Social networking patterns/hazards among teenagers.
Social Networking Sites (SNSs) have grown substantially, posing new hazards to teenagers. This study aimed to determine general patterns of Internet usage among Irish teenagers aged 11-16 years, and to identify potential hazards, including; bullying, inappropriate contact, overuse, addiction and invasion of users' privacy. A cross-sectional study design was employed to survey students at three Irish secondary schools, with a sample of 474 completing a questionnaire. 202 (44%) (n = 460) accessed the Internet using a shared home computer. Two hours or less were spent online daily by 285(62%), of whom 450 (98%) were unsupervised. 306 (72%) (n = 425) reported frequent usage of SNSs, 403 (95%) of whom were Facebook users. 42 (10%) males and 51 (12%) females experienced bullying online, while 114 (27%) reported inappropriate contact from others. Concerning overuse and the risk of addiction, 140 (33%) felt they accessed SNSs too often. These patterns among Irish teenagers suggest that SNS usage poses significant dangers, which are going largely unaddressed.


The Prediction of Intracranial Injury After Minor Head Trauma in the Pediatric Population.
Reference: Dunning J, Batchelor J, Stratford-Smith P, et al. A meta-analysis of variables that predict significant intracranial injury in minor head trauma. Arch Dis Child. 2004;89:653-659.Clinical Question: Which clinical signs or symptoms of minor head trauma are predictive of intracranial hemorrhage in children and adolescents?Data Sources: Investigations were identified by MEDLINE and EMBASE searches from 1990 through 2002 by a search of the grey literature and by contacting experts for additional papers. The search terms were selected to find all studies reporting intracranial hemorrhage (ICH) or complications after head trauma.Study Selection: A full systematic review was conducted, and all cohort or nested cohort studies that presented data on minor head injuries in children less than 18 years old, with or without ICH, were identified. Studies were then judged for inclusion based on the presentation of a series of at least 100 patients and a documented reliable standard for the detection of ICH for all patients in the study. The use of computed tomography (CT) and medical follow-up was considered an acceptable gold standard. Intracranial hemorrhage was defined as any abnormality detected on the CT scan due to the traumatic presence of extravascular blood. Minor head trauma was defined as patients presenting with a Glasgow Coma Scale (GCS) score of 13-15.Data Extraction: Seven clinical correlates were used for data extraction, including skull fracture, headache, vomiting, focal neurology, seizure, loss of consciousness, and a GCS score of less than 15. Data were analyzed using a pooled estimate of the relative risk ratio with a random-effects model.Main Results: The searches identified a total of 2134 studies for the initial review. After an abstract review by 2 independent examiners, 98 studies were identified for a full-paper review. Each study was graded on a 4-point scale according to the level of evidence provided, using scales consistent with the Oxford Centre for Evidence-Based Medicine and the National Institute for Clinical Excellence. Thirty-four of these articles were of adequate quality for inclusion; however, many did not include data that could be separated into a specific data set for children, had too small a sample size, or lacked enough data on individual correlates to head trauma. Nineteen studies provided data on children, but 3 of these were excluded due to poor quality or lack of a reported CT scan, leaving a total of 16 studies for the meta-analysis.The analysis included a total of 22 420 patients ranging between 0 and 18 years of age. The meta-analysis showed a significant increased relative risk of ICH for patients sustaining loss of consciousness (2.23), GCS <15 (5.51), skull fracture (6.13), and focal neurology (9.43). No significant increases in risk for headache (1.02), vomiting (0.878), or seizure (2.82) were noted; however, heterogeneity was significant for this last correlate. The prevalence of ICH ranged from 1.3 to 36%, supporting the notion of a large amount of heterogeneity or variability in the inclusion criteria among the studies.Conclusions: These findings demonstrate that loss of consciousness, decreased level of consciousness (GCS <15), skull fracture, and focal neurology are risk factors for ICH in the pediatric population. However, these findings are not definitive enough to establish pediatric head-injury guidelines regarding CT scanning or admission to hospital after minor head trauma.


Dynamic competition of inflation and delamination in the finite deformation of thin membranes.
The mechanics of blister delamination and growth plays a major role in a diversity of areas including medicine (skin pathology and mechanics of cell membranes), materials (adhesive and fracture) or soft robotics (actuation and morphing). The behavior of a blister in this context is typically difficult to grasp as it arises from the interplay of two highly nonlinear and time-dependent processes: membrane attachment and decohesion from a substrate. In the present work, we device a simplified approach, based on experimental systems, to predict the deformation path of a blister under various conditions. For this, we consider the problem of a growing blister made of a rubber-like membrane adhered on a rigid substrate, and develop a theoretical and experimental framework to study its stability and growth. We start by constructing a theoretical model of viscoelastic blister growth which we later validate with an experimental setup. We show that blister growth is controlled by the competition between two instabilities: one inherent to the rubber, and a second one pertaining to the adhesion with the substrate. Using these concepts, we show that a "targeted" stable blister shape can be achieved by controlling two parameters: the thickness of the film and the inflation rate.


Viral Infections and Neonatal Necrotizing Enterocolitis: A Meta-analysis.
Necrotizing enterocolitis (NEC) is a devastating intestinal disease affecting preterm infants. Studies implicate viral infections in etiopathogenesis. To summarize the association of viral infections with NEC by systematic review and meta-analysis. We searched Ovid-Medline, Embase, Web of Science, and Cochrane databases in November 2022. We included observational studies that examined the association between viral infections and NEC in newborn infants. We extracted data regarding the methodology, participant characteristics, and outcome measures. We included 29 and 24 studies in the qualitative review and meta-analysis, respectively. The meta-analysis demonstrated a significant association between viral infections and NEC (odds ratio [OR], 3.81, 95% confidence interval: 1.99-7.30, 24 studies). The association remained significant after excluding the outliers (OR, 2.89 [1.56-5.36], 22 studies) and studies with poor methodology (OR, 3.33 [1.73-6.43], 22 studies). In subgroup analysis based on participants' birth weight, studies including very low birth weight infants only (OR, 3.62 [1.63-8.03], 8 studies) and non-very low birth weight infants only (OR, 5.28 [1.69-16.54], 6 studies) showed a significant association. In subgroup analysis based on specific viruses, infection with rotavirus (OR, 3.96 [1.12-13.95], 10 studies), cytomegalovirus (OR, 3.50 [1.60-7.65], 5 studies), norovirus (OR, 11.95 [2.05-69.84], 2 studies), and astrovirus (OR, 6.32 [2.49-16.02], 2 studies) was significantly associated with NEC. Heterogeneity of the included studies. Viral infection is associated with an increased risk of NEC in newborn infants. We need methodologically sound prospective studies to assess the effect of preventing or treating viral infections on NEC incidence.


School-based prevention for illicit drugs' use.
Drug addiction is a chronic, relapsing disease. Primary interventions should be aimed to reduce first use, or prevent the transition from experimental use to addiction. School is the appropriate setting for preventive interventions. To evaluate the effectiveness of school-based interventions in improving knowledge, developing skills, promoting change, and preventing or reducing drug use versus usual curricular activities or a different school-based intervention . MEDLINE , EMBASE, ERIC, PSYCHINFO, Cochrane Library, ACP Journal Club, Cochrane Drug and Alcohol Group Register, updated to February 2004, were searched. Bibliography of papers was checked and personal contacts were made to identify other relevant studies. RCTs, CCTs or Controlled Prospective Studies (CPS) evaluating school-based interventions designed to prevent substance use. Data were selected and extracted independently by two reviewers. Quality was assessed with the CDAG checklist. Interventions were classified as skills, affective, knowledge-focused and other characteristics were also studied (teaching, follow-up implementation, context activation). 32 studies (29 RCTs and 3 CPSs) were included. 28 were conducted in the USA; most were focused on 6th-7th grade students, and based on post-test assessment. RCTs: (1) Knowledge vs usual curricula: Knowledge focused programs improve drug knowledge (SMD=0.91; 95% CI: 0.42, 1.39).(2) Skills vs usual curricula: Skills based interventions increase drug knowledge (WMD=2.60; 95% CI: 1.17-4.03), decision making skills (SMD=0.78; CI95%: 0.46-1.09), self-esteem (SMD=0.22; CI95%: 0.03-0.40), peer pressure resistance (RR=2.05; CI95%: 1.24-3.42), drug use (RR=0.81; CI95%: 0.64, 1.02), marijuana use (RR=0.82; CI95%: 0.73, 0.92) and hard drug use (RR=0.45; CI95%: 0.24-0.85). (3) Skills vs knowledge: No differences are evident.(4) Skills vs affective: Skills-based interventions are only better than affective ones in self-efficacy (WMD=1.90; CI95%: 0.25, 3.55). (5) Affective vs usual curricula: Affective interventions improve drug knowledge (SMD=1.88; CI95%: 1.27, 2.50) and decision making skills (SMD=1.35; CI95%: 0.79, 1.9). (6) Affective vs knowledge: Affective interventions improve drug knowledge (SMD=0.60; CI95%: 0.18,1.03), and decision making skills (SMD=1.22; CI95%: 0.33, 2.12). Results from CPSs: No statistically significant results emerge from CPSs. Skills based programs appear to be effective in deterring early-stage drug use. The replication of results with well designed, long term randomised trials, and the evaluation of single components of intervention (peer, parents, booster sessions) are the priorities for research. All new studies should control for cluster effect.


Lipolymph nodes of the mesentery.
Although lipolymph nodes have previously involved only pelvic or retroperitoneal lymph nodes, two patients are presented with lipolymph nodes involving the intestinal mesentery. The definitive diagnoses were made by exploratory laparotomy and multiple biopsies of intrabdominal lymph nodes. Both patients with lipolymph nodes are obese, middle-aged, and female, which is the typical clinical presentation. The microscopic picture is distinctive. The lymph nodes are entirely replaced by adipose tissue and have a thin outer rim of nodal tissue. The patient with a diagnosis of lipolymph nodes of the mesentery or the pelvis and retroperitoneum should receive conservative surgical treatment. Since the disease appears to have a benign course, surgical extirpation of abnormal lymph nodes is not needed or warranted.


An increase in tolerogenic dendritic cell and natural regulatory T cell numbers during experimental autoimmune encephalomyelitis in Rras-/- mice results in attenuated disease.
R-Ras is a member of the Ras superfamily of small GTPases, which are regulators of various cellular processes, including adhesion, survival, proliferation, trafficking, and cytokine production. R-Ras is expressed by immune cells and has been shown to modulate dendritic cell (DC) function in vitro and has been associated with liver autoimmunity. We used Rras-deficient mice to study the mechanism whereby R-Ras contributes to autoimmunity using experimental autoimmune encephalomyelitis (EAE), a mouse model of the CNS autoimmune disease multiple sclerosis. We found that a lack of R-Ras in peripheral immune cells resulted in attenuated EAE disease. Further investigation revealed that, during EAE, absence of R-Ras promoted the formation of MHC II(low) DC concomitant with a significant increase in proliferation of natural regulatory T cells, resulting in an increase in their cell numbers in the periphery. Our study suggests a novel role for R-Ras in promoting autoimmunity through negative regulation of natural regulatory T cell numbers by inhibiting the development of MHCII(low) DC with tolerogenic potential.


Meta-analysis of Complex Diseases at Gene Level with Generalized Functional Linear Models.
We developed generalized functional linear models (GFLMs) to perform a meta-analysis of multiple case-control studies to evaluate the relationship of genetic data to dichotomous traits adjusting for covariates. Unlike the previously developed meta-analysis for sequence kernel association tests (MetaSKATs), which are based on mixed-effect models to make the contributions of major gene loci random, GFLMs are fixed models; i.e., genetic effects of multiple genetic variants are fixed. Based on GFLMs, we developed chi-squared-distributed Rao's efficient score test and likelihood-ratio test (LRT) statistics to test for an association between a complex dichotomous trait and multiple genetic variants. We then performed extensive simulations to evaluate the empirical type I error rates and power performance of the proposed tests. The Rao's efficient score test statistics of GFLMs are very conservative and have higher power than MetaSKATs when some causal variants are rare and some are common. When the causal variants are all rare [i.e., minor allele frequencies (MAF) < 0.03], the Rao's efficient score test statistics have similar or slightly lower power than MetaSKATs. The LRT statistics generate accurate type I error rates for homogeneous genetic-effect models and may inflate type I error rates for heterogeneous genetic-effect models owing to the large numbers of degrees of freedom and have similar or slightly higher power than the Rao's efficient score test statistics. GFLMs were applied to analyze genetic data of 22 gene regions of type 2 diabetes data from a meta-analysis of eight European studies and detected significant association for 18 genes (P < 3.10 × 10(-6)), tentative association for 2 genes (HHEX and HMGA2; P ≈ 10(-5)), and no association for 2 genes, while MetaSKATs detected none. In addition, the traditional additive-effect model detects association at gene HHEX. GFLMs and related tests can analyze rare or common variants or a combination of the two and can be useful in whole-genome and whole-exome association studies.


Incomplete refolding of a fragment of the N-terminal domain of pig muscle 3-phosphoglycerate kinase that lacks a subdomain. Comparison with refolding of the complementary C-terminal fragment.
Refolding of pig muscle 3-phosphoglycerate kinase (PGK) from a mixture of its complementary proteolytic fragments that did not correspond to the individual domains resulted in a high degree of reactivation [Vas, M., Sinev, M.A., Kotova, N. & Semisotnov, G.V. (1990) Eur. J. Biochem. 189, 575--579]. An independent refolding of the 27.7 kDa C-terminal proteolytic fragment (which encompasses the whole C domain) has been noted, but the refolding ability of the 16.8-kDa N-terminal proteolytic fragment, which lacks a single subdomain from the N domain, remained to be seen. Here the refolding processes of the isolated fragments are compared. Within the first few seconds of initiation of refolding, pulse-proteolysis experiments show the formation of a structure with moderate protease resistance for both fragments. This structure, however, remains unchanged upon further incubation of the N-terminal fragment, whereas refolding of the C-terminal fragment continues as detected by a further increase in proteolytic resistance. The non-native character of the folding intermediate of the N fragment is indicated by the elevated fluorescence intensity of the bound hydrophobic probe 8-anilino-1-naphtalene sulphonate. Its CD spectrum shows the formation of secondary structure distinct from the native one. The noncooperative phase-transition observed in microcalorimetry indicates the absence of a rigid tertiary structure, in contrast with the refolded C-terminal fragment for which a cooperative transition is seen. Size-exclusion chromatography supported the globular character of the intermediate, and showed its propensity to form dimers. No binding of the substrate, 3-phosphoglycerate (3-PGri), to the isolated N-terminal fragment, could be detected but the presence of the complementary C-terminal fragment led to restoration of the substrate binding ability of the N domain. Thus, refolding of the isolated N-terminal fragment yields a highly flexible, globular, potentially productive intermediate with non-native secondary structure and highly exposed hydrophobic clusters, which favour dimerization.


Histone acetyltransferase complexes can mediate transcriptional activation by the major glucocorticoid receptor activation domain.
Previous studies have shown that the Ada adapter proteins are important for glucocorticoid receptor (GR)-mediated gene activation in yeast. The N-terminal transactivation domain of GR, tau1, is dependent upon Ada2, Ada3, and Gcn5 for transactivation in vitro and in vivo. Using in vitro techniques, we demonstrate that the GR-tau1 interacts directly with the native Ada containing histone acetyltransferase (HAT) complex SAGA but not the related Ada complex. Mutations in tau1 that reduce tau1 transactivation activity in vivo lead to a reduced binding of tau1 to the SAGA complex and conversely, mutations increasing the transactivation activity of tau1 lead to an increased binding of tau1 to SAGA. In addition, the Ada-independent NuA4 HAT complex also interacts with tau1. GAL4-tau1-driven transcription from chromatin templates is stimulated by SAGA and NuA4 in an acetyl coenzyme A-dependent manner. Low-activity tau1 mutants reduce SAGA- and NuA4-stimulated transcription while high-activity tau1 mutants increase transcriptional activation, specifically from chromatin templates. Our results demonstrate that the targeting of native HAT complexes by the GR-tau1 activation domain mediates transcriptional stimulation from chromatin templates.


Outcome measurements following palatal soft tissue graft harvesting: A review.
Free gingival graft (FGG) and connective tissue graft (CTG) are two of the most commonly techniques performed in periodontal and peri-implant plastic surgery. Although several outcome measurements have been proposed for evaluation of palatal wound healing and patient morbidity, a comprehensive review about these variables is lacking. The objective of this review is to present comprehensive information about outcome measurements related to postoperative palatal wound healing and postoperative patient-reported morbidity after FGG or CTG procedures. An electronic search of English language dental literature in the Medline database via PubMed access was conducted from May 1994 to May 2020 following the PRISMA guidelines. Electronic search strategy complemented by hand search of impacting related dental journals, and the reference list of all included studies were used to complete data collection considering only clinical trials. Finally, inclusion criteria were applied to identify articles after full-text evaluation. A total of 111 articles were identified. After the exclusion of 34 articles based on title and abstract evaluation, 77 articles were full text screened. Following, 46 articles were excluded since they evaluated other surgical areas. Finally, 31 studies were selected and included for final evaluation. Outcome measurements were classified in variables collected by indexes and systems assessed professionally and patient-centered measurements. Visually-assessed measurements include indexes, photographs, bleeding and use of laboratory-aided measurements. Patients-centered outcomes comprise pain, discomfort and quality-of life, among others. The most commonly used outcome measurements related to postoperative palatal wound healing are hydrogen peroxide test, tissue color match, visual inspection, and bleeding evaluation. Pain perception, analgesic consumption, discomfort sensation, burning sensation, and changes in feeling habits are the most commonly used outcome measurements related to postoperative patient-reported morbidity. Key words:Morbidity, patient comfort, periodontics, tissue harvesting, wound healing.


Dialysis pioneers of New Jersey.
Dialysis was an experimental procedure when New Jersey's earliest dialysis programs were started by physicians three decades ago. New Jersey's dialysis pioneers recall their early days in a new subspecialty. Patients were fortunate to have such programs available.


Cytotoxicity mediated by the Fas ligand (FasL)-activated apoptotic pathway in stem cells.
Whereas it is now clear that human bone marrow stromal cells (BMSCs) can be immunosuppressive and escape cytotoxic lymphocytes (CTLs) in vitro and in vivo, the mechanisms of this phenomenon remain controversial. Here, we test the hypothesis that BMSCs suppress immune responses by Fas-mediated apoptosis of activated lymphocytes and find both Fas and FasL expression by primary BMSCs. Jurkat cells or activated lymphocytes were each killed by BMSCs after 72 h of co-incubation. In comparison, the cytotoxic effect of BMSCs on non-activated lymphocytes and on caspase-8(-/-) Jurkat cells was extremely low. Fas/Fc fusion protein strongly inhibited BMSC-induced lymphocyte apoptosis. Although we detected a high level of Fas expression in BMSCs, stimulation of Fas with anti-Fas antibody did not result in the expected BMSC apoptosis, regardless of concentration, suggesting a disruption of the Fas activation pathway. Thus BMSCs may have an endogenous mechanism to evade Fas-mediated apoptosis. Cumulatively, these data provide a parallel between adult stem/progenitor cells and cancer cells, consistent with the idea that stem/progenitor cells can use FasL to prevent lymphocyte attack by inducing lymphocyte apoptosis during the regeneration of injured tissues.


Phytochemicals and antioxidant activity of milled fractions of different wheat varieties.
The health-promoting effects of whole-grain consumption have been attributed in part to their unique phytochemical contents and profiles that complement those found in fruits and vegetables. Wheat is an important component of the human diet; however, little is known about the phytochemical profiles and total antioxidant activities of milled fractions of different wheat varieties. The objectives of this study were to investigate the distribution of phytochemicals (total phenolics, flavonoids, ferulic acid, and carotenoids) and to determine hydrophilic and lipophilic antioxidant activity in milled fractions (endosperm and bran/germ) of three different wheat varieties, two of which were grown in two environments. Grain samples of each of the wheat varieties were milled into endosperm and bran/germ fractions. Each fraction was extracted and analyzed for total phenolics, ferulic acid, flavonoids, carotenoid contents, and hydrophilic and lipophilic antioxidant activities. Total phenolic content of bran/germ fractions (2867-3120 micromol of gallic acid equiv/100 g) was 15-18-fold higher (p < 0.01) than that of respective endosperm fractions. Ferulic acid content ranged from 1005 to 1130 micromol/100 g in bran/germ fractions and from 15 to 21 micromol/100 g in the endosperm fractions. The bran/germ fraction flavonoid content was 740-940 micromol of catechin equiv/100 g. On average, bran/germ fractions of wheat had 4-fold more lutein, 12-fold more zeaxanthin, and 2-fold more beta-cryptoxanthin than the endosperm fractions. Hydrophilic antioxidant activity of bran/germ samples (7.1-16.4 micromol of vitamin C equiv/g) was 13-27-fold higher than that of the respective endosperm samples. Similarly, lipophilic antioxidant activity was 28-89-fold higher in the bran/germ fractions (1785-4669 nmol of vitamin E equiv/g). Hydrophilic antioxidant activity contribution to the total antioxidant activity (hydrophilic + lipophilic) was >80%. In whole-wheat flour, the bran/germ fraction contributed 83% of the total phenolic content, 79% of the total flavonoid content, 51% of the total lutein, 78% of the total zeaxanthin, 42% of the total beta-cryptoxanthin, 85% of the total hydrophilic antioxidant activity, and 94% of the total lipophilic antioxidant activity. Our results showed that different milled fractions of wheat have different profiles of both hydrophilic and lipophilic phytochemicals. These findings provide information necessary for evaluating contributions to good health and disease prevention from whole-wheat consumption.


Inhaled anti-infective agents: emphasis on colistin.
The administration of antibiotics by the inhaled route is a widely recognized treatment in patients with cystic fibrosis (CF) and bronchiectasis. Tobramycin solution for inhalation (TOBI) has been available for many years and is licensed in the USA and Europe. While strong data support the use of aerosolized antibiotics for the treatment of respiratory infections in patients with CF or bronchiectasis, only a few clinical studies have examined the role of aerosolized antibiotics in the treatment of pneumonia, including ventilator-associated pneumonia (VAP) in these patients. During the last decade increasing interest has been directed towards alternative treatments to the systemic administration of antimicrobial agents for the treatment of patients with hospital-acquired pneumonia or VAP due to multidrug-resistant (MDR) Gram-negative bacteria. Recent publications demonstrate the clinical benefits from administering inhaled aminoglycosides or polymyxins in patients with hospital-acquired pneumonia or VAP. In addition to antibiotics, antifungals, and antivirals have been administered by inhalation to specific groups of critically ill patients. However, randomized controlled trials dealing with the administration of anti-infective agents via the respiratory tract are necessary in order to validate the efficacy, safety, advantages, and disadvantages of this therapeutic approach for the treatment of nosocomial pneumonia.


The NTPase/helicase domain of hepatitis C virus nonstructural protein 3 inhibits protein kinase C independently of its NTPase activity.
Helicase motif VI is a short arginine-rich motif within the NTPase/helicase domain of the non-structural protein 3 (NS3) of the hepatitis C virus (HCV). We previously demonstrated that it reduces the catalytic activity and intracellular shuttling of protein kinase C (PKC). Thus, NS3-mediated PKC inhibition may be involved in HCV-associated hepatocellular carcinoma (HCC). In this study, we expand on our earlier results, which were obtained in experiments with short fragments of NS3, to show for the first time that the catalytically active, longer C-terminal NTPase/helicase of NS3 acts as a potent PKC inhibitor in vitro. PKC inhibition assays with the NTPase-inactive mutant NS3h-D1316A revealed a mixed type kinetic inhibition pattern. A broad range of 11 PKC isotypes was tested and all of the PKC isotypes were inhibited with IC₅₀-values in the low micromolar range. These findings were confirmed for the wild-type NTPase/helicase domain in a non-radiometric PKC inhibition assay with ATP regeneration to rule out any effect of ATP hydrolysis caused by its NTPase activity. PKCα was inhibited with a micromolar IC₅₀ in this assay, which compares well with our result for NS3h-D1316A (IC₅₀ = 0.7 μM). In summary, these results confirm that catalytically active NS3 NTPase/helicase can act in an analogous manner to shorter NS3 fragments as a pseudosubstrate inhibitor of PKC.


Thalassemia and premarital screening: potential for implementation of a screening program among young people in Pakistan.
Pakistan has a high prevalence of β-thalassemia (β-thal) but lacks a screening program for its prevention. This questionnaire-based cross-sectional study was conducted in six randomly chosen non medical universities to assess the students' knowledge of β-thal and premarital screening, and their attitude towards such a program. Comparison was made between the respondents' attitude towards premarital screening before and after providing them some information regarding the disease. Only 54.5% (207) of 380 students had heard of β-thal, with a mean knowledge score of 13.0 ± 4.4 out of 27 questions. Most respondents were aware of the concept of premarital screening. Out of 207 students, 60.4% wanted to know if they were carriers, 69.1% wanted to know their spouse's carrier status and 59.4% wanted premarital screening to be made mandatory in Pakistan. These figures increased to 72.5, 78.3 and 67.6%, respectively after provision of written information (p values: 0.03, 0.02, and 0.01, respectively). The positive attitude towards premarital screening with low background knowledge of the disease highlights the need of a mass awareness campaign and subsequent implementation of a premarital screening program.


Food insecurity and diet quality in households accessing food membership clubs in Wessex: a mixed-methods study.
Food membership clubs that charge a small fee for a set number of items are in place in Wessex to address food insecurity (inadequate reliable access to sufficient affordable, nutritious food). These clubs incorporate longer-term solutions such as budgeting support, benefit maximisation, and cooking skills. The Wessex DIET project was established to measure acceptability and impact of these clubs. Given the paucity of evidence on the prevalence of food insecurity in those accessing such clubs, we aimed to quantify food insecurity and assess diet quality and wellbeing at recruitment. In this mixed-methods study, we recruited individuals accessing food clubs in Wessex from March 31 to July 31, 2022. Participants provided informed consent and completed a survey (paper or online) at recruitment that collected data on diet and health. We used the modified six-item US Department of Agriculture (USDA) food security survey module. Follow-up surveys were administered after use of clubs (planned for 3, 6, and 12 months). Participants were invited to participate in a semi-structured interview. We used data from the baseline survey to quantify food insecurity and assess diet quality and wellbeing at point of first access to food clubs. Of 97 participants recruited, five (5%) were aged 18-24 years, 15 (15%) 25-34 years, 48 (49%) 35-54 years, 13 (13%) 55-64 years, and nine (9%) 65 years and older (seven [7%] did not report their age). 69 (71%) participants were female and 23 (24%) were male (five [5%] did not respond to this question), 79 (81%) were White, and 65 (67%) reported having at least one dependent child. 55 (57%) reported skipping or cutting size of meals because there was not enough money for food. Food security status was calculated in 74 participants who answered all six questions of the USDA module, with 30 (41%) reporting low food security and 32 (43%) reporting very low food security. 31 (32%) of 97 participants reported rarely or never eating fruit, with 23 (24%) eating fruit at least once a day. The most common reported frequency of vegetable consumption was 2-3 times a week (26, 27%) and 4-6 times a week (23, 24%). 12 participants agreed to an interview. The clubs were well received, with participants noticing an improvement in their diet and finances. This study highlights the high prevalence of food insecurity in those accessing food clubs in Wessex, which is expected in a population using food aid, and positive reflections from participants regarding their diet quality after using this service. Findings might not be generalisable nationally. Follow-up will assess impact of the clubs on food insecurity, diet quality and wellbeing, contributing to the evidence base of the effectiveness of food clubs to address these outcomes. National Institute for Health and Care Research (NIHR) Applied Research Collaboration Wessex.


Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation.
Patients with pulmonary arterial hypertension (PAH) have reduced expression of apolipoprotein E (apoE) and peroxisome proliferator-activated receptor-gamma in lung tissues, and deficiency of both has been linked to insulin resistance. ApoE deficiency leads to enhanced platelet-derived growth factor signaling, which is important in the pathobiology of PAH. We therefore hypothesized that insulin-resistant apoE-deficient (apoE-/-) mice would develop PAH that could be reversed by a peroxisome proliferator-activated receptor-gamma agonist (eg, rosiglitazone). We report that apoE-/- mice on a high-fat diet develop PAH as judged by elevated right ventricular systolic pressure. Compared with females, male apoE-/- were insulin resistant, had lower plasma adiponectin, and had higher right ventricular systolic pressure associated with right ventricular hypertrophy and increased peripheral pulmonary artery muscularization. Because male apoE-/- mice were insulin resistant and had more severe PAH than female apoE-/- mice, we treated them with rosiglitazone for 4 and 10 weeks. This treatment resulted in markedly higher plasma adiponectin, improved insulin sensitivity, and complete regression of PAH, right ventricular hypertrophy, and abnormal pulmonary artery muscularization in male apoE-/- mice. We further show that recombinant apoE and adiponectin suppress platelet-derived growth factor-BB-mediated proliferation of pulmonary artery smooth muscle cells harvested from apoE-/- or C57Bl/6 control mice. We have shown that insulin resistance, low plasma adiponectin levels, and deficiency of apoE may be risk factors for PAH and that peroxisome proliferator-activated receptor-gamma activation can reverse PAH in an animal model.


Functional results of reconstruction after subtotal or total gastrectomy.
The aim of surgical treatment of gastric cancer must be complete removal of the tumor including systematic lymphadenectomy. The performance of R0-resection has to take into consideration tumor site as well as the histomorphological type described by Lauren. Therefore, subtotal distal- or total gastrectomy are complementary operative procedures nowadays. From the oncological point of view proximal gastrectomy might be indicated in some situation but increased postoperative morbidity including severe reflux-esophagitis can be obtained. According to the functional outcome subtotal distal gastrectomy should be preferred whenever justified oncologically in comparison to total gastrectomy. Among the different reconstructive methods after total gastrectomy the Roux-en-Y technique is one of the most common procedure performed. Furthermore, some patients can benefit from a reconstruction of a gastric substitute and maintenance of duodenal passage but the superiority of this technique must be evaluated in further prospective studies. The question of the optimal mode of reconstruction of the upper gastrointestinal tract is still open.


Early fetal anatomy screening: who, what, when and why?
This article reviews the potential benefits and downsides of early anatomy screening. There is increasing evidence that about 50% of severe fetal anomalies can be diagnosed prior to 14 weeks of gestation. 'Red flags' such as an increased nuchal or intracranial translucency, tricuspid valve regurgitation, a small biparietal diameter, a single umbilical artery or an abnormal retronasal triangle should raise the sonographer's suspicion of a congenital defect and warrant a more thorough fetal assessment, which often includes transvaginal scanning. Care should, however, be taken not to overinterpret first-trimester findings as false-positive rates of 3-4% have been reported. With more subtle findings, and especially if a heart defect is suspected, a sonographic reassessment after 15 weeks' gestation is indicated. Patients should be counseled that findings could worsen but also improve with time. Basic fetal anomaly screening should be recommended, piggybacked on the routine first-trimester (aneuploidy screening) ultrasound, both for low and high-risk populations. First-trimester anatomy screening seems particularly useful in obese women, whose fetuses are difficult to screen at the midtrimester ultrasound and in multiple gestation. Noninvasive prenatal testing using cell-free fetal DNA can complement but should not replace first-trimester ultrasound.


Men ask more questions than women at a scientific conference.
Gender inequity in science and academia, especially in senior positions, is a recognised problem. The reasons are poorly understood, but include the persistence of historical gender ratios, discrimination and other factors, including gender-based behavioural differences. We studied participation in a professional context by observing question-asking behaviour at a large international conference with a clear equality code of conduct that prohibited any form of discrimination. Accounting for audience gender ratio, male attendees asked 1.8 questions for each question asked by a female attendee. Amongst only younger researchers, male attendees also asked 1.8 questions per female question, suggesting the pattern cannot be attributed to the temporary problem of demographic inertia. We link our findings to the 'chilly' climate for women in STEM, including wider experiences of discrimination likely encountered by women throughout their education and careers. We call for a broader and coordinated approach to understanding and addressing the barriers to women and other under-represented groups. We encourage the scientific community to recognise the context in which these gender differences occur, and evaluate and develop methods to support full participation from all attendees.


Self-Assembly of Designed Peptides with DNA to Accelerate the DNA Strand Displacement Process for Dynamic Regulation of DNAzymes.
Toehold-mediated DNA strand displacement (TMSD) is a powerful tool for controlling DNA-based molecular reactions and devices. However, the slow kinetics of TMSD reactions often limit their efficiency and practical applications. Inspired by the chemical structures of natural DNA-operating enzymes (e.g., helicase), we designed lysine-rich peptides to self-assemble with DNA-based systems. Our approach allows for accelerating the TMSD reactions, even during multiple displacement events, enhancing their overall efficiency and utility. We found that the acceleration is dependent on the peptide's sequence, length, and concentration as well as the length of the DNA toehold domain. Molecular dynamics simulations revealed that the peptides promote toehold binding between the double-stranded target and the single-stranded invader, thereby facilitating strand displacement. Furthermore, we integrated our approach into a horseradish peroxidase-mimicking DNAzyme, enabling the dynamic modulation of enzymatic functions on and off. We anticipate that the established acceleration of strand displacement reactions and the modulation of enzymatic activities offer enhanced functionality and control in the design of programmable DNA-based nanodevices.


In vitro studies of the rabbit immune system. V. Suppressor T cells activated by concanavalin A block the proliferation, not the induction of antierythrocyte plaque-forming cells.
The late B-cell proliferative phase of the in vitro antibody response by rabbit spleen cells is highly susceptible to suppression by activated T cells. The in vitro antisheep erythrocyte plaque-forming cell (PFC) response by spleen cells from normal or primed rabbits can be suppressed by adding concanavalin A (Con A), Con A-prestimulated peripheral blood or spleen lymphocytes, or supernates from Con A-prestimulated peripheral blood lymphocytes. The suppression is not mediated by a direct interaction of Con A with responding cells as shown by the effectiveness of prestimulated cells. Primed spleen cultures remain sensitive to Con A suppression as late as 72 h after initiation, and the addition of Con A after 24-72 h rapidly stops the increase in the number of PFC. T cells are required for Con A addition to be effective but the suppression can be induced at a time when T-helper cells are no longer necessary. Further, the suppressive effect of Con A addition is abrogated by specific antisera to rabbit T cells. We propose that Con A activates suppressor T cells which then exert their effects on proliferating PFC or their immediate precursor B cells. The early inductive or recruitment phase of the response is probably not blocked by suppressor cells. Also, there is an apparent relationship between the number of proliferating B cells and the number of suppressor cells required. Finally, the difficulties in inducing a stimulatory effect by Con A and the prolonged period that Con A addition is suppressive suggests that the rabbit has relatively more and/or longer-lived suppressor cells than the mouse and may be a particularly useful species for studying suppressive phenomena and their mechanisms.


[Intensity of the synthesis of RNA precursors in blood lymphocytes of cattle infected with leukemia virus].
The peripheral blood lymphocytes of the cattle with lymphatic leukemia experimentally induced by BLV and of the animals from the same group with persistent lymphocytosis show the lower level of the pre-RNA-synthetic activity per cell when compared with the lymphocytes of healthy cattle (as evaluated by autoradiography with 3H-uridine as a precursor). At the same time the RNA-synthetic activity in the population as a whole increases as a result of growth of the RNA synthesizing cells (a labelling index), which is confirmed by enhancement of DNA-dependent RNA-polymerase activities and 3H-uridine in vitro incorporation into lymphocytes revealed by the liquid scintillation counting method.


A prospective study of psychological predictors of body fat gain among children at high risk for adult obesity.
Limited data suggest that psychological factors, including binge eating, dieting, and depressive symptoms, may predispose children to excessive weight gain. We investigated the relationship between baseline psychological measures and changes in body fat (measured with dual-energy x-ray absorptiometry) over time among children thought to be at high risk for adult obesity. A cohort study of a convenience sample of children (age: 6-12 years) recruited from Washington, DC, and its suburbs was performed. Subjects were selected to be at increased risk for adult obesity, either because they were overweight when first examined or because their parents were overweight. Children completed questionnaires at baseline that assessed dieting, binge eating, disordered eating attitudes, and depressive symptoms; they underwent measurements of body fat mass at baseline and annually for an average of 4.2 years (SD: 1.8 years). Five hundred sixty-eight measurements were obtained between July 1996 and December 2004, for 146 children. Both binge eating and dieting predicted increases in body fat. Neither depressive symptoms nor disturbed eating attitudes served as significant predictors. Children who reported binge eating gained, on average, 15% more fat mass, compared with children who did not report binge eating. Children's reports of binge eating and dieting were salient predictors of gains in fat mass during middle childhood among children at high risk for adult obesity. Interventions targeting disordered eating behaviors may be useful in preventing excessive fat gain in this high-risk group.


Alpha-galactosidase production and use in a hollow-fiber reactor.
Soybean milk serves as a base for a variety of beverages designed for consumption in developing countries. Soybean flour contains raffinose and stachyose considered to be responsible for flatulence often associated with these products (J.J. Rackis, D.H. Honig, D.J. Sessa, and F.R. Steggerda, 1970). alpha-Galactosidase, produced on wheat bran, hydrolyzes the galactooligosaccharides of soybean milk.


Binding of Pseudomonas aeruginosa AlgZ to sites upstream of the algZ promoter leads to repression of transcription.
Mucoid variants of the opportunistic pathogen Pseudomonas aeruginosa produce the exopolysaccharide alginate and colonize the respiratory tracts of cystic fibrosis patients. The genes encoding the alginate biosynthetic enzymes are clustered in a single operon, which is under tight transcriptional control. One essential activator of the alginate operon is AlgZ, a proposed ribbon-helix-helix DNA binding protein that shares 30% amino acid identity with the Mnt repressor of Salmonella enterica serovar Typhimurium bacteriophage P22. In the current study, we examined the role of AlgZ as an autoregulator. Using single-copy algZ-lacZ transcription fusions, an increase in algZ transcription was observed in an algZ mutant compared to the isogenic wild-type strain, suggesting that AlgZ may have an additional role as a repressor. To identify the AlgZ binding site, overlapping regions upstream of algZ were incubated with AlgZ and analyzed by electrophoretic mobility shift assays. Specific binding activity was localized to a region spanning from 66 to 185 base pairs upstream of the algZ transcriptional start site. Two AlgZ binding sites were defined using copper-phenanthroline footprinting and deletion analyses, with one site centered at 93 base pairs and the other centered at 161 base pairs upstream of the algZ promoter. Deletion of both binding sites resulted in the loss of AlgZ binding. These results indicate that AlgZ represses algZ transcription, and this activity is mediated by multiple AlgZ-DNA interactions.


PTCA--clinical aspects.
At Emory University Hospital, 7,000 coronary angioplasty procedures have been performed since 1980. The overall success rate remains around 90% despite extensive broadening of the indications. Complications include emergency surgery in 2.5%, acute infarction in 2.5%, and a mortality of 0.2%. Major problems are acute closure and recurrence of stenosis. Factors predisposing to acute closure include lesion length, female gender, bend in the artery at the area of stenosis, branch point location, thrombus in the artery and other lesions in the same vessel. Therapy for acute closure includes prolonged balloon inflations, the use of the bail-out catheter, and for the future, intracoronary stenting devices. Restenosis occurs in approximately 25% of the patients and is influenced by male gender, unstable angina, total occlusion, location of the lesions, and incomplete results of angioplasty. Attempts at modifying restenosis included anti-platelet therapy, anticoagulation and calcium antagonists. At the present it is felt that more potent antiplatelet agents will be required to make additional improvements in the restenosis rate. Long-term follow-up of the Emory cohort reveals a 4 1/2 year survival of over 96% with 89% free from death, myocardial infarction or the need for coronary bypass surgery. In order to identify the proper role of angioplasty in multivessel disease, a prospective randomized trial is now being instituted at Emory to evaluate the relative merits of angioplasty and coronary bypass surgery.


Prevalence of antibodies against avian influenza A (H5N1) virus among Cullers and poultry workers in Ho Chi Minh City, 2005.
Between 2003 and 2005, highly pathogenic avian influenza A (H5N1) viruses caused large scale outbreaks in poultry in the Ho Chi Minh City area in Vietnam. We studied the prevalence of antibodies against H5N1 in poultry workers and cullers who were active in the program in Ho Chi Minh City in 2004 and 2005. Single sera from 500 poultry workers and poultry cullers exposed to infected birds were tested for antibodies to avian influenza H5N1, using microneutralization assays and hemagglutination inhibition assay with horse blood. All sera tested negative using microneutralization tests. Three samples showed a 1ratio80 titer in the hemagglutination inhibition assay. This study provides additional support for the low transmissibility of clade 1 H5N1 to humans, but limited transmission to highly exposed persons cannot be excluded given the presence of low antibody titers in some individuals.


Biologic fixation arthroplasty in the treatment of osteonecrosis.
To provide a possible solution to the problem of aseptic loosening of prosthetic hip replacement components, the authors treated selected patients who had stage IV, V, or VI osteonecrosis with uncemented, porous-coated components on the femoral side. These stems are designed for bone ingrowth, with the goal of attaining a more viable and permanent interlocking bone between the implant and host bone. This article presents the necessary surgical principles and techniques for biologic fixation arthroplasty and reports the early results that have been obtained.


Multinucleated floret-like giant cells in sporadic and NF1-associated neurofibromas: a clinicopathologic study of 94 cases.
Multinucleated floret-like giant cells (MNFGCs), similar to those commonly observed in pleomorphic lipoma and giant cell fibroblastoma, have been occasionally reported in gynecomastia and neurofibromas from patients affected by neurofibromatosis type 1 (NF1). Accordingly, it has been suggested that their detection, especially in an otherwise typical neurofibroma, could be a morphological clue to diagnosis of NF1. The aim of the present study was the identification of MNFGCs in a large series (94 cases) of sporadic and NF1-associated neurofibromas, to assess if their presence may indeed be a morphological marker of NF1. Numerous MNFGCs, namely, those that were easily apparent at low magnification (x50 and x100), were identified only in 5.3% of cases. In 18.1% of cases, a low number of these cells could be observed but only after a careful search, especially at higher magnification (x200 and x400). Immunohistochemically, all MNFGCs were stained with vimentin and CD34, but not with S-100 protein. Interestingly, there was no statistically significant correlation between MNFGCs (presence or absence) and NF1 (p = 0.73), gender (p = 0.59), age (p = 0.43), and site of tumor (cutaneous vs deep-seated soft tissue; p = 0.27). Our clinicopathologic findings suggest that MNFGCs in an otherwise typical neurofibroma are not a reliable marker of NF1, likely representing a morphological reactive change of the indigenous dermal or endoneurial fibroblasts or dendritic cells in response to unknown microenvironmental stimuli.


Treatment of Ras-induced cancers by the F-actin cappers tensin and chaetoglobosin K, in combination with the caspase-1 inhibitor N1445.
For transforming normal fibroblasts to malignant cells, oncogenic Ras mutants such as v-Ha-ras require Rho family GTPases (Rho, Rac, and CDC42) that are responsible for controlling actin-cytoskeleton organization. Ras activates Rac through a PI-3 kinase-mediated pathway. Rac causes uncapping of actin filaments (F-actin) at the plus-ends, through phosphatidylinositol 4,5 bisphosphate (PIP2), and eventually induces membrane ruffling. Several distinct F-actin/PIP2-binding proteins, such as gelsolin, which severs and caps the plus-ends of actin filaments, or HS1, which cross-links actin filaments, have been shown to suppress v-Ha-Ras-induced malignant transformation when they are overexpressed. Interestingly, an F-actin cross-linking drug (photosensitizer) called MKT-077 suppresses Ras transformation. Thus, an F-actin capping/severing drug might also have an anticancer potential. This study was conducted to determine first whether Ras-induced malignant phenotype (anchorage-independent growth) is suppressed by overexpression of the gene encoding a large plus-end F-actin capping protein called tensin and second to test the anti-Ras potential of a unique fungal antibiotic (small compound) called chaetoglobosin K (CK) that also caps the plus-ends of actin filaments. DNA transfection with a retroviral vector carrying the tensin cDNA was used to overexpress tensin in v-Ha-Ras-transformed NIH 3T3 cells. All stable tensin transfectants rarely formed colonies in soft agar, indicating that tensin suppresses the anchorage-independent growth. The anti-Ras action of CK was determined by incubating the Ras-transformants in the presence of CK in soft agar. Two microM CK almost completely inhibited their colony formation, indicating that CK also suppresses the malignant phenotype. However, unlike tensin, CK causes an apoptosis of Ras-transformed NIH 3T3 cells and, less effectively, of normal NIH 3T3 cells, indicating that CK has an F-actin capping-independent side effect(s). CK-induced apoptosis is at least in part caused by CK-induced inhibition of the kinase PKB/AKT. However, a specific ICE/caspase-1 inhibitor called N1445 completely abolished the CK-induced apoptosis by reactivating PKB, but without affecting the CK-induced suppression of Ras transformation. Like the F-actin cross-linking drug MKT-077, the F-actin capping drug CK may be useful for the treatment of Ras-associated cancers if it is combined with the ICE inhibitor N1445, which abolishes the side effect of CK. Our observations that two distinct F-actin capping molecules (i.e., tensin and CK) suppress Ras-induced malignant phenotype strongly suggest, if not prove, that capping of actin filaments at the plus-ends alone is sufficient to block one of the Ras signaling pathways essential for its oncogenicity. This notion is compatible with the fact that Ras induces the uncapping of actin filaments at the plus-ends through the Rac/PIP2 pathway.


A bivariate whole genome linkage study identified genomic regions influencing both BMD and bone structure.
Areal BMD (aBMD) and areal bone size (ABS) are biologically correlated traits and are each important determinants of bone strength and risk of fractures. Studies showed that aBMD and ABS are genetically correlated, indicating that they may share some common genetic factors, which, however, are largely unknown. To study the genetic factors influencing both aBMD and ABS, bivariate whole genome linkage analyses were conducted for aBMD-ABS at the femoral neck (FN), lumbar spine (LS), and ultradistal (UD)-forearm in a large sample of 451 white pedigrees made up of 4498 individuals. We detected significant linkage on chromosome Xq27 (LOD = 4.89) for LS aBMD-ABS. In addition, we detected suggestive linkages at 20q11 (LOD = 3.65) and Xp11 (LOD = 2.96) for FN aBMD-ABS; at 12p11 (LOD = 3.39) and 17q21 (LOD = 2.94) for LS aBMD-ABS; and at 5q23 (LOD = 3.54), 7p15 (LOD = 3.45), Xq27 (LOD = 2.93), and 12p11 (LOD = 2.92) for UD-forearm aBMD-ABS. Subsequent discrimination analyses indicated that quantitative trait loci (QTLs) at 12p11 and 17q21 may have pleiotropic effects on aBMD and ABS. This study identified several genomic regions that may contain QTLs important for both aBMD and ABS. Further endeavors are necessary to follow these regions to eventually pinpoint the genetic variants affecting bone strength and risk of fractures.


Links between geographic location, environmental factors, and microbial community composition in sediments of the Eastern Mediterranean Sea.
The bacterial community composition of marine surface sediments originating from various regions of the Eastern Mediterranean Sea (12 sampling sites) was compared by parallel use of three fingerprinting methods: analysis of 16S rRNA gene fragment heterogeneity by denaturing gradient electrophoresis (DGGE), terminal restriction fragment length polymorphism (T-RFLP), and analysis of phospholipid-linked fatty acid composition (PLFA). Sampling sites were located at variable depths (30-2860 m; water column depth above the sediments) and the sediments differed greatly also in their degree of petroleum contamination (0.4-18 microg g(-1)), organic carbon (0.38-1.5%), and chlorophyll a content (0.01-7.7 microg g(-1)). Despite a high degree of correlation between the three different community fingerprint methods, some major differences were observed. DGGE banding patterns showed a significant separation of sediment communities from the northern, more productive waters of the Thermaikos Gulf and the oligotrophic waters of the Cretan, S. Ionian, and Levantine Sea. T-RFLP analysis clearly separated the communities of deep sediments (>1494 m depth) from their shallow (<617 m) counterparts. PLFA analysis grouped a shallow station from the productive waters of the north with the deep oligotrophic sediments from the Ionian and Levantine Sea, with low concentrations of PLFAs, and hence low microbial biomass, as the common denominator. The degree of petroleum contamination was not significantly correlated to the apparent composition of the microbial communities for any of the three methods, whereas organic carbon content and sediment chlorophyll a were important in this regard.


Use of aromatic compounds for growth and isolation of Zoogloea.
Nine Zoogloea strains, were examined for their ability to utilize 35 aromatic compounds. Benzoate, m-toluate, and p-toluate, as well as phenol, o-cresol, m-cresol, and p-cresol, were utilized by eight strains. These strains exhibited meta cleavage of catechol and of methyl-substituted catechols. With the exception of L-tyrosine, none of the aromatic compounds tested supported growth of Z. ramigera ATCC 19623. A medium containing sodium m-toluate was used to isolate 37 zoogloea-forming bacteria from various polluted environments. The isolates were identified as strains of Zoogloea.


Case Report: 5 Cases of Variant Hypoplastic Left Heart Syndrome Diagnosed on Prenatal Fetal Ultrasound.
BACKGROUND Hypoplastic left heart syndrome (HLHS) is a complex left-sided obstructive congenital cardiac condition with several variants. This report is of 5 cases with varying morphology of HLHS diagnosed by fetal prenatal ultrasound at the 4-chamber view (4CV) level. CASE REPORT Five cases were referred by obstetrics and gynecology specialists with preliminary information on visible congenital abnormalities in the third trimester. Fetal echocardiography showed that several morphological variants of HLHS were found. The patient in the first case had the most frequently found variant; this variation is usually linked to mitral valve stenosis (MVS). The second case had the characteristic of mitral valve atresia (MVA), and as a consequence, blood flow was not visible in this variant and the left ventricle (LV) was not clear or not adequately visualized by ultrasound. In the third case, the patient suffered from severe MVS and perhaps a small aorta. Uni-atrial conditions were described in the third case. In the fourth case, the patient had a narrow LV, MVA, ventricular septal defect, nearly united atrium, and tricuspid regurgitation. The fifth case was a case of HLHS with congenital diaphragmatic hernia. Further, 4 out of 5 of the cases were associated with widening of the cisterna magna and Dandy Walker syndrome-associated posterior fossa disorder malformations. The overall maternal age was over 35 years old in 4 cases. Karyotyping examination was not performed in all cases. CONCLUSIONS The role of ultrasound is very important in determining the diagnosis and the degree of development of hypoplastic LV. However, visualization at the 4CV level can detect abnormalities found in the LV.


Membranous Nephropathy: Core Curriculum 2021.
The understanding and management of membranous nephropathy, a common cause of nephrotic syndrome that is more frequently encountered in adults than in children, has rapidly evolved over the past decade. Identification of target antigens has allowed for more precise molecular diagnoses, and the ability to monitor circulating autoantibodies has added a new vantage point in terms of disease monitoring and decisions about immunosuppression. Although immunosuppression with alkylating agents combined with corticosteroids, or with calcineurin inhibitor-based regimens, has been the historical mainstay of treatment, observational and now randomized controlled trials with the B-cell-depleting agent rituximab have moved this agent to the forefront of therapy for primary membranous nephropathy. In this Core Curriculum, we discuss the typical features of primary and secondary disease; highlight the target antigens such as the phospholipase A2 receptor, thrombospondin type 1 domain-containing 7A, neural epidermal growth factor-like 1, and semaphorin-3B; describe the relationship between the immunologic and clinical courses of disease; and review modern management with supportive care or immunosuppressive treatment based on these composite parameters.


Clinical and imaging findings, treatments, and outcomes in 27 dogs with imaging diagnosed trigeminal nerve sheath tumors: A multi-center study.
The clinical behavior of canine trigeminal nerve sheath tumors and benefits of previously reported treatments are incompletely defined. Aims of this retrospective, multicenter, observational study were to describe clinical signs, tumor localization characteristics, treatments, and clinical outcomes in a group of dogs with this neoplasm. Databases at four hospitals were reviewed for dogs with a trigeminal nerve sheath tumor diagnosis, magnetic resonance imaging (MRI) studies, and presentation between 2004 and 2014. A single observer recorded medical record findings and two observers recorded MRI characteristics by consensus. A total of 27 dogs met inclusion criteria (15 treated with stereotactic radiation therapy and 12 unirradiated). Two unirradiated dogs were excluded from outcome analyses. The most common presenting signs were masticatory muscle atrophy (26 dogs), neurologic signs referable to intracranial disease (13), and ocular disease (12). Based on MRI findings, all dogs had disease extending centrally at the level of the brainstem. The most commonly affected trigeminal nerve branches were the mandibular (26 dogs), maxillary (22), and ophthalmic (10). Of 15 dogs treated with stereotactic radiation therapy, one had improved muscle atrophy, and six had poor ocular health after treatment. Neurologic signs improved in 4/5 dogs with intracranial signs. Overall median survival time for the 10 unirradiated dogs with available follow-up was 12 days and 441 days for the 15 stereotactic radiation therapy dogs. Mean survival times between these groups were not significantly different (mean 95% CI for unirradiated dogs was 44-424 days and mean 95% CI for stereotactic radiation therapy dogs was 260-518 days).


A Refined Prediction Parameter for Molecular Alignability in Stretched Polymers and a New Light-Harvesting Material for AlGaAs Photovoltaics.
Light-harvesting concentrators have a high potential to make highly efficient but precious energy converters, such as multijunction photovoltaics, more affordable for everyday applications. They collect sunlight, including diffusively scattered light, on large areas and redirect it to much smaller areas of the highly efficiency solar cells. Among the best current concepts are pools of randomly oriented light-collecting donor molecules that transfer all excitons to few aligned acceptors reemitting the light in the direction of the photovoltaics. So far, this system has only been realized for the 350-550 nm wavelength range, suitable for AlGaInP photovoltaics. This was achieved by using acceptor molecules that aligned during mechanical stretching of polymers together with donors, that stay random in that very same material and procedure. However, until recently, very little was known about the factors that are responsible for the alignability of molecules in stretched polymers and therefore it was difficult to find suitable donors and acceptors, as well as for other spectral ranges. Recently, a structural parameter was introduced with a high predictivity for the alignability of molecules that contain rigid band-like structures or linear aromatic π-systems. However, for light concentrators in more red spectral ranges, molecular systems often contain larger and extended, planar-like π-systems for which the previously reported parameter is not directly applicable. Here, we present a refined prediction parameter also suitable for larger plane-like structures. The new parameter depends on the number of in-plane atoms divided by out-of-plane atoms as determined by computational geometry optimization and additionally the planar aspect ratio for molecules that contain only in-plane atoms. With the help of this parameter, we found a new system that can efficiently collect and redirect light for the second 500-700 nm AlGaAs layer of current world-record multijunction photovoltaics. Similarly, as the previously reported system for the blue-green layer, it has also overall absorption and re-directioning quantum efficiencies close to 80-100%. Both layers, together, already cover about 75% of the energy in the solar spectrum.


Enterolactone glucuronide and β-glucuronidase in antibody directed enzyme prodrug therapy for targeted prostate cancer cell treatment.
Evidence from preclinical and animal studies demonstrated an anticancer effect of flaxseed lignans, particularly enterolactone (ENL), against prostate cancer. However, extensive first-pass metabolism following oral lignan consumption results in their systemic availability primarily as glucuronic acid conjugates (ENL-Gluc) and their modest in vivo effects. To overcome the unfavorable pharmacokinetics and improve their effectiveness in prostate cancer, antibody-directed enzyme prodrug therapy (ADEPT) might offer a novel strategy to allow for restricted activation of ENL from circulating ENL-Gluc within the tumor environment. The anti-prostate-specific membrane antigen (PSMA) antibody D7 was fused with human β-glucuronidase (hβG) via a flexible linker. The binding property of the fusion construct, D7-hβG, against purified or cell surface PSMA was determined by flow cytometry and Octet Red 384 system, respectively, with a binding rate constant, K d, of 2.5 nM. The enzymatic activity of D7-hβG was first tested using the probe, 4-methylumbelliferone glucuronide. A 3.8-fold greater fluorescence intensity was observed at pH 4.5 at 2 h compared with pH 7.4. The ability of D7-hβG to activate ENL from ENL-Gluc was tested and detected using LC-MS/MS. Enhanced generation of ENL was observed with increasing ENL-Gluc concentrations and reached 3613.2 ng/mL following incubation with 100 μM ENL-Gluc at pH 4.5 for 0.5 h. D7-hβG also decreased docetaxel IC50 value from 23 nM to 14.9 nM in C4-2 cells. These results confirmed the binding and activity of D7-hβG and additional in vitro investigation is needed to support the future possibility of introducing this ADEPT system to animal models.


Synchronizing Motor Imagery Cue in fNIRS Brain-Computer Interface to reduce confounding effects of respiration.
Functional near-infrared spectroscopy (fNIRS) is a neuroimaging method that measures oxygenated hemoglobin (HbO) levels in the brain to infer neural activity using near-infrared light. Measured HbO levels are directly affected by a person's respiration. Hence, respiration cycles tend to confound fNIRS readings in motor imagery-based fNIRS Brain-Computer Interfaces (BCI). To reduce this confounding effect, we propose a method of synchronizing the motor imagery cue timing with the subject's respiration cycle using a breathing sensor. We conducted an experiment to collect 160 single trials from 10 subjects performing motor imagery using an fNIRS-based BCI and the breathing sensor. We then compared the HbO levels in trials with and without respiration synchronization. The results showed that respiration synchronization yielded HbO levels that were less dispersed across trials, and a negative correlation between the dispersion index of HbO levels with MI decoding accuracies was found across the 10 subjects. This showed that synchronizing motor imagery cues to respiration can yield increased HbO level consistency leading to better MI performance. Hence, the proposed method holds promise to improve the decoding performance of fNIRS-BCI by reducing the confounding effects of respiration.


Suppressor lymphokine produced by rat T-cells in response to syngeneic mammary adenocarcinoma 13762A.
An antiproliferative suppressor lymphokine was produced from rat T-cells specifically in response to the poorly immunogenic syngeneic mammary adenocarcinoma 13762A. The tumor-induced suppressor lymphokine (TISL) was produced late in culture (peak production on Days 4 and 5) and showed strong but selective inhibitory activity on a variety of immune responses. The immune peritoneal exudate cell response to a highly immunogenic clone from the parental tumor (clone 18A) and the concanavalin A-stimulated response of nonimmune spleen cells were inhibited strongly by TISL. In contrast, the immune spleen cell response to 13762A and the lipopolysaccharide response of nonimmume spleen cells were unaffected. Preliminary molecular weight and physicochemical analysis of TISL indicated that the molecule was large (Mr greater than 350,000); partially sensitive to 75 degrees C treatment for 15 min and to pH 2.0 treatment; only partly degraded by the enzymes trypsin, chymotrypsin, and proteinase K; and completely destroyed by boiling. Although TISL was produced specifically in response to 13762A tumor, prior immunization in vivo was not necessary for the induction of the suppressor lymphokine. These results indicate that populations of rat lymphocytes contain naturally occurring TISL secreting cells, which can be activated specifically by tumor antigens such as those expressed by 13762A.


Perindopril Improves Cardiac Function by Enhancing the Expression of SIRT3 and PGC-1α in a Rat Model of Isoproterenol-Induced Cardiomyopathy.
Mitochondrial biosynthesis regulated by the PGC-1α-NRF1-TFAM pathway is considered a novel potential therapeutic target to treat heart failure (HF). Perindopril (PER) is an angiotensin-converting enzyme inhibitor that has proven efficacy in the prevention of HF; however, its mechanism is not well established. In this study, to investigate the mechanisms of PER in cardiac protection, a rat model of cardiomyopathy was established by continuous isoproterenol (ISO) stimulation. Changes in the body weight, heart weight index, echocardiography, histological staining, mitochondrial microstructure, and biochemical indicators were examined. Our results demonstrate that PER reduced myocardial remodeling, inhibited deterioration of cardiac function, and delayed HF onset in rats with ISO-induced cardiomyopathy. PER markedly reduced reactive oxygen species (ROS) production, increased the levels of antioxidant enzymes, inhibited mitochondrial structural destruction and increases the number of mitochondria, improved the function of the mitochondrial respiratory chain, and promoted ATP production in myocardial tissues. In addition, PER inhibited cytochrome C release in mitochondria and caspase-3 activation in the cytosol, thereby reducing the apoptosis of myocardial cells. Notably, PER remarkably up-regulated the mRNA and protein expression levels of Sirtuin 3 (SIRT3), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), nuclear respiratory factor 1 (NRF1), and mitochondrial transcription factor A (TFAM) in myocardial cells. Collectively, our results suggest that PER induces mitochondrial biosynthesis-mediated enhancement of SIRT3 and PGC-1α expression, thereby improving the cardiac function in rats with ISO-induced cardiomyopathy.


Reverse genetics in zebrafish.
The zebrafish has become a popular model system for the study of vertebrate developmental biology because of its numerous strengths as a molecular genetic and embryological system. To determine the requirement for specific genes during embryogenesis, it is necessary to generate organisms carrying loss-of-function mutations. This can be accomplished in zebrafish through a reverse genetic approach. This review discusses the current techniques for generating mutations in known genes in zebrafish. These techniques include the generation of chromosomal deletions and the subsequent identification of complementation groups within deletions through noncomplementation assays. In addition, this review will discuss methods currently being evaluated that may improve the methods for finding mutations in a known sequence, including screening for randomly induced small deletions within genes and screening for randomly induced point mutations within specific genes.


Artificial antibodies for affinity chromatography of homologous proteins: application to blood clotting proteins.
A method to readily isolate antibodies that bind to only one member of a family of homologous proteins is described. A library of different single chain antibody fragments can be displayed on the surface of a bacteriophage vector. Individual antibodies from this library recognizing a particular protein from a family of homologous proteins can be readily isolated by a two-step affinity screening process. In the first step antibodies which bind specifically to the undesired proteins or to homologous regions of the proteins are removed. In the second step, those antibodies specifically recognizing the desired protein are then isolated. Using this procedure and starting with a naive antibody library, a single chain antibody fragment specific to the blood clotting protein, Protein C, which did not recognize either of the homologous proteins, Factor IX or Factor X, was isolated. Similarly an antibody specific to Factor IX, but not Factor X or Protein C, was also isolated. The isolated antibodies can be readily produced, purified, and affixed to sepharose beads for affinity chromatography of the blood clotting factors. One of the key advantages to this procedure over conventional monoclonal antibody isolation is that the antibodies are isolated and produced in vitro so a broad range of related proteins, toxins, viruses, or other products can be targeted.


Hypertriiodothyroninemia in hypothyroidism treated with thyroglobulin.
Hypertriiodothyroninemia during therapy with thyroglobulin was noted in six hypothyroid patients aged 9 to 25 years. Causes of hypothyroidism were thyroiditis, congenital athyreosis, cryptothyroidism, or goitrous hypothyroidism. Serum thyroxine level, measured at the same time, was below normal in three patients. Findings attributable to excess of thyroid hormones were none other than slight nervousness or transitory heat intolerance. Substitution of levothyroxine for thyroglobulin was done in all patients and was associated with return to normal of serum triiodothyronine (T3) values in those tested. A high content of T3 in thyroglobulin used for medication seems the most probable cause of the observed hypertriiodothyroninemia. Since similar findings have been reported previously for hypothyroid patients treated with desiccated thyroid preparations, it seems clear that therapy with levothyroxine offers a significant advantage over the use of desiccated thyroid or thyroglobulin.


D-Asp upregulates PREP and GluA2/3 expressions and induces p-ERK1/2 and p-Akt in rat testis.
D-Aspartate (D-Asp) is an endogenous amino acid that plays a central role in the development of the central nervous system (CNS) and functioning of the neuroendocrine system. In line with its functions, it is abundantly present in the CNS and reproductive systems of vertebrates and invertebrates. It has been implicated in the biosynthesis and/or secretion of hormones and factors that are involved in various reproductive functions, such as GnRH from the hypothalamus and testosterone from the testis. We conducted an in vivo study consisting of acute (i.p. injection of 2 µmol/g body weight) and chronic (15 days drinking solution) administration of D-Asp to adult rats to understand the signaling pathways elicited by D-Asp in the rat testis. We found that D-Asp upregulated the expression of prolyl endopeptidase (PREP), a serine protease having a pivotal role in the regulation of mammalian spermatogenesis and spermiogenesis. Immunofluorescence analysis revealed its overexpression in Leydig cells, Sertoli cells and spermatogonia. Moreover, PREP was found to co-localize with GluA2/3, an AMPA receptor subunit, whose protein expression also increased after D-Asp treatments. Finally, we found a significant increase in ERK and Akt activities in the testis of rats treated with D-Asp. Since PREP is known to be involved in regulating GnRH levels and in germ cell differentiation, we hypothesize D-Asp to play a pivotal role in regulating hormone homeostasis and spermatogenesis through activation of PREP, AMPAR, ERK and Akt.


A Japanese-Russian collaborative study on aging and atherosclerosis.
In Russia, the average life span is decreasing. This phenomenon has not been previously observed in the western hemisphere during periods of relative peace. Although this trend can be attributed to various causes, the available statistics suggest that approximately 55% of the total mortality in Russia at the present time is due to cardiovascular events. Similarly, cardiovascular events are also increasing in Japan and are associated with changes in eating habits. A Japanese-Russian international collaborative study was therefore initiated to investigate this. Data on 102 normal Russian subjects were obtained from a total of 345 patients treated at the Smolensk State Medical Academy outpatients' clinic. The data on the Japanese patients were collected at Tohoku University, Tohoku Rosai Hospital, and Fukuda Denshi Company. Sixty-seven healthy male Japanese volunteers were compared with 44 healthy male Russian patients. In this study, Vasera VS1000 (Fukuda Denshi, Tokyo) was utilized to measure pulse wave velocity (PWV). Linear regression analysis was performed, and the results showed that brachial-ankle PWV (baPWV) was significantly higher in the Russian compared with the Japanese study group. With regard to aging, PWV was found to increase both in the Japanese and Russian subjects, with a significant increase in the latter group during their 40s compared with the Japanese, and with this tendency being carried forward into the 50s. This may be the principal cause for the higher incidence of cardiovascular events reported among Russians. Furthermore, when a straight line regression analysis was performed, the zero axis intercept in both cases showed almost the same value. These results indicated that the PWV may be almost the same in Japanese and Russian populations at the time of birth. In conclusion, at the time of birth, there is no difference in the atherosclerotic status of Japanese and Russian infants. However, over time atherosclerosis becomes more apparent and progresses significantly in the case of Russian subjects. This finding is observed through the analysis of PWV. The present authors intend to continue their study aimed at preventing the further development of atherosclerosis through medical intervention.


Using ecological momentary assessments to understand how drinking during special occasions relates to parenting behaviors.
Drinking on special occasions (e.g., Super Bowl, Christmas) often results in more alcohol consumed. Further, police often report higher levels of crime, such as assaults and domestic violence, on days of major sporting events (e.g., Super Bowl, World Cup). Yet, drinking behaviors of parents during special occasions or large sporting events have not been assessed for their effects on parenting behaviors. Here, we assess the relationship between drinking during the Super Bowl and on Valentine's Day to determine whether they differ. Participants, recruited from social media, completed a 40-min baseline survey and 14 days of three daily Ecological Momentary Assessments (EMAs) about parenting. Two hundred fifty-five participants (with 684 EMAs) were enrolled on the Super Bowl and 184 (492 EMAs) were enrolled on Valentine's day. Measures of parenting include aggressive, punitive, and nonpunitive discipline and positive techniques. Drinking was assessed on days 7 and 14 of the EMA and corresponded to the EMA time frame during the previous week. Participants were largely White, well-educated mothers. Data were analyzed using multilevel logistic regression models. Parents who reported drinking on the day of the Super Bowl were more likely to use aggressive discipline (OR = 2.560; 95% CI: 1.308, 5.150) and punitive parenting (OR = 2.701; 95% CI: 1.394, 5.257) during the time that drinking occurred. In contrast, parents who reported drinking on Valentine's Day were less likely to use aggressive discipline (OR = 0.197; 95% CI: 0.077, 0.502). The differential relationship between drinking and parenting measures could be the result of differing norms or differences in who is present during the special occasions studied here. Identifying and understanding how alcohol use on special occasions contributes to parenting could help to create environments that are most conducive to positive parenting behaviors and reduce harms related to harsh or aggressive parenting.


CCNs, fibulin-1C and S100A4 expression in leiomyoma and myometrium: inverse association with TGF-beta and regulation by TGF-beta in leiomyoma and myometrial smooth muscle cells.
Connective tissue growth factor (CTGF; CCN2) is considered to serve as downstream midiator of TGF-beta action in tissue fibrosis. We tested this hypothesis in paired leiomyoma and myometrium by evaluating the expression of TGF-beta1/TGF-beta3 and CCN2, the other members of the CCN family, CCN3 and CCN4, as well as fibulin-1C and S100A4, calcium-binding proteins that interact with CCNs. The regulatory function of TGF-beta1 on the expression of these genes was further evaluated using leiomyoma (L) and myometrial (M) smooth muscle cells (SMC). Real-time PCR, Western blotting and immunohistochemistry revealed that leiomyomas and myometrium express CCNs, fibulin-1C and S100A4, whose levels of expression with the exception of fibulin-1C were lower in leiomyomas and inversely correlated with the expression of TGF-beta1 and TGF-beta3 (P<0.05). The expression of these genes was menstrual cycle-independent and GnRHa therapy increased the expression of CCN2 in leiomyomas, while inhibiting CCN3, CCN4 and S100A4 in myometrium (P<0.05). TGF-beta (2.5 ng/ml) in a time- and cell-dependent manner, and through MAPK and Smad pathways, differentially regulated the expression of these genes in LSMC and MSMC. We concluded that CCNs, fibulin-1C and S100A4 are expressed in leiomyomas/myometrium with relative expression levels inversely correlating with TGF-betas and influenced by GnRHa and TGF-beta regulatory actions. The results suggest that unlike other fibrotic disorders, CCN2 (CTGF), at least at tissue level, may not serve as a downstream mediator of TGF-beta action in leiomyomas.


Mitochondrial DNA polymorphism in populations of Siberian and European roe deer (Capreolus pygargus and C. capreolus).
We have amplified and sequenced 679 nucleotides of the mitochondrial DNA control-region in 45 Siberian (Capreolus pygargus) and European (C. capreolus) roe deer from two localities in Russia and seven in Italy. Average interspecific sequence divergence was 4.9%. Six different haplotypes were found in Siberian roe deer, and 14 haplotypes in Alpine European roe deer. A population of the endemic Italian subspecies C. c. italicus was monomorphic bearing a single haplotype with one unique nucleotide deletion and a fixed transversion. Phylogenetic relationships among haplotypes indicated that the two species were separated with 100% bootstrap support, and there were two distinct population clusters within each species. These clusters correspond to different geographical locations of the samples: Siberian roe deer were subdivided into west Siberia (Kurgan region) and east Siberia (Amur region), and European roe deer were subdivided into an eastern and a western Alpine group. Average sequence divergence among conspecific populations was 1.2%. Calibrations of evolutionary rates of the different domains of the control-region suggest that Siberian and European roe deer speciated about 2-3 million years ago, and haplotype diversity within species was generated during the last 150,000-370,000 years. Geographical structuring of sequence variability in roe deer allows us to identify historical and recent intraspecific population differences, including the effects of human disturbance. The genetic peculiarities of the endemic Italian subspecies C. c. italicus call for careful conservation of its surviving populations.


Ethanol inhibits chemoreflex excitation of reticulospinal vasomotor neurons.
In anesthetized and ventilated rats, activation of carotid chemoreceptors with intracarotid administration of 100 nmol sodium cyanide rapidly excited the spinal cord-projecting vasomotor neurons in the rostroventrolateral reticular nucleus (RVL) of the medulla oblongata and sympathetic nerves and increased arterial pressure. The chemoreflex sympathoexcitatory pressor responses were attenuated by an acute systemic administration of ethanol at 0.45 g/kg, but not at 45 mg/kg. The ethanol effects were observed at the level of RVL-spinal vasomotor neurons, in attenuating the neuronal responses to the chemoreflex excitation and direct iontophoresis of N-methyl-D-aspartic acid (NMDA) but without altering responses of the carotid sinus nerves to intracarotid cyanide. The effect of ethanol on the RVL neurons was further defined as blocking NMDA-evoked inward current in the corresponding spontaneously active RVL neurons in vitro. The results indicate that acute ethanol intoxication markedly influences NMDA receptor activation and arterial chemoreflexes. The relevance of the type of action to clinical hypertension in chronic and heavy drinkers is discussed.


Studies on the role of specific cell surface receptors in the removal of lipoprotein (a) in man.
The binding of 125I-lipoprotein (a) [Lp(a)] to cell surface receptors was studied on cultured human fibroblasts. The results were compared with corresponding data obtained with 125I-low density lipoproteins (LDL). Equilibrium binding studies showed that Lp(a) is bound with high affinity by the cell surface receptors. The maximum binding capacity for Lp(a) was 37% lower than for LDL. For Lp(a) and LDL, the Scatchard plots displayed linearity, indicating a single category of binding sites. Half-maximal saturation occurred at a concentration of 9.52 +/- 1.04 nM for Lp(a) and 7.76 +/- 1.29 nM for LDL. Competition binding experiments revealed that Lp(a) and LDL are nearly equally potent in competing each other for the binding sites. Binding of Lp(a) and LDL were followed by suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Cyclohexanedione treatment of Lp(a) and LDL completely abolished receptor binding. Neither Lp(a) nor LDL were specifically bound by fibroblasts obtained from a patient with homozygous familial hypercholesterolemia (FH). The removal mechanisms for Lp(a) and LDL were further compared by in vivo studies. Radioiodinated Lp(a) and LDL were injected intravenously into 12 normolipemic individuals to measure kinetic parameters of these two lipoproteins simultaneously in each subject. Mean fractional catabolic rate (FCR) of Lp(a) was 0.260 +/- 0.060 and mean FCR of LDL was 0.377 +/- 0.077 (mean +/- SD). In each subject, FCR of Lp(a) was lower than the FCR of LDL; the mean difference was 31%. The absolute synthetic rate of Lp(a) was significantly lower than the corresponding value of LDL. In each individual, the percentage of total Lp(a) that was contained in the intravascular space was higher than the corresponding value of LDL; the mean difference was 19%. A highly significant positive correlation was found between FCR of LDL and FCR of Lp(a) (r = 0.853, P less than 0.01). No relationship was found between the serum concentration of LDL-apolipoprotein B and Lp(a). The serum level of Lp(a) was positively related to the absolute rate of Lp(a) synthesis (r = 0.979, P less than 0.01). The serum level of LDL-apolipoprotein B was inversely related to FCR of LDL (r = 0.613, P less than 0.05). In a patient with homozygous FH, FCR of LDL was 0.205 and FCR of Lp(a) was 0.210. The results of these studies show that Lp(a) is specifically bound with high affinity to the same receptors of human fibroblasts as LDL. The affinity and maximum binding capacity are slightly lower for Lp(a) than for LDL. The results of the turnover studies are consistent with the assumption that Lp(a) is removed from the plasma by similar mechanisms as LDL.


Interference effects in the Raman scattering intensity from thin films.
Exact theoretical expressions including absorption, multiple reflections, and interference effects are derived for the intensity of Raman scattering from thin films. A concept of interference enhanced Raman scattering is presented based on a two-layer configuration that has been verified experimentally by Raman scattering measurements on thin amorphous hydrogenated carbon films deposited on crystalline Si substrates. It is shown how the model can be generalized to describe the Raman scattering intensity for a sample layer inside a multilayer structure.


A genome scan for QTL influencing milk production and health traits in dairy cattle.
A genome scan was conducted in the North American Holstein-Friesian population for quantitative trait loci (QTL) affecting production and health traits using the granddaughter design. Resource families consisted of 1,068 sons of eight elite sires. Genome coverage was estimated to be 2,551 cM (85%) for 174 genotyped markers. Each marker was tested for effects on milk yield, fat yield, protein yield, fat percentage, protein percentage, somatic cell score, and productive herd life using analysis of variance. Joint analysis of all families identified marker effects on 11 chromosomes that exceeded the genomewide, suggestive, or nominal significance threshold for QTL effects. Large marker effects on fat percentage were found on chromosomes 3 and 14, and multimarker regression analysis was used to refine the position of these QTL. Half-sibling families from Israeli Holstein dairy herds were used in a daughter design to confirm the presence of the QTL for fat percentage on chromosome 14. The QTL identified in this study may be useful for marker-assisted selection and for selection of a refined set of candidate genes affecting these traits.


Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses.
The trafficking of receptor tyrosine kinases (RTKs) to distinct subcellular locations is essential for the specificity and fidelity of signal transduction and biological responses. This is particularly important in the PNS and CNS in which RTKs mediate key events in the development and maintenance of neurons and glia through a wide range of neural processes, including survival, proliferation, differentiation, neurite outgrowth, and synaptogenesis. The mechanisms that regulate the targeting of RTKs to their subcellular destinations for appropriate signal transduction, however, are still elusive. In this review, we discuss evidence for the spatial organization of signaling machinery into distinct subcellular compartments, as well as the role for ligand specificity, receptor sorting signals, and lipid raft microdomains in RTK targeting and the resultant cellular responses in neural cells.


SetDB1 and Su(var)3-9 play non-overlapping roles in somatic cell chromosomes of Drosophila melanogaster.
We explored functional roles of two H3K9-specific histone methyltransferases of Drosophila melanogaster, SetDB1 (also known as Eggless) and Su(var)3-9. Using the DamID approach, we generated the binding profile for SetDB1 in Drosophila salivary gland chromosomes, and matched it to the profile of Su(var)3-9. Unlike Su(var)3-9, SetDB1 turned out to be an euchromatic protein that is absent from repeated DNA compartments, and is largely restricted to transcription start sites (TSSs) and 5' untranslated regions (5'UTRs) of ubiquitously expressed genes. Significant SetDB1 association is also observed at binding sites for the insulator protein CP190. SetDB1 and H3K9 di- and tri-methylated (me2 and me3)-enriched sites tend to display poor overlap. At the same time, SetDB1 has a clear connection with the distribution of H3K27me3 mark. SetDB1 binds outside the domains possessing this modification, and about half of the borders of H3K27me3 domains are decorated by SetDB1 together with actively transcribed genes. On the basis of poor correlation between the distribution of SetDB1 and H3K9 methylation marks, we speculate that, in somatic cells, SetDB1 may contribute to the methylation of a broader set of chromosomal proteins than just H3K9. In addition, SetDB1 can be expected to play a role in the establishment of chromatin functional domains.


p53-mediated induction of Noxa and p53AIP1 requires NFkappaB.
The intricate regulation of cell survival and cell death is critical for the existence of both normal and transformed cells. Two factors central to these processes are p53 and NFkappaB, with both factors having ascribed roles in both promoting and repressing cell death. Not surprisingly, a number of studies have previously reported interplay between p53 and NFkappaB. The mechanistic basis behind these observations, however, is currently incomplete. We report here further insights into this interplay using a system where blockade of NFkappaB inhibits cell death from p53, but at the same time sensitizes cells to death by TNFalpha. We found in agreement with a recent report showing that NFkappaB is required for the efficient activation of the BH3-only protein Noxa by the p53 family member p73, that p53's ability to induce Noxa is also impeded by inhibition of NFkappaB. In contrast to the regulation by p73, however, blockade of NFkappaB downstream of p53 decreases Noxa protein levels without effects on Noxa mRNA. Our further analysis of the effects of NFkappaB inhibition on p53 target gene expression revealed that while most target genes analysed where unaffected by blockade of NFkappaB, the p53-mediated induction of the pro-apoptotic gene p53AIP1 was significantly dependent on NFkappaB. These studies therefore add further insight into the complex relationship of p53 and NFkappaB. In addition, since both Noxa and p53AIP1 have been shown to be important components of p53-mediated cell death responses, these findings may also indicate critical points where NFkappaB plays a pro-apoptotic role downstream of p53.


Prevalence and course of lower limb disease activity and walking disability over the first 5 years of juvenile idiopathic arthritis: results from the childhood arthritis prospective study.
The aim was to investigate the time course of lower limb disease activity and walking disability in children with JIA over a 5-year course. The Childhood Arthritis Prospective Study is a longitudinal study of children with a new JIA diagnosis. Childhood Arthritis Prospective Study data include demographics and core outcome variables at baseline, 6 months and yearly thereafter. Prevalence and transition rates from baseline to 5 years were obtained for active and limited joint counts at the hip, knee, ankle and foot joints; and walking disability, measured using the Childhood Health Assessment Questionnaire walking subscale. Missing data were accounted for using multiple imputation. A total of 1041 children (64% female), with a median age of 7.7 years at first visit, were included. Baseline knee and ankle synovitis prevalence was 71 and 34%, respectively, decreasing to 8-20 and 6-12%, respectively, after 1 year. Baseline hip and foot synovitis prevalence was <11%, decreasing to <5% after 6 months. At least mild walking disability was present in 52% at baseline, stabilizing at 25-30% after 1 year. Lower limb synovitis and walking disability are relatively common around the time of initial presentation in children and young people with JIA. Mild to moderate walking disability persisted in ∼25% of patients for the duration of the study, despite a significant reduction in the frequency of lower limb synovitis. This suggests that there is an unmet need for non-medical strategies designed to prevent and/or resolve persistent walking disability in JIA.


Antioxidant enzymes and survival of normal and simian virus 40-transformed mouse embryo cells after hyperthermia.
Relative cell survival and activity of the free radical scavenging enzymes superoxide dismutase, catalase, and glutathione peroxidase were measured in cloned normal (MEA) and SV40-transformed (SVMEA) mouse embryo cells exposed at 44 degrees C for 0-3 h. At 37 degrees C, all three enzymes were 2-5 times higher in MEA than in SVMEA. Hyperthermia did not significantly alter enzyme levels in either cell line but selectively reduced transformed cell survival to less than 5% while relative survival of normal cells remained above 75%. The latter, however, could be reduced to 25% when normal cells were pretreated with 3 mM diethyldithiocarbamate, an inhibitor of copper- and zinc-containing superoxide dismutase. Similar treatment rendered SVMEA extremely thermosensitive. On the other hand, sublethal heat treatment (15 min at 45 degrees C) of cultured cells resulted in a relative thermal resistance upon subsequent exposure to 45 degrees C for 1-4 h. This induced thermotolerance was associated with a rise in antioxidant enzyme levels and both became significant only 4-6 h after the initial heat treatment. Induced enzyme and thermotolerance levels in transformed cells remained, nonetheless, far below those of normal cells. The data show that inherent (in MEA) as well as induced (in SVMEA) thermotolerance is associated with high antioxidant enzyme levels while the reverse is true in the case of inherent (in SVMEA) and induced (in MEA) thermosensitivity. These findings suggest that increased production of oxygen free radicals may be involved in hyperthermic cell injury, which then becomes a function of basal or inducible levels of antioxidant enzymes. Induction of the latter by hyperthermia is apparently inefficient in transformed cells making them more vulnerable. Enzyme induction seems also to require a lag period of 4-6 h suggesting the possible involvement of an intermediate inducer(s) at molecular level. The so-called heat shock proteins may be candidates for such a role.