approach consisting of: Identification of all relevant studies exploring the collection of evidence, data searches, the nature of the scientific evidence, sources of scientific data (including human intervention studies, human observational studies, animal studies and in vitro studies, and the use of biomarkers in human studies. Evaluation of the quality of individual studies to ensure good experimental design and interpretation. Interpretation of the totality of evidence to apply scientific judgement to interpret the weight of evidence as a whole. Assessment of significant scientific agreement on a case-by-case basis to agree within the relevant scientific community that an association between a food or a food component and a health benefit is valid. Annexes include an international comparison of regulatory approaches to health claims, suggestions for the documentation and presentation of evidence, and a procedure for reviewing the evidence.


beta 2 M-amyloidosis and gastrointestinal bleeding after renal transplantation.
Dialysis-related amyloidosis is a disorder that commonly develops in long-term dialysis with an incidence that is linked to the duration of hemodialysis. The amyloid deposits are composed of the amyloid precursor beta 2 microglobulin, mainly affecting the osteoarticular system, but also involving extra-osteoarticular tissues. We present a patient with repeated rectal bleeding caused by a circumferential atone ulcer in the immediate posttransplantation period due to the use of a rectal canula after 27 years of treatment with hemodialysis. Histopathological examination of the rectal ulcer biopsy specimens revealed positive Congo red stain and additional immunohistochemical investigation showed the presence of beta 2-microglobulin in a blood vessel wall of the rectum. Although dialysis related amyloidosis may be partially prevented, it is important to remain alert for dialysis related amyloidosis complications after renal transplantation in patients with a longstanding history of dialysis.


Erythrocyte Na+, K+-ATPase and serum digoxin concentrations.
Digoxin therapy has been made more rational by the measurement of serum digoxin concentrations. However, difficulties remain because of the overlap between "therapeutic" and "toxic" serum concentrations and the lack of an obvious therapeutic endpoint in many patients. An assay which measures the degree of interaction between digoxin and its putative receptor, the membrane Na+, K+-ATPase, might be capable of resolving some of these difficulties. Therefore, as a first approach in this direction we evaluated the relationship between serum digoxin concentration and the degree of inhibition of RBC ghost Na+, K+-ATPase activity in patients receiving digoxin therapy. Utilizing an improved micro-assay technique, Na+, K+-ATPase activity was determined in aliquots of RBC ghosts before and after removal of bound digoxin. In 27 patients a significant relationship was present between serum digoxin concentration and the degree of RBC ghost Na+, K+-ATPase inhibition. However, at any serum digoxin concentration, there was a variation in the magnitude of enzyme inhibition from patient to patient. This study confirms the feasibility of determining the degree of in vivo RBC Na+, K+-ATPase inhibition in man and demonstrates, for the first time, a highly significant but somewhat variable relationship between serum digoxin concentrations and the magnitude of RBC digoxin receptor inactivation. This quantitative, functional, individualized assay of digoxin effects may prove to be of clinical value in the future.


1. The chemistry and pharmacology of indole-3-carbinol (indole-3-methanol) and 3-(methoxymethyl)indole. [Part II].
Indole-3-carbinol (I3C) (2) is produced endogenously from naturally occurring glucosinolates contained in a wide variety of plant food substances including members of the family Cruciferae, and particularly members of the genus Brassica, whenever they are crushed or cooked. The acid environment of the gut very facilely converts it into a range of polyaromatic indolic compounds, e.g. (3, 4,5), which appear to be responsible for many of the physiological effects observed following the ingestion of these foods. These so-called chemopreventive compounds are important because of their enzyme induction and suppression, mutagenic, carcinogenic and, particularly, antimutagenic and anticarcinogenic properties against a variety of classes of carcinogens. These properties as well as other miscellaneous properties of these substances are critically reviewed in detail in this paper of >170 references, the second of two parts. At the present time it appears that I3C and its congeners have considerable potential as natural prophylactic anticancer agents against certain common neoplasms, especially inasmuch modern diets are increasingly deficient in these vegetable-derived substances. A short general assessment of the substantial potential of the title compounds concludes the review.


Factors related to a negative birth experience - A mixed methods study.
this study aimed to explore factors associated with a negative childbirth experience including descriptions from women themselves. we performed a mixed methods study based on data from the Norwegian cohort of the Bidens study, including a total of 1352 multiparous women. Quantitative information was analysed in addition to thematic analysis of 103 free-text comments provided by women with a prior negative childbirth experience. the total prevalence of a negative birth experience was 21.1%. A negative experience was associated with fear of birth (AOR: 5.00 95% CI 3.40-7.23) and a history of abuse (AOR 1.34 95% CI 1.01-1.79) in multivariate analysis. Women who indicated they were para 2 were less likely or report a negative childbirth (AOR 0.66 95% CI 0.46-0.94). Three major themes were identified: 'complications for mother, child or both', 'not being seen or heard'; and 'experience of pain and loss of control'. The majority of respondents reported experiences of unexpected and dramatic complications during childbirth. Further, several of the respondents felt a lack of support, that they had not been treated with respect or included in decisions regarding their birth. A minority described pain and loss of control as the main reason for their negative birth experience. comments by the women show that they were unprepared for complications and inadequate care during birth. The feeling of not being seen or heard during childbirth contributed to a negative experience. Midwives can use the information gained from this study to prevent negative birth experiences.


Risk for Thyroid Cancer Recurrence Is Higher in Men Than in Women Independent of Disease Stage at Presentation.
Background: Well-differentiated thyroid cancer (DTC) presents at a more advanced stage in men than in women, and the mortality in men is higher than that in women. However, it is not clear whether DTC recurrence is affected by sex independent of stage at presentation. The objective of the present study was to assess if male sex is an independent risk factor for recurrence of DTC. Methods: The Canadian Collaborative Network for Cancer of the Thyroid (CANNECT) is a collaborative registry to describe patterns of care for thyroid cancer. We included patients from the CANNECT registry with DTC diagnosed at age 18 or older between 2000 and 2010. We compared men and women with respect to presentation, management, and recurrence risk, stratified for American Joint Committee on Cancer (AJCC) stage. Results: We included 2595 patients, 2067 (79.7%) women and 528 (20.3%) men. Men presented with more advanced AJCC stage (p < 0.001), T stage (p < 0.001), N stage (p < 0.001), and M stage (p = 0.002) There was no difference in follow-up duration between women (7.7 ± 4.0 [mean ± standard deviation] years) and men (7.7 ± 4.0 years, p = 0.985). Overall recurrence was 2.2% (n = 46) for women and 8.5% (n = 45) for men (p < 0.001). In multivariate analysis adjusted for AJCC stage, men were at significantly greater risk for DTC recurrence than women (adjusted hazard ratio 2.72 [95% confidence interval [CI] 1.78-4.20]; p < 0.001). In multivariate analysis adjusted for tumor-node-metastasis (TNM) stage, men were at significantly greater risk for DTC recurrence than women (adjusted hazard ratio 2.31 [CI 1.48-3.60]; p < 0.001). Conclusions: Our study confirms that the risk for recurrence of DTC is higher in men than in women. Although men tend to present with more advanced-stage disease, the difference in recurrence risk persists when adjusted for stage of presentation. It needs to be determined whether sex should influence follow-up intensity and/or duration.


Brain biochemical effects of methylphenidate treatment using proton magnetic spectroscopy in youth with attention-deficit hyperactivity disorder: a controlled pilot study.
This study conducted spectroscopic analyses using proton (1H) Magnetic Resonance Spectroscopy (at 4 Tesla) in a sample of adolescents with Attention Deficit Hyperactivity Disorder (ADHD), before and after treatment with extended release methylphenidate (OROS MPH), as compared to a sample of healthy comparators. The main aim of this study is to use 1H MRS to measure differences in brain biochemistry between adolescents with and without ADHD, and to assess changes in cerebral biochemistry, before and after stimulant treatment in ADHD youth. Subjects with ADHD were medically healthy adolescents treated in an open label fashion with OROS MPH (mean dose: 54 mg/day; 0.90 mg/kg/day). Subjects with ADHD were scanned before and after OROS MPH treatment. Healthy comparators were scanned once. Magnetic resonance (MR) spectroscopy studies were performed on a 4.0 T Varian Unity/Inova MR scanner; proton spectra were acquired from the Anterior Cingulate Cortex (ACC). Data were analyzed using MANOVA and repeated measurement ANOVA. Higher metabolite ratios (Glutamate/myo-inositol, Glutamine/myo-inositol, Glutamate + Glutamine/myo-inositol) were observed in the ACC in untreated ADHD subjects as compared to controls, and to treated ADHD youth; these group differences did not reach the a priori threshold for statistical significance. These preliminary findings suggest the presence of glutamatergic abnormalities in adolescents with ADHD, which may normalize with MPH treatment. Larger sample, controlled studies are needed to confirm these preliminary findings.


Reduced blood flow to contracting skeletal muscle in ageing humans: is it all an effect of sand through the hourglass?
The ability to sustain a given absolute submaximal workload declines with advancing age, likely to be due to a lower level of blood flow and O2 delivery to the exercising muscles. Given that physical inactivity mimics many of the physiological changes associated with ageing, separating the physiological consequences of ageing and physical inactivity can be challenging; yet, observations from cross-sectional and longitudinal studies on the effects of physical activity have provided some insight. Physical activity has the potential to offset the age-related decline in blood flow to contracting skeletal muscle during exercise where systemic blood flow is not limited by cardiac output, thereby improving O2 delivery and allowing for an enhanced energy production from oxidative metabolism. The mechanisms underlying the increase in blood flow with regular physical activity include improved endothelial function and the ability for functional sympatholysis - an attenuation of the vasoconstrictor effect of sympathetic nervous activity. These vascular adaptations with physical activity are likely to be an effect of improved nitric oxide and ATP signalling. Collectively, precise matching of blood flow and O2 delivery to meet the O2 demand of the active skeletal muscle of aged individuals during conditions where systemic blood flow is not limited by cardiac output seems to a large extent to be related to the level of physical activity.


Functional inactivation of endogenous MDM2 and CHIP by HSP90 causes aberrant stabilization of mutant p53 in human cancer cells.
The tight control of wild-type p53 by mainly MDM2 in normal cells is permanently lost in tumors harboring mutant p53, which exhibit dramatic constitutive p53 hyperstabilization that far exceeds that of wild-type p53 tumors. Importantly, mutant p53 hyperstabilization is critical for oncogenic gain of function of mutant p53 in vivo. Current insight into the mechanism of this dysregulation is fragmentary and largely derived from ectopically constructed cell systems. Importantly, mutant p53 knock-in mice established that normal mutant p53 tissues have sufficient enzymatic reserves in MDM2 and other E3 ligases to maintain full control of mutant p53. We find that in human cancer cells, endogenous mutant p53, despite its ability to interact with MDM2, suffers from a profound lack of ubiquitination as the root of its degradation defect. In contrast to wild-type p53, the many mutant p53 proteins which are conformationally aberrant are engaged in complexes with the HSP90 chaperone machinery to prevent its aggregation. In contrast to wild-type p53 cancer cells, we show that in mutant p53 cancer cells, this HSP90 interaction blocks the endogenous MDM2 and CHIP (carboxy-terminus of Hsp70-interacting protein) E3 ligase activity. Interference with HSP90 either by RNA interference against HSF1, the transcriptional regulator of the HSP90 pathway, or by direct knockdown of Hsp90 protein or by pharmacologic inhibition of Hsp90 activity with 17AAG (17-allylamino-17-demethoxygeldanamycin) destroys the complex, liberates mutant p53, and reactivates endogenous MDM2 and CHIP to degrade mutant p53. Of note, 17AAG induces a stronger viability loss in mutant p53 than in wild-type p53 cancer cells. Our data support the rationale that suppression of mutant p53 levels in vivo in established cancers might achieve clinically significant effects.


Prosomes (proteasomes) of higher plants.
From different plant tissues such as tobacco (Nicotiana rustica), potato (Solanum tuberosum), and mung bean (Phaseolus radiatus), ring- or cylinder-shaped particles called prosomes were isolated by either sucrose gradient centrifugation or fast protein liquid chromatography (FPLC). These particles have a diameter of 12 to 14 nm and a length of 16 to 18 nm. They migrate under conditions of nondenaturing gel electrophoresis as one distinct band. Sedimentation coefficient and buoyant density in Cs2SO4 of the plant prosomes were determined by analytical ultracentrifugation to be approximately 23S and 1.23 g/cm3, respectively. The total molecular mass was estimated by gel filtration to be 650 kDa. Plant prosomes are composed of 12 to 15 proteins with molecular masses in the range of 24 to 35 kDa with isoelectric points of pH 5 to 7 as revealed by two-dimensional gel electrophoresis. The protein patterns of prosomes from the three different plant species are very similar. Polyclonal antisera against potato prosomes reacted in Western blots with prosomal proteins of all three plant species. They also bind to some prosomal proteins of animal species. Antisera against animal prosomes react with some proteins of plant prosomes. As shown by lectin blotting, plant prosomes are glycosylated carrying glucosyl- or mannosyl, and N-acetylgalactosaminyl residues. Prosomal preparations contain non-stoichiometric amounts of small RNA of about 80 kDa. These results suggest that plant prosomes are structurally and functionally homologous to prosomes of other eukaryotic cells.


Coronary-prone behavior and coronary heart disease: a critical review. The review panel on coronary-prone behavior and coronary heart disease.
A panel of biomedical and behavioral scientists were charged with the task of critically evaluating all available research and theory linking behavior to coronary heart disease. The task was divided into five topic areas: (1) association of coronary-prone behavior and coronary heart disease; (2) assessment of the "type A" behavior pattern; (3) physiologic mechanisms linking behavior to coronary heart disease; (4) cultural and developmental factors; and (5) intervention strategies. The review panels developed summary statements which delineated the perceived strengths and short-comings of the theory and data for their respective sections and provided recommendations to the National Heart, Lung, and Blood Institute concerning future research.


Pericentromeric instability and spontaneous emergence of human neoacrocentric and minute chromosomes in the alternative pathway of telomere lengthening.
In the alternative pathway of telomere lengthening (ALT), neoplastic cell growth is prolonged by telomere recombination. We show that ALT is unexpectedly characterized by high rates of ongoing pericentromeric chromosomal instability. Combined with telomeric recombination, ALT pericentromeric instability generates neoacrocentric chromosomes. In the present studies, we describe a subgroup of ALT neoacrocentric minute chromosomes, composed of DNA entities two to five times smaller in size than human chromosome 21. The frequencies of ALT minute chromosomes were increased by gamma-irradiation and suppressed by telomerase. Continuous growth after telomerase inhibition/depletion was followed by increased rates of telomeric sister chromatid recombination and the emergence of minute chromosomes. We show that ALT minute chromosomes were derived from true centromeric fissions and/or chromosomal breakage/fusion/bridge cycles. They exhibit a two-chromatid structure, carry genomic DNA, centromeric and telomeric repeats, and display regular mitotic functionality. These observations are important in understanding the global genomic instability that characterizes most human advanced malignancies.


Comparative safety of the low transverse versus the low vertical uterine incision for cesarean delivery of breech infants.
Little is known about the comparative safety of the low transverse versus the low vertical uterine incision for cesarean delivery of singleton infants in breech presentation. To address this question, the short-term maternal and infant complications of 221 breech deliveries by low transverse incision and 195 by low vertical incision were analyzed. The perinatal mortality rate associated with the low transverse incision was significantly lower than that associated with the low vertical incision (41 versus 92 deaths per 1000 births; P less than .05). When standardized for birth weight or gestational age, the difference was no longer statistically significant (P greater than .05). The incidences of an Apgar score of 6 or lower, extension of the uterine incision, a decrease in hematocrit by 6 points or more, blood transfusion, and maternal fever were not significantly different. Since these types of incisions appear to have comparable safety, the possibility of a vaginal delivery with later pregnancies suggests that the low transverse uterine incision is preferable to the low vertical incision.


CRIPTO-based micro-heterogeneity of mouse muscle satellite cells enables adaptive response to regenerative microenvironment.
Skeletal muscle repair relies on heterogeneous populations of satellite cells (SCs). The mechanisms that regulate SC homeostasis and state transition during activation are currently unknown. Here, we investigated the emerging role of non-genetic micro-heterogeneity, i.e., intrinsic cell-to-cell variability of a population, in this process. We demonstrate that micro-heterogeneity of the membrane protein CRIPTO in mouse-activated SCs (ASCs) identifies metastable cell states that allow a rapid response of the population to environmental changes. Mechanistically, CRIPTO micro-heterogeneity is generated and maintained through a process of intracellular trafficking coupled with active shedding of CRIPTO from the plasma membrane. Irreversible perturbation of CRIPTO micro-heterogeneity affects the balance of proliferation, self-renewal, and myogenic commitment in ASCs, resulting in increased self-renewal in vivo. Our findings demonstrate that CRIPTO micro-heterogeneity regulates the adaptative response of ASCs to microenvironmental changes, providing insights into the role of intrinsic heterogeneity in preserving stem cell population diversity during tissue repair.


Cryosectioning and Immunohistochemistry Using Frozen Adult Murine Brain Neural Tissue.
Cryopreservation and immunohistochemistry offer a comprehensive, robust, and simple methodology to investigate neural patterning and cellular function. Rapid freezing of the whole brain allows excellent preservation of neural ultrastructure and tissue architecture without destroying sensitive protein epitopes that are often compromised following standard paraffin embedding histological techniques. Here, we present a rapid and simple protocol for employing cryosectioning and subsequent immunohistochemistry in the study of adult murine brain neural tissue.


Inflammasome gene profile is modulated in septic patients, with a greater magnitude in non-survivors.
Inflammasome signalling induces the processing and secretion of interleukin (IL)-1β and IL-18 which, coupled with pyroptosis, activate further the inflammatory response. In the present study we evaluated the expression of genes involved in inflammasome signalling pathways in septic patients, their interaction networks and the predicted functions modulated in survivors and non-survivors. Twenty-seven patients with sepsis secondary to community-acquired pneumonia admitted to intensive care units from three general hospitals in São Paulo were included into the study. We performed a polymerase chain reaction (PCR) array encompassing 35 genes related to the nucleotide-binding oligomerization domain and leucine-rich repeat-containing (NLR)-inflammasome in peripheral blood mononuclear cells obtained at admission and after 7 days of follow-up. Eleven healthy volunteers were used as the reference group. Increased NLRC4 and NLRP3 and decreased nucleotide-binding oligomerization domain (NOD1), and NLRP1 expression was observed in septic patients compared to healthy individuals; the IL-1β and IL-18 expression levels were also high in the patients. The gene expression changes followed the same patterns in surviving and non-surviving patients, with higher magnitudes observed in non-survivors. Functional analyses revealed, however, that activation and inhibition intensity for representing functions were different in survivors and non-survivors, as for production of reactive oxygen species, synthesis of nitric oxide and for the control of bacterial infections. Our results showed that the genes involved in the activation of the NLR-inflammasome cascades were altered substantially in septic patients, with a higher number of altered genes and a higher intensity in the disturbance of gene expression found among patients dying of sepsis.


Monoclonal antibodies that inhibit the enzyme activity of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase.
Three hybridoma cell lines secreting antibodies against human placental NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-OH-PGDH) were produced. Purified IgG2b from these cell lines recognized a distinct band of Mr 28,000 on SDS/PAGE from the purified enzyme as well as a band of Mr 56,000 from the crude enzyme preparation. These three monoclonal antibodies inhibited 15-OH-PGDH activity to different degrees. Inhibition of the enzyme activity could be prevented by prior incubation of the enzyme with NAD+ but not with prostaglandin E2 (PGE2) or NADP+. Inhibition by monoclonal antibodies appears to be non-competitive with respect to NAD+ and PGE2. An increased concentration of antibodies alters the apparent Km for NAD+ but not for PGE2, further supporting the notion that the antibodies bind to the coenzyme-binding site. The availability of these monoclonal antibodies should be valuable for probing the structure of the active site.


Gafchromic XR-QA2 film as a complementary dosimeter for hand-monitoring in CTF-guided biopsies.
Computed tomography fluoroscopy (CTF) is a useful imaging technique to guide biopsies, particularly lung biopsies, but it also has the potential for very high hand exposures, despite use of quick-check method and needle holders whenever feasible. Therefore, reliable monitoring is crucial to ensure the safe use of CTF. This is a challenge, because ring dosimeters monitor exposure only at the base of one finger, while the fingertips may be exposed to the highly collimated CT beam. In this work we have explored the possibility of using Gafchromic XR-QA2 self-developing film as a complementary dosimeter to quantify hand exposure during CTF-guided biopsies. A glove used in a previous study and designed to contain 11 TLDs was adapted to include Gafchromic strips 7 mm wide, covering the fingers. A total of 22 biopsies were successfully performed wearing this GafTLD glove under sterile gloves, and the IR reported no difficulty or reduction of dexterity while wearing it. Comparison of dose distributions obtained from digitization of the Gafchromic film strips and absolute Hp(0.07) readings from TLDs showed good agreement, despite some positional uncertainty due to relative movement. Per procedure, doses at the base of the ring finger can be as low as 3%-8% of hand dose maximum. Accumulated dose at the base of the ring finger was four times lower than the dose maximum.


Pancoast's syndrome due to chronic pneumonia by Pasteurella multocida.
Infectious causes of Pancoast's syndrome are extremely rare. We describe the case of a patient with Pancoast's syndrome due to chronic pneumonia resulting from Pasteurella multocida. The patient was not immunosuppressed and had had no contact with animals. The diagnosis was made by transthoracic needle aspiration and institution of therapy with cefuroxime-axetil resulted in resolution of his symptoms.


Calcein release assay as a method for monitoring serum complement activity during monoclonal antibody therapy in patients with B-cell malignancies.
Monoclonal antibodies ofatumumab (anti-CD20) and alemtuzumab (anti-CD52) which are approved for usage in patients with chronic lymphocytic leukemia (CLL), efficiently activate the classical complement pathway. However complement is an exhaustible component and high doses of its activators may deplete complement-dependent cytotoxicity (CDC) potential, thus reducing the effect of repeated mAb dosing. Widely used method to measure CDC activity of patients' serum is hemolytic assay (CH50) on sheep erythrocytes. Despite its simplicity, such CH50 assay may not reflect pivotal interactions between patient serum and human complement inhibitors on the surface of target cells. We propose calcein release assay performed on tumor cells similar to those targeted by therapeutic antibodies as an alternative method. We analyzed serum samples collected from 12 patients participating in the clinical study, receiving s.c. 30 mg alemtuzumab three times per week combined with i.v. ofatumumab at an initial dose of 300 mg in week 3 further escalated to 2000 mg every other week. All serum samples were measured by hemolytic assay on sheep erythrocytes as well as using calcein release assay on CD20-positive Raji cells. Our data show that results obtained from both assays are related to each other at the level of the whole group (n = 96 samples, Spearman r = 0.504, p < .001) but may substantially differ when analyzing individual patients. Furthermore, by using CDC assay on Raji cells, we found that in the presented clinical study CDC serum potential was not significantly affected when measured before consecutive administrations in most of the patients.


Detection of SARS-CoV-2 variants by Abbott molecular, antigen, and serological tests.
Viral diversity presents an ongoing challenge for diagnostic tests, which need to accurately detect all circulating variants. The Abbott Global Surveillance program monitors severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants and their impact on diagnostic test performance. To evaluate the capacity of Abbott molecular, antigen, and serologic assays to detect circulating SARS-CoV-2 variants, including all current variants of concern (VOC): B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma) and B.1.617.2 (delta). Dilutions of variant virus cultures (B.1.1.7, B.1.351, B.1.429, B.1.526.1, B.1.526.2, B.1.617.1, B.1.617.2, P.1, R.1 and control isolate WA1) and a panel of N = 248 clinical samples from patients with sequence confirmed variant infections (B.1.1.7, B.1.351, B.1.427, B.1.429, B.1.526, B.1.526.1, B.1.526.2, P.1, P.2, R.1) were evaluated on at least one assay: Abbott ID NOW COVID-19, m2000 RealTime SARS-CoV-2, Alinity m SARS-CoV-2, and Alinity m Resp-4-Plex molecular assays; the BinaxNOW COVID-19 Ag Card and Panbio COVID-19 Ag Rapid Test Device; and the ARCHITECT/Alinity i SARS-CoV-2 IgG and AdviseDx IgM assays, Panbio COVID-19 IgG assay, and ARCHITECT/Alinity i AdviseDx SARS-CoV-2 IgG II assay. Consistent with in silico predictions, each molecular and antigen assay detected VOC virus cultures with equivalent sensitivity to the WA1 control strain. Notably, 100% of all tested variant patient specimens were detected by molecular assays (N = 197 m2000, N = 88 Alinity m, N = 99 ID NOW), and lateral flow assays had a sensitivity of >94% for specimens with genome equivalents (GE) per device above 4 log (85/88, Panbio; 54/57 Binax). Furthermore, Abbott antibody assays detected IgG and IgM in 94-100% of sera from immune competent B.1.1.7 patients 15-26 days after symptom onset. These data confirm variant detection for 11 SARS-CoV-2 assays, which is consistent with each assay target region being highly conserved. Importantly, alpha, beta, gamma, and delta VOCs were detected by molecular and antigen assays, indicating that these tests may be suitable for widescale use where VOCs predominate.


Evaluation of a potential transporter-mediated drug interaction between rosuvastatin and pradigastat, a novel DGAT-1 inhibitor.
An in vitro drugdrug interaction (DDI) study was performed to assess the potential for pradigastat to inhibit breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP), and organic anion transporter 3 (OAT3) transport activities. To understand the relevance of these in vitro findings, a clinical pharmacokinetic DDI study using rosuvastatin as a BCRP, OATP, and OAT3 probe substrate was conducted. The study used cell lines that stably expressed or over-expressed the respective transporters. The clinical study was an open-label, single sequence study where subjects (n = 36) received pradigastat (100 mg once daily x 3 days thereafter 40 mg once daily) and rosuvastatin (10 mg once daily), alone and in combination. Pradigastat inhibited BCRP-mediated efflux activity in a dose-dependent fashion in a BCRP over-expressing human ovarian cancer cell line with an IC(50) value of 5 μM. Similarly, pradigastat inhibited OATP1B1, OATP1B3 (estradiol 17β glucuronide transport), and OAT3 (estrone 3 sulfate transport) activity in a concentrationdependent manner with estimated IC(50) values of 1.66 ± 0.95 μM, 3.34 ± 0.64 μM, and 0.973 ± 0.11 μM, respectively. In the presence of steady state pradigastat concentrations, AUC(τ, ss) of rosuvastatin was unchanged and its Cmax,ss decreased by 14% (5.30 and 4.61 ng/mL when administered alone and coadministered with pradigastat, respectively). Pradigastat AUC(τ, ss) and C(max, ss) were unchanged when coadministered with rosuvastatin at steady state. Both rosuvastatin and pradigastat were well tolerated. These data indicate no clinically relevant pharmacokinetic interaction between pradigastat and rosuvastatin.


Glycemic control in type 2 diabetes mellitus prevents coronary arterial wall infection.
Diabetes mellitus (DM) is a very well-known risk factor for development of atherosclerosis, and it has been hypothesized that poor glycemic control and hyperglycemia plays a major role in this process. In the current study, we aimed to evaluate the associates of poor glycemic control in Iranian patients who have already undergone coronary artery bypass grafting (CABG), with especial focus on the inhabitation of infectious agents within the coronary arterial wall. In January 2010, 52 consecutive patients with type 2 DM who undergone CABG at the Department of Cardiovascular Surgery of Baqiyatallah University of Medical Sciences (Tehran, Iran) were included into this cross-sectional study and biopsy specimens from their coronary plaques were taken and analyzed by polymerase chain reaction (PCR) methods for detecting Helicobacter species, cytomegalovirus (CMV) and Chlamydia pneumoniae, and their potential relation to the glycemic control status in these patients. Compared to that in diabetic patients with mean fasting blood sugar (FBS) levels FBS < 126, atherosclerotic lesions in type 2 diabetic patients with poor glycemic control (FBS > 126) were significantly more likely to be positive for CMV PCR test (41% vs. 9%, respectively; P = 0.05). In laboratorial test results, mean triglyceride level was significantly higher among patients of poor glycemic control (168 ± 89 vs. 222 ± 125 mg/dl, respectively; P = 0.033). Hypertension was also significantly more prevalent in this population (73% vs. 36%, respectively; P = 0.034). Type 2 diabetic patients with poor glycemic control can be at higher risk for developing CMV infection in their coronary arterial wall, which can promote atherosclerosis formation process in this patient population. According to the findings of this study, we recommend better control of serum glucose levels in type 2 diabetic patients to prevent formation/progression of atherosclerosis.


Aflatoxin M1 in Nicaraguan and locally made hard white cheeses marketed in El Salvador.
Aflatoxin M1 is a carcinogenic and genotoxic metabolite of Aflatoxins present in food contaminated by fungi for lactating cattle, it is excreted through milk and when used to make cheese, the toxin will also be transferred to the dairy. The contamination of unripened hard white cheese with AFM1 seems to vary according to the season of the year, possibly due to the change of foodstuff, from fresh pasture in the rainy season to dried foods in the dry season and vice versa. This research determined both the prevalence and contents of AFM1 in cheeses of local and Nicaraguan origin marketed in El Salvador, as well as the changes occurred according to the season and the association between levels of AFM1 with meteorological parameters. The significantly higher prevalence of AFM1 contamination in both local cheeses and Nicaraguans, was found in the dry season and the lowest in the rainy season (41 % vs. 20 %; 31 % vs. 0%, respectively), the same trend was observed in AFM1 contents (0.076 vs. 0.036 μg/kg; 0.050 vs. 0.021 μg/kg, respectively). A significant association was demonstrated between levels of AFM1 with the averages of accumulated rainfall and relative humidity according to the sampled season. The prevalence of AFM1 in cheeses indicate that El Salvador and Nicaragua are endemic to dairy contamination by that mycotoxin. Seasonal variation may be due to a lack of rainfall, that promotes the growth of aflatoxigenic fungi in the crops of raw materials, which will be used for feedstuff intended for dairy cattle, thus, the consumption of contaminated food will cause the temporary increase of AFM1 in milk and their derivatives.


An ant colony optimisation algorithm for the 2D and 3D hydrophobic polar protein folding problem.
The protein folding problem is a fundamental problems in computational molecular biology and biochemical physics. Various optimisation methods have been applied to formulations of the ab-initio folding problem that are based on reduced models of protein structure, including Monte Carlo methods, Evolutionary Algorithms, Tabu Search and hybrid approaches. In our work, we have introduced an ant colony optimisation (ACO) algorithm to address the non-deterministic polynomial-time hard (NP-hard) combinatorial problem of predicting a protein's conformation from its amino acid sequence under a widely studied, conceptually simple model - the 2-dimensional (2D) and 3-dimensional (3D) hydrophobic-polar (HP) model. We present an improvement of our previous ACO algorithm for the 2D HP model and its extension to the 3D HP model. We show that this new algorithm, dubbed ACO-HPPFP-3, performs better than previous state-of-the-art algorithms on sequences whose native conformations do not contain structural nuclei (parts of the native fold that predominantly consist of local interactions) at the ends, but rather in the middle of the sequence, and that it generally finds a more diverse set of native conformations. The application of ACO to this bioinformatics problem compares favourably with specialised, state-of-the-art methods for the 2D and 3D HP protein folding problem; our empirical results indicate that our rather simple ACO algorithm scales worse with sequence length but usually finds a more diverse ensemble of native states. Therefore the development of ACO algorithms for more complex and realistic models of protein structure holds significant promise.


Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group Bone Tumor Committee.
The Children's Oncology Group (COG) is a multi-institutional cooperative group dedicated to childhood cancer research that has helped to increase the survival of children with cancer through clinical trials. These clinical trials include a standardized regimen of imaging examinations performed prior to, during, and following therapy. This article presents imaging guidelines developed by a multidisciplinary group from the COG Bone Tumor Committee. These guidelines provide both required and recommended studies. Recommended examinations may become required in the future. These guidelines should be considered a work in progress that will evolve with advances in imaging and childhood cancer research.


[Microdatasus: a package for downloading and preprocessing microdata from Brazilian Health Informatics Department (DATASUS)].
This study aimed to develop an algorithm for downloading and preprocessing microdata furnished by the Brazilian Health Informatics Department (DATASUS) for various health information systems, using the R statistical programming language. The package allows downloading and preprocessing data from various health information systems, with the inclusion of labeling categorical fields in the files. The download function was capable of directly accessing and reducing the workload for the selection of microdata files and variables in DATASUS, while the preprocessing function enabled automatic coding of various categorical fields. The package thus enables a continuous workflow in the same program, in which the algorithm allows downloading and preprocessing and other packages in R allow analyzing data from the health information systems in the Brazilian Unified National Health System (SUS).


Stem cell therapy in oral and maxillofacial region: An overview.
Cells with unique capacity for self-renewal and potency are called stem cells. With appropriate biochemical signals stem cells can be transformed into desirable cells. The idea behind this article is to shortly review the obtained literature on stem cell with respect to their properties, types and advantages of dental stem cells. Emphasis has been given to the possibilities of stem cell therapy in the oral and maxillofacial region including regeneration of tooth and craniofacial defects.


Enhancement of nerve regeneration through Schwann cell-mediated healing in a 3D printed polyacrylonitrile conduit incorporating hydrogel and graphene quantum dots: a study on rat sciatic nerve injury model.
Despite recent technological advancements, effective healing from sciatic nerve damage remains inadequate. Cell-based therapies offer a promising alternative to autograft restoration for peripheral nerve injuries, and 3D printing techniques can be used to manufacture conduits with controlled diameter and size. In this study, we investigated the potential of Wharton's jelly-derived mesenchymal stem cells (WJMSCs) differentiated into schwann cells, using a polyacrylonitrile (PAN) conduit filled with fibrin hydrogel and graphene quantum dots (GQDs) to promote nerve regeneration in a rat sciatic nerve injury model. We investigated the potential of WJMSCs, extracted from the umbilical cord, to differentiate into schwann cells and promote nerve regeneration in a rat sciatic nerve injury model. WJMSCs were 3D cultured and differentiated into schwann cells within fibrin gel for two weeks. A 3-mm defect was created in the sciatic nerve of the rat model, which was then regenerated using a conduit/fibrin, conduit covered with schwann cells in fibrin/GQDs, GQDs in fibrin, and a control group without any treatment (n=6/group). At 10 weeks after transplantation, motor and sensory functions and histological improvement were assessed. The WJMSCs were extracted, identified, and differentiated. The differentiated cells expressed typical schwann cell markers, S100 and P75. In vivo investigations established the durability and efficacy of the conduit to resist the pressures over two months of implantation. Histological measurements showed conduit efficiency, schwann cell infiltration, and association within the fibrin gel and lumen. Rats treated with the composite hydrogel-filled PAN conduit with GQDs showed significantly higher sensorial recovery than the other groups. Histological results showed that this group had significantly more axon numbers and remyelination than others. Our findings suggest that the conduit/schwann approach has the potential to improve nerve regeneration in peripheral nerve injuries, with future therapeutic implications.


Adaptive liquid microlenses activated by stimuli-responsive hydrogels.
Despite its compactness, the human eye can easily focus on different distances by adjusting the shape of its lens with the help of ciliary muscles. In contrast, traditional man-made optical systems achieve focusing by physical displacement of the lenses used. But in recent years, advances in miniaturization technology have led to optical systems that no longer require complicated mechanical systems to tune and adjust optical performance. These systems have found wide use in photonics, displays and biomedical systems. They are either based on arrays of microlenses with fixed focal lengths, or use external control to adjust the microlens focal length. An intriguing example is the tunable liquid lens, where electrowetting or external pressure manipulates the shape of a liquid droplet and thereby adjusts its optical properties. Here we demonstrate a liquid lens system that allows for autonomous focusing. The central component is a stimuli-responsive hydrogel integrated into a microfluidic system and serving as the container for a liquid droplet, with the hydrogel simultaneously sensing the presence of stimuli and actuating adjustments to the shape--and hence focal length--of the droplet. By working at the micrometre scale where ionic diffusion and surface tension scale favourably, we can use pinned liquid-liquid interfaces to obtain stable devices and realize response times of ten to a few tens of seconds. The microlenses, which can have a focal length ranging from -infinity to +infinity (divergent and convergent), are also readily integrated into arrays that may find use in applications such as sensing, medical diagnostics and lab-on-a-chip technologies.


Peripheral blood biomarkers in idiopathic pulmonary fibrosis.
In this article, we review the evidence for peripheral blood biomarkers in idiopathic pulmonary fibrosis (IPF), a life-threatening fibrotic lung disease of unknown etiology. We focus on selected biomarkers present in peripheral blood, as they are easy to obtain, can be measured longitudinally, and have the greatest likelihood of achieving clinical utility. This article concentrates on biomarkers with mechanistic plausibility that may be directly involved in the development of IPF, including KL-6, surfactant proteins A and D, matrix metalloproteases (MMP) 1 and 7, CCL18, VEGF, YKL-40, osteopontin, circulating fibrocytes, and T cells. After reviewing the evidence base for each, we designate the biomarkers that may have utility as: (1) diagnostic biomarkers to distinguish IPF from other interstitial lung diseases, (2) prognostic biomarkers that are correlated with disease progression or mortality, or (3) biomarkers that can be used as tools for serial monitoring of disease severity. Although there are no validated biomarkers that are currently available, the need for surrogates of diagnosis, prognosis, and monitoring of disease course with emerging therapies is great.


Overlapping genes of Aedes aegypti: evolutionary implications from comparison with orthologs of Anopheles gambiae and other insects.
Although gene overlapping is a common feature of prokaryote and mitochondria genomes, such genes have also been identified in many eukaryotes. The overlapping genes in eukaryotes are extensively rearranged even between closely related species. In this study, we investigated retention and rearrangement of positionally overlapping genes between the mosquitoes Aedes aegypti (dengue virus vector) and Anopheles gambiae (malaria vector). The overlapping gene pairs of A. aegypti were further compared with orthologs of other selected insects to conduct several hypothesis driven investigations relating to the evolution and rearrangement of overlapping genes. The results show that as much as ~10% of the predicted genes of A. aegypti and A. gambiae are localized in positional overlapping manner. Furthermore, the study shows that differential abundance of introns and simple sequence repeats have significant association with positional rearrangement of overlapping genes between the two species. Gene expression analysis further suggests that antisense transcripts generated from the oppositely oriented overlapping genes are differentially regulated and may have important regulatory functions in these mosquitoes. Our data further shows that synonymous and non-synonymous mutations have differential but non-significant effect on overlapping localization of orthologous genes in other insect genomes. Gene overlapping in insects may be a species-specific evolutionary process as evident from non-dependency of gene overlapping with species phylogeny. Based on the results, our study suggests that overlapping genes may have played an important role in genome evolution of insects.


The transcription factor Tfap2e/AP-2ε plays a pivotal role in maintaining the identity of basal vomeronasal sensory neurons.
The identity of individual neuronal cell types is defined and maintained by the expression of specific combinations of transcriptional regulators that control cell type-specific genetic programs. The epithelium of the vomeronasal organ of mice contains two major types of vomeronasal sensory neurons (VSNs): 1) the apical VSNs which express vomeronasal 1 receptors (V1r) and the G-protein subunit Gαi2 and; 2) the basal VSNs which express vomeronasal 2 receptors (V2r) and the G-protein subunit Gαo. Both cell types originate from a common pool of progenitors and eventually acquire apical or basal identity through largely unknown mechanisms. The transcription factor AP-2ε, encoded by the Tfap2e gene, plays a role in controlling the development of GABAergic interneurons in the main and accessory olfactory bulb (AOB), moreover AP-2ε has been previously described to be expressed in the basal VSNs. Here we show that AP-2ε is expressed in post-mitotic VSNs after they commit to the basal differentiation program. Loss of AP-2ε function resulted in reduced number of basal VSNs and in an increased number of neurons expressing markers of the apical lineage. Our work suggests that AP-2ε, which is expressed in late phases of differentiation, is not needed to initiate the apical-basal differentiation dichotomy but for maintaining the basal VSNs' identity. In AP-2ε mutants we observed a large number of cells that entered the basal program can express apical genes, our data suggest that differentiated VSNs of mice retain a notable level of plasticity.


Duplication and deletion in the human immunoglobulin epsilon genes.
The human IgE gene encodes a polypeptide chain that is involved in allergic reactions and in the immune response to parasitic disease in man. We have cloned three chromosomal regions corresponding to this sequence and find that two of them derive from curiously duplicated gene segments that also encode IgA constant-region genes. One of the IgE sequences corresponds to the active gene, and its structure defines a complete amino acid sequence of the human IgE constant region. The other cloned segment is a pseudogene from which the first two IgE coding domains have been deleted and replaced by a switch-like sequence that also occurs close to the normal IgE gene. The third IgE segment remains unlinked to the other heavy-chain genes. Evidently, the epsilon-alpha locus has been the site of several complicated genetic rearrangements during recent evolutionary time.


Natural history of early gastric cancer: a non-concurrent, long term, follow up study.
Controversy has arisen on the natural history of early gastric cancer (EGC). While some emphasise the effectiveness of early detection in reducing mortality from gastric cancer, others insist that EGC is a pseudo-cancer. AIMS/PATIENTS/METHODS: To elucidate the natural history of EGC, a non-concurrent, long term, follow up study was conducted in 71 patients who were diagnosed endoscopically as having EGC, which was confirmed as cancer on biopsy, but in whom surgical resection was not conducted or delayed by more than six months. The natural course of EGC was observed in 56 cases. Over a period of 6-137 months, 20 remained in the early stage while 36 progressed to the advanced stage. The proportion remaining in the early stage consistently decreased with time. Median duration of those who remained in the early stage was estimated as 44 months. The cumulative five year risk for progressing to the advanced stage was 63.0%. In 38 cases there was no evidence for undergoing surgical resection for gastric cancer. The cumulative five year corrected survival was estimated as 62.8% among those unresected. Hazard rate ratio for gastric cancer mortality was 0.65 (p=0.34) for screening detected versus non-screening detected. Hazard rate ratio for gastric cancer mortality was 0.51, significantly lower for patients whose operations were delayed compared with those unresected. Although EGC showed a relatively long natural history in general, it progressed to the advanced stage with time and led to death from gastric cancer for the most part if left untreated.


Effects of a whole body vibration (WBV) exercise intervention for institutionalized older people: a randomized, multicentre, parallel, clinical trial.
To assess the efficacy of an exercise program on a whole-body vibration platform (WBV) in improving body balance and muscle performance and preventing falls in institutionalized elderly people. A multicentre randomized parallel assessor-blinded clinical trial was conducted in elderly persons living in nursing homes. Participants were randomized to an exercise program performed either on a whole body vibratory platform (WBV plus exercise group) or on a stationary surface (exercise group). The exercise program for both groups consisted of static and dynamic exercises (balance and strength training over a 6-week training period of 3 sessions per week). The frequency applied on the vibratory platform was 30 to 35 Hz and amplitude was 2 to 4 mm. The primary outcome measurement was static/dynamic body balance. Secondary outcomes were muscle strength and number of falls. Efficacy was analyzed on an intention-to-treat basis and per protocol. The effects of the intervention were evaluated using the t test, Mann-Whitney test, or chi-square test, depending on the type of outcome. Follow-up measurements were collected 6 weeks and 6 months after randomization. A total of 159 participants from 10 centers were included: 81 in the WBV plus exercise group and 78 in the control group. Mean age was 82 years, and 67.29% were women. The Tinetti test score showed a significant overall improvement in both groups (P < .001). No significant differences were found between groups at week 6 (P = .890) or month 6 (P = .718). The Timed Up and Go test did not improve (P = .599) in either group over time, and no significant differences were found between groups at week 6 (P = .757) or month 6 (P = .959). Muscle performance results from the 5 Sit-To-Stand tests improved significantly across time (P = .001), but no statistically significant differences were found between groups at week 6 (P = .709) or month 6 (P = .841). A total of 57 falls (35.8%) were recorded during the follow-up period, with no differences between groups (P = .406). Exercise program on a vibratory platform provides benefits similar to those with exercise program on a stationary surface in relation to body balance, gait, functional mobility, and muscle strength in institutionalized elderly people. Longer studies in larger samples are needed to assess falls.


Antiproliferative and apoptotic activities of extracts of Asclepias subulata.
Asclepias subulata Decne. (Apocynaceae) is a shrub used in the Mexican traditional medicine for the treatment of cancer. The objective of this study was to evaluate the antiproliferative activity of methanol extract of aerial parts of A. subulata and its fractions against different cancer cell lines. Additionally, we analyzed the mechanism of action of the active fractions. Methanol extract fractions were prepared by serial extraction with n-hexane, ethyl acetate, and ethanol. The antiproliferative activity of methanol extract and its fractions was evaluated, against several murine (M12.C3.F6, RAW 264.7, and L929) and human (HeLa, A549, PC-3, LS 180, and ARPE-19) cell lines by the MTT assay, using concentrations of 0.4-400 µg/mL for 48 h. Ethanol and residual fractions were separated using silica gel column. Apoptosis induction of cancer cells was evaluated by Annexin and JC-1 staining using flow cytometry. Methanol extract and its fractions showed antiproliferative activity against all human cancer cell lines tested. Methanol extract had the highest antiproliferative activity on A549 and HeLa cells (IC50 values < 0.4 and 8.7 µg/mL, respectively). Ethanol and residual fractions exerted significant antiproliferative effect on A549 (IC50 < 0.4 µg/mL) and PC3 cells (IC50 1.4 and 5.1 µg/mL). Apoptotic assays showed that CEF7, CEF9, CRF6, and CRF5 fractions induced mitochondrial depolarization in A549 cells, 70, 73, 77, and 80%, respectively. Those fractions triggered the apoptosis mitochondrial pathway. Our data show that A. subulata extracts have potent antiproliferative properties on human cancer cell lines. This plant should be considered an important source of potent anticancer compounds.


Use of hyaluronic acid gel filler versus sterile water in the treatment of intractable plantar keratomas: a pilot study.
Intractable plantar keratoma is a common concern in the podiatric medical office. Different treatment options are available, ranging from trimming and padding to surgery. We sought to investigate the use of hyaluronic acid gel injections as a possible minimally invasive alternative in the treatment of intractable plantar keratomas. Seventeen patients with intractable plantar keratomas were randomly assigned to receive a hyaluronic acid gel injection or a sterile water injection at the site of a previously trimmed plantar lesion. There was no significant difference between the two groups in the evaluation of pain and function at 12 weeks, but both groups showed a clinically relevant improvement. No significant change was observed in plantar tissue thickness in both groups. A minor adverse reaction was seen in the hyaluronic acid group. The use of a hyaluronic acid gel injection at the site of a trimmed intractable plantar keratoma did not seem more effective than the use of a sterile water injection. Sterile water injections seemed safe and efficient in reducing pain associated with plantar keratomas. Further investigations should concentrate on whether these results are reproducible in a larger sample and on the most effective sequence of treatment.


Polychlorinated biphenyls and organochlorine pesticides as intrinsic tracer tags of foraging grounds of bluefin tuna in the northwest Atlantic Ocean.
Researchers have utilized chemical fingerprints in the determination of habitat utilization and movements of the aquatic animals. In the present effort, we analyzed polychlorinated biphenyl (PCB) congeners and organochlorine pesticides in the samples of juvenile bluefin tuna caught offshore of Virginia, and in larger bluefin tuna from the Gulf of Maine and near Nova Scotia. For a given specimen, or a given location, PCB concentrations were highest, followed by DDTs, and chlordanes. Average contaminant concentrations from fish captured from the three locations were not significantly different; and PCBs, DDTs, and chlordanes correlated well with each other. Trans-nonachlor/PCB 153 ratios in bluefin tuna of eastern Atlantic (i.e., Mediterranean) origin are low compared to the corresponding ratios in fish in the western Atlantic. As the former migrate to the western Atlantic, these ratios gradually turnover due to the accumulation of biomass from forage contaminated with higher trans-nonachlor/PCB 153 ratio reflecting dissimilar use of chlordane pesticides on two sides of the Atlantic Ocean. The trans-nonachlor/PCB 153 ratio indicated that one juvenile bluefin tuna from offshore of Virginia and one large bluefin tuna from Gulf of Maine in the present study originated from foraging grounds in the Mediterranean Sea, and that they have made the trans-Atlantic migrations. The remaining individuals were determined to be either spawned in the Gulf of Mexico or the trans-nonachlor/PCB 153 ratio for the putative Mediterranean bluefin tuna was completely turned over to resemble the ratio characteristic to the western Atlantic. Based on the turnover time for trans-nonachlor/PCB 153 ratio previously determined, the residence time of juvenile bluefin tuna offshore Virginia was estimated to be at least 0.8 to 1.6years. A discriminant function analysis (DFA) plot of total PCB normalized signatures of PCB congeners showed three separate clusters, which suggested that bluefin tuna from offshore Virginia, Gulf of Maine, and Nova Scotia could have had extended residences and foraging within the areas of capture to be able to sustain the stable signatures of PCB congeners. The DFA cluster results supported the concept of metapopulation theory of spatial ecology comprising discrete aggregates of local populations of bluefin tuna where the desired prey species are likely to be abundant. Despite their highly migratory trait and endothermic advantage of foraging in broader and colder habitats, the movements and mixing across the aggregation ranges related to feeding did not appear to be extensive. Advancement in the understanding of bluefin tuna population dynamics beyond the coarse concept of trans-Atlantic migrations to the metapopulation hypothesis provides a novel exploratory tool in the stock assessment and resource management. As the chemical tracer tags are fortified naturally and document the time- and space-integrated foraging history, they promise to serve as the low-cost alternatives to the high-cost electronic data recording tags employed for addressing the migratory movements of bluefin tuna. Between the different potential chemical tracer tags, a distinct advantage of PCB/pesticide analysis over the otolith micro-constituent analysis is that the muscle tissue of a given individual bluefin tuna can be sampled repeatedly for PCB/pesticide analysis over different spatial and temporal scales in a non-lethal manner.


Aflatoxin occurrence on raw and cooked york soybeans inoculated with three aspergillus isolates.
Raw and cooked soybean media were inoculated in separate experiments with Aspergillus flavus NRRL 3251, A. flavus ATCC 15548, and A. parasiticus NRRL 2999 isolates. The toatl quantity of aflatoxins produced and the percentage distribution of aflatoxins B1, B2, G1, and G2 varied with the state of the medium (raw or cooked) and with the fungal isolate used. Cooked soybean medium supported higher aflatoxin productions by A. flavus NRRL 3251 and A. parasiticus NRRL 2999 than did raw medium. Larger quantities of aflatoxins B1, B2, G1, and G2 were produced by A. flavus ATCC 15548 on raw soybean medium than were produced by any of the isolates on cooked medium. Application of these data is discussed briefly in relation to possible use of soybean media as a source of aflatoxin production.


Unipolar radiofrequency treatment to improve the appearance of cellulite.
Previous studies suggest that radiofrequency (RF) energy may be effective as a treatment for cellulite. This bilateral paired blinded comparative study assesses the efficacy and safety of a unipolar RF device for improving the appearance of cellulite using a new quantitative cellulite grading system. In this randomized, blinded, split-design study, 10 individuals (aged 32-57 years) with a clinically observable excess of subcutaneous fat and cellulite (minimum grade 2 out of 4) on the thighs received up to six unilateral treatments (number of treatments at the investigator's discretion) at 2-week intervals with unipolar RF. The untreated side of the thigh served as an internal control. Treated thighs were randomly assigned by alternate allocation. Results were evaluated using study participant questionnaires and by two blinded evaluators (JSD, KAA) using photographs and the author's (MAA) cellulite grading scale at each treatment visit and at 1-month and 3-month follow-up visits after the final treatment. A novel quantitative four-point cellulite grading system is presented and applied, which separately grades dimple density, dimple distribution, dimple depth, diameter and contour. All participants responded to treatment (mean of 4.22 and range of three to six treatments). The blinded evaluations of photographs using the cellulite grading scale demonstrated the following mean grading scores for the treated leg versus the control leg: dimple density of 2.73 vs 3.18 (11.25% mean improvement), dimple distribution 2.89 vs 3.32 (10.75% mean improvement), dimple depth 1.47 vs 1.54 (2.5% mean improvement), and mean score of 2.36 (SEM 0.45) vs 2.68 (SEM 0.57) (8.00+/-2.84% mean improvement). The treatment was painless and side effects included minimal to moderate erythema which resolved within 1 to 3 hours. No crusting, scarring or dyspigmentation was observed. This randomized, blinded, split-design, controlled study employing a quantitative four-point grading scale demonstrated that this unipolar RF device is safe for the treatment of cellulite. Clinically visible and quantified improvement which did not achieve statistical significance but showed a trend toward improvement was observed in all patients following a mean of four treatments at 2-week intervals.


Forskolin stimulation of acid and pepsinogen secretion in isolated gastric glands.
Forskolin, a specific diterpene activator of adenylate cyclase in intact cells and cellular homogenates, was used to examine the relationship among adenosine 3',5'-cyclic monophosphate (cAMP) metabolism, gastric acid, and pepsinogen secretion in isolated gastric glands. This agent was found to stimulate [14C]aminopyrine (AP) accumulation and respiration, both measurements of which are indexes of parietal cell acid secretory responsiveness and pepsinogen secretion, which is a measure of chief cell activity. Forskolin also increased cAMP content and activated cAMP-dependent protein kinase in the glands. The histamine H2-receptor antagonist, cimetidine, inhibited forskolin-stimulated increases in AP accumulation and respiration when submaximal concentrations of forskolin were used but had not effect on the other response parameters. Forskolin also potentiated the action of the muscarinic agonist, carbachol, in both the presence and absence of cimetidine. Since there was a close kinetic and temporal correlation between the secretory response parameters and cAMP-dependent protein kinase activation, it appears that cAMP plays an important role in the mediation of gastric acid and pepsinogen secretion. The inhibitory action of cimetidine on forskolin-stimulated AP accumulation and respiration suggest that forskolin potentiates the action of endogenous histamine present in the glands. Forskolin potentiation of carbachol in the presence of maximum inhibitory concentrations of cimetidine indicates that previously observed potentiating interactions between carbachol and histamine, secretagogues which appear to act via cAMP-independent and cAMP-dependent mechanisms, respectively, involve intracellular events that occur subsequent to the binding of these agents to their respective receptors and subsequent to an increase in intracellular cAMP content.


Research Review: Developmental origins of depression - a systematic review and meta-analysis.
Many observational studies have found a direct association between adverse in utero, perinatal and postnatal exposures and offspring's depression. These findings are consistent with the 'developmental origins of disease hypothesis'. But no review has comprehensively summarized the roles of these exposures. This review aims to systematically scrutinize the strength of associations between individual prenatal, perinatal, and postnatal exposures and subsequent depression in offspring. We conducted a systematic review and meta-analysis to synthesize the literature from the EMBASE, HealthStar, PsychoInfo, and Medline databases since their inception to September 1, 2019. English language articles on population-based prospective cohort studies examining the associations between in utero, perinatal, and postnatal exposures and offspring's depression were searched. Random-effects models were used to calculate pooled estimates, and heterogeneity and sensitivity tests were conducted to explore potential confounders in the relationships of depression and early-life factors. Qualitative analysis was also conducted. Sixty-four prospective cohort studies with 28 exposures studied in the relationships to offspring's depression met inclusion criteria. The meta-analysis found 12 prenatal, perinatal, and postnatal characteristics were associated with an increased risk of depression in offspring: low birth weight, premature birth, small gestational age, maternal education, socioeconomic status, having younger parents (<20 years), having older parents (≥35 years), maternal smoking, paternal smoking, maternal stress, maternal anxiety, and prenatal depression. Heterogeneity and sensitivity tests supported the findings. By and large, study characteristics had no effects on conclusions. Qualitative analyses generally supported the findings of meta-analysis and reported on additional risk factors. This review provides a robust and comprehensive overview of the lasting psychopathological effects of in utero, perinatal, and postnatal exposures. The findings highlight the need for clinical and public health interventions focusing on the identified risk factors. Large prospective cohort studies are warranted to investigate the combined effects of multiple co-existing early-life exposures.


The flowering time regulator CONSTANS is recruited to the FLOWERING LOCUS T promoter via a unique cis-element.
CONSTANS is an evolutionarily-conserved central component of the genetic pathway that controls the onset of flowering in response to daylength. However, the specific biochemical mechanism by which the CONSTANS protein regulates the expression of its target genes remains largely unknown. *By using a combination of cell-based expression analysis and in vitro DNA binding studies, we have demonstrated that CONSTANS possesses transcriptional activation potential and is capable of directly binding to DNA. *CONSTANS was found to bind DNA via a unique sequence element containing a consensus TGTG(N2-3)ATG motif. This element is present in tandem within the FLOWERING LOCUS T promoter and is sufficient for CO binding and activity. The conserved CCT (CONSTANS, CONSTANS-like and TOC1) domain of CONSTANS was shown to be required for its recruitment to the DNA motif and other CCT-containing proteins were also found to have the ability to regulate gene expression via this element. *The CCAAT box, which has been previously hypothesized as a recruitment site for complexes containing the CONSTANS protein, potentiated CONSTANS-mediated activation but was not essential for CONSTANS recruitment to a target promoter or for its activity as a transcriptional factor.


Preliminary analysis of immune-related markers in thymic carcinoid.
The immune-related microenvironment of thymic carcinoid has rarely been reported. We analyzed the expression of PD-L1 and VISTA, and the distribution of CD4+ T cells, CD8+ T cells and CD68+ macrophages in the thymic carcinoid by immunohistochemical staining, and showed the correlation between these markers and clinical survival, indicating the potential therapeutic prospects.


Multifocal visual evoked potential for evaluation of open-angle glaucoma.
To correlate multifocal visual evoked potential (mfVEP) findings with static automated perimetry (SAP) and spectral-domain optical coherence tomography (SD-OCT) in eyes with primary open- angle glaucoma (POAG). This cross-sectional study included a consecutive sample of 40 eyes of 40 patients with POAG. The participants underwent a complete ophthalmologic assessment, axial length (AL) measurement, and assessments with SAP, SD-OCT, and mfVEP. POAG cases were aged 49.70 (14.16) years (mean [SD]) and most were females (n = 24, 60%). For eyes of patients with POAG, the mfVEP upper-ring signal-to-noise ratio (SNR) showed a significant negative correlation with best-corrected logMAR visual acuity (r = - 0.33; P = 0.038), and a significant positive correlation with the superior hemifield of the visual field (VF) and the inferior-quadrant retinal nerve fiber layer (RNFL) thickness (r = + 0.34; P = 0.030; r = + 0.51; P < 0.001, respectively). Similarly, the mfVEP lower-ring SNR showed a significant negative correlation with best-corrected logMAR visual acuity (r = - 0.36; P = 0.024) and a significant positive correlation with the inferior hemifield of the VF and superior quadrant RNFL thickness (r = + 0.55; P < 0.001 and r = + 0.70; P < 0.001, respectively). mfVEP is a promising tool for objective assessment of the VF in patients with POAG, as it is positively correlated with the VF and OCT RNFL thickness. Future longitudinal studies with a larger sample size and a specific glaucoma subtype, along with multiple follow-up evaluations, are warranted to confirm our preliminary results.