Role of the cell surface in bacterial mating: requirement for intact mucopeptide in donors for the expression of surface exclusion in R+ strains of Escherichia coli.
Two derivatives of the F-like R factor R1drd19 carrying mutually exclusive resistance determinants were used to study the role of the mucopeptide in the expression of conjugal functions. The use of metabolically active penicillin spheroplasts in R+ times R- matings had no effect on the ability of the cells to donate or accept a plasmid. However, in R+ times R+ matings it was found that surface exclusion was totally abolished if the donor, but not the recipient, was a spheroplast. This result implies that the traS gene, expressed by the excluding plasmid, is dependent for its action on an intact mucopeptide layer in the donor cell, and that this interaction is independent of the transfer ability of the excluding plasmid.


Convergence of economic growth and health expenditures in OECD countries: Evidence from non-linear unit root tests.
The relationship between human capital, health spending, and economic growth is frequently neglected in the literature. However, one of the main determinants of human capital is health expenditures, where human capital is one of the driving forces of growth. Consequently, health expenditures affect growth through this link. In the study, these findings have been attempted to be empirically tested. Along this axis, health expenditure per qualified worker was chosen as an indicator of health expenditure, and output per qualified worker was chosen as an indicator of economic growth. The variables were treated with the convergence hypothesis. Due to the non-linear nature of the variables, the convergence hypothesis was carried out with non-linear unit root tests. The analysis of 22 OECD countries from 1976 to 2020 showed that health expenditure converged for all countries, and there was a significant degree of growth convergence (except for two countries). These findings show that health expenditure convergence has significantly contributed to growth convergence. Policymakers should consider the inclusiveness and effectiveness of health policies while making their economic policies, as health expenditure convergence can significantly impact growth convergence. Further research is needed to understand the mechanisms behind this relationship and identify specific health policies most effective in promoting economic growth.


8q24 amplified segments involve novel fusion genes between NSMCE2 and long noncoding RNAs in acute myelogenous leukemia.
The pathogenetic roles of 8q24 amplified segments in leukemic cells with double minute chromosomes remain to be verified. Through comprehensive molecular analyses of 8q24 amplicons in leukemic cells from an acute myelogenous leukemia (AML) patient and AML-derived cell line HL60 cells, we identified two novel fusion genes between NSMCE2 and long noncoding RNAs (lncRNAs), namely, PVT1-NSMCE2 and BF104016-NSMCE2. Our study suggests that 8q24 amplicons are associated with the emergence of aberrant chimeric genes between NSMCE2 and oncogenic lncRNAs, and also implicate that the chimeric genes involving lncRNAs potentially possess as-yet-unknown oncogenic functional roles.


The role of an independent and interdisciplinary assessment of research studies with human subjects in Europe and worldwide.
The author reviews the history of human experimentation beginning as documented by holes in human sculls 6000 years before, addressing the first controlled experiments by James Lind and Edward Jenner in the 18th century and ending with the inhuman experiments in Nazi Camps and the Tuskegee case in Alabama in the 20th century. Resting on the Declaration of Helsinki, quite a number of declarations, scientific, national and international guidelines was issued since aiming at enhancing medical research as well as protecting the subjects from harm. Now a dense ethical, legal, scientific and social network exists for investigator initiated and commercial trials for a rich market of the Pharmaceutical Industry. However, pitfalls still occur (e.g., the cases of thalidomide, VIOXX and TGN 1412) as examples that can only be prevented by even more stringent rules and well informed, conscientious, compassionate and responsible performance of all parties involved.


Psychological normality and abnormality in persistent headache patients.
One hundred and three patients referred to a neurological outpatient clinic were examined to assess the relationship between persistent headache, not due to significant physical illness, and emotional disturbance. Overall, the patients showed slightly more evidence of emotional disturbance than a general practice population but less than psychiatric outpatients. Thus, with cut-off points of 4/5 and 9/10 on the General Health Questionnaire (GHQ 28) the whole group had 52% or 20% of psychiatric 'cases' respectively. On the Crown-Crisp Experiential Index the 70 females had mean total scores of 37.19 +/- 11.11 and the 33 males had scores of 31.79 +/- 11.36. In addition the childhood experiences measured by the Parental Bonding Instrument appeared to be normal. Seven patients had significant depressive illness, according to the Levine-Pilowsky Depression Questionnaire. Statistically significant differences in psychological state did not emerge between the diagnoses of cluster headache, classical migraine, common migraine, tension headache or combined headache. However, negative correlations were found between the duration of illness and measures of anxiety. It is concluded that although the emotional state contributes to the development of pain and headache in some patients, there are others in whom comparable headaches are unlikely to be due to emotional factors. Selection effects are held to be important and some of the emotional changes will vary at different phases of a chronic disorder. A new symptom may initially cause anxiety but when a condition persists some patients will be increasingly concerned or depressed whilst others develop tolerance for the situation.


Mutations in melanocortin-4 receptor and human obesity.
Multiple lines of investigations demonstrated that the melanocortin-4 receptor (MC4R) is a critical regulator of energy homeostasis from fishes to humans. Clinical studies in humans showed that mutations in the MC4R gene are the most prevalent form of monogenic obesity. More than 150 mutations have been identified from subjects of different ethnic backgrounds. Functional analyses of the mutant MC4Rs revealed multiple defects, including cell-surface expression, ligand binding, and signaling. Based on the defects, the mutants can be classified into five classes. Potential therapeutic implications from the analyses of the naturally occurring MC4R mutations, such as novel ligands and pharmacological chaperones, are highlighted.


Physiological and antioxidant response of wheat (Triticum aestivum) seedlings to fluoroquinolone antibiotics.
Combinations of antibiotics occur in terrestrial environments due to excessive prescription, consumption, and disposal and have adverse effects, including crop toxicity. We examined short-term (20-d) toxicity of the fluoroquinolone antibiotics ciprofloxacin, enrofloxacin, levofloxacin, and their mixture in a germination and a greenhouse sand culture study with wheat. We tested the hypothesis that oxidative stress plays a role in toxicity by examining stress products and antioxidants involved in detoxifying reactive oxygen species (ROS) during stress. Germination was unaffected by any antibiotic concentration or mixture used. The highest antibiotic concentrations, 100 and 300 mg L-1, significantly decreased wheat growth. In 20 days exposure the maximum malondialdehyde production (2.45 μmol g-1 fresh weight), total phenols (16.40 mg g-1 of extract), and total antioxidant capacity (17.74 mg of Vitamin C g-1 of extract) and maximum activities of superoxide dismutase (7.99 units mg-1 protein min-1) and ascorbate peroxidase (0.69 μmol ascorbate mg-1 protein min-1) significantly increased compared to the control. In contrast, catalase (0.45 mmol H2O2 mg-1 protein min-1) and peroxidase (0.0005 units mg-1 protein min-1) activity significantly decreased compared to the control. We conclude that high antibiotic concentrations in the plant growth medium reduced wheat growth by causing oxidative stress. The capacity to respond to oxidative stress was compromised by increasingly higher antibiotic concentrations in some enzyme systems. This stress damaged the physiological structure of the young plants and could reduce crop productivity in the long term. Consequently, fluoroquinolone-contaminated water challenges developing countries with constraints on available water for irrigation.


Female preponderance in genetic generalized epilepsies.
Epilepsy is more prevalent in men but Genetic Generalized Epilepsies (GGE) seem to be more common in women. A predominant maternal inheritance has been previously described in GGE. Our objective was to determine sex and inheritance patterns in a GGE population compared to mesial temporal lobe epilepsy with hippocampal sclerosis (MTLEHS). We performed a prospective observational study including adult GGE and MTLEHS patients followed up at a tertiary epilepsy center from January 2016 to December 2019. Patients' familial history was obtained by a detailed questionnaire. Clinical and demographic data was retrieved from clinical notes. A cohort of 641 patients, 403 with GGE and 238 with MTLEHS, was analyzed. GGE was more common in women than MTLEHS (58.8% vs 44.5%, OR=1.63, p = 0.004). Compared to MTLEHS patients, more GGE patients had familial history of epilepsy (45.4% vs 25.2%; p<0.001). The GGE group had a higher percentage of female relatives with epilepsy (55% vs 37%; p = 0.006). The prevalence of maternal inheritance was not different between GGE and MTLEHS groups (62.9% vs 57.7%; p = 0.596). Photosensitivity was more common in females than in males (44.7% vs 34.3%, p = 0.036). There is a female preponderance in GGE when compared to MTLEHS, as both GGE patients and their affected relatives are more frequently women. The prevalence of maternal inheritance was not higher in GGE than in MTLEHS.


The vas after vasectomy: comparison of cauterization methods.
A histologic study of the vas ends was carried out in 21 patients undergoing vasovasostomy. All had undergone prior vasectomy by the same surgeon, with a technique identical except for the type of cautery used to seal the vas ends. A superior sealing of the vas, as shown by fewer cases of vasitis nodosa and spermatic granuloma, followed use of the thermal cautery ("red-hot wire") than the electrosurgical cautery (23% vs 60.7% suboptimal sealing rate). The thermal cautery is a superior method of sealing the vas at vasectomy.


Design and fabrication of nickel microdisk-arrayed diamond electrodes for a non-enzymatic glucose sensor based on control of diffusion profiles.
A non-enzymatic glucose sensor, consisting of a regular array of nickel microdisks on a diamond electrode substrate designed to control the diffusion processes of glucose and interfering species such as ascorbic acid and uric acid, was fabricated. Each nickel microdisk acts as a microelectrode for glucose (hemispherical diffusion) due to the inactive diamond surface for glucose oxidation while interfering species are oxidized at the diamond surface (linear diffusion). The difference in diffusion profiles gives a difference in the time dependence of the amperometric response. That is, the glucose concentration gives rise to a constant amperometric response whereas the concentration of mixed interfering species gives rise to a time dependent response, because the hemispherical diffusion profile yields a constant response and the linear diffusion profile yields a transient current following Cottrell's equation. The results show that the fabricated electrodes exhibit a high selectivity for glucose in solutions containing ascorbic and uric acids.


Endocrine and pubertal disturbances in optic nerve hypoplasia, from infancy to adolescence.
Endocrinologic abnormalities are a common co-morbidity in patients with optic nerve hypoplasia (ONH), however the impact on puberty is unknown. The purpose of this study was to examine rates of endocrine dysfunction and pubertal disturbances in a pediatric population of ONH. A retrospective chart review was conducted on a cohort of children with ONH between January 2005 and March 2013. Endocrine dysfunction was determined based on laboratory evidence of hormone deficiency or hormone replacement. Pubertal disturbances were characterized based on presence of micropenis, tanner staging, menarche and hormone replacement. Pituitary abnormalities were classified using MRI findings. Descriptive statistics were used, and comparisons between groups were performed using the chi-square test. During the study period, 101 patients underwent an endocrine evaluation (median age: 2.3 years [0.76 - 6.5]). Hypopituitarism was present in 73% of patients with growth hormone deficiency (56%) and hypothyroidism (54%) being the most common. Pubertal disturbances (n = 19) were common; micropenis in 31% (13/42) of males and 2% with precocious puberty. Half of adolescents (n = 4/8) were diagnosed with gonadotropin deficiency. Patients with MRI pituitary abnormalities were more likely to have endocrine dysfunction than those without (p = 0.004). The sensitivity and specificity of MRI pituitary abnormalities for hypopituitarism was 54% and 92%, respectively. A significant proportion of children with ONH have endocrine dysfunction. The high frequency of pubertal disturbances in this study emphasizes the need for long-term monitoring of developing endocrinopathy. While pituitary gland abnormalities are a good predictor of endocrine dysfunction, a normal pituitary gland does not rule out endocrinopathy.


The Pharmacology of Two-Pore Domain Potassium Channels.
Two-pore domain potassium channels are formed by subunits that each contain two pore-loops moieties. Whether the channels are expressed in yeast or the human central nervous system, two subunits come together to form a single potassium selective pore. TOK1, the first two-domain channel was cloned from Saccharomyces cerevisiae in 1995 and soon thereafter, 15 distinct K2P subunits were identified in the human genome. The human K2P channels are stratified into six K2P subfamilies based on sequence as well as physiological or pharmacological similarities. Functional K2P channels pass background (or "leak") K+ currents that shape the membrane potential and excitability of cells in a broad range of tissues. In the years since they were first described, classical functional assays, latterly coupled with state-of-the-art structural and computational studies have revealed the mechanistic basis of K2P channel gating in response to specific physicochemical or pharmacological stimuli. The growing appreciation that K2P channels can play a pivotal role in the pathophysiology of a growing spectrum of diseases makes a compelling case for K2P channels as targets for drug discovery. Here, we summarize recent advances in unraveling the structure, function, and pharmacology of the K2P channels.


The balancing act of autoimmunity: central and peripheral tolerance versus infection control.
Genetic associations with autoimmune disease are enriched in immune response regulators. The immune system in individuals at genetic risk of autoimmunity must balance pressures on the innate and adaptive immune system, most notably infection control, with those of maintaining self-tolerance or controlling autoimmune inflammation. In spite of multiple tolerance mechanisms, inflammation becomes chronic in autoimmune disease, and complete resolution is difficult. This article proposes a perspective on the pathogenesis of autoimmunity-focusing on rheumatoid arthritis and type 1 diabetes-integrating clinical advances and animal models with the role that colonizing micro-organisms play in the balance between tolerance and autoimmunity.


Linking hsp90's role as an evolutionary capacitator to the development of cancer.
This paper links Heat Shock Protein Hsp90 as an evolutionary capacitator with the development of cancer. Hsp90 stabilises proteins associated with cancer in a number of ways. Canalisation allows for the accumulation of malignant mutations in the genome, and selection of beneficial phenotypes when cancer cells are stressed, allowing oncogenic development and progression. Hsp90 may allow for mutational 'big bangs' that can trigger primary malignant transformation. Hsp90 buffers catastrophic mutations in the oncogenome to prevent protein degradation and cellular apoptosis. Hsp90 was found to prevent the degradation of mutated p53, encouraging uncontrolled proliferation of cancer cells. Hsp90 buffering of mutations in response to cytotoxic therapy can lead to expression of beneficial phenotypes when Hsp90 is supressed and development of drug resistance. Trials with Hsp90 inhibitors have shown some success as an adjunctive therapy in preventing cancer progression, development of drug resistance, and even re-sensitisation to therapy after chemoresistance has developed.


Physiological and gene expression responses involved in teak (Tectona grandis L.) seedlings exposed to osmotic and salt stressors.
Teak (Tectona grandis L.) is a forest tree having 2n = 2x = 36 diploid chromosomes. Plants are continually subjected to variety of abiotic stresses due to climate change, which alter their physiological processes and gene expression. The current study sought to examine the physiological and differential gene expression of teak seedlings exposed to abiotic stresses (150 mM NaCl and 15% PEG-6000). Chlorophyll content, membrane stability index and relative water content were measured at 0, 2, 7 and 12 days after treatment. These parameters were initially numerically reduced, but they were significantly reduced during a longer period of treatment. Seedlings treated with 150 mM NaCl displayed more harmful effect on the plant than other treatments. The results showed that variety of stresses significantly affect the physiology of seedlings because they cause membrane damage, ROS generation, chlorophyll degradation, and reduction in water absorption. The gene expression of treated and control seedlings was also evaluated at 12 days after treatment. Ten stress-related genes were examined for their differential expression using RT-PCR under applied stress. The stress-treated seedlings' leaves showed an up-regulated expression of the genes MYB-3, HSP-1, BI-1 and CS-2. Up-regulation of the genes confirmed the protective function of these genes in plants under abiotic stress. However, gene expression was affected by treatments, the extent of stress and the species of plant. This study came to the conclusion that physiological parameters could be utilized as marker indices to assess a tree's capability to withstand stress at seedling stage. The up-regulated genes will be further investigated and utilized to validate stress tolerance and susceptible teak seedlings.


Adolescent Fathers' Perceptions and Experiences of Fatherhood: A Qualitative Exploration with Hispanic Adolescent Fathers.
The purpose of this secondary analysis of qualitative data was to understand the multifactorial influences that impact the health and health behaviors of Hispanic adolescent fathers DESIGN & METHODS: Qualitative description was the method used for this secondary analysis. The theoretical domains of the Vulnerable Populations Conceptual Framework were used to guide this study. The semi-structured interviews of 17 participants were analyzed using qualitative content analysis. Participants were Hispanic adolescent fathers, between the ages of 16 and 23 years, who were attending a fatherhood program. Most participants came from socioeconomically disadvantaged backgrounds and unstable families. Additionally, their exposure to widespread neighborhood and domestic violence resulted in gang involvement and illegal activities. The cumulative impact of adverse childhood events resulted in substance use and psychological distress. However, becoming a father was transformative, motivating adolescents to stop engaging in destructive, unhealthy behaviors. Adolescent fathers' well-being is an important component of perinatal health because it affects family functioning and health outcomes in their children. The perinatal period presents a "golden" opportunity to promote health and should be leveraged by nurses to allow adolescent fathers to become involved during the perinatal period. A family-centered approach is critical in addressing the complex needs of this population. An assessment of their psychosocial environment, including childhood trauma, is necessary to help nurses identify at-risk fathers. Additionally, trauma informed care is a valuable tool that nurses can utilize to foster trust in Hispanic adolescent fathers.


Two decades of seagrass area change: Organic carbon sources and stock.
Although seagrass ecosystems provide various ecosystem services, the implications in correspondence with temporal changes of the meadows is lacking. In this study, we analyzed two-decade changes of the seagrass area with the organic carbon storage and the sources at Libong island in Thailand. The seagrass area covered 841 ha in 2019, after two decades of decline (3.2 and 0.6% yr-1 between 2004 and 2009 and 2009-2019, respectively). Although δ13C was not significant between depth layers (p > 0.05), the general trend suggested that the terrestrial source of carbon is dominating bottom depth layer (31.7-37.2%), mixture of terrestrial (19.7-30.3%), seagrass (22.9-29.6%), mangrove (16.8-43.0%) and CPOM (11.2-25.4%) in the middle, and mangroves and seagrasses are dominating surface layer (28.3-66.2 and 29.3-36.5%, respectively). These trends approximately correspond to the areal changes of the meadows, as well as changes of urban area and water quality, providing detailed information on the meadow changes and possible causes.


Implementation of functional assessment scales in geriatric practice: a feasibility study.
A study was undertaken to evaluate the feasibility of functional assessment scales regarding completion rate and ability to document functional changes in geriatric rehabilitation patients. Five functional assessment scales were implemented, and used on admission and discharge as part of standard care. Of 2,812 patients, 90 patients (3.2%) had no scales administered, 2,330 patients (82.9%) had between one and six scales administered and 392 (13.9%) had a complete data set (seven scales). The percentage of inpatients who were independent or almost independent in basic ADL functions improved from 30% to 60% during hospitalization; 53% had cognitive impairment, while 19% expressed depressive thoughts or depression on admission. Functional assessment scales were feasible in the clinical routine, gave important information on patients' functional status at baseline, and showed that patients improved their physical function considerably during hospitalization. Interdisciplinary teamwork and management affect the success of the implementation of assessment scales.


Genomics and personalized medicine.
The role of genomics in personalized medicine continues to undergo profound changes, in step with dramatic technological advances. Ability to sequence the entire human genome with relative ease raises expectations that we can use an individual's complete genomic blueprint to understand disease risk and predicting therapy outcomes, thereby, optimizing drug therapy. Yet, doubts persist as to what extent genetic/genomic factors influence disease and treatment outcomes or whether robust predictive biomarker tests can be developed. Encompassing more than just DNA sequences, the definition of genomics now often is taken to include transcriptomics, proteomics, metabolomics, and epigenomics, with integration of genomic and environmental factors, in an area referred to systems biology. While we can learn much about a cell's innermost workings, summation of these diverse areas is far from enabling the prediction of therapeutic outcomes. Typically, only a handful of specific biomarkers, genetic or otherwise, are 'actionable', i.e., they can be used to guide therapy. I will focus on pharmacogenetic biomarkers, highlighting current successes but also the main challenges that remain in optimizing individualized therapy.


Hypernatraemic dehydration. A prospective study in children with diarrhoeal disease.
Hypernatraemia occurs in a significant number of infants with dehydrating diarrhoea. There are some diagnostic clinical features, but these are not specific, and without routine electrolyte estimations many with hypernatraemia would go undetected. The standard fluid therapy schedule used at the Red Cross War Memorial Children's Hospital gave satisfactory results in both hypernatraemic and non-hypernatraemic patients. It is suitable for use in situations when electrolyte estimations on all patients are not possible.


Worm-like micelles in water solutions of 1, 4 poly (1, 3-butadiene)-polyethylene oxide diblock copolymer.
The main purpose of this study is to determine for the first time the structure of the self-assembled aggregates in the system made of 1,4 poly(1,3-butadiene)-polyethylene oxide diblock copolymer (IUPAC name: poly(but-2-ene-1,4-diyl)-block-polyoxyethylene) and water, and the rheological behavior of the solution. The degree of polymerization of the polybutadiene and polyethylene oxide blocks is 37 and 45, respectively. The diblock copolymer concentration was limited to be ≤2.5 wt% to avoid phase separation. Small X-ray scattering revealed that the diblock copolymer self-assembles in worm-like micelles with a diameter of ∼ 12 nm. This system does not closely follow the rheological behavior of worm-like micelle solutions made of typical surfactants. The system steadily shear thins reaching very low viscosity values at large shear rates, however there are not shear-thickening peaks. In thixotropic loops, the micellar solution does not present hysteresis. The viscoelastic spectra do not follow the Maxwell model at low and intermediate frequencies. This uncommon behavior for a worm-like micellar system is explained by the slow dynamics of the self-assembly. The extremely high hydrophobicity of the polybutadiene block does not allow any micellar rearrangement.


Modelling and optimization of process parameters for production of desiccated Chhana-murki (Indian cottage cheese-based dessert).
In the present study, process parameters were optimized for the production of desiccated chhana-murki (Indian cottage cheese-based dessert). Response Surface Methodology (RSM) was employed to explore the mutual effects of coagulation temperature (CT) of milk (70-90 °C), % fat level in milk (3.5%-5.5%), and sugar-to-paneer cube (SP) ratio (0.6-0.9) on instrumental hardness (N), water activity (aw), yield (%), sensory sweetness and overall acceptability (on 100-point intensity scale) of chhana-murki. The resulted responses were evaluated by analysis of variance (ANOVA), and the second-order polynomial response surface equations were fitted using multiple regression analysis. Determination coefficients (R 2) were equal to 80% or higher for individual responses stated that the developed models were well fitted to the experimental results. The optimized product was prepared using CT 79.22 °C, milk fat 4.8%, and SP ratio 0.7. Confirmatory experiment values for instrument hardness, water activity (aw), yield (%), sensory sweetness and overall acceptability were 105.05 N, 0.85, 115.2%, 61.2 and 78.8, respectively.


Association of birth mode of delivery with infant faecal microbiota, potential pathobionts, and short chain fatty acids: a longitudinal study over the first year of life.
Caesarean section (CS) interrupts mother-to-newborn microbial transfer at birth. Beyond the neonatal period, the impact of CS on offspring gut microbiota and their short-chain fatty acids (SCFAs) remains unclear. Here, we examine birth delivery mode (CS versus vaginal delivery) with the infant gut microbiota and faecal SCFAs measured 3 and 12 months after birth. Longitudinal study. North Carolina. In 2013-15, we enrolled pregnant women and followed up their offspring for 12 months. We asked a subset of participants, enrolled over a 3-month period, to provide faecal samples at the 3- and 12-month follow-up visits. We sequenced the 16S rRNA V4 region with Illumina MiSeq and quantified SCFA concentrations using gas chromatography. We examined delivery mode with differential abundance of microbiota amplicon sequence variants (ASVs) using beta-binomial regression and faecal SCFAs using linear regression. We adjusted models for confounders. Of the 70 infants in our sample, 25 (36%) were delivered by CS. Compared with vaginal delivery, CS was associated with differential abundance of 14 infant bacterial ASVs at 3 months and 13 ASVs at 12 months (all FDR P < 0.05). Of note, CS infants had a higher abundance of the potential pathobionts Clostridium neonatale (P = 0.04) and Clostridium perfringens (P = 0.04) and a lower abundance of potentially beneficial Bifidobacterium and Bacteroides spp. (both P < 0.05) at 3 months. Other ASVs were differentially abundant at 12 months. Infants delivered by CS also had higher faecal butyrate concentration at 3 months (P < 0.005) but not at 12 months. Caesarean section was associated with increased butyrate excretion, decreased Bifidobacterium and Bacteroides spp., and more colonisation of the infant gut by pathobionts at 3 months of age. CS was also associated with altered gut microbiota composition, but not faecal SCFAs, at 12 months. Caesarean section delivery was associated with increased butyrate excretion, decreased Bifidobacterium, and increased colonisation of the infant gut by pathobionts at 3 months of age.


Effects of sexual experience on conspecific odor preference and male odor-induced activation of the vomeronasal projection pathway and the nucleus accumbens in female rats.
In the present study in estrogen-progesterone primed ovariectomized female rats, we examined the expression of a preference for male odors and male odor-induced Fos immunoreactivity throughout the vomeronasal projection pathway and the nucleus accumbens (NAcc), using both sexually experienced and sexually naive subjects. Female rats significantly preferred airborne odors and soiled bedding from sexually active males over those from estrous females, irrespective of the presence or absence of prior sexual experience. On the other hand, the brain regions in which exposure to male-soiled bedding significantly increased Fos expression were different between sexually experienced and sexually naive subjects. Significant increment of Fos expression in the posterior-dorsal medial amygdala (MePD) and the bed nucleus of stria terminalis (BNST) in forebrain, as well as the accessory olfactory bulb, was observed in both groups of subjects. Fos expression in the anterior-dorsal medial amygdala (MeAD), the medial preoptic area (mPOA) and the NAcc core, however, was significantly increased only in the sexually experienced subjects. These results suggested that male odor-induced activations of the MePD and/or the BNST, but not of the MeAD, the mPOA and the NAcc core, are required for the expression of a male-directed odor preference in female rats.


Postprocedural anticoagulation for specific therapeutic indications after revascularization for ST-segment elevation myocardial infarction (from the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction Trial).
Postprocedural anticoagulation (AC) after primary percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI) may be administered for a number of specific therapeutic indications (e.g. atrial fibrillation or left ventricular thrombus). However, the safety and effectiveness of such post-PCI AC for specific indications are not well defined. Thus, we sought to study outcomes after postprocedural AC for specific indications in patients undergoing primary PCI for STEMI in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction trial. Patients who underwent primary PCI for STEMI in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction trial were grouped according to whether they received specific indication AC. Adverse outcomes were assessed using propensity-adjusted multivariate analyses. After excluding patients who received post-PCI AC solely for routine prophylaxis, 410 patients (16.6%) received postprocedural AC for specific indications and 2,063 patients (83.4%) received no post-PCI AC. After propensity adjustment, use of postprocedural AC for specific indications was associated with higher rates of cardiac mortality, reinfarction, stent thrombosis, and major bleeding at 30 days compared with patients who received no AC post-PCI. In conclusion, in this large prospective study, use of postprocedural AC for specific indications after primary PCI for STEMI was independently associated with early rates of adverse ischemic and hemorrhagic outcomes. Post-PCI AC for specific indications was also associated with worse outcomes from 30 days to 3 years. Further studies are warranted to determine the optimal use of postprocedural AC after primary PCI in STEMI.


Structures of chaperone-associated assembly intermediates reveal coordinated mechanisms of proteasome biogenesis.
The proteasome mediates most selective protein degradation. Proteolysis occurs within the 20S core particle (CP), a barrel-shaped chamber with an α7β7β7α7 configuration. CP biogenesis proceeds through an ordered multistep pathway requiring five chaperones, Pba1-4 and Ump1. Using Saccharomyces cerevisiae, we report high-resolution structures of CP assembly intermediates by cryogenic-electron microscopy. The first structure corresponds to the 13S particle, which consists of a complete α-ring, partial β-ring (β2-4), Ump1 and Pba1/2. The second structure contains two additional subunits (β5-6) and represents a later pre-15S intermediate. These structures reveal the architecture and positions of Ump1 and β2/β5 propeptides, with important implications for their functions. Unexpectedly, Pba1's N terminus extends through an open CP pore, accessing the CP interior to contact Ump1 and the β5 propeptide. These results reveal how the coordinated activity of Ump1, Pba1 and the active site propeptides orchestrate key aspects of CP assembly.


The impact of capitation on physician organizations' cost structures: an exploratory analysis.
This paper aims to evaluate the relationship between capitation payment methodology and the physician organization cost function. The paper provides evidence supporting a positive relationship between overhead rates and the level of capitation. Based on sample data, US medical practices whose net medical revenue consists of 11 percent or more capitation payments have significantly higher overhead costs per physician FTE.


Driver gene alterations profiling of Chinese non-small cell lung cancer and the effects of co-occurring alterations on immunotherapy.
Molecular testing for alterations in oncogenic driver genes and targeted therapies have become standard procedures for non-small cell lung cancer (NSCLC) patients. However, little evidence has shed light on the pattern of co-existence of driver genes in NSCLC, and whether they may have different tumor features affecting immunotherapy is still unclarified. Genomic alterations in 14 lung cancer-related genes were conducted in 3440 Chinese NSCLC patients using next-generation sequencing. Meanwhile, tumor mutational burden and immunotherapy dataset from the Memorial sloan kettering cancer center (MSKCC) and lung adenocarcinoma dataset from The Cancer Genome Atlas (TCGA) were utilized for analyzing the impact of the co-occurring alterations on patients' survival following immunotherapy. In this cohort, 90.17% of patients had at least one somatic alteration in the 14 genes, including 51% of co-occurring alterations. TP53 and epidermal growth factor receptor (EGFR) were the most prevalent genes (54.74% and 53.55%, respectively), followed by KRAS, ERBB2, ALK, PIK3CA, ROS1, RET, MET, BRAF, KIT, FGFR1, PDGFRA, and NRAS. The prevalence of TP53, EGFR, and ERBB2 in our cohort were significantly higher than that from the TCGA database, whereas KRAS, BRAF, and PDGFRA were significantly lower than the latter. Furthermore, the patients who harbored multiple alterations (8.86%, 31/350) in eight driver genes survived longer and have a higher tumor mutation burden compared to the patients with a single alteration. Similar result was found between the patients with co-occurring alteration of EGFR and other driver genes and the patients with single EGFR alteration. Meanwhile, we found a distinct immune cell infiltration feature between patients with single and multiple driver gene alterations, as well as between patients with only EGFR alteration and co-occurring groups. This study identified a unique driver gene feature and found patients harboring co-occurring alterations of EGFR and other driver genes may benefit from immunotherapy, which may provide more therapeutic selections for EGFR-mutated NSCLC patients and merit additional investigation.


High-risk patients with acute coronary syndromes treated with low-molecular-weight or unfractionated heparin: outcomes at 6 months and 1 year in the SYNERGY trial.
The SYNERGY trial comparing enoxaparin and unfractionated heparin in high-risk patients with acute coronary syndromes (ACS) showed that enoxaparin was not inferior to unfractionated heparin in reducing death or nonfatal myocardial infarction (MI) at 30 days. To evaluate continued risk in this patient cohort through 6-month and 1-year follow-up. Overall, 9978 patients were randomized from August 2001 through December 2003 in 487 hospitals in 12 countries. Patients were followed up for 6 months and for 1 year. Six-month outcomes were death, nonfatal MI, revascularization procedures, stroke, and site-investigator-reported need for rehospitalization; 1-year outcome was all-cause death. Six-month and 1-year follow-up data were available for 9957 (99.8%) and 9608 (96.3%) of 9978 patients, respectively; 541 patients (5.4%) had died at 6 months and 739 (7.4%) at 1 year. Death or nonfatal MI at 6 months occurred in 872 patients receiving enoxaparin (17.6%) vs 884 receiving unfractionated heparin (17.8%) (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.89-1.07; P = .65). In the subgroup of patients receiving consistent therapy, ie, only enoxaparin or unfractionated heparin during the index hospitalization (n = 6138), a reduction in death or nonfatal MI with enoxaparin was maintained at 180 days (HR, 0.85; 95% CI, 0.75-0.95; P = .006). Rehospitalization within 180 days occurred in 858 patients receiving enoxaparin (17.9%) and 911 receiving unfractionated heparin (19.0%) (HR, 0.94; 95% CI, 0.85-1.03; P = .17). One-year all-cause death rates were similar in the 2 treatment groups (380/4974 [7.6%] for enoxaparin vs 359/4948 [7.3%] for unfractionated heparin; HR, 1.06; 95% CI, 0.92-1.22; P = .44). One-year death rates in patients receiving consistent therapy were also similar (251/3386 [7.4%] for enoxaparin vs 213/2720 [7.8%] for unfractionated heparin; HR, 0.95; 95% CI, 0.79-1.14; P = .55). In the SYNERGY trial, patients continued to experience adverse cardiac events through long-term follow-up. The effect of enoxaparin on death or MI compared with that of unfractionated heparin at 6 months was similar to that observed at 30 days in the overall trial and in the consistent-therapy group. One-year death rates were also similar in both groups. High-risk patients with ACS remain susceptible to continued cardiac events despite aggressive therapies.ClinicalTrials.gov Identifier: NCT00043784.


Levodopa-induced dyskinesias are associated with transient down-regulation of cAMP and cGMP in the caudate-putamen of hemiparkinsonian rats: reduced synthesis or increased catabolism?
Second messenger cAMP and cGMP represent a key step in the action of dopamine that modulates directly or indirectly their synthesis. We aimed to verify whether levodopa-induced dyskinesias are associated with changes of the time course of levodopa/dopamine stimulated cAMP and cGMP levels, and/or with changes of their catabolism by phosphodiesterase activity in rats with experimental hemiparkinsonism. Microdialysis and tissue homogenates of the striatal tissues demonstrated that extracellular and intracellular cAMP/cGMP levels were lower in dyskinetic animals during the increasing phase of dyskinesias compared to eukinetic animals, but cAMP/cGMP levels increased in dyskinetic animals during the phase of decreasing and extinction of dyskinesias. Dyskinesias and the abnormal lowering of striatal cGMP and cAMP after levodopa were prevented by pretreatment with the multipotent drug amantadine, outlining the inverse relationship of cAMP/cGMP to dyskinesias. Moreover, dyskinetic animals showed higher striatal hydrolyzing cGMP-phosphodiesterase but not hydrolyzing cAMP-phosphodiesterase activity, suggesting that low cGMP but not cAMP levels could be due to increased catabolism. However, expressions of isozyme phosphodiesterase-1B and -10A highly and specifically located in the basal ganglia were not changed after levodopa in dyskinetic and eukinetic animals: accordingly, selective inhibitors of phosphodiesterase-1B and -10A were ineffective on levodopa dyskinesias. Therefore, the isozyme(s) expressing higher cGMP-phosphodiesterase activity in the striatum of dyskinetic animal should be determined. These observations suggest that dopamine-mediated processes of synthesis and/or degradation of cAMP/cGMP could be acutely impaired in levodopa dyskinesias, opening new ways to understanding physiopathology and treatment.


Non-lithifying microbial ecosystem dissolves peritidal lime sand.
Microbialites accrete where environmental conditions and microbial metabolisms promote lithification, commonly through carbonate cementation. On Little Ambergris Cay, Turks and Caicos Islands, microbial mats occur widely in peritidal environments above ooid sand but do not become lithified or preserved. Sediment cores and porewater geochemistry indicated that aerobic respiration and sulfide oxidation inhibit lithification and dissolve calcium carbonate sand despite widespread aragonite precipitation from platform surface waters. Here, we report that in tidally pumped environments, microbial metabolisms can negate the effects of taphonomically-favorable seawater chemistry on carbonate mineral saturation and microbialite development.


Parkinsonism and rest tremor secondary to supratentorial tumours sparing the basal ganglia.
Intracranial neoplasms are an uncommon cause of symptomatic Parkinsonism and rest tremor. We found an incidence of 0.3% in a prospective evaluation of 907 patients with supratentorial tumours. Eight patients with Parkinsonism and rest tremor secondary to supratentorial tumours sparing the basal ganglia are reported. Neuro-imaging revealed compression and distortion of the basal ganglia by large tumours which were identified histopathologically as meningiomas in four patients and as an epidermoid, a fibrillary astrocytoma, an anaplastic oligodendroglioma and a glioblastoma. Six patients underwent tumour removal by craniotomy, in two the histopathology was obtained by stereotactic biopsy. Four patients were free of Parkinsonian symptoms and signs on long-term follow-up. The possible pathophysiological mechanisms involved are discussed. Since some of these patients closely resemble cases of idiopathic Parkinson's disease, and the movement disorder can precede other symptoms and signs or will remain isolated in the further course, the diagnosis of an intracranial neoplasm was generally delayed in these patients. Increased awareness of this rare entity may lead to an earlier diagnosis. Early computed tomography in patients with Parkinsonism might help to detect these patients with a potentially curable cause of their condition.


Utilization of recombinant activated factor VII for intracranial hematoma evacuation in coagulopathic nonhemophilic neurosurgical patients with normal international normalized ratios.
Recombinant activated Factor VII (rFVIIa) has recently gained popularity for rapid reversal of coagulopathy during operative neurosurgery. Patients undergoing chronic subdural hematoma (CSDH) or epidural hematoma (EDH) evacuation often have their coagulation status judged by preoperative international normalized ratio (INR). We present our experience in two patients with significant clinical coagulopathy who were successfully reversed with rFVIIa in the setting of normal INR. Patient one was a 79-year-old man with history of prostate cancer and three previous operative left CSDH evacuations, each complicated by coagulopathic bleeding, who presented with new-onset left EDH. Patient two was a 27-year-old woman with relapsed acute myelogenous leukemia with bilateral CSDH and mass effect on MRI. Neither patient had hemophilia, and preoperative INR was 1.2 in each case. Both patients underwent evacuation in the operating room, preceded by rFVIIa administration. Patient one underwent removal of his previous craniotomy flap followed by EDH evacuation. In patient two, coagulopathic bleeding upon surgical approach necessitated an additional dose of rFVIIa. Burrhole evacuation was well-tolerated with visible brain re-expansion following irrigation. Each case occurred with minimal blood loss and relatively easy hemostasis, with postoperative CT and clinical course revealing adequate evacuation. Neither patient experienced thromboembolic complications or required re-operation. These two patients are the first to be examined for the use of rFVIIa for reversal of clinical coagulopathy in the setting of normal INR. Our experience suggests that normal INR should not be a deterrent for patients to receive rFVIIa in the setting of strong neurosurgical suspicion for underlying clinical coagulopathy.


Editorial: cell movement.
Cell movement is a fundamental process of normal cellular physiology and pathophysiology. Abnormal regulation of cell migration is a common denominator of many medical disorders, including cancer metastasis, autoimmune disease and inflammation. Increased interest in the targeting of cell migration and invasion, which has potential for therapeutic intervention in many diseases are behind this special themed issue. Thus, the focus of this issue is centred on the control of cellular cytoskeletal dynamics and cellular or tissue microenvironment sensors. Novel therapeutic opportunities targeting regulation of cell migration are discussed including the emerging roles of tetraspanins, phosphoinositides, transient receptor potential cation channels, stromal interaction molecules and calcium release-activated calcium modulators. Better understanding of these regulatory factors will hopefully bring greater attention to strategically targeting aberrant cell migration, which has many therapeutic implications for common human diseases. This article is part of a themed section on Cytoskeleton, Extracellular Matrix, Cell Migration, Wound Healing and Related Topics. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-24


Store-operated Ca2+ entry is exaggerated in fresh preglomerular vascular smooth muscle cells of SHR.
Regulation of preglomerular vasomotor tone vessels ultimately control glomerular filtration rate, sodium reabsorption and systemic blood pressure. To gain insight into the complex renal hemodynamic factors that may result in hypertension, we studied calcium signaling pathways. Fresh, single, preglomerular vascular smooth muscle cells (VSMC) were isolated from 5- to 6-week-old SHR and WKY utilizing a magnetized microsphere/sieving technique. Cytosolic Ca2+ ([Ca2+]i) was measured with fura-2 ratiometric fluorescence. To examine store-operated calcium entry (SOC), VSMC were activated in calcium-free buffer containing nifedipine. To deplete the sarcoplasmic reticulum (SR) of Ca2+, vasopressin-1 receptor agonist [V1R; inositol trisphosphate (IP3)-mediated mobilization], ryanodine (non-IP3 induced mobilization), and cyclopiazonic acid (CPA; Ca2+-ATPase inhibition) were utilized. Addition of external calcium followed by quenching of the fura/Ca2+ signal with Mn2+ permitted assessment of divalent cation entry via SOC. V1R caused greater mobilization in SHR than WKY (P < 0.01) as well as greater calcium entry (P < 0.001). Ryanodine and CPA both caused SR calcium depletion that was not statistically different between strains, but absolute calcium entry through SOC was more than double in SHR following either maneuver (P < 0.001). 2-Amino-ethoxybiphenyl borane (2-APB), an inhibitor not only of IP3 receptors, but also of SOC, blocked calcium entry in the ryanodine and CPA experiments independent of IP3. As well, Gd3+, a selective inhibitor of SOC, inhibited the Ca2+ response. We also studied L-channel calcium entry stimulated by V1R. The total calcium response was greater in SHR as was the absolute inhibition by nifedipine. As a percent of the total response, participation of L-type channels sensitive to nifedipine was about 45% in both strains of rat. Utilizing three separate mechanisms to deplete the SR of Ca2+ in order to activate SOC, we show for the first time, that SOC is exaggerated in preglomerular VSMC of young SHR.


Automated operative phase identification in peroral endoscopic myotomy.
Artificial intelligence (AI) and computer vision (CV) have revolutionized image analysis. In surgery, CV applications have focused on surgical phase identification in laparoscopic videos. We proposed to apply CV techniques to identify phases in an endoscopic procedure, peroral endoscopic myotomy (POEM). POEM videos were collected from Massachusetts General and Showa University Koto Toyosu Hospitals. Videos were labeled by surgeons with the following ground truth phases: (1) Submucosal injection, (2) Mucosotomy, (3) Submucosal tunnel, (4) Myotomy, and (5) Mucosotomy closure. The deep-learning CV model-Convolutional Neural Network (CNN) plus Long Short-Term Memory (LSTM)-was trained on 30 videos to create POEMNet. We then used POEMNet to identify operative phases in the remaining 20 videos. The model's performance was compared to surgeon annotated ground truth. POEMNet's overall phase identification accuracy was 87.6% (95% CI 87.4-87.9%). When evaluated on a per-phase basis, the model performed well, with mean unweighted and prevalence-weighted F1 scores of 0.766 and 0.875, respectively. The model performed best with longer phases, with 70.6% accuracy for phases that had a duration under 5 min and 88.3% accuracy for longer phases. A deep-learning-based approach to CV, previously successful in laparoscopic video phase identification, translates well to endoscopic procedures. With continued refinements, AI could contribute to intra-operative decision-support systems and post-operative risk prediction.


Is there evidence to link acid reflux with chronic sinusitis or any nasal symptoms? A review of the evidence.
Acid reflux into the oesophagus, larynx, pharynx or nasopharynx has been suggested as a causal factor in chronic rhino-sinusitis (CRS), which can then be refractory to nasal treatments. The aim of this review was to conclude on the strength of the link between GORD, LPR, nasopharyngeal reflux, nasal symptoms and CRS. Medline and Embase search. Nineteen papers describing varying studies on CRS, GORD, LPR and PPI therapy were found. Four adult case-controlled studies showed more acid reflux events/symptoms in refractory CRS patients. Paediatric cohort studies showed more reflux events in rhinosinusitis patients than the general paediatric population, but they are not conclusive. Many papers do not use robust CRS diagnostic criteria for inclusion into studies and take no confounding factors into consideration. The evidence of a link is poor with no good randomised controlled trials available. The few adult studies that show any link between acid reflux and nasal symptoms are small case-controlled studies with moderate levels of potential bias. There is not enough evidence to consider anti-reflux therapy for adult refractory CRS and there is no evidence that acid reflux is a significant causal factor in CRS.


Washability and fabric-staining properties of a novel phospholipid-structured coal tar formulation.
Coal tar is one of the most preferred and frequently used medicinal agents in various dermatological diseases. However, the coal tar formulations available for clinical use suffer from the limitation of staining clothes and skin, eventually leading to a high degree of patient non-compliance. To test the staining property of a lecithinized formulation vis-a-vis a conventional formulation of coal tar employing different types of fabric. Six fabrics with different blends of cotton and polyester were employed to test the staining and washability of two coal tar formulations following application for 24 hours and 48 hours. The study revealed the distinct superiority of the lecithinized coal tar formulation vis-a-vis the conventional marketed formulation due to its markedly reduced staining and easier washability. A significant reduction in the staining of fabrics containing polyester was observed with the lecithinized formulation, with the stain becoming progressively worse as the proportion of polyester in the fabric increased. The stains washed off completely with detergent in the case of the lecithinized coal tar formulation, whereas stains from the conventional coal tar formulation remained intact. The developed lecithinized formulation, owing to its superior non-staining and washability characteristics, would potentially increase the acceptability of coal tar amongst patients.


Partial agonism in the glucagon receptor system is a consequence of the two-state rat hepatic receptor.
We have previously demonstrated that the glucagon receptor binds hormone to form a low affinity complex which, by a time- and temperature-dependent mechanism, is converted to a high affinity complex (Horwitz, E.M., Jenkins, W.T., Hoosein, N.M., and Gurd, R.S. (1985) J. Biol. Chem. 260, 9307-9315). In this report we have investigated the effects of agonist concentration, potency, and intrinsic activity on the characteristics of the two, interconvertible states of the glucagon receptor. As the glucagon concentration is increased from 0.02 to 0.50 nM, the initial velocity of binding increases. The conversion of a low affinity to a high affinity complex is the rate-limiting step in the overall binding reaction and approaches its maximal velocity as the hormone concentration exceeds 0.20 nM. At equilibrium, 87-90% of the hormone-receptor complexes are in the high affinity state at all hormone concentrations examined. [S-methyl-Met27]glucagon, a full agonist with reduced potency, binds to the two-state system in a manner analogous to that of native glucagon. The binding of N alpha-biotinyl-N epsilon-acetimidoglucagon, a partial agonist with reduced potency, effects a two-state system where the high affinity state accounts for only 35% of the total hormone-receptor complexes at equilibrium. We conclude that the formation of the high affinity complex is the rate-limiting step involved in glucagon binding; reduction in binding potency with full agonism is due to a reduction in the affinity of the ligand for the unoccupied receptor and not to an alteration of the interconversion of the two states, and decreased intrinsic activity is due to a quantitative decrease in conversion of the low to high affinity state.


Assessment of biomarkers of early kidney damage and exposure to pollutants in artisanal mercury mining workers from Mexico.
Artisanal mercury mining (AMM) is an informal economic activity that employs low technology and limited protection, and poses a risk to workers and their families; due to the extraction process, these scenarios involve exposure to complex mixtures of pollutants that synergistically aggravate the health of miners and people living near the site. Although mercury is the predominant pollutant, there are others such as polycyclic aromatic hydrocarbons (PAHs), toluene, arsenic, and lead which have been classified as nephrotoxic pollutants. Therefore, the purpose of this research was to evaluate the association between exposure to a complex mixture of pollutants (mercury, lead, arsenic, PAHs, and toluene) and kidney damage in artisanal Hg mining workers through early kidney damage proteins (KIM-1, OPN, RBP-4, NGAL, and Cys-C). The results demonstrate the presence of OH-PAHs at concentrations of 9.21 (6.57-80.63) μg/L, hippuric acid as a biomarker of exposure to toluene, As and Pb (655. 1 (203.8-1231) mg/L, 24.05 (1.24-42.98) g/g creatinine, and 4.74 (2.71-8.14) g/dL, respectively), and urinary Hg (503.4 (177.9-878.7) g/g creatinine) in the study population. As well as biomarkers of kidney damage, NGAL and RPB-4 were found in 100% of the samples, KIM-1 and Cys-C in 44.1%, and OPN in 41% of the miners. Significant correlations were found between several of the evaluated pollutants and early kidney damage proteins. Our results demonstrate the application of the early kidney damage biomarkers for the assessment of damage caused by the exposure to mixtures of pollutants and, therefore, the urgent need for monitoring in AMM areas.


Design of Sonosensitizers Integrated with Resveratrol Motif for Synergetic Sonodynamic Therapy and Nuclear Factor Kappa B Transcription Suppression of Breast Cancer.
Sonodynamic therapy (SDT) has been recognized as a spatial-temporal and noninvasive modality for the treatment of deep-seated tumors. However, current sonosensitizers suffer from low sonodynamic efficacy. Herein, we reported the design of nuclear factor kappa B (NF-κB) targeting sonosensitizers (TR1, TR2, and TR3) by integrating a resveratrol motif into a conjugated electron donor-acceptor (triphenylamine benzothiazole) skeleton. Among these sonosensitizers, TR2 with two resveratrol units in one molecule was the most potent for inhibiting NF-κB signaling. Owing to the synergy of high sonodynamic efficacy and NF-κB activation inhibition, TR2 displayed a remarkable sonocytotoxicity to MCF-7 breast cancer cells. Xenograft mice studies demonstrated that TR2 had excellent anticancer potency and biosafety. This study thus opens up a new avenue for the development of efficient organic sonosensitizers for cancer ablation.


Adult onset Leigh syndrome with mitochondrial DNA 8344 A>G mutation.
We report a pedigree of adult-onset Leigh syndrome (LS) with mitochondrial mutation 8344 A>G. A 38-year-old woman presented with optic neuropathy, weakness and cognitive impairment. Family history of optic neuropathy and systemic involvement was suggestive of mitochondrial encephalopathy. Genetic and radiologic studies showed m.8344 A>G mutation with characteristics of LS. To our knowledge this is the first case of adult-onset LS demonstrating the m.8344 A>G mutation.


FTO effect on energy demand versus food intake.
An intronic single nucleotide polymorphism (SNP) (rs9939609) close to the fat mass and obesity associated gene (FTO) was the first SNP to be discovered with common variants linked to body mass index; at least seven studies in humans have implicated this SNP with variations in food intake and satiety, and four studies have rejected an effect on energy expenditure normalized for body weight. Fischer et al. recently constructed a mouse in which the homologous Fto gene was inactivated (Fto(-/-)) and showed that these mice were protected from obesity. This observation strongly implicates the effects of the intronic SNP rs9939609 as arising due to an effect on the closest gene (FTO). However, the suggested mechanism underlying this effect in mice was opposite to that in humans. The Fto(-/-) mice showed no significant differences in food intake relative to wild-types litter-mates but had an elevated metabolic rate. The apparent contrasting effects of the gene in humans and mice is worthy of closer investigation.


Simultaneous perfusion of rat isolated superior mesenteric arterial and venous beds: comparison of their vasoconstrictor and vasodilator responses to agonists.
1. A new isolated perfused preparation is described that allows a direct comparison to be made of the responses of the perfused arterial and retrogradely perfused venous circulations of the rat superior mesenteric vascular bed. 2. In experiments comparing the responses of the intact arterially perfused mesentery and small intestine to those of the same preparation following removal of the intestine and division of the circulations, the increases in perfusion pressure produced by arginine-vasopressin (30 pmol) and noradrenaline (1 nmol) were retained by the arterial circulation and those induced by angiotensin II (30 pmol) by the venous circulation. Endothelin-1 (30 pmol) constricted both portions of the vasculature but the prolonged nature of its response was associated with only the venous vessels. 3. In the simultaneously perfused arterial and venous preparation arginine vasopressin (3-100 pmol) was a selective constrictor of the arterial circulation and angiotensin II (3-100 pmol) of the venous circulation. In addition, noradrenaline (0.3-10 nmol), 5-hydroxytryptamine (0.3-10 nmol) and KCl (1-60 micromol) were more active as constrictors of the arterial than the venous vessels, and U46619 (10-300 pmol) a more active constrictor of the venous than the arterial vessels. Endothelin-1 (3-100 pmol) constricted both the arterial and venous portions of the vasculature but was significantly longer acting as a venoconstrictor than an arterioconstrictor. 4. Angiotensin I (300 pmol) caused constrictions of the venous circulation which were dependent upon the presence of angiotensin converting enzyme for captopril (10 microM) abolished constrictions caused by angiotensin I but not by angiotensin II. 5. In preparations preconstricted by U46619 (0.3-3 microM), acetylcholine (0.01-100 nmol), bradykinin (0.001-nmol), sodium nitroprusside (0.01-lOnmol) or isoprenaline (1-l00pmol) produced dose-related dilatations of both the arterial and the venous vasculatures, whereas adenosine diphosphate (ADP, 0.01-lOOnmol) caused dose-dependent dilatations of the arterial circulation but principally constrictions of the venous circulation. The dilatations caused by acetylcholine and bradykinin in both portions of the circulation, and by ADP in the arterial circulation, were endothelium-dependent as they were inhibited by gossypol (3 microM), whereas dilatations to sodium nitroprusside were not. 6. This preparation allows the responses of the arteries and veins of a single perfused mesenteric bed to be compared. In addition, with this preparation it is possible to demonstrate that veins, as well as arteries, show significant endothelium-dependent relaxations. It is concluded that the venous portion of the vasculature is significantly involved in the responses of the intact circulation.


Evaluation of training, patient and practitioner perspectives on community-based monitoring of patients with stable age-related macular degeneration compared to hospital-based care: The FENETRE study report no. 1.
Describe the development, delivery, acceptability and evaluation of a modular training programme for community-based, non-medical practitioners monitoring patients with quiescent neovascular age related macular degeneration (QnAMD). Also, report on a qualitative process evaluation conducted during the pilot phase of a randomised control trial (the FENETRE Study) exploring patient and practitioner acceptability of community-based QnAMD care relative to hospital-based care. Learning outcomes from The College of Optometrists' Medical Retina higher qualifications and the Royal College of Ophthalmologists' Common Clinical Competency Framework were used to develop a competency framework for QnAMD care. Training was delivered online, comprising six asynchronous lectures followed by two synchronous case-based discussion webinars, with an accredited assessment of 24 case vignettes. An anonymous evaluation survey was conducted with the first two FENETRE cohorts (n = 38). Separately, we undertook a qualitative process evaluation, sampling purposively in four hospitals and five community-based practices, interviewing nine patients and eight practitioners. Survey responses (n = 26) showed community optometrists were very satisfied (n = 12; 46%) or satisfied (n = 14; 54%) with the training; feedback reflected by qualitative process evaluation data. Overall, optometrists also felt either confident (n = 15; 58%) or very confident (n = 8; 31%) in conducting AMD monitoring appointments following training, a finding also corroborated by interview data from optometrists participating in the initial pilot phase roll-out. Optometrists identified patient convenience and alleviating pressures in hospital care as the primary reasons for acceptability of community pathways. Data from patients entering community practices suggested they largely found this at least as safe and convenient as hospital care, although some patients randomised to hospital care perceived that as safer. This pilot study has shown the development and implementation of a collaborative community monitoring model is feasible, with satisfaction from community optometrists for training and accreditation, and broad acceptance for the pathway by both patients and practitioners.


Cystic Hygroma with Multiple Benign Bone Lymphangiomas in an Adult Patient: A Rare Entity in the Differential Diagnosis of Multiple Osseous Lesions in Oncology Practice.
Cystic lymphangioma presenting with multiple bone lesions in an adult patient is a rare occurrence, with a limited number of reported cases in the literature. In this case report, we describe a 32-year old female patient with chronic neck and pelvic pain, and multiple lytic bone lesions on radiological imaging, which were eventually discovered to originate from cystic hygroma and widespread bone lymphangiomas that were present for more than 10 years. It should be kept in mind that there may be multiple benign causes of differential diagnosis in patients presenting with findings suggestive of diffuse bone metastasis. Misdiagnosis may cause the patient to receive unnecessary treatments, especially radiotherapy. In this case, we reached the diagnosis of benign disease, diffuse bone lymphangiomatosis. For this purpose, we also examine the long and stable medical history of the patient with the findings of BT, ultrasound, and bone scintigraphy. We think that as long as there are no stable and serious results ofclinical and radiological findings of the patient, the patient should be approached with medical follow-up without treatment.


Macrophage membrane proteins: possible role in the regulation of priming for enhanced respiratory burst activity.
Brief exposure of macrophages to the proteolytic enzymes papain, elastase, or trypsin primed them for enhanced production of superoxide anion (O2-) in response to stimulation by phorbol myristate acetate (PMA). Priming by trypsin was achieved at 0 degree C, at which temperature trypsin functions as a protease but is not internalized, supporting the concept that protease priming depends on modification of the plasma membrane. Analysis of external membrane proteins after radioiodination of intact cells and separation by gel electrophoresis indicated that papain treatment of macrophages resulted in the cleavage of a membrane protein with a molecular weight of approximately 305K. Membranes from macrophages primed by elicitation with Corynebacterium parvum also demonstrated a reduced amount of the membrane protein at approximately 305 kDa, as well as a reduction of a protein at about 270 kDa. Lipopolysaccharide-elicited macrophages showed a reduced amount of a protein at about 175 kDa. Continuous spectrophotometric assays of O2- release from adherent macrophages indicated that after exposure to a stimulus, protease-treated cells produced O2- more quickly than did control cells (reduced lag time). Inhibitors of protein synthesis augmented the priming effect of papain when added with the protease. These results suggest that protease-induced priming results from inactivation of a membrane protein (or proteins) that exerts a down-regulating effect on the respiratory burst.


Mechanisms of selection and differentiation in germinal centers.
The choice between death and survival, a feature of early B cell development, is a choice also faced by mature B cells. If they survive this early developmental decision, mature B cells then face a second choice: either to undergo either terminal differentiation into plasma cells or to differentiate into memory B cells. Antigens, T cell signals (cytokines, CD40 ligand and Fas ligand) as well as the activation state of B cells determine their ultimate fate.


[Establishing longitudinal cohort studies based on domestic and foreign experiences and promoting the prevention and control of cardiovascular diseases in childhood].
There is a "trajectory" of cardiovascular risk factors from childhood to adulthood, and cardiovascular disease in adulthood originates in childhood. Several childhood cardiovascular follow-up cohorts have been established at home and abroad and participants have been followed up to middle-age or early old-age period, which have provided evidence support for prevention of cardiovascular disease in adulthood. However, at present, Chinese residents are in nutritional transition period. Given the evolving socio-economic context in China and the differences in growth and development patterns between contemporary Chinese children and western children or Chinese children in the 1990s, it is necessary to establish new childhood cardiovascular follow-up cohorts with Chinese features, to inform prevention of cardiovascular disease in Chinese adults.


Structure and thermodynamics of transient protein-protein complexes by chemometric decomposition of SAXS datasets.
Transient biomolecular interactions play crucial roles in many cellular signaling and regulation processes. However, deciphering the structure of these assemblies is challenging owing to the difficulties in isolating complexes from the individual partners. The additive nature of small-angle X-ray scattering (SAXS) data allows for probing the species present in these mixtures, but decomposition into structural and thermodynamic information is difficult. We present a chemometric approach enabling the decomposition of titration SAXS data into species-specific information. Using extensive synthetic SAXS data, we demonstrate that robust decomposition can be achieved for titrations with a maximum fraction of complex of 0.5 that can be extended to 0.3 when two orthogonal titrations are simultaneously analyzed. The effect of the structural features, titration points, relative concentrations, and noise are thoroughly analyzed. The validation of the strategy with experimental data highlights the power of the approach to provide unique insights into this family of biomolecular assemblies.


Suppression of lymphocyte proliferation through the nitric oxide synthesizing pathway.
The amino acid L-arginine can be metabolized through a nitric oxide-synthesizing pathway (NOSP) to produce L-citrulline and reactive nitrogen intermediates. Among these nitrogen intermediates, NO has been implicated as the mediator of a variety of biological effects including vasodilatation, inhibition of platelet aggregation, tumor cytotoxicity and microbiostasis by activated macrophages and generalized suppression of macrophage functions. Work reported here demonstrated that the NOSP is expressed in Con A-stimulated rat splenic cell (SC) cultures and is associated with a profound suppression of lymphocyte proliferation. Inhibition of the NOSP by NG-monomethyl-L-arginine (N-MMA) or binding of its products by hemoglobin, either free in solution or contained in RBC, markedly promotes rat SC mitogenic response to Con A. Mouse SC do not express the NOSP under the conditions used in these experiments. Consequently, their mitogenic response to Con A is not affected by N-MMA or hemoglobin. These data confirm and expand the apparent role of NO as a regulator of immune responses while indicating potentially important species differences.


Acquired Gastric Dieulafoy-Like Lesion due to Aberrant Blood Supply Diverted From the Left Phrenic Artery to an Enlarged Splenule.
Dieulafoy lesion is an aberrant submucosal vessel that can erode into the overlying tissue leading to hemorrhage. It is a rare but important cause of gastrointestinal bleeding. We present a case of a patient who developed an acquired Dieulafoy lesion 39 years after splenectomy. Abdominal computed tomography showed an aberrant vessel from a branch of the left phrenic artery, coursing through the gastric fundus to supply a splenule. Angiography with embolization of the aberrant vessel resulted in no further bleeding.


Source apportionment of carbonaceous aerosols in diverse atmospheric environments of China by dual-carbon isotope method.
Carbonaceous aerosols are major components in PM2.5 of both polluted and clean atmosphere. Accurate source apportionment of carbonaceous aerosols may support effective PM2.5 control. Dual-carbon isotope method (14C and 13C) was adopted to identify the contribution of three main air pollution sources biogenic and biomass (fbb), liquid fossil (fliq.fossil) and coal (fcoal). The aerosol samples were collected at three types of sites with distinctly different degree of air pollution: urban, rural and regional background. The seasonal variation of source apportionment of the carbonaceous aerosols in urban Beijing was discussed. Modern biogenic and biomass made an absolute dominance of 92.9 ± 0.5% contribution to the carbonaceous aerosols at the background site Mt. Yulong due to long-range transport from Southeast Asia. The three main sources contributed jointly to the atmospheric carbonaceous aerosols at the rural site Wangdu and the urban site Beijing. The biogenic and biomass source was the major contribution in summer (47.0 ± 0.3%) and autumn (49.3 ± 0.3%) of Beijing, while coal source increased from summer (26.8 ± 13.8%) to autumn (34.7 ± 11.5%). Heating significantly increased the coal source to the dominant contribution (47.0 ± 16.9%) in winter of Beijing. Separate day and night time coal contributions were used to evaluate the two origins of coal combustion: industrial use vs. residential use. The results of source apportionment for carbonaceous aerosols provide scientific support for the prevention and control of air pollution.


Age-related changes in liver metabolism and antioxidant capacity of laying hens.
This study aimed to investigate the age-related changes of hepatic metabolism and antioxidant capacity of laying hens at 3 different ages. A total of 192 Hy-line Brown laying hens were assigned into 3 groups: 1) 195-day-old (D195 group); 2) 340-day-old (D340 group); 3) 525-day-old (D525 group). Each group replicated 8 times with 8 hens at the same age. Higher activity of aspartate aminotransferase and lower contents of total protein and globulin were observed in the serum of 525-day-old hens in comparison with their 195-day-old counterparts (P < 0.05). The 525-day-old hens accumulated higher contents of total cholesterol and triglyceride in the liver than 195-day-old birds. Additionally, compared with hens from D195 or D340 group, 525-day-old birds exhibited a lower circulating estradiol level (P < 0.05). For antioxidant capacity, birds in the D525 group showed a higher malondialdehyde concentration in both serum and liver as compared with D195 or D340 group (P < 0.05). The 525-day-old hens also exhibited lower glutathione peroxidase activities in both serum and liver when compared with 195-day-old birds (P < 0.05). Simultaneously, there was a decline of hepatic superoxide dismutase activity in the D525 group in comparison with D195 group (P < 0.05). Compared with 195-day-old counterparts, 340-day-old birds upregulated the mRNA abundance of nuclear factor erythroid-2 related factor 2 and glutathione peroxidase 1 in the liver (P < 0.05). In contrast, hens from D525 group showed the downregulation of hepatic nuclear factor erythroid-2 related factor 2, NAD(P)H quinone dehydrogenase 1, and superoxide dismutase 1 when compared with D340 group (P < 0.05). These results indicated that increasing age can adversely affect liver metabolism and function of laying hens.


Malignant astrocytoma-derived region of common amplification in chromosomal band 17p12 is frequently amplified in high-grade osteosarcomas.
Recently, we reported a new amplification event that involves marker D17S67 in 17p12 in three malignant astrocytomas of patients with a very short survival. The amplified region may contain an oncogene implicated in astrocytoma tumorigenesis. To determine the extent of the amplified regions, we constructed a yeast artificial chromosome contig spanning the D17S67 region and tested the amplification status of markers that map to the contig. We determined a commonly amplified region between markers D17S1311 and D17S1875 with a maximal length of 1,630 kb. By using marker 745R, from within the commonly amplified region, we screened 60 high-grade astrocytomas but could not detect additional tumors with the amplification event. This suggests that the incidence of the amplification event in high-grade astrocytoma is low (5%). It has recently been shown by comparative genomic hybridization that amplification of 17p11-p12 is a frequent event in high-grade osteosarcomas, occurring in 20-30% of cases. Since the commonly amplified region is within 17p12, we tested 745R in 20 osteosarcomas, including 6 lung metastases, and detected amplification in 9 cases (45%). Marker 745R was found to be amplified in 4 of the 6 lung metastases (66%). From this frequent involvement and the association with clinically aggressive astrocytomas we conclude that for both tumor types presence of the amplification event seems to correlate with aggressive clinical behaviour.


Serum biomarkers of remodeling in severe asthma with fixed airway obstruction and the potential role of KL-6.
Over 3% of asthmatic patients are affected by a particularly severe form of the disease ("severe asthma", SA) which is often refractory to standard treatment. Airway remodeling (AR), which can be considered a critical characteristic of approximately half of all patients with SA and currently thought to be the main mechanism triggering fixed airway obstruction (FAO), seems to be a key factor affecting a patient's outcome. Despite the collective efforts of internationally renowned experts, to date only a few biomarkers indicative of AR and no recognizable biomarkers of lung parenchymal remodeling have been identified. This work examines the pathogenesis of airway and lung parenchymal remodeling and the serum biomarkers that may be able to identify the severe asthmatic patients who may develop FAO. The study also aims to examine if Krebs von den Lungen-6 (KL-6) could be considered a diagnostic biomarker of lung structural damage in SA.


High doses of butyrate induce a reversible body temperature drop through transient proton leak in mitochondria of brain neurons.
Sodium butyrate (SB) is a major product of gut microbiota with signaling activity in the human body. It has become a dietary supplement in the treatment of intestinal disorders. However, the toxic effect of overdosed SB and treatment strategy remain unknown. The two issues are addressed in current study. SB (0.3-2.5 g/kg) was administrated through a single peritoneal injection in mice. The core body temperature and mitochondrial function in the brown adipose tissue and brain were monitored. Pharmacodynamics, targeted metabolomics, electron microscope, oxygen consumption rate and gene knockdown were employed to dissect the mechanism for the toxic effect. The temperature was reduced by SB (1.2-2.5 g/kg) in a dose-dependent manner in mice for 2-4 h. In the brain, the effect was associated with SB elevation and neurotransmitter reduction. Metabolites changes were seen in the glycolysis, TCA cycle and pentose phosphate pathways. Adenine nucleotide translocase (ANT) was activated by butyrate for proton transportation leading to a transient potential collapse through proton leak. The SB activity was attenuated by ANT inhibition from gene knockdown or pharmacological blocker. ROS was elevated by SB for the increased ANT activity in proton leak in Neuro-2a. Excessive SB generated an immediate and reversible toxic effect for inhibition of body temperature through transient mitochondrial dysfunction in the brain. The mechanism was quick activation of ANT proteins for potential collapse in mitochondria. ROS may be a factor in the ANT activation by SB.


Renal cell carcinoma in children, adolescents and young adults: a National Cancer Database study.
We compared the presentation and outcomes of patients younger than 21 years with renal cell carcinoma and determined risk factors associated with mortality. We searched the National Cancer Database for patients diagnosed with renal cell carcinoma between 1998 and 2011. We evaluated patients younger than 30 years with renal cell carcinoma, including clear cell, chromophobe, papillary and not otherwise specified subcategories. We used logistic regression to compare presenting cancer, demographics and treatment variables in patients 0 to 15 years, 15 to 21 years and 21 to 30 years old. Cox regression analysis was used to determine risk factors for mortality in patients younger than 21. Of 3,658 patients younger than 30 years included in the study 161 were younger than 15 and 337 were 15 to 21 years old. A higher proportion of younger patients had renal cell carcinoma not otherwise specified and papillary histology compared to those 21 to 30 years (p < 0.001). Younger patients presented with higher stage (p < 0.0001), higher grade (p < 0.0001) and larger tumors (p < 0.0001) than those 21 to 30 years. A higher percentage of younger patients underwent lymph node dissection (p < 0.0001) or chemotherapy as first-line treatment (p < 0.0001) compared to those 21 to 30 years. Cox regression analysis demonstrated that stage 4 presentation, government insurance status, nonchromophobic pathology results and not undergoing surgery as first-line treatment were independently associated with increased mortality in patients younger than 21 years. Children and adolescents with renal cell carcinoma present with more advanced disease than those 21 to 30 years old. In patients younger than 21 years mortality was associated with the nonchromophobe histological subtype, stage 4 disease, government insurance and not undergoing surgery as first-line therapy.


Ginkgolide B treatment regulated intestinal flora to improve high-fat diet induced atherosclerosis in ApoE-/- mice.
Intestinal flora plays a major role in cardiovascular diseases, like atherosclerosis (AS). Ginkgolide B (GB), a natural substance extracted from Ginkgo biloba L., is recently acknowledged as a potential therapeutic drug of AS. However, the underlying mechanism of GB is not fully clear. Thus, we evaluated whether the antiatherosclerotic effect of GB was related to alterations in gut microbial structure and if so, whether specific bacterial taxa contributed to the beneficial effects of GB. We constructed a high fat diet (HFD)-induced ApoE-/- mice model to explore the antiatherosclerotic effects of GB. The effects of GB on lipid metabolism, hypoglycemia, inflammation and gut barrier integrity were also investigated. Then HFD inventories and high throughput sequencing of the V3-V4 region of the bacterial 16S ribosomal RNA gene were used to characterize how GB modulated gut microbiome composition. We found that HFD-induced dyslipidemia, inflammation, increased atherosclerotic plaque and gut barrier dysfunction were reduced by GB treatment. Moreover, GB treatment obviously inhibited the mRNA level and protein expression of FMO3, and then decreased the concentrations of TMA and TMAO, which was related to changes of gut microbiota in HFD-fed mice. Modulation of gut microbiota, specifically the increased abundance of Bacteroides and decreased abundance of Helicobacter, might contribute to the antiatherosclerotic effects of GB. Our findings first support the therapeutic value of GB on gut microbiota manipulation in treating AS, which still need to further study.


Co-occurrence of oculocutaneous albinism type 2 and mild sickle cell disease explained by HbS/βthal genotype in an individual from the Democratic Republic of Congo.
Oculocutaneous albinism type 2 (OCA2) is a pigmentation disorder characterized by hypopigmentation of the skin, hair and eyes and ocular features. Sickle cell disease (SCD) is caused either by homozygosity of the beta globin gene variant c.20A > T/p.Glu6Val giving rise to severe anemia or by combined abnormal hemoglobins (HbS/βthal) leading to mild SCD. We report a 45 years old female patient from the Democratic Republic of Congo affected with these two disorders. She presented with creamy white skin and numerous pigmented patches called dendritic freckles, nystagmus, foveal hypoplasia grade 2, photophobia and very poor visual acuity. Sequencing of the OCA2 gene identified the common exon 7 deletion and a new pathogenic variant c.1444A > C/p.Thr482Pro. She had mild SCD with a total Hb level of 101 g/l. Hbβ sequencing identified variants c.20A > T giving rise to HbS and c.315 + 1 G > A characteristic of β-thalassemia. A heterozygous 3.7 kb deletion of the α globin gene was also found. The combined Hbβ/α globin genotype explains the mild SCD phenotype. Co-occurrence of OCA2 and SCD raises the question whether the patient's phenotype simply results from the addition of the two diseases' phenotypes or whether interaction between the two diseases modulates the phenotype of each other.


Tumor lysis syndrome following cabazitaxel administration for metastatic castration-resistant prostate cancer: A case report.
Tumor lysis syndrome is a rare and potentially fatal complication of oncological treatment. It is characterized by biochemical changes associated with the rapid lysis of malignant cells, usually after chemotherapy. Tumor lysis syndrome is typically noted in patients with hematological malignancies, and it rarely occurs in patients with solid tumors. We report a case of tumor lysis syndrome after cabazitaxel administration for metastatic castration-resistant prostate cancer. To our knowledge, tumor lysis syndrome after cabazitaxel therapy has not been reported previously. The patient was a 77-year-old man who developed clinical tumor lysis syndrome after a single dose of cabazitaxel for metastatic castration-resistant prostate cancer. He was treated with hydration and the recombinant uricolytic agent rasburicase, and his condition improved. It is extremely important to assess the risk factors for tumor lysis syndrome and to perform active prevention procedures in order to avoid fatal outcomes. It may be beneficial to use rasburicase in patients with established tumor lysis syndrome.


Studying dynamic events in the developing myocardium.
Differentiation and conduction properties of the cardiomyocytes are critically dependent on physical conditioning both in vitro and in vivo. Historically, various techniques were introduced to study dynamic events such as electrical currents and changes in ionic concentrations in live cells, multicellular preparations, or entire hearts. Here we review this technological progress demonstrating how each improvement in spatial or temporal resolution provided answers to old and provoked new questions. We further demonstrate how high-speed optical mapping of voltage and calcium can uncover pacemaking potential within the outflow tract myocardium, providing a developmental explanation of ectopic beats originating from this region in the clinical settings.


Nontransplant surgical alternatives for heart failure.
Heart failure is a tremendous burden on society, and on the health care system in particular. Historically, medical treatments have been the only therapies available because patients were felt to be too high risk to undergo conventional cardiac surgical procedures. Cardiac transplantation remains an established therapy for certain patients with end-stage heart failure but it is limited by donor availability and the need for lifelong immunosuppression. Recent advances in myocardial protection, operative techniques, and perioperative care have made it possible for conventional surgery, such as coronary bypass, ventricular reconstruction, and valve repair, to be offered to many patients with advanced heart failure with good short- and long-term results. In 2005, few patients are inoperable.


Prevalence of Severe Acute Respiratory Syndrome Coronavirus 2 Antibodies Among Market and City Bus Depot Workers in Lima, Peru.
We report severe acute respiratory syndrome coronavirus 2 antibody positivity among market and city bus depot workers in Lima, Peru. Among 1285 vendors from 8 markets, prevalence ranged from 27% to 73%. Among 488 workers from 3 city bus depots, prevalence ranged from 11% to 47%. Self-reported symptoms were infrequent.


Derivatives of pheophorbide-a and pheophorbide-b from photocytotoxic Piper penangense extract.
In our screening program for new photosensitizers from Malaysian biodiversity for photodynamic therapy (PDT) of cancer, MeOH extracts of ten terrestrial plants from Cameron Highlands in Pahang, Peninsular Malaysia, were tested. In a short-term 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, 20 μg/ml each of these extracts were incubated in a pro-myelocytic leukemia cell-line, HL60, with or without irradiation with 9.6 J/cm(2) of a broad spectrum light. Three samples, Labisia longistyla, Dichroa febrifuga, and Piper penangense, were photocytotoxic by having at least twofold lower cell viability when irradiated compared to the unirradiated assay. The extract of the leaves of Piper penangense, a shrub belonging to the family Piperaceae and widely distributed in the tropical and subtropical regions in the world, was subsequently subjected to bioassay-guided fractionation using standard chromatography methods. Eight derivatives of pheophorbide-a and -b were identified from the fractions that exhibited strong photocytotoxicity. By spectroscopic analysis, these compounds were identified as pheophorbide-a methyl ester (1), (R,S)-13(2) -hydroxypheophorbide-a methyl ester (2 and 3), pheophorbide-b methyl ester (4), 13(2) -hydroxypheophorbide-b methyl ester (5), 15(2) -hydroxylactone pheophorbide-a methyl ester (6), 15(2) -methoxylactone pheophorbide-a methyl ester (7), 15(2) -methoxylactone pheophorbide-b methyl ester (8).


Sporadic Myotonic Dystrophy Type 2 in a Japanese Patient.
We herein report a Japanese patient with myotonic dystrophy type 2 (DM2), which is rare in Japan. A 64-year-oldman had proximal muscle weakness and grip myotonia. Electromyography showed myotonic discharges, but dystrophia-myotonica protein kinase (DMPK) was negative for CTG repeats. A muscle biopsy revealed increased central nuclei, pyknotic nuclear clumps and muscle fiber atrophy, mainly in type 2 fibers, raising the possibility of DM2. The diagnosis was genetically confirmed by the abnormal CCTG repeat size in cellular nucleic acid-binding protein (CNBP) on repeat-primed polymerase chain reaction, which was estimated to be around 4,500 repeats by Southern blotting.


Interstitial lung diseases.
Over 200 interstitial lung diseases, from ultra rare to relatively common, are recognised. Most interstitial lung diseases are characterised by inflammation or fibrosis within the interstitial space, the primary consequence of which is impaired gas exchange, resulting in breathlessness, diminished exercise tolerance, and decreased quality of life. Outcomes vary considerably for each of the different interstitial lung diseases. In some conditions, spontaneous reversibility or stabilisation can occur, but unfortunately in many people with interstitial lung disease, especially in those manifesting progressive pulmonary fibrosis, respiratory failure and death are a sad reality. Over the past 3 years, the field of interstitial lung disease has had important advances, with the approval of drugs to treat systemic sclerosis-associated interstitial lung disease, interstitial lung disease-associated pulmonary hypertension, and different forms of progressive pulmonary fibrosis. This Seminar provides an update on epidemiology, pathogenesis, presentation, diagnosis, disease course, and management of the interstitial lung diseases that are most frequently encountered in clinical practice. Furthermore, we describe how developments have led to a shift in the classification and treatment of interstitial lung diseases that exhibit progressive pulmonary fibrosis and summarise the latest practice-changing guidelines. We conclude with an outline of controversies, uncertainties, and future directions.


Surveillance of sexually transmitted diseases in Switzerland, 1973-1994: evidence of declining trends in gonorrhoea and syphilis.
The HIV/AIDS epidemic has led to growing interest in the epidemiology of sexually transmitted diseases (STDs) in Switzerland. STD surveillance data from three sources are presented: reports from six policlinics of dermatovenereology since 1973, laboratory reports of Neisseria gonorrhoeae, Treponema pallidum and Chlamydia trachomatis since 1988, and reports by the Swiss Sentinel Network between June 1991 and December 1993. The data indicate that there has been a decline in the number of cases of syphilis and, in particular, gonorrhoea since the early 1980s in Switzerland. Since many factors could explain the declines (e.g. more effective treatments, more widespread use of antibiotics, marked changes in behaviour such as increased levels of condom use) it is difficult to identify their exact causes. Evidence for two of the before-mentioned factors exists and these probably played important roles in the declines. Firstly, as a result of the emergence of penicillinase producing strains of N. gonorrhoeae, the introduction of new treatments for gonorrhoea in the early 1980s which were simpler to administer and more effective (in particular the use of spectinomycin). Secondly, the national AIDS prevention campaign which began in 1987 and has been associated with major increases in condom use in the Swiss population.


Blood protein conjugates and acetylation of aromatic amines. New findings on biological monitoring.
Internal stress of aromatic amines has so far been evaluated by their determination in blood or urine and by the degree of methemoglobin formation. Animal experiments have shown that these materials can form adducts and conjugates with proteins and nucleic acids. Our investigations show that these processes can also occur in human metabolism. For this the degree of such a formation of protein conjugates depends on an individually different potential for acetylation. In a positive sense it influences the magnitude and the rate of renal excretion of aminoaromates and their conjugates and metabolites formed by this metabolism. In contrast, only free nonacetylated aminoaromates can lead to the formation of conjugates with hemoglobin. These aminoaromates or their metabolites can then be detected quantitatively in intact erythrocytes during their lifespan. The degree of this protein conjugate formation correlates inversely with the magnitude of the acetylation potential depending on the availability of free non-acetylated aminoaromates. According to these results a clearer assessment of past stress or the presence of strain can be obtained with Biological Monitoring by a single determination of such hemoglobin adducts rather than by the traditional quantitative determination of aminoaromates or their metabolites in blood and/or urine or the methemoglobin concentration.


Evaluation dimensions for collaborative mental health services in primary care systems in latin america: results of a Delphi group.
This article presents the results of a Delphi group to identify the dimensions of an evaluation framework for collaborative mental health care (CMHC) in Latin America. A three-round Delphi process was implemented with 26 experts from Latin America and Canada to identify main areas of consensus, as well as disagreements, about the importance and feasibility of potential evaluation dimensions previously identified in Mexico, Nicaragua and Chile. Participants validated 40 evaluation dimensions. They strongly endorsed a comprehensive evaluation framework for CMHC in Latin America. This study represents a solid foundation for developing an evaluation framework for CMHC.


Early adverse life events and post-traumatic stress disorder in patients with constipation and suspected disordered defecation.
Early adverse life events (EALs) and post-traumatic stress disorder (PTSD) are associated with irritable bowel syndrome (IBS). Disordered defecation (DD) presents with symptoms of IBS or functional constipation (FC) and is associated with psychological distress. However, the role of trauma and stress in chronic constipation is poorly defined. We aimed to examine EALS, PTSD, and psychological symptoms in patients with constipation and suspected DD. We conducted a survey study among adults with constipation who completed anorectal manometry (ARM) and balloon expulsion testing (BET). Data were collected on socio-demographics, EALs, PTSD, bowel symptoms, quality of life, and anxiety and depression. We performed comparisons between individuals with normal versus abnormal ARM or BET, subgroup analysis by detailed ARM and BET findings, and latent class analysis using individual EAL domains. Among 712 eligible patients, 69 completed the study. EALs and provisional PTSD were present in 75.4% and 27.5%, respectively; rates did not differ between those with normal versus abnormal ARM or BET. Normal testing was associated with higher rates of specific EAL domains (emotional abuse and mental illness), higher depression scores, and poorer mental component scores in both primary and subgroup comparisons (all p < 0.05). Normal testing was associated with a lower likelihood of high-EAL latent class (p = 0.01) membership. Presence of IBS or FC did not influence associations. Early adverse life events and PTSD are prevalent in patients with constipation and suspected DD. Those with normal ARM and BET have higher rates of prior emotional abuse and poorer mental health.