The three-dimensional structure of codakine and related marine C-type lectins.
Codakine is a new Ca(2+)-dependent mannose-binding C-type lectin (MBL) isolated from the gill tissue of the tropical clam, Codakia orbicularis. Bioinformatic analyses with the BLAST program have revealed similarities with marine lectins involved in immunity whose three-dimensional (3D) structures were unknown up until recently. In this article, we present bioinformatic analyses of marine lectins that are homologous to codakine, in particular lectins from the sea worm Laxus oneistus, named mermaid. These lectins are involved in the symbiotic association with sulphur-oxidizing bacteria which are closely related to the C. orbicularis gill symbiont. Using homology modelling, folding that is characteristic of C-type lectins was observed in all the marine Ca(2+)-dependent lectins studied, with conservation of random coiled structures of the carbohydrate recognition domain (CRD) and Ca(2+)-binding sites. Like codakine, the marine lectins analysed contain a signal peptide commonly found in secreted and transmembrane proteins. The majority of the predictive 3D models established from the lectins exhibit a common feature, namely the involvement in invertebrate and vertebrate immunity (dendritic cell receptor, macrophage receptor, etc.). These bioinformatic analyses and the literature data support the hypothesis that codakine, like the L. oneistus mermaids, is probably involved in the cellular mediation of symbiosis and defence against pathogenic microorganisms.


Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) infection during late pregnancy: a report of 18 patients from Wuhan, China.
Compared with Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), Corona Virus Disease 2019(COVID-19) spread more rapidly and widely. The population was generally susceptible. However, reports on pregnant women infected with SARS-CoV-2 were very limited. By sharing the clinical characteristics, treatments and outcomes of 18 patients with COVID-19 during late pregnancy, we hope to provide some references for obstetric treatment and management. A total of 18 patients with COVID-19 treated at Renmin Hospital of Wuhan University were collected. The epidemiological characteristics, clinical manifestations, laboratory tests, chest CT and pregnancy outcomes were performed for analysis. 1. 18 cases of late pregnancy infected with SARS-CoV-2 pneumonia were delivered at 35 + 5 weeks to 41 weeks. According to the clinical classification of COVID-19, 1 case was mild type, 16 cases were ordinary type, and 1 case was severe type. 2. According to imaging examinations: 15 (83%) cases showed unilateral or bilateral pneumonia, 2 (11%) cases had pulmonary infection with pleural effusion, and 1 (6%) case had no abnormal imaging changes. 8 (44%) cases were positive and 10 (56%) cases were negative for nasopharyngeal-swab tests of SARS-CoV-2. 3. Among the 18 newborns, there were 3 (17%) premature infants, 1 (6%) case of mild asphyxia, 5 (28%) cases of bacterial pneumonia, 1 (6%) case of gastrointestinal bleeding, 1 (6%) case of necrotizing enteritis, 2 (11%) cases of hyperbilirubinemia and 1 (6%) case of diarrhea. All the newborns were negative for the first throat swab test of SARS-CoV-2 after birth. 4. Follow-up to Mar 7, 2020, no maternal and neonatal deaths occurred. The majority of patients in late term pregnancy with COVID-19 were of ordinary type, and they were less likely to develop into critical pneumonia after early isolation and antiviral treatment. Vertical transmission of SARS-CoV-2 was not detected, but the proportion of neonatal bacterial pneumonia was higher than other neonatal diseases in newborns.


An Occupational Paradox: Why Do We Love Really Tough Jobs?
Sometimes we come upon unexpected or counterfactual results during research that make us wonder and lead us into unknown territory. Such was the experience of a team of Air Force researchers exploring aeromedical evacuation crew members' experiences of safety and patient care concerns throughout the en route care system. To explore what it is about the aeromedical evacuation crew members' occupation that generates a strong motivation to the mission despite the demands it places on its workers. Eight focus groups were conducted with 69 Air Force aeromedical evacuation and staging facility active duty, Air National Guard, and Air Force Reserve Command nurses and medical technicians between May 2012 and April 2013 at 5 locations in the contiguous and outside the contiguous United States. An unexpected finding was that despite the austere nature of the Air Force en route care mission and the acuity of the patients being transported, nurses and medical technicians were passionate about bringing home the wounded, sick, and injured warriors and were committed to providing the best and safest care possible. It is plausible that a high level of commitment and mission focus contributes significantly to the safety and well-being of those transported. Still, we must wonder why nurses and technicians voluntarily serve in such a demanding and sometimes dangerous occupation, and yet find such a high degree of satisfaction and contentment with this type of job.


Uptake of cancer screenings among a multiethnic refugee population in North Texas, 2014-2018.
Refugees are less likely than US born populations to receive cancer screenings. Building Bridges is a community health worker prevention program designed to increase refugee's cancer screening uptake. The purpose of this cross sectional analysis was to assess differences in uptake of cervical, breast, liver, and colorectal screens across six cultural groups. Data was abstracted in 2018 for this analysis. Participants were categorized into six cultural groups (Myanmar, Central Africa, Bhutan, Somalia, Arabic Speaking Countries, and Other) to assess differences in sociodemographic measures and screening uptake. Uptake proportions were calculated for each cancer type (cervical, breast, liver, and colon) among eligible participants, by gender and cultural group. Differences in uptake across groups were assessed using stratified analysis and logistic regression. Prevalence odds ratios (POR) and 95% confidence intervals (CIs) were calculated for each group to assess the association between screening completion and cultural group. 874 refugees were asked about cancer screening history. The majority of participants were either 'never had been screened' or 'not up-to-date' for every cancer screening. Among age eligible, 82% had no prior pap exam within the past 3 years, 81% had no prior mammogram within the past year, 69% didn't know their Hepatitis B status and 87% never had a colon cancer screening. Overall, higher uptake of all types of cancer screenings was observed in Myanmar and Bhutanese groups, except colon cancer screening which was higher among Central African Region and Arabic Speaking participants. Screening uptake varied by ethnic group and screening type. The program reached an under and never screened population, however, the proportion of refugees who received a cancer screening remained low compared to the US population. Diversity within refugee communities requires adaptation to specific cultural and linguistic needs to include new Americans in cancer elimination efforts.


A phylogenetic analysis of heterorhabditis (nemata: rhabditidae) based on internal transcribed spacer 1 DNA sequence data.
Internal transcribed spacer 1 sequences were used to infer phylogenetic relationships among 8 of the 9 described species and one putative species of the entomopathogenic nematode genus Heterorhabditis. Sequences were aligned and optimized based on pairwise genetic distance and parsimony criteria and subjected to a variety of sequence alignment parameters. Phylogenetic trees were constructed with maximum parsimony, cladistic, distance, and maximum likelihood algorithms. Our results gave strong support for four pairs of sister species, while relationships between these pairs also were resolved but less well supported. The ITS1 region of the nuclear ribosomal repeat was a reliable source of homologous characters for resolving relationships between closely related taxa but provided more tenuous resolution among more divergent lineages. A high degree of sequence identity and lack of autapomorphic characters suggest that sister species pairs within three distinct lineages may be mutually conspecific. Application of these molecular data and current morphological knowledge to the delimitation of species is hindered by an incomplete understanding of their variability in natural populations.


Evaluation of bone with quantitative ultrasound in healthy Turkish children.
In this study bone status was assessed using a quantitative ultrasound (QUS) technique at the calcaneus in 141 healthy, prepubertal, Turkish schoolchildren (80 girls, 61 boys) aged 6-12 years. Broadband ultrasound attenuation (BUA, DB/MHz) was measured with a prototype pediatric contact bone analyzer (CUBA, McCue Ultrasonics Ltd). The relation of age, body weight and height to BUA was assessed. BUA increased linearly with age in boys and girls (R=0.448, p=0.0001 and R=0.382, p=0.002, respectively). BUA values in boys tended to be higher than in girls, reaching significance only at the age of seven years with a 95% confidence interval. In conclusion, the measurement of BUA in the calcaneus with QUS has important clinical implications in assessing bone mass in children. Further studies in not only healthy children but also in those with metabolic bone diseases would be helpful in order to evaluate its sensitivity and reproducibility.


Voltage-gated potassium channel (K(v) 1) autoantibodies in patients with chagasic gut dysmotility and distribution of K(v) 1 channels in human enteric neuromusculature (autoantibodies in GI dysmotility).
Autoantibodies directed against specific neuronal antigens are found in a significant number of patients with gastrointestinal neuromuscular diseases (GINMDs) secondary to neoplasia. This study examined the presence of antineuronal antibodies in idiopathic GINMD and GINMD secondary to South American Trypanosomiasis. The GI distribution of voltage-gated potassium channels (VGKCs) was also investigated. Seventy-three patients were included in the study with diagnoses of primary achalasia, enteric dysmotility, chronic intestinal pseudo-obstruction, esophageal or colonic dysmotility secondary to Chagas' disease. Sera were screened for specific antibodies to glutamic acid decarboxylase, voltage-gated calcium channels (VGCCs; P/Q subtype), nicotinic acetylcholine receptors (nAChRs; α3 subtype), and voltage-gated potassium channels (VGKCs, K(V) 1 subtype) using validated immunoprecipitation assays. The distribution of six VGKC subunits (K(V) 1.1-1.6), including those known to be antigenic targets of anti-VGKC antibodies was immunohistochemically investigated in all main human GI tract regions. Three patients (14%) with chagasic GI dysmotility were found to have positive anti-VGKC antibody titers. No antibodies were detected in patients with idiopathic GINMD. The VGKCs were found in enteric neurons at every level of the gut in unique yet overlapping distributions. The VGKC expression in GI smooth muscle was found to be limited to the esophagus. A small proportion of patients with GI dysfunction secondary to Chagas' disease have antibodies against VGKCs. The presence of these channels in the human enteric nervous system may have pathological relevance to the growing number of GINMDs with which anti-VGKC antibodies have been associated.


Searching for Archaea in infections of endodontic origin.
Archaea is a highly diverse group of prokaryotes, whose members have been traditionally recognized as extremophiles. Recently, some of these microorganisms have also been found to thrive in nonextreme environments, including the human body. Methanogenic archaea have been detected in samples from subgingival plaque associated with periodontal disease and a pathogenetic role is suspected. The purpose of this study was to survey samples taken from different types of endodontic infections for the presence of archaea. Samples were taken from untreated and treated root canals associated with asymptomatic chronic periradicular lesions as well as from cases diagnosed as acute periradicular abscesses. Overall, 96 samples were obtained. DNA from samples was extracted by using two different protocols and used as template for polymerase chain reaction amplification using oligonucleotide universal primers for the domains Archaea or Bacteria. Samples were also checked for the presence of spirochetes by making use of a group-specific primer. While bacteria were present in all samples, no case yielded archaeal DNA. Spirochetes occurred in a high number of cases. Our findings suggested that members of the Archaea domain are not members of the microbiota present in different types of endodontic infections and thereby may not be implicated in the etiology of apical periodontitis.


Anti-SARS-CoV-2 receptor-binding domain antibody evolution after mRNA vaccination.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection produces B cell responses that continue to evolve for at least a year. During that time, memory B cells express increasingly broad and potent antibodies that are resistant to mutations found in variants of concern1. As a result, vaccination of coronavirus disease 2019 (COVID-19) convalescent individuals with currently available mRNA vaccines produces high levels of plasma neutralizing activity against all variants tested1,2. Here we examine memory B cell evolution five months after vaccination with either Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) mRNA vaccine in a cohort of SARS-CoV-2-naive individuals. Between prime and boost, memory B cells produce antibodies that evolve increased neutralizing activity, but there is no further increase in potency or breadth thereafter. Instead, memory B cells that emerge five months after vaccination of naive individuals express antibodies that are similar to those that dominate the initial response. While individual memory antibodies selected over time by natural infection have greater potency and breadth than antibodies elicited by vaccination, the overall neutralizing potency of plasma is greater following vaccination. These results suggest that boosting vaccinated individuals with currently available mRNA vaccines will increase plasma neutralizing activity but may not produce antibodies with equivalent breadth to those obtained by vaccinating convalescent individuals.


A phenomenological study of nurses' understanding of honesty in palliative care.
Honesty is essential for the care of seriously ill and dying patients. The current study aimed to describe how nurses experience honesty in their work with patients receiving palliative care at home. The interviews in this phenomenological study were conducted with 16 nurses working with children and adults in palliative home-based care. Three categories emerged from analyses of the interviews: the meaning of honesty, the reason for being honest and, finally, moral conflict when dealing with honesty. The essence of these descriptions was that honesty is seen as a virtue, a good quality that a nurse should have. The nurses' ethical standpoint was shown in the moral character they show in their work and in their intention to do good. This study could help nurses to identify different ways of looking at honesty to promote more consciousness and openness in ethical discussions between colleagues and other staff members.


An international multi-stakeholder delphi consensus exercise to develop a core outcomes set (COS) for surgical fixation of rib fractures.
A patient-relevant, focused Core Outcome Set (COS) is essential to the design of clinical trials dealing with chest wall trauma, in order to maximise quality of evidence regarding impact of interventions and to reduce research waste. Outcome measures were collated by way of systematic review and entered into a three round Delphi consensus completed anonymously online. Participants were international clinicians and allied health professionals (AHP) involved in the treatment of rib fractures as well as patients who had experienced severe chest trauma. Consensus thresholds for statements were defined a priori as a group rating of more than 70% or less than 15% for 'important' or 'not important'. Sixty-five participants responded to the first round and the final round Final round consisted of five AHP, two patients and 16 clinicians from eight different countries. Twenty-three outcomes were regarded as important for the COS; eight adverse events, three mortality, five clinical or physiological outcomes, six life impact and one resource-related. Health related quality of life was rated highest of the life impact outcomes but participants thought it was also important to assess disability, physical function, quality of life, return to activities and return to work. Collecting serious adverse outcomes was important to all stakeholders as were life impact outcomes such as quality of life, physical function and return to activities. Resource use outcomes were considered less important. We recommend this Core Outcome Set, developed with multiple relevant stakeholders, for use in future clinical trials, following further work on the most appropriate methods and instruments for measurement.


Strategies to increase living donor kidney transplants.
There is an insufficient supply of deceased donor kidneys for transplantation. One solution is to increase the number of living donor kidney transplants. Our kidney transplant database was reviewed for 3 periods of 12 months each, separated by 5 years, to show the trends in kidney transplant donor sources and the influence of biologically unrelated living renal donors, minimally invasive living renal donor surgery, transplantation of ABO-incompatible kidneys from living donors, and transplantation in spite of positive cross-matches on the numbers of renal transplants and 1-year kidney transplant survival rates at our center. When results for 1993 were compared with 2003, the annual number of living donor renal transplants increased from 25 to 86, and the annual number of deceased donor renal transplants decreased from 108 to 63. The total number of kidney transplants increased by 12%. However, 1-year living donor kidney transplant survivals were not significantly different (94% for transplants done in 1993 vs 98% for transplants done in 2003). The strategies of living donor renal transplants from genetically unrelated donors, ABO-incompatible donors, and cross-match positive donors as well as the introduction of hand-assisted laparoscopic donor nephrectomy increased the number of living renal donor renal transplants at our center without compromising short-term kidney transplant survival rates.


The ageing of the low-frequency water disturbances caused by swimming goldfish and its possible relevance to prey detection.
Wakes caused by swimming goldfish (Carassius auratus) were measured with a particle image velocimetry system and analyzed using a cross-correlation technique. Particle velocities in a horizontal plane (size of measuring plane 24 cmx32 cm or 20 cmx27 cm) were determined, and the vorticity in the plane was derived from these data. The wake behind a swimming goldfish can show a clear vortex structure for at least 30 s. Particle velocities significantly higher than background noise could still be detected 3 min after a fish (body length 10 cm) had passed through the measuring plane. Within this time span, the lateral spread of fish-generated wakes could exceed 30 cm for a 10 cm fish and 20 cm for a 6 cm fish. Measurements in a man-made open-air pond showed that water velocities in a quasi-natural still water environment can be as small as 1 mm s(-)(1). Background velocities did not exceed 3 mm s(-)(1) as long as no moving animal was present in the measuring plane. The possible advantage for piscivorous predators of being able to detect and analyze fish-generated wakes is discussed.


Randomized controlled study demonstrating failure of LPV/r monotherapy in HIV: the role of compartment and CD4-nadir.
Long-term side-effects and cost of HIV treatment motivate the development of simplified maintenance. Monotherapy with ritonavir-boosted lopinavir (LPV/r-MT) is the most widely studied strategy. However, efficacy of LPV/r-MT in compartments remains to be shown. Randomized controlled open-label trial comparing LPV/r-MT with continued treatment for 48 weeks in treated patients with fully suppressed viral load. The primary endpoint was treatment failure in the central nervous system [cerebrospinal fluid (CSF)] and/or genital tract. Treatment failure in blood was defined as two consecutive HIV RNA levels more than 400 copies/ml. The trial was prematurely stopped when six patients on monotherapy (none in continued treatment-arm) demonstrated a viral failure in blood. At study termination, 60 patients were included, 29 randomized to monotherapy and 13 additional patients switched from continued treatment to monotherapy after 48 weeks. All failures occurred in patients with a nadir CD4 cell count below 200/microl and within the first 24 weeks of monotherapy. Among failing patients, all five patients with a lumbar puncture had an elevated HIV RNA load in CSF and four of six had neurological symptoms. Viral load was fully resuppressed in all failing patients after resumption of the original combination therapy. No drug resistant virus was found. The only predictor of failure was low nadir CD4 cell count (P < 0.02). Maintenance of HIV therapy with LPV/r alone should not be recommended as a standard strategy; particularly not in patients with a CD4 cell count nadir less than 200/microl. Further studies are warranted to elucidate the role of the central nervous system compartment in monotherapy-failure.


Emerging from depression: the experiential process of Healing Touch explored through grounded theory and case study.
This study aimed to explore and analyse the experiential process of Healing Touch (HT) for people with moderate depression. Grounded theory and case study were chosen as the most appropriate methodology to address the objectives of the research. The grounded theory analysis uncovered the basic psychosocial problem, the stages of the process of emergence from depression and the strategies used within that process. The middle range theory describes the experiential process for people with moderate depression in four stages: belief in practitioner, self and future self, integrating all aspects of self, accessing inner strength and resources and engaging with life. The case study aspect of the research entailed placing the information gathered during the HT sessions on a trajectory for each person thereby honouring each individual's process.


Does a positive neer impingement sign reflect rotator cuff contact with the acromion?
One possible cause of shoulder pain is rotator cuff contact with the superior glenoid (cuff-glenoid contact) with the arm in flexion, as occurs during a Neer impingement sign. It has been assumed that the pain with a Neer impingement sign on physical examination of the shoulder was secondary to the rotator cuff making contact with the anterior and lateral acromion. We determined if the arm position where pain occurs with a Neer impingement sign would correlate with the position where the rotator cuff made contact with the superior glenoid, as determined by arthroscopic evaluation. We prospectively studied 398 consecutive patients with a positive Neer impingement sign during office examination and used a handheld goniometer to measure (in degrees of flexion) the arm position in which impingement pain occurred. During subsequent arthroscopy, the arm was moved into a similar position, and we measured the arm's position in flexion at the point the rotator cuff made contact with the superior glenoid using a handheld goniometer. We compared the degrees of flexion at which pain occurred preoperatively and at which there was cuff-glenoid contact. Among the 398 patients, 302 (76%) had arthroscopically documented cuff-glenoid contact, whereas 96 did not. For the 302 patients with a positive Neer sign preoperatively and with arthroscopically documented cuff-glenoid contact, the average preoperative impingement pain position was 120.1°±26.7°, similar to that of the average intraoperative cuff-glenoid contact position of 120.6°±14.7°. Our data suggest pain associated with a positive Neer sign more often relates to contact of the rotator cuff with the superior glenoid than to contact between the rotator cuff and acromion. Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.


Predicting compulsive Internet use: it's all about sex!
The objective of this research was to assess the predictive power of various Internet applications on the development of compulsive Internet use (CIU). The study has a two-wave longitudinal design with an interval of 1 year. The first measurement contained 447 adult heavy Internet users who used the Internet at least 16 h per week and had Internet access at home for at least 1 year. For the second measurement, all participants were invited again, of whom 229 responded. By means of an online questionnaire, the respondents were asked about the time spent on various Internet applications and CIU. On a cross-sectional basis, gaming and erotica seem the most important Internet applications related to CIU. On a longitudinal basis, spending a lot of time on erotica predicted an increase in CIU 1 year later. The addictive potential of the different applications varies; erotica appears to have the highest potential.


Cement migration after THR. A comparison of charnley elite and exeter femoral stems using RSA.
Studies using roentgen stereophotogrammetric analysis (RSA) have shown that the femoral components of cemented total hip replacements (THR) migrate distally relative to the bone, but it is not clear whether this occurs at the cement-implant or the cement-bone interface or within the cement mantle. Our aim was to determine where this migration occurred, since this has important implications for the way in which implants function and fail. Using RSA we compared for two years the migration of the tip of the stem with that of the cement restrictor for two different designs of THR, the Exeter and Charnley Elite. We have assumed that if the cement restrictor migrates, then at least part of the cement mantle also migrates. Our results have shown that the Exeter migrates distally three times faster than the Charnley Elite and at different interfaces. With the Exeter migration was at the cement-implant interface whereas with the Charnley Elite there was migration at both the cement-bone and the cement-implant interfaces.


Obesity-induced excess of 17-hydroxyprogesterone promotes hyperglycemia through activation of glucocorticoid receptor.
Type 2 diabetes mellitus (T2DM) has become an expanding global public health problem. Although the glucocorticoid receptor (GR) is an important regulator of glucose metabolism, the relationship between circulating glucocorticoids (GCs) and the features of T2DM remains controversial. Here, we show that 17-hydroxyprogesterone (17-OHP), an intermediate steroid in the biosynthetic pathway that converts cholesterol to cortisol, binds to and stimulates the transcriptional activity of GR. Hepatic 17-OHP concentrations are increased in diabetic mice and patients due to aberrantly increased expression of Cyp17A1. Systemic administration of 17-OHP or overexpression of Cyp17A1 in the livers of lean mice promoted the pathogenesis of hyperglycemia and insulin resistance, whereas knockdown of Cyp17A1 abrogated metabolic disorders in obese mice. Therefore, our results identify a Cyp17A1/17-OHP/GR-dependent pathway in the liver that mediates obesity-induced hyperglycemia, suggesting that selectively targeting hepatic Cyp17A1 may provide a therapeutic avenue for treating T2DM.


Negative performance beliefs and negative symptoms in individuals at ultra-high risk of psychosis: a preliminary study.
Negative beliefs regarding task performance have been shown to correlate with negative symptom severity in patients with chronic schizophrenia. We conducted a pilot study to determine whether the association also exists in individuals at ultra-high risk of psychosis. The sample consisted of 38 individuals at ultra-high risk of psychosis and 51 controls. All participants completed the Abbreviated Dysfunctional Attitudes Scale; the ultra-high-risk participants were assessed with the Positive and Negative Syndrome Scale. High-risk participants endorsed negative performance beliefs to a greater extent than controls and these beliefs were associated with greater negative symptom severity, independent of depression and positive symptoms. The findings are consistent with previous results in chronic patients, and suggest that negative performance beliefs may be a promising psychological factor worthy of further attention in individuals at high risk of psychosis. Longitudinal research with more comprehensive assessment is needed to elucidate the potential role of negative performance beliefs in this population.


A murine model of variant late infantile ceroid lipofuscinosis recapitulates behavioral and pathological phenotypes of human disease.
Neuronal ceroid lipofuscinoses (NCLs; also known collectively as Batten Disease) are a family of autosomal recessive lysosomal storage disorders. Mutations in as many as 13 genes give rise to ∼10 variants of NCL, all with overlapping clinical symptomatology including visual impairment, motor and cognitive dysfunction, seizures, and premature death. Mutations in CLN6 result in both a variant late infantile onset neuronal ceroid lipofuscinosis (vLINCL) as well as an adult-onset form of the disease called Type A Kufs. CLN6 is a non-glycosylated membrane protein of unknown function localized to the endoplasmic reticulum (ER). In this study, we perform a detailed characterization of a naturally occurring Cln6 mutant (Cln6(nclf)) mouse line to validate its utility for translational research. We demonstrate that this Cln6(nclf) mutation leads to deficits in motor coordination, vision, memory, and learning. Pathologically, we demonstrate loss of neurons within specific subregions and lamina of the cortex that correlate to behavioral phenotypes. As in other NCL models, this model displays selective loss of GABAergic interneuron sub-populations in the cortex and the hippocampus with profound, early-onset glial activation. Finally, we demonstrate a novel deficit in memory and learning, including a dramatic reduction in dendritic spine density in the cerebral cortex, which suggests a reduction in synaptic strength following disruption in CLN6. Together, these findings highlight the behavioral and pathological similarities between the Cln6(nclf) mouse model and human NCL patients, validating this model as a reliable format for screening potential therapeutics.


Quantifying distortions in two-photon remote focussing microscope images using a volumetric calibration specimen.
Remote focussing microscopy allows sharp, in-focus images to be acquired at high speed from outside of the focal plane of an objective lens without any agitation of the specimen. However, without careful optical alignment, the advantages of remote focussing microscopy could be compromised by the introduction of depth-dependent scaling artifacts. To achieve an ideal alignment in a point-scanning remote focussing microscope, the lateral (XY) scan mirror pair must be imaged onto the back focal plane of both the reference and imaging objectives, in a telecentric arrangement. However, for many commercial objective lenses, it can be difficult to accurately locate the position of the back focal plane. This paper investigates the impact of this limitation on the fidelity of three-dimensional data sets of living cardiac tissue, specifically the introduction of distortions. These distortions limit the accuracy of sarcomere measurements taken directly from raw volumetric data. The origin of the distortion is first identified through simulation of a remote focussing microscope. Using a novel three-dimensional calibration specimen it was then possible to quantify experimentally the size of the distortion as a function of objective misalignment. Finally, by first approximating and then compensating the distortion in imaging data from whole heart rodent studies, the variance of sarcomere length (SL) measurements was reduced by almost 50%.


The Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases.
Many long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration has established a central database on over 1.1 million participants from 104 prospective population-based studies, in which subsets have information on lipid and inflammatory markers, other characteristics, as well as major cardiovascular morbidity and cause-specific mortality. Information on repeat measurements on relevant characteristics has been collected in approximately 340,000 participants to enable estimation of and correction for within-person variability. Re-analysis of individual data will yield up to approximately 69,000 incident fatal or nonfatal first ever major cardiovascular outcomes recorded during about 11.7 million person years at risk. The primary analyses will involve age-specific regression models in people without known baseline cardiovascular disease in relation to fatal or nonfatal first ever coronary heart disease outcomes. This initiative will characterize more precisely and in greater detail than has previously been possible the shape and strength of the age- and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily, with other incident cardiovascular outcomes) under a wide range of circumstances. It will, therefore, help to determine to what extent such associations are independent from possible confounding factors and to what extent such markers (separately and in combination) provide incremental predictive value.


Gamma Glutamyl Transpeptidase, Smokeless Tobacco, Chronic Periodontitis: Exploring the Link.
Oxidative Stress (OS) is implicated in the pathogenesis of many systemic and oral diseases such as periodontal disease. Smokeless tobacco extract produces apoptosis and causes an imbalance between reactive oxygen species and antioxidants, such as Gamma Glutamyl Transpeptidase (GGT). Epidemiological research implied serum GGT within its normal range to be an early sensitive enzyme related to OS. To assess how GGT fares as a biomarker in periodontitis subjects with or without the usage of smokeless tobacco and correlate it with clinical parameters. Ninety subjects were divided into three groups of healthy, chronic periodontitis, and smokeless tobacco users with chronic periodontitis from the dental outpatient department of P.M. Nadagouda Memorial Dental College and Hospital. Serum samples of patients were collected after obtaining consent and analyzed for GGT. Statistical Analysis was performed using ANOVA, and Pearson's correlation coefficient. GGT levels were found to be significantly higher in chronic periodontitis patients compared to smokeless tobacco users with chronic periodontitis and healthy subjects. Conclusion: GGT may be used as a quick, easy and precise marker for measuring OS in patients with chronic periodontitis and smokeless tobacco users.


Antineutrophil cytoplasm autoantibodies against bactericidal/permeability-increasing protein in inflammatory bowel disease.
Bactericidal/permeability-increasing protein (BPI), a constituent of primary neutrophil granules, is a potent natural antibiotic and an antineutrophil cytoplasm antibody (ANCA) antigen in cases of vasculitis in which the target antigen is neither myeloperoxidase (MPO) nor proteinase-3 (PR3). To investigate BPI as a possible target antigen for ANCAs in inflammatory bowel disease. ANCAs were detected by routine immunofluorescence (IIF) and solid phase enzyme linked immunosorbent assay (ELISA) performed for antibodies to the purified neutrophil granule proteins; MPO, PR3, cathepsin-G, lactoferrin, and BPI in serum samples from 88 patients with inflammatory bowel disease (36 with Crohn's disease, 52 with ulcerative colitis). Thirty patients with bacterial enteritis acted as controls. Significantly more patients with ulcerative colitis were ANCA positive by IIF (60%) than patients with Crohn's disease (28%) or infectious enteritis (23%) (p < 0.001). IgG anti-BPI antibodies were present in 29% of patients with ulcerative colitis, 14% of patients with Crohn's disease, and 23% of patients with infectious enteritis, occurring in 44% of those patients with inflammatory bowel disease who were ANCA positive by IIF. Antibodies to other ANCA antigens were rare. The presence of ANCAs was not related to either disease activity or extent; presence of anti-BPI antibodies was significantly related to both a lower serum albumin concentration (p = 0.001) and a higher erythrocyte sedimentation rate (p = 0.02) in patients with ulcerative colitis, and to colonic involvement in patients with Crohn's disease (p = 0.01). BPI is a significant minority target antigen for ANCAs in inflammatory bowel disease that seems related to colonic Crohn's disease and disease activity in ulcerative colitis. Anti-BPI antibodies occur in infectious enteritis.


Systematic evaluation of the teaching qualities of Obstetrics and Gynecology faculty: reliability and validity of the SETQ tools.
The importance of effective clinical teaching for the quality of future patient care is globally understood. Due to recent changes in graduate medical education, new tools are needed to provide faculty with reliable and individualized feedback on their teaching qualities. This study validates two instruments underlying the System for Evaluation of Teaching Qualities (SETQ) aimed at measuring and improving the teaching qualities of obstetrics and gynecology faculty. This cross-sectional multi-center questionnaire study was set in seven general teaching hospitals and two academic medical centers in the Netherlands. Seventy-seven residents and 114 faculty were invited to complete the SETQ instruments in the duration of one month from September 2008 to September 2009. To assess reliability and validity of the instruments, we used exploratory factor analysis, inter-item correlation, reliability coefficient alpha and inter-scale correlations. We also compared composite scales from factor analysis to global ratings. Finally, the number of residents' evaluations needed per faculty for reliable assessments was calculated. A total of 613 evaluations were completed by 66 residents (85.7% response rate). 99 faculty (86.8% response rate) participated in self-evaluation. Factor analysis yielded five scales with high reliability (Cronbach's alpha for residents' and faculty): learning climate (0.86 and 0.75), professional attitude (0.89 and 0.81), communication of learning goals (0.89 and 0.82), evaluation of residents (0.87 and 0.79) and feedback (0.87 and 0.86). Item-total, inter-scale and scale-global rating correlation coefficients were significant (P<0.01). Four to six residents' evaluations are needed per faculty (reliability coefficient 0.60-0.80). Both SETQ instruments were found reliable and valid for evaluating teaching qualities of obstetrics and gynecology faculty. Future research should examine improvement of teaching qualities when using SETQ.


Human T-cell leukemia virus type 1 Tax protein binds to assembled nuclear proteasomes and enhances their proteolytic activity.
The human T-cell leukemia virus type 1 (HTLV-1) Tax protein activates the HTLV-1 long terminal repeat and key regulatory proteins involved in inflammation, activation, and proliferation and may induce cell transformation. Tax is also the immunodominant target antigen for cytotoxic T cells in HTLV-1 infection. We found that Tax bound to assembled nuclear proteasomes, but Tax could not be detected in the cytoplasm. Confocal microscopy revealed a partial colocalization of Tax with nuclear proteasomes. As Tax translocated into the nucleus very quickly after synthesis, this process probably takes place prior to and independent of proteasome association. Tax mutants revealed that both the Tax N and C termini play a role in proteasome binding. We also found that proteasomes from Tax-transfected cells had enhanced proteolytic activity on prototypic peptide substrates. This effect was not due to the induction of the LMP2 and LMP7 proteasome subunits. Furthermore, Tax appeared to be a long-lived protein, with a half-life of around 15 h. These data suggest that the association of Tax with the proteasome and the enhanced proteolytic activity do not target Tax for rapid degradation and may not determine its immunodominance.


Ultrasound-based transient elastography for the detection of hepatic fibrosis: systematic review and meta-analysis.
Ultrasound-based transient elastography is a promising noninvasive alternative to liver biopsy for detecting hepatic fibrosis. However, its overall test performance in various settings remains unknown. The aims of this study were to perform a systematic review and meta-analysis of diagnostic accuracy studies comparing ultrasound-based transient elastography with liver biopsy for hepatic fibrosis. Electronic and manual bibliographic searches to identify potential studies were performed. Selection of studies was based on reported accuracy of ultrasound-based transient elastography compared with liver biopsy. Data extraction was performed independently by 2 reviewers. Meta-analysis combined the sensitivities, specificities, and likelihood ratios of individual studies. Extent and reasons for heterogeneity were assessed. Nine studies in full publication were identified. For patients with stage IV fibrosis (cirrhosis), the pooled estimates for sensitivity were 87% (95% confidence interval [CI], 84%-90%), specificity 91% (95% CI, 89%-92%), positive likelihood ratio 11.7 (95% CI, 7.9-17.1), and negative likelihood ratio 0.14 (95% CI, 0.10-0.20). Among 7 investigations reporting patients with stages II-IV fibrosis, the pooled estimates for sensitivity were 70% (95% CI, 67%-73%), specificity 84% (95% CI, 80%-88%), positive likelihood ratio 4.2 (95% CI, 2.4-7.2), and negative likelihood ratio 0.31 (95% CI, 0.23-0.43). Diagnostic threshold (or cut-off value) bias was identified as an important cause of heterogeneity for pooled results in both patient groups. Ultrasound-based transient elastography appears to be a clinically useful test for detecting cirrhosis.


A randomized, controlled pilot study of MDMA (± 3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD).
Psychiatrists and psychotherapists in the US (1970s to 1985) and Switzerland (1988-1993) used MDMA legally as a prescription drug, to enhance the effectiveness of psychotherapy. Early reports suggest that it is useful in treating trauma-related disorders. Recently, the first completed pilot study of MDMA-assisted psychotherapy for PTSD yielded encouraging results. Designed to test the safety and efficacy of MDMA-assisted psychotherapy in patients with treatment-resistant PTSD; our randomized, double-blind, active-placebo controlled trial enrolled 12 patients for treatment with either low-dose (25 mg, plus 12.5 mg supplemental dose) or full-dose MDMA (125 mg, plus 62.5 mg supplemental dose). MDMA was administered during three experimental sessions, interspersed with weekly non-drug-based psychotherapy sessions. Outcome measures used were the Clinician-Administered PTSD Scale (CAPS) and the Posttraumatic Diagnostic Scale (PDS). Patients were assessed at baseline, three weeks after the second and third MDMA session (end of treatment), and at the 2-month and 1-year follow-ups. We found that MDMA-assisted psychotherapy can be safely administered in a clinical setting. No drug-related serious adverse events occurred. We did not see statistically significant reductions in CAPS scores (p = 0.066), although there was clinically and statistically significant self-reported (PDS) improvement (p = 0.014). CAPS scores improved further at the 1-year follow-up. In addition, three MDMA sessions were more effective than two (p = 0.016).


Nuclear fuel in a reactor accident.
Nuclear accidents that lead to melting of a reactor core create heterogeneous materials containing hundreds of radionuclides, many with short half-lives. The long-lived fission products and transuranium elements within damaged fuel remain a concern for millennia. Currently, accurate fundamental models for the prediction of release rates of radionuclides from fuel, especially in contact with water, after an accident remain limited. Relatively little is known about fuel corrosion and radionuclide release under the extreme chemical, radiation, and thermal conditions during and subsequent to a nuclear accident. We review the current understanding of nuclear fuel interactions with the environment, including studies over the relatively narrow range of geochemical, hydrological, and radiation environments relevant to geological repository performance, and discuss priorities for research needed to develop future predictive models.


Multi-centre European experience with intragastric balloon in overweight populations: 13 years of experience.
The request to lose weight is expanding not only in obese and morbidly obese patients but also in overweight patients affected by co-morbidities as diabetes and hypertension and who do not tolerate diet regimen or lifestyle changes. The aim of this study is a multicenter evaluation of outcomes of intragastric balloon in overweight patients. Patients (BMI 27-30 kg/m2) treated with a BioEnterics Intragastric Balloon (BIB) between 1996 and 2010 were extracted from the database of the participating centres in Rome (Italy), Liège (Belgium) and Madrid (Spain). Primary endpoints were the efficacy and safety at 6 and 42 months from balloon positioning. Secondary endpoints included resolution of co-morbidities. A total of 261 patients were included in this study. The most common indication for balloon placement was a psychological disorder (54%). Mean body mass index (BMI) fell from 28.6 ± 0.4 at baseline to 25.4 ± 2.6 kg/m2 at 6 months and to 27.0 ± 3.1 kg/m2 at 3 years from BIB removal. The mean %EWL was 55.6% at 6 months and 29.1% at 3 years. Forty-seven patients (18%) had complications associated with placement of the intragastric balloon (leak = 28, intolerance = 14, duodenal ulcer = 2, gastritis = 1, oesophagitis = 1, duodenal polyps = 1). The rate of patients with hypertension decreased from 29% at baseline to 16% at 3 years. Diabetes decreased from 15 to 10%, dyslipidaemia decreased from 20 to 18%, hypercholesterolaemia decreased from 32 to 21% and osteoarthropathy decreased from 25 to 13%. The intragastric balloon is safe and effective in overweight patients, helping to reduce progression to obesity and decreasing the prevalence of a number of important co-morbidities.


First plasma wave observations at neptune.
The Voyager 2 plasma wave instrument detected many familiar plasma waves during the encounter with Neptune, including electron plasma oscillations in the solar wind upstream of the bow shock, electrostatic turbulence at the bow shock, and chorus, hiss, electron cyclotron waves, and upper hybrid resonance waves in the inner magnetosphere. Low-frequency radio emissions, believed to be generated by mode conversion from the upper hybrid resonance emissions, were also observed propagating outward in a disklike beam along the magnetic equatorial plane. At the two ring plane crossings many small micrometer-sized dust particles were detected striking the spacecraft. The maximum impact rates were about 280 impacts per second at the inbound ring plane crossing, and about 110 impacts per second at the outbound ring plane crossing. Most of the particles are concentrated in a dense disk, about 1000 kilometers thick, centered on the equatorial plane. However, a broader, more tenuous distribution also extends many tens of thousands of kilometers from the equatorial plane, including over the northern polar region.


Pure Intrathoracic Scapular Dislocation.
Scapular dislocation, also known as locked scapula or scapulothoracic dislocation, is a rare entity that can be identified as extrathoracic or intrathoracic dislocation, depending on the penetration of the scapula into the thoracic cavity. The 3 reported cases of intrathoracic scapular dislocations in the literature are associated with a preexisting condition, such as sternoclavicular separation, prior rib fracture, thoracotomy for a lung transplant procedure, or surgical resection of superior ribs during breast or pulmonary tumor excisions. There are also 3 published cases of intrathoracic scapular impaction, involving comminuted scapular fractures with intrathoracic impaction of the inferior fragment through intercostal space. We report an intrathoracic scapular dislocation that was not associated with fracture of the scapula or predisposing factors. To our knowledge, this is the first case of pure intrathoracic dislocation.


Incidence of fractures in a geographically defined population.
The aim was to describe the population based age and sex specific incidence of fractures at different sites in a large English health district. Recording of fractures was accomplished by a specially constructed outpatient index and by record linkage to hospital inpatient information, for the three years surrounding the 1981 census. The fracture index was held by the Department of Community Health in Leicester using data from the fracture clinic at the central large district general hospital, supplemented by hospital inpatient data from Trent Region and the two adjoining regions. The denominator population was the Leicestershire Health Authority resident population. In the three years, 12,711 fractures amongst males and 10,565 amongst females were recorded. The overall estimated annual incidence of fractures was 100 per 10,000 population for males and 81 per 10,000 population for females. Below the age of 55 years all fractures showed a higher incidence amongst males but amongst the over 55s, there was a consistent fall in the male:female incidence ratio with some sites showing a striking female preponderance. The results also show an apparent age specific temporal increase in incidence at certain fracture sites compared with earlier British data, but fracture incidence figures still suggest lower rates in this country than in North America and some Scandinavian countries. These findings provide population based incidence data on a major public health problem and are consistent with the major determinants of osteoporosis and increase in falls in postmenopausal women. The temporal and geographical variation in fracture incidence remain to be explained.


What influences whether parents recognise COVID-19 symptoms, request a test and self-isolate: A qualitative study.
Using test, trace and isolate systems can help reduce the spread of COVID-19. Parents have the additional responsibility of using these systems for themselves and acting on behalf of their children to help control COVID-19. We explored factors associated with the use of England's NHS Test and Trace service among parents of school-aged children. One-to-one telephone interviews with parents (n = 18) of school-aged (4 to 18 years) children living in England between 30 November to 11 December 2020. Data were explored using thematic analysis. Three themes and eight sub-themes emerged. In terms of recognising symptoms of COVID-19, parents needed prompting before recalling the main symptoms described by the NHS. Parents suggested several factors relating to the nature of the symptom(s) and contextual information that might lead to or prevent them from seeking a test. Although parents supported symptomatic testing and described trusting official sources of information (e.g., Government and NHS websites). However, some concerns were raised regarding the accuracy of test results, safety at testing centres and logistics of testing but none of the concerns appeared to prevent engagement with testing. Parents perceived adherence to testing and self-isolation as pro-social behaviour, although family resources and circumstances impacted their ability to adhere fully. Our study identified several barriers to parents using NHS Test and Trace as needed. Information about the eligibility of testing (main symptoms of COVID-19 and the age of eligibility) needs to be more precise and resources provided to enable families to adhere to self-isolation if the efficiency of test, trace and isolate systems is to be optimised.


Dracorhodin perchlorate induced human breast cancer MCF-7 apoptosis through mitochondrial pathways.
Dracorhodin perchlorate (DP) was a synthetic analogue of the antimicrobial anthocyanin red pigment dracorhodin. It was reported that DP could induce apoptosis in human prostate cancer, human gastric tumor cells and human melanoma, but the cytotoxic effect of DP on human breast cancer was not investigated. This study would investigate whether DP was a candidate chemical of anti-human breast cancer. The MTT assay reflected the number of viable cells through measuring the activity of cellular enzymes. Phase contrast microscopy visualized cell morphology. Fluorescence microscopy detected nuclear fragmentation after Hoechst 33258 staining. Flowcytometric analysis of Annexin V-PI staining and Rodamine 123 staining was used to detect cell apoptosis and mitochondrial membrane potential (MMP). Real time PCR detected mRNA level. Western blot examined protein expression. DP dose and time-dependently inhibited the growth of MCF-7 cells. DP inhibited MCF-7 cell growth through apoptosis. DP regulated the expression of Bcl-2 and Bax, which were mitochondrial pathway proteins, to decrease MMP, and DP promoted the transcription of Bax and inhibited Bcl-2. Apoptosis-inducing factor (AIF) and cytochrome c which localized in mitochondrial in physiological condition were released into cytoplasm when MMP was decreased. DP activated caspase-9, which was the downstream of mitochondrial pathway. Therefore DP decreased MMP to release AIF and cytochrome c into cytoplasm, further activating caspase 9, lastly led to apoptosis. Therefore DP was a candidate for anti-breast cancer, DP induced apoptosis of MCF-7 through mitochondrial pathway.


The Inhibition of microRNA-128 on IGF-1-Activating mTOR Signaling Involves in Temozolomide-Induced Glioma Cell Apoptotic Death.
Temozolomide (TMZ), an alkylating agent of the imidazotetrazine series, is a first-line chemotherapeutic drug used in the clinical therapy of glioblastoma multiforme, the most common and high-grade primary glioma in adults. Micro (mi)RNAs, which are small noncoding RNAs, post-transcriptionally regulate gene expressions and are involved in gliomagenesis. However, no studies have reported relationships between TMZ and miRNA gene regulation. We investigated TMZ-mediated miRNA profiles and its molecular mechanisms underlying the induction of glioma cell death. By performing miRNA microarray and bioinformatics analyses, we observed that expression of 248 miRNAs was altered, including five significantly upregulated and 17 significantly downregulated miRNAs, in TMZ-treated U87MG cells. miR-128 expression levels were lower in different glioma cells and strongly associated with poor survival. TMZ treatment significantly upregulated miR-128 expression. TMZ significantly enhanced miR-128-1 promoter activity and transcriptionally regulated miR-128 levels through c-Jun N-terminal kinase 2/c-Jun pathways. The overexpression and knockdown of miR-128 expression significantly affected TMZ-mediated cell viability and apoptosis-related protein expression. Furthermore, the overexpression of miR-128 alone enhanced apoptotic death of glioma cells through caspase-3/9 activation, poly(ADP ribose) polymerase degradation, reactive oxygen species generation, mitochondrial membrane potential loss, and non-protective autophagy formation. Finally, we identified that key members in mammalian target of rapamycin (mTOR) signaling including mTOR, rapamycin-insensitive companion of mTOR, insulin-like growth factor 1, and PIK3R1, but not PDK1, were direct target genes of miR-128. TMZ inhibited mTOR signaling through miR-128 regulation. These results indicate that miR-128-inhibited mTOR signaling is involved in TMZ-mediated cytotoxicity. Our findings may provide a better understanding of cytotoxic mechanisms of TMZ involved in glioblastoma development.


The diagnosis and management of mild cognitive impairment: a clinical review.
Cognitive decline is a common and feared aspect of aging. Mild cognitive impairment (MCI) is defined as the symptomatic predementia stage on the continuum of cognitive decline, characterized by objective impairment in cognition that is not severe enough to require help with usual activities of daily living. To present evidence on the diagnosis, treatment, and prognosis of MCI and to provide physicians with an evidence-based framework for caring for older patients with MCI and their caregivers. We searched PubMed for English-language articles in peer-reviewed journals and the Cochrane Library database from inception through July 2014. Relevant references from retrieved articles were also evaluated. The prevalence of MCI in adults aged 65 years and older is 10% to 20%; risk increases with age and men appear to be at higher risk than women. In older patients with MCI, clinicians should consider depression, polypharmacy, and uncontrolled cardiovascular risk factors, all of which may increase risk for cognitive impairment and other negative outcomes. Currently, no medications have proven effective for MCI; treatments and interventions should be aimed at reducing cardiovascular risk factors and prevention of stroke. Aerobic exercise, mental activity, and social engagement may help decrease risk of further cognitive decline. Although patients with MCI are at greater risk for developing dementia compared with the general population, there is currently substantial variation in risk estimates (from <5% to 20% annual conversion rates), depending on the population studied. Current research targets improving early detection and treatment of MCI, particularly in patients at high risk for progression to dementia. Cognitive decline and MCI have important implications for patients and their families and will require that primary care clinicians be skilled in identifying and managing this common disorder as the number of older adults increases in coming decades. Current evidence supports aerobic exercise, mental activity, and cardiovascular risk factor control in patients with MCI.


Identification of G protein-coupled receptor signaling pathway proteins in marine diatoms using comparative genomics.
The G protein-coupled receptor (GPCR) signaling pathway plays an essential role in signal transmission and response to external stimuli in mammalian cells. Protein components of this pathway have been characterized in plants and simpler eukaryotes such as yeast, but their presence and role in unicellular photosynthetic eukaryotes have not been determined. We use a comparative genomics approach using whole genome sequences and gene expression libraries of four diatoms (Pseudo-nitzschia multiseries, Thalassiosira pseudonana, Phaeodactylum tricornutum and Fragilariopsis cylindrus) to search for evidence of GPCR signaling pathway proteins that share sequence conservation to known GPCR pathway proteins. The majority of the core components of GPCR signaling were well conserved in all four diatoms, with protein sequence similarity to GPCRs, human G protein α- and β-subunits and downstream effectors. There was evidence for the Gγ-subunit and thus a full heterotrimeric G protein only in T. pseudonana. Phylogenetic analysis of putative diatom GPCRs indicated similarity but deep divergence to the class C GPCRs, with branches basal to the GABAB receptor subfamily. The extracellular and intracellular regions of these putative diatom GPCR sequences exhibited large variation in sequence length, and seven of these sequences contained the necessary ligand binding domain for class C GPCR activation. Transcriptional data indicated that a number of the putative GPCR sequences are expressed in diatoms under various stress conditions in culture, and that many of the GPCR-activated signaling proteins, including the G protein, are also expressed. The presence of sequences in all four diatoms that code for the proteins required for a functional mammalian GPCR pathway highlights the highly conserved nature of this pathway and suggests a complex signaling machinery related to environmental perception and response in these unicellular organisms. The lack of evidence for some GPCR pathway proteins in one or more of the diatoms, such as the Gγ-subunit, may be due to differences in genome completeness and genome coverage for the four diatoms. The high divergence of putative diatom GPCR sequences to known class C GPCRs suggests these sequences may represent another, potentially ancestral, subfamily of class C GPCRs.


Racial differences in the impact of comorbidities on survival among elderly men with prostate cancer.
This study investigates differences in the effects of comorbidities on survival in Medicare beneficiaries with prostate cancer. Medicare data were used to assemble a cohort of 65- to 76-year-old Black (n = 6,402) and White (n = 47,458) men with incident localized prostate cancer in 1999 who survived >or=1 year postdiagnosis. Comorbidities were more prevalent among Blacks than among Whites. For both races, greater comorbidity was associated with decreasing survival rates; however, the effect among Blacks was smaller than in Whites. After adjusting for age, socioeconomic status, and community characteristics, the association between increasing comorbidities and survival remained weaker for Blacks than for Whites, and racial disparity in survival decreased with increasing number of comorbidities. Differential effects of comorbidities on survival were also evident when examining different classes of comorbid conditions. Adjusting for treatment had little impact on these results, despite variation in the racial difference in receipt of prostatectomy with differing comorbidity levels.


JAK2V617F mutation screening as part of the hypercoagulable work-up in the absence of splanchnic venous thrombosis or overt myeloproliferative neoplasm: assessment of value in a series of 664 consecutive patients.
The JAK2V617F mutation is recurrent in polycythemia vera and essential thrombocythemia, which are myeloproliferative neoplasms (MPNs) frequently associated with arterial and/or venous thromboembolism. More recently, the JAK2V617F mutation has been identified as a surrogate marker for subclinical or "occult" clonal myeloproliferation in patients with splanchnic venous thrombosis. However, information is limited regarding JAK2V617F-associated thrombosis outside the splanchnic district in patients without overt MPN. To address this issue, we retrospectively studied a consecutive series of 664 such patients who experienced thrombotic events characteristic of an MPN (500 with venous thromboembolism, 136 with stroke, and 28 with myocardial infarction at a young age). The JAK2V617F mutation was detected in only 6 (<1.0%) patients (5 with recurrent venous thromboembolism and 1 with stroke), and the mutant allele burden was low in all instances (range, 2.2%-7.5%). None of these 6 patients developed either overt MPN or recurrent thrombosis after a median follow-up of 40 months. We conclude that the prevalence of the JAK2V617F mutation in patients with nonsplanchnic venous thrombosis in the absence of MPN is too low to warrant mutation screening as part of the hypercoagulable work-up. Our study also suggests that the natural history of a JAK2V617F-positive "occult" MPN might be different from that of a typical MPN.


Ultrafast intersystem crossing for nitrophenols: ab initio nonadiabatic molecular dynamics simulation.
Ultrafast intersystem crossing mechanisms for two p- and m-nitrophenol groups (PNP and MNP) have been investigated using ab initio nonadiabatic molecular dynamics simulations at the 6SA-CASSCF level of theory. Trajectory surface hopping simulation has been performed within an intersystem crossing network constructed from two low-lying singlets (S0 and S1) and two low-lying triplets (T1 and T2). It is found that the dominant relaxation S1 → T2 pathway accounts for 65.4% (85.0%) of the quantum yield with a time constant of 13.4 fs (22 fs) and the S1 → T2 → S0 pathway accounts for 33.1% (13.5%) with a time constant of 275 fs (375 fs) for PNP (MNP). In comparison with the previously studied excited-state proton transfer process for ONP, the dominant relaxation S1 → T2 → T1 pathway accounts for 49.3% with a time constant of 40 fs and the S1 → T2 → T1 → S0 pathway accounts for 47.5% with a time constant of 300 fs. The relaxation mechanisms and electronic structures of the intersystem crossings are in close relation with the relative motion between the torsion motions of the nitro-group and the hydroxyl group. The present simulation provides new physical insight for understanding ultrafast photochemical intersystem crossing dynamics.


Effects of modafinil on working memory processes in humans.
Modafinil is a well-tolerated psychostimulant drug with low addictive potential that is used to treat patients with narcolepsy or attention deficit disorders and to enhance vigilance in sleep-deprived military personal. So far, understanding of the cognitive enhancing effects of modafinil and the relevant neurobiological mechanisms are incomplete. The aim of this study was to investigate the effects of modafinil on working memory processes in humans and how they are related to noradrenergic stimulation of the prefrontal cortex. Sixteen healthy volunteers (aged 20-29 years) received either modafinil 200 mg or placebo using a double blind crossover design. Two computerized working memory tasks were administered, a numeric manipulation task that requires short-term maintenance of digit-sequences and different degrees of manipulation as well as delayed matching task that assesses maintenance of visuo-spatial information over varying delay lengths. The battery was supplemented by standardized paper pencil tasks of attentional functions. Modafinil significantly reduced error rates in the long delay condition of the visuo-spatial task and in the manipulation conditions, but not in the maintenance condition of the numeric task. Analyses of reaction times showed no speed-accuracy trade-off. Attentional control tasks (letter cancellation, trail-making, catch trials) were not affected by modafinil. In healthy volunteers without sleep deprivation modafinil has subtle stimulating effects on maintenance and manipulation processes in relatively difficult and monotonous working memory tasks, especially in lower performing subjects. Overlapping attentional and working memory processes have to be considered when studying the noradrenergic modulation of the prefrontal cortex.


AAV-encoded CaV2.2 peptide aptamer CBD3A6K for primary sensory neuron-targeted treatment of established neuropathic pain.
Transmission of pain signals from primary sensory neurons to secondary neurons of the central nervous system is critically dependent on presynaptic voltage-gated calcium channels. Calcium channel-binding domain 3 (CBD3), derived from the collapsin response mediator protein 2 (CRMP2), is a peptide aptamer that is effective in blocking N-type voltage-gated calcium channel (CaV2.2) activity. We previously reported that recombinant adeno-associated virus (AAV)-mediated restricted expression of CBD3 affixed to enhanced green fluorescent protein (EGFP) in primary sensory neurons prevents the development of cutaneous mechanical hypersensitivity in a rat neuropathic pain model. In this study, we tested whether this strategy is effective in treating established pain. We constructed AAV6-EGFP-CBD3A6K (AAV6-CBD3A6K) expressing a fluorescent CBD3A6K (replacing A to K at position 6 of CBD3 peptide), which is an optimized variant of the parental CBD3 peptide that is a more potent blocker of CaV2.2. Delivery of AAV6-CBD3A6K into lumbar (L) 4 and 5 dorsal root ganglia (DRG) of rats 2 weeks following tibial nerve injury (TNI) induced transgene expression in neurons of these DRG and their axonal projections, accompanied by attenuation of pain behavior. We additionally observed that the increased CaV2.2α1b immunoreactivity in the ipsilateral spinal cord dorsal horn and DRG following TNI was significantly normalized by AAV6-CBD3A6K treatment. Finally, the increased neuronal activity in the ipsilateral dorsal horn that developed after TNI was reduced by AAV6-CBD3A6K treatment. Collectively, these results indicate that DRG-restricted AAV6 delivery of CBD3A6K is an effective analgesic molecular strategy for the treatment of established neuropathic pain.


A randomised phase II trial of three dosing regimens of radium-223 in patients with bone metastatic castration-resistant prostate cancer.
Radium-223 prolongs overall survival and delays symptomatic skeletal events (SSEs) in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. The approved radium-223 regimen is 55 kBq/kg every 4 weeks (q4w) for six cycles (standard dose). We investigated different radium-223 regimens in patients with mCRPC. Patients were randomised 1 : 1 : 1 to radium-223 standard-dose, high-dose (88 kBq/kg q4w for six cycles) or extended-schedule arms (55 kBq/kg q4w for 12 cycles). The primary end point, SSE-free survival (SSE-FS), was compared in patients treated with a high- versus standard-dose regimen, or with a standard dose in an extended (>6 to 12 cycles) versus standard schedule (six cycles). A total of 391 patients were randomised; baseline characteristics were balanced between arms. On-treatment SSEs developed in 37/130 (28%), 42/130 (32%) and 48/131 (37%) patients in the standard-dose, high-dose and extended-schedule arms, respectively. There was no statistically significant difference in SSE-FS in the high- versus standard-dose arms [median 12.9 months versus 12.3 months; hazard ratio (HR) 1.06, 80% confidence interval (CI) 0.88-1.27, P = 0.70], and in the extended- versus standard-schedule arms (median 10.8 months versus 13.2 months; HR 1.26, 80% CI 0.94-1.69, P = 0.31). Overall survival in the three treatment arms was similar. As many as 370 (95%) patients received treatment (median of six cycles) in each arm. Grade ≥3 treatment-emergent adverse events (TEAEs) affected 34% of patients in the standard-dose, 48% in the high-dose and 53% in the extended-schedule arm, causing permanent discontinuation in 9%, 16% and 17% of patients, respectively. Radium-223 high-dose or extended-schedule regimens resulted in no change in SSE-FS or other efficacy end points and were associated with more grade ≥3 TEAEs. The extended-schedule regimen (beyond six doses) could not be implemented in a large proportion of patients due to disease progression. Therefore, the standard-dose schedule remains one of the standard therapies for patients with symptomatic mCRPC. ClinicalTrials.govNCT02023697.


Reference lines in dynamic magnetic resonance imaging of the pelvic floor.
: To compare the variability in two commonly used reference lines in pelvic magnetic resonance imaging (MRI), the pubococcygeal line (PCL) and the sacrococcygeal to inferior pubis (SCIPP) line, with respect to their distance from pelvic floor points of interest. : We obtained pelvic MR images of 20 asymptomatic nulliparous women who are part of an ongoing pelvic floor nerve injury postpartum study. The subjects underwent a high-resolution two-dimensional, T2-weighted sagittal pelvic MRI in the supine position using a GE Signa scanner with a body phased-array coil. We also obtained dynamic T2-weighted sagittal MR images in supine position during Kegel and Valsalva maneuvers. Using the midsagittal image, we measured the length of two reference lines: the PCL and the more cephalad SCIPP line. From each line, we then measured the perpendicular distance to the bladder neck and to the posterior margin of the anorectal angle (M-line). We compared the mean values of all measurements between the two reference lines with paired Student t tests. : The SCIPP line (mean [SD], 11.60 [0.91] cm) is longer than the PCL (mean [SD], 10.54 [0.85] cm) at rest (P < 0.001). There is no significant change in length from resting to Kegel maneuver or from resting to Valsalva maneuver in either reference line. Only the resting to Valsalva maneuver for the M-line was significantly different between the 2 reference lines (P = 0.02). The resting to Kegel for the perpendicular distance to the bladder neck and the M-line was not significantly different between the two lines. : Both reference lines remain stable during pelvic floor maneuvers.


Analytical study of diffraction effects in extremely large segmented telescopes.
We present an analysis of the diffraction effects from a segmented aperture with a very large number of segments-prototype of the next generation of extremely large telescopes. This analysis is based on the point-spread-function analytical calculation for Keck-type hexagonal segmentation geometry. We concentrate on the effects that lead to the appearance of speckles and/or a regular pattern of diffraction peaks. These effects are related to random piston and tip-tilt errors on each segment, gaps between segments, and segment edge distortion. We deliver formulas and the typical numerical values for the Strehl ratio, the relative intensity of higher-order diffraction peaks, and the averaged intensity of speckles associated with each particular case of segmentation error.


Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C.
It is unclear whether the current antiviral treatment for chronic hepatitis C virus (HCV) infection results in complete elimination of the virus, or whether small quantities of virus persist. Our study group comprised 17 patients with chronic HCV who had sustained virological response (SVR) after interferon/ribavirin treatment. Serum and peripheral blood mononudear cells were collected 2 to 3 times at 3- to 6-month intervals starting 40 to 109 months (mean, 64.2 +/- 18.5 months) after the end of therapy. In addition, lymphocyte and macrophage cultures were established at each point. In 11 patients, frozen liver tissue samples were available from follow-up biopsies performed 41 to 98 months (mean, 63.6 +/- 16.7 months) after therapy. Presence of HCV RNA was determined by sensitive reverse-transcriptase polymerase chain reaction, and concentration of positive and negative strands was determined by a novel quantitative real-time reverse transcriptase polymerase chain reaction. Only 2 of 17 patients remained consistently HCV RNA negative in all analyzed compartments. HCV RNA was detected in macrophages from 11 patients (65%) and in lymphocytes from 7 patients (41%). Viral sequences were also detected in 3 of 11 livers and in sera from 4 patients. Viral replicative forms were found in lymphocytes from 2 and in macrophages from 4 patients. In conclusion, our results suggest that in patients with SVR after therapy, small quantities of HCV RNA may persist in liver or macrophages and lymphocytes for up to 9 years. This continuous viral presence could result in persistence of humoral and cellular immunity for many years after therapy and could present a potential risk for infection reactivation.


Violence-related injury in emergency departments in Brazil.
This article describes the characteristics of violence-related injury (VRI) cases presenting at emergency departments (EDs) in Brazil and compares circumstances for assault-related and self-inflicted cases. The study is cross-sectional. The data describe cases seen in September 2006 in 62 EDs, representing all 26 states and the Federal District. A total of 4 835 case records were analyzed. Basic statistical tabulations were complemented by logistic regression analysis to assess potential associations between type of violence (assault or self-harm) and multiple factors. Males comprised 72.8% of cases while those aged 20 to 29 comprised 35.4%. Alcohol use was reported or suspected in 42.7% of cases, more commonly among males. Assault victims comprised 91.4% of cases versus self-inflicted injuries, which accounted for 8.6%. Three-fourths of the assault victims were male, while over half of the self-inflicted injury victims were female. The leading mechanism for assaults was physical force/blunt objects (46.2%), whereas poisoning was the predominant mechanism for self-inflicted injuries (71.4%). Younger females were significantly more likely to have been victims of self-inflicted injuries than younger males, while younger males were more likely to have been victims of assault; this finding is more pronounced in cases where alcohol use was reported. Self-inflicted injuries were significantly more likely to occur in residences, while assaults were more likely to occur away from home. These results can improve understanding of the scope and characteristics of VRIs in Brazil (and thus contribute to national injury prevention efforts), and help identify areas for future research.


Effect of a Self-management Support Intervention on Asthma Outcomes in Older Adults: The SAMBA Study Randomized Clinical Trial.
Older adults with asthma have worse control and outcomes than younger adults. Interventions to address suboptimal self-management among older adults with asthma are typically not tailored to the specific needs of the patient. To test the effect of a comprehensive, patient-tailored asthma self-management support intervention for older adults on clinical and self-management outcomes. Three-arm randomized clinical trial conducted between February 2014 and December 2017 at primary care practices and personal residences in New York City. Adults 60 years and older with persistent, uncontrolled asthma were identified from electronic medical records at an academic medical center and a federally qualified health center. Of 1349 patients assessed for eligibility, 406 met eligibility criteria, consented to participate, and were randomized to 1 of 3 groups: home-based intervention, clinic-based intervention, or control (usual care). A total of 391 patients received the allocated treatment. Screening for psychosocial, physical, cognitive, and environmental barriers to asthma control and self-management with actions to address identified barriers. The intervention was delivered in the home or primary care practices by asthma care coaches. Primary outcomes were the Asthma Control Test, Mini Asthma Quality of Life Questionnaire, Medication Adherence Rating Scale, metered dose inhaler technique, and emergency department visits for asthma care. Primary analyses compared intervention (home or clinic based) with usual care. Of the 391 patients who received treatment, 58 (15.1%) were men, and the mean (SD) age was 67.8 (7.4) years. After accounting for baseline scores, scores on the asthma control test were better in the intervention groups vs the control group (difference-in-differences at 3 months, 1.2; 95% CI, 0.2-2.2; P = .02; 6 months, 1.0; 95% CI, 0.0-2.1; P = .049; 12 months, 0.6; 95% CI, -0.5 to 1.8; P = .28; and overall, χ2 = 13.4, with 4 degrees of freedom; P = .01). Emergency department visits were lower at 12 months for the intervention groups vs the control group (16 [6.2%] vs 17 [12.7%]; P = .03; adjusted odds ratio, 0.8; 95% CI, 0.6-0.99; P = .03). Statistically significant improvements were observed for the intervention vs control patients in quality of life (overall effect: χ2 = 10.5, with 4 degrees of freedom; P = .01), medication adherence (overall effect: χ2 = 9.5, with 4 degrees of freedom; P = .049), and inhaler technique (metered-dose inhaler technique, correctly completed steps at 12 months, median [range]: 75% [0%-100%] vs 58% [0%-100%]). No significant differences in outcomes were observed between patients receiving the intervention in home vs practice settings. An intervention directed by patients' needs and barriers improved asthma outcomes and self-management behaviors among older adults. ClinicalTrials.gov identifier: NCT02316223.


Past, present & future scenario of thalassaemic care & control in India.
The first case of thalassaemia, described in a non-Mediterranean person, was from India. Subsequently, cases of thalassaemia were documented in all parts of India. Centres for care of thalassaemics were started in the mid-1970s in Mumbai and Delhi, and then in other cities. The parent's associations, with the help of International Thalassemia Federation, greatly helped in improving the care of thalassaemics. Obtaining blood for transfusion was difficult, but the Indian Red Cross Society and the parent's associations played a crucial role in arranging voluntary donations of blood. Chelation with deferoxamine was used sparingly due to the high cost. The Indian physicians conducted trials with deferiprone, and the drug was first approved and marketed in India. Deferasirox is also now being administered. Studies of physical and pubertal growth documented significant retardation, suggesting that generally patients receive inadequate chelation and transfusions. Bone marrow transplantation is available at a number of centres, and cord blood stem cell storage facilities have been established. Information about mutations in different parts of India is available, and ThalInd, an Indian database has been set up. There is a need to set up preimplantation genetic diagnosis and non-invasive prenatal diagnosis. It is argued that too much emphasis should not be placed on premarital screening. The focus should be on screening pregnant women to yield immediate results in reducing the burden of this disorder. Care of thalassaemia has been included in the 12 th 5-year Plan of the Government of India. Many States now provide blood transfusions and chelation free of cost. Although inadequacies in care of thalassaemia remain, but the outlook is bright, and the stage is set for initiating a control programme in the high risk States.


A Review on Various Uses of N-Acetyl Cysteine.
N-acetyl cysteine (NAC), as a nutritional supplement, is a greatly applied antioxidant in vivo and in vitro. NAC is a precursor of L-cysteine that results in glutathione elevation biosynthesis. It acts directly as a scavenger of free radicals, especially oxygen radicals. NAC is a powerful antioxidant. It is also recommended as a potential treatment option for different disorders resulted from generation of free oxygen radicals. Additionally, it is a protected and endured mucolytic drug that mellows tenacious mucous discharges. It has been used for treatment of various diseases in a direct action or in a combination with some other medications. This paper presents a review on various applications of NAC in treatment of several diseases.


Overexpression of suppressor of cytokine signaling-3 in T cells exacerbates acetaminophen-induced hepatotoxicity.
Cytokines have been implicated in the progression of acetaminophen (APAP)-induced acute liver injury. Suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling by inhibiting the JAK-STAT pathway, but their role in APAP hepatotoxicity is unknown. In this present study, we attempted to explore the role of SOCS3 in T cells in APAP-induced liver injury. Mice with a cell-specific overexpression of SOCS3 in T cells (SOCS3Tg, in which Tg is transgenic) exhibited exaggerated hepatic injury after APAP challenge, as evidenced by increased serum alanine aminotransferase levels, augmented hepatic necrosis, and decreased survival relative to the wild-type mice. Adaptive transfer of SOCS3Tg-CD4(+) T cells into T and B cell-deficient RAG-2(-/-) mice resulted in an exacerbated liver injury relative to the control. In SOCS3Tg mice, hepatocyte apoptosis was enhanced with decreased expression of antiapoptotic protein bcl-2, whereas hepatocyte proliferation was reduced with altered cell cycle-regulatory proteins. Levels of IFN-gamma and TNF-alpha in the circulation were augmented in SOCS3Tg mice relative to the control. Studies using neutralizing Abs indicated that elevated IFN-gamma and TNF-alpha were responsible for the exacerbated hepatotoxicity in SOCS3Tg mice. Activation of STAT1 that is harmful in liver injury was augmented in SOCS3Tg hepatocytes. Alternatively, hepatoprotective STAT3 activation was decreased in SOCS3Tg hepatocytes, an event that was associated with augmented SOCS3 expression in the hepatocytes. Altogether, these results suggest that forced expression of SOCS3 in T cells is deleterious in APAP hepatotoxicity by increasing STAT1 activation while decreasing STAT3 activation in hepatocytes, possibly through elevated IFN-gamma and TNF-alpha.


Visual Outcome of Preterm Infants Screened in a Tertiary Care Hospital.
The aim of this study is to assess the incidence of retinopathy of prematurity (ROP) in preterm infants and to compare the visual outcomes in babies with and without ROP. A consecutive cohort of 812 preterm babies were recruited with gestational age ≤32 weeks and or birth weight ≤1500 g. The outcome was assessed at the end of 15 months by determining fixation behavior, cycloplegic refraction, and vision by Cardiff cards. Incidence of visual outcomes with 95% confidence limits and relative risks were estimated. Chi-squared test and t-test were used as tests of significance. The incidence of ROP was 25%. The incidence of myopia, hypermetropia, astigmatism, and strabismus were 15.8% (14.3-17.3), 6% (5.1-7.1), 55.6% (53.6-57.7), and 1.8% (1.4%-2.5%), respectively, in the cohort. The most common refractive error in terms of spherical equivalence was myopia (19.8% in ROP and 14.4% in non-ROP group). The mean visual acuity measured by Cardiff Acuity cards was 0.282 and 0.27 logarithm of the minimum angle of resolution units (right eye) and 0.293 and 0.277 (left eye) in patients with and without ROP, respectively. Strabismus was present in 5% of ROP group and 0.8% of non-ROP group babies. Babies with ROP had six times (risk ratio-6.02; 95% confidence interval 2.8-12.8) higher chance of developing strabismus than those without ROP. Ophthalmological morbidities in premature infants such as refractive errors and strabismus are high in addition to complications like ROP. The incidence of these conditions is more in infants with ROP when compared to non-ROP group.


The turnover of phosphate bound to myosin light chain-2 in perfused rat heart.
The rate of exchange of phosphate bound to ventricular myosin light chain-2 (LC2-P) was measured in rat hearts perfused with [32P]Pi at various levels of perfusate Ca2+. Computer simulations of the light-chain labelling suggested the presence of two isotopically distinct pools of LC2-P, one large pool comprising 90% of the total and a small pool consisting of the remaining 10%. At control levels of perfusate Ca2+ the phosphate of the large pool turned over very slowly (t 1/2 congruent to 250 min), whereas that of the small pool turned over much more rapidly (t 1/2 congruent to 1 min). At high levels of perfusate free Ca2+ (5mM) the turnover of the phosphate of the small pool decreased markedly, whereas that of the large pool remained little changed. Conversely, at low perfusate free Ca2+ (0.2 mM), the turnover of the large pool decreased, whereas that of the small pool remained unchanged. The possible identity of these two pools is discussed. The total myosin-light-chain kinase activity of rat ventricle was found to be only 2-3-fold higher than the kinase activity expressed in the heart under control conditions. This, coupled with the very low turnover of most of the LC2-bound phosphate, implies that, in heart, there is insufficient myosin-light-chain kinase activity to cause a rapid rise in the overall level of light-chain phosphorylation, even under conditions of increased cytoplasmic Ca2+.


IgM-mediated autoimmune responses directed against anchorage epitopes are greater in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) than in major depression.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and depression are considered to be neuro-immune disorders (Maes and Twisk, BMC Medicine 8:35, 2010). There is also evidence that depression and ME/CFS are accompanied by oxidative and nitrosative stress (O&NS) and by increased autoantibodies to a number of self-epitopes some of which have become immunogenic due to damage by O&NS. The aim of this study is to examine IgM-mediated autoimmune responses to different self-epitopes in ME/CFS versus depression. We examined serum IgM antibodies to three anchorage molecules (palmitic and myristic acid and S-farnesyl-L-cysteine); acetylcholine; and conjugated NO-modified adducts in 26 patients with major depression; 16 patients with ME/CFS, 15 with chronic fatigue; and 17 normal controls. Severity of fatigue and physio-somatic (F&S) symptoms was measured with the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale. Serum IgM antibodies to the three anchorage molecules and NO-phenylalanine were significantly higher in ME/CFS than in depression. The autoimmune responses to oxidatively, but not nitrosatively, modified self-epitopes were significantly higher in ME/CFS than in depression and were associated with F&S symptoms. The autoimmune activity directed against conjugated acetylcholine did not differ significantly between ME/CFS and depression, but was greater in the patients than controls. Partially overlapping pathways, i.e. increased IgM antibodies to a multitude of neo-epitopes, underpin both ME/CFS and depression, while greater autoimmune responses directed against anchorage molecules and oxidatively modified neo-epitopes discriminate patients with ME/CFS from those with depression. These autoimmune responses directed against neoantigenic determinants may play a role in the dysregulation of key cellular functions in both disorders, e.g. intracellular signal transduction, cellular differentiation and apoptosis, but their impact may be more important in ME/CFS than in depression.


Laparoscopic Heller myotomy and Dor fundoplication for achalasia: analysis of successes and failures.
In the treatment of achalasia, surgery has been traditionally reserved for patients with residual dysphagia after pneumatic dilatation. The results of laparoscopic Heller myotomy have proven to be so good, however, that most experts now consider surgery the primary treatment. The outcome of laparoscopic myotomy and fundoplication for achalasia is dictated by technical factors. University hospital tertiary care center. Retrospective study. One hundred two patients with esophageal achalasia underwent laparoscopic Heller myotomy and Dor fundoplication. Fifty-seven patients had been previously treated by pneumatic dilatation or botulinum toxin. The design of the operation involved a 7-cm myotomy, which extended 1.5 cm onto the gastric wall, and a Dor fundoplication. Esophagrams, esophageal manometric findings, and video records of the procedure were analyzed to determine the technical factors that contributed to the clinical success or failure of the operation. Swallowing status. In 91 (89%) of the 102 patients, good or excellent results were obtained after the first operation. A second operation was performed in 5 patients to either lengthen the myotomy (3 patients) or take down the fundoplication (2 patients). Dysphagia resolved in 4 of these patients. The remaining 6 patients were treated by pneumatic dilatation, but dysphagia improved in only 1. At the conclusion of treatment, excellent or good results had been obtained in 96 (94%) of the 102 patients. These data show that a Heller myotomy was unsuccessful in patients with an esophageal stricture; a short myotomy and a constricting Dor fundoplication were the avoidable causes of residual dysphagia; a second operation, but not pneumatic dilatation, was able to correct most failures; and that the identified technical flaws were eliminated from the last half of the patients in the series.


Pharmaco-toxicological study of Kageneckia oblonga, Rosaceae.
The probable antipyretic, antiinflammatory, analgesic and antioxidant properties of Kageneckia oblonga, Rosaceae, were investigated and the major compounds of its active extracts were isolated. The study comprised the acute toxicity of the extracts of global methanol, hexane, dichloromethane and methanol. The cytotoxicity of global methanol extract was studied in three tumoral cell lines. All the extracts exhibited the pharmacological activities under study. Methanol and dichloromethane were the most toxic extracts. From the global methanol extract, isolations were performed of prunasin, 23,24- dihydro-cucurbitacin F, and a new cucurbitacin, 3beta-(beta-D-glucosyloxy)-16alpha,23alpha-epoxycucurbita-5,24-diene-11-one. The cytotoxicity of both cucurbitacins on human neutrophils at the assayed concentrations was not statistically significant. In-vitro assays showed that both cucurbitacins can be partly responsible for the analgesic, antipyretic, and anti-inflammatory activities. Evaluation was done of the cytotoxicity of global methanol extract, 23, 24-dihydrocucurbitacin F, aqueous extracts and prunasin against P-388 murine leukaemia, A-549 human lung carcinoma and HT-29 colon carcinoma. Since global methanol extract presented a strong cytotoxicity against P-388 murine leukaemia, A-549 human lung carcinoma, and HT-29 cell lines, it is highly probable that this extract contain one or more cytotoxic compounds that could be investigated for their potential use as an agent against cancer.


Age-related decrease in beta adrenergic receptor-mediated vascular smooth muscle relaxation.
Beta adrenergic receptor-mediated vascular smooth muscle relaxation decreases with increasing age. We have examined the mechanism responsible for this phenomenon using rat mesenteric arteries from young (5-6 weeks) and older (10-12 months) rats. The beta adrenergic agonist isoproterenol produced a dose-dependent relaxation of serotonin-constricted mesenteric artery rings from young rats, whereas the maximal ability of isoproterenol to relax arterial rings from the older rats was found to be reduced markedly (92.7 vs. 27.6%, P less than .0001). The relaxation responses caused by acetylcholine and nitroglycerin, which appear to act independently of cyclic AMP (cAMP), are similar in the two groups. The loss in responsiveness of the mesenteric artery to isoproterenol was not explained by a change in beta receptor number in the vessels (29 +/- 4 in young rats vs. 31 +/- 7 fmol/mg of protein in the older rats). The maximal stimulation of cAMP accumulation by isoproterenol was lower in the older vessels; forskolin activated cAMP accumulation equally in the two groups. However, the vessels from the older rats were less sensitive to forskolin-induced vascular relaxation. Also, the ability of dibutyryl cAMP to promote vascular relaxation was diminished in the older vessels. These data suggest that the diminished cAMP accumulation in older vessels in response to isoproterenol might not necessarily in itself explain completely the reduced physiological response and that an additional defect in the beta adrenergic-mediated relaxation in the vascular smooth muscle of older rats may lie at the level of cAMP-dependent protein kinase activation or more distally.


Zinc: the missing link in combating micronutrient malnutrition in developing countries.
The first cases of human Zn deficiency were described in the 1960s in the Middle East. Nevertheless, it was not until 2002 that Zn deficiency was included as a major risk factor in the global burden of disease, and only in 2004 did WHO/UNICEF include Zn supplements in the treatment of acute diarrhoea. Despite this recognition Zn is still not included in the UN micronutrient priority list, an omission that will continue to hinder efforts to reduce child and maternal mortality, combat HIV/AIDS, malaria and other diseases and achieve the UN Millennium Development Goals for improved nutrition in developing countries. Reasons for this omission include a lack of awareness of the importance of Zn in human nutrition, paucity of Zn and phytate food composition values and difficulties in identifying Zn deficiency. Major factors associated with the aetiology of Zn deficiency include dietary inadequacies, disease states inducing excessive losses or impairing utilization and physiological states increasing Zn requirements. To categorize countries according to likely risk of Zn deficiency the International Zinc Nutrition Consultative Group has developed indirect indicators based on the adequacy of Zn in the national food supplies and/or prevalence of childhood growth stunting. For countries identified as at risk confirmation is required through direct measurements of dietary Zn intake and/or serum Zn in a representative sample. Finally, in at risk countries either national or targeted Zn interventions such as supplementation, fortification, dietary diversification or modification, or biofortification should be implemented, where appropriate, by incorporating them into pre-existing micronutrient intervention programmes.


Dimerization of MLL fusion proteins immortalizes hematopoietic cells.
MLL fusion proteins are leukemogenic, but their mechanism is unclear. Induced dimerization of a truncated MLL immortalizes bone marrow and imposes a reversible block on myeloid differentiation associated with upregulation of Hox a7, a9, and Meis1. Both dimerized MLL and exon-duplicated MLL are potent transcriptional activators, suggesting a link between dimerization and partial tandem duplication of DNA binding domains of MLL. Dimerized MLL binds with higher affinity than undimerized MLL to a CpG island within the Hox a9 locus. However, MLL-AF9 is not dimerized in vivo. The data support a model in which either MLL dimerization/exon duplication or fusion to a transcriptional activator results in Hox gene upregulation and ultimately transformation.