Association of postural instability with asymptomatic cerebrovascular damage and cognitive decline: the Japan Shimanami health promoting program study.
Asymptomatic cerebral small-vessel disease (cSVD) in elderly individuals are potent risk factors for stroke. In addition to common clinical risk factors, postural instability has been postulated to be associated with cSVD in older frail patients. Here, we conducted a cross-sectional study to understand the possible link between postural instability and asymptomatic cSVD further, namely periventricular hyperintensity, lacunar infarction, and microbleeds, as well as cognitive function, in a middle-aged to elderly general population (n=1387). Postural instability was assessed based on one-leg standing time (OLST) and posturography findings. cSVD was evaluated by brain MRI. Mild cognitive impairment was assessed using a computer-based questionnaire, and carotid intima-media thickness as an index of atherosclerosis was measured via ultrasonography. Frequency of short OLST, in particular <20 s, increased linearly with severity of cSVD (lacunar infarction lesion: none, 9.7%; 1, 16.0%; >2, 34.5%; microbleeds lesion: none, 10.1%; 1, 15.3%; >2, 30.0%; periventricular hyperintensity grade: 0, 5.7%; 1, 11.5%; >2, 23.7%). The association of short OLST with lacunar infarction and microbleeds but not periventricular hyperintensity remained significant even after adjustment for possible covariates (lacunar infarction, P=0.009; microbleeds, P=0.003; periventricular hyperintensity, P=0.601). In contrast, no significant association was found between posturographic parameters and cSVD, whereas these parameters were linearly associated with OLST. Short OLST was also significantly associated with reduced cognitive function independent of covariates, including cSVD (P=0.002). Postural instability was found to be associated with early pathological changes in the brain and functional decline, even in apparently healthy subjects.


The angiotensin converting enzyme I/D polymorphism in long distance runners.
There is an assumption that ACE I/D polymorphism represents one of the possible genetic factors that might be associated with sports excellence. Recent studies have identified an increased frequency of I allele in elite endurance athletes, long distance runners, rowers and mountaineers. The aim of this study was to test the hypothesis that the ACE I/D polymorphism is associated with enhanced endurance performance. We examined this hypothesis by determining ACE I/D allele frequency in 215 marathon runners, 222 half-marathon runners and 18 inline skaters classified by performance (marathon competition results). ACE genotype and allele frequencies were compared with 252 healthy controls. ACE genotype frequency in the whole cohort did not differ from that in the sedentary controls (P < 0.56). However, there was an increase of the I/I genotype incidence amongst successful marathon runners scoring on places from 1st to 150th (P < 0.01). These findings were confirmed in the group of inline skaters, similarly demonstrating an increase of the I/I genotype (P < 0.01). There was no association found between half marathon runners and the ACE genotype (P < 0.59). An excess of the I allele in long distance runners confirms the association between the ACE I/D polymorphism and endurance sports performance.


Novel antibody hinge regions for efficient production of CH2 domain-deleted antibodies.
HuCC49 deltaCH2 is a heavy chain constant domain 2 domain-deleted antibody under development as a radioimmunotherapeutic for treating carcinomas overexpressing the TAG-72 tumor antigen. Mammalian cell culture biosynthesis of HuCC49 deltaCH2 produces two isoforms (form A and form B) in an approximate 1:1 ratio, and consequently separation and purification of the desired form A isoform adversely impact process and yield. A protein engineering strategy was used to develop a panel of hinge-engineered HuCC49 deltaCH2 antibodies to identify hinge sequences to optimize production of the form A isoform. We found that adding a single proline residue at Kabat position 243, immediately adjacent to the carboxyl end of the core middle hinge CPPC domain, resulted in an increase from 39 to 51% form A isoform relative to the parent HuCC49 deltaCH2 antibody. Insertion of the amino acids proline-alanine-proline (PAP) at positions 243-245 enhanced production of the form A isoform to 72%. Insertion of a cysteine-rich 15-amino acid IgG3 hinge motif (CPEPKSCDTPPPCPR) in both of these mutant antibodies resulted in secretion of predominantly form A isoform with little or no detectable form B. Yields exceeding 98% of the form A isoform have been realized. Preliminary peptide mapping and mass spectrometry analysis suggest that at least two, and as many as five, inter-heavy chain disulfide linkages may be present.


Enhanced Electrochemical Stability of a Zwitterionic-Polymer-Functionalized Electrode for Capacitive Deionization.
In capacitive deionization, the salt-adsorption capacity of the electrode is critical for the efficient softening of brackish water. To improve the water-deionization capacity, the carbon electrode surface is modified with ion-exchange resins. Herein, we introduce the encapsulation of zwitterionic polymers over activated carbon to provide a resistant barrier that stabilizes the structure of electrode during electrochemical performance and enhances the capacitive deionization efficiency. Compared to conventional activated carbon, the surface-modified activated carbon exhibits significantly enhanced capacitive deionization, with a salt adsorption capacity of ∼2.0 × 10-4 mg/mL and a minimum conductivity of ∼43 μS/cm in the alkali-metal ions solution. Encapsulating the activated-carbon surface increased the number of ions adsorption sites and the surface area of the electrode, which improved the charge separation and deionization efficiency. In addition, the coating layer suppresses side reactions between the electrode and electrolyte, thus providing a stable cyclability. Our experimental findings suggest that the well-distributed coating layer leads to a synergistic effect on the enhanced electrochemical performance. In addition, density functional theory calculation reveals that a favorable binding affinity exists between the alkali-metal ion and zwitterionic polymer, which supports the preferable salt ions adsorption on the coating layer. The results provide useful information for designing more efficient capacitive-deionization electrodes that require high electrochemical stability.


XUV/X-ray light and fast ions for ultrafast chemistry.
The deposition of large amounts of energy in a molecule by XUV/X-ray photon absorption or fast-ion collision, triggers a set of complex ultrafast electronic and nuclear dynamics that allow a deep understanding and control of chemical reactivity. This themed issue showcases the research performed in the understanding, monitoring and control of these processes.


A new anterior total hip arthroplasty reduction technique for patients who require leg lengthening.
When performing anterior total hip arthroplasty (THA) for patients who require leg lengthening, surgeons often encounter difficulties during reduction due to soft tissue tightness. The purpose of this study was to introduce a new THA reduction technique for these patients. Between October 2018 and September 2019, 545 THAs were performed. In 15 hips (2.8%), reduction was not achieved with a traditional technique. The preoperative diagnosis was Crowe grade II in 4 hips, Crowe grade III in 4 hips, Crowe grade IV in 1 hip, and sequelae of Legg-Calvé-Perthes disease in 6 hips. All procedures were performed using a direct anterior approach. The new reduction technique was to use a lever hooked on the acetabular teardrop as a counter force against the preserved muscles. The lever was connected to the impactor with a wire and the counterforce was transmitted to the impactor. Reduction was achieved in all cases without shortening osteotomy or muscle release. The mean lengthening of the operated limb was 30 mm (range 13-59 mm). Neither sciatic nor femoral nerve palsy were observed. We developed a new anterior THA reduction technique for patients who require leg lengthening. When the centre of the femoral head was reduced to the superior edge of the cup with the traditional technique, reduction was safely achieved with this technique.


The invisible string of coagulation, complement, iron, and inflammation in sickle cell disease.
This review provides an update on recent advances in mechanistic studies of thromboinflammatory mechanisms that contribute to the disease pathology in sickle cell disease (SCD). There is a focus on novel pathways, clinical relevance, and translational potential of these findings. We hope to encourage more advances in this area to reduce organ damage in young patients prior to gene therapy, and to serve the aging SCD patient population. Novel insights into the roles of neutrophils, the ADAMTS-13/VWF axis, oxidative stress, and the intrinsic coagulation cascade, as well as relevant clinical trials, are discussed. Several studies implicate dysregulation of the ADAMTS-13/VWF axis as playing a major role in vaso-occlusive events (VOE) in SCD. Another highlight is reducing iron overload, which has beneficial effects on erythrocyte and neutrophil function that reduce VOE and inflammation. Multiple studies suggest that targeting HO-1/ROS in erythrocytes, platelets, and endothelium can attenuate disease pathology. New insights into coagulation activation identify intrinsic coagulation factor XII as a central regulator of many thromboinflammatory pathologies in SCD. The complement cascade and modulators of neutrophil function and release of neutrophil extracellular traps are also discussed.


Engineered heart tissue maturation inhibits cardiomyocyte proliferative response to cryoinjury.
The cellular and molecular mechanisms that are responsible for the poor regenerative capacity of the adult heart after myocardial infarction (MI) are still unclear and their understanding is crucial to develop novel regenerative therapies. Considering the lack of reliable in vitro tissue-like models to evaluate the molecular mechanisms of cardiac regeneration, we used cryoinjury on rat Engineered Heart Tissues (rEHTs) as a new model which recapitulates in part the in vivo response after myocardial injury of neonatal and adult heart. When we subjected to cryoinjury immature and mature rEHTs, we observed a significant increase in cardiomyocyte (CM) DNA synthesis when compared to the controls. As expected, the number of mitotic CMs significantly increases in immature rEHTs when compared to mature rEHTs, suggesting that the extent of CM maturation plays a crucial role in their proliferative response after cryoinjury. Moreover, we show that cryoinjury induces a temporary activation of fibroblast response in mature EHTs, similar to the early response after MI, that is however incomplete in immature EHTs. Our results support the hypothesis that the endogenous maturation program in cardiac myocytes plays a major role in determining the proliferative response to injury. Therefore, we propose rEHTs as a robust, novel tool to in vitro investigate critical aspects of cardiac regeneration in a tissue-like asset free from confounding factors in response to injury, such as the immune system response or circulating inflammatory cytokines.


Transcriptional control of the factor IX gene: analysis of five cis-acting elements and the deleterious effects of naturally occurring hemophilia B Leyden mutations.
Hemophilia B Leyden is a rare form of inherited factor IX deficiency in which patients experience spontaneous postpubertal recovery of factor IX levels. The mutations resulting in this disorder are localized in a 40-nucleotide region encompassing the major transcriptional start site for factor IX. Here we report the further characterization of five cis-acting elements in the factor IX promoter and the effects on protein binding and transcriptional activation of five Leyden mutations (at nucleotides +13, -5, -6, -20, and -26) that occur within the proximal three elements (sites 1 through 3). Bandshift studies using nuclear extracts from four different rat tissues have shown that at least some of the proteins binding to each of the five sites are ubiquitous in nature. The pattern of DNA binding at site 1 suggests that this element plays an important role in mediating the liver-specific expression of factor IX. Additional studies with liver nuclear extracts obtained at several different points in development have shown an increase in DNA binding at sites 1, 4, and 5 between 1 day and 1 week. Using DNase I footprint analysis and competition bandshift studies, we have shown that the binding of nuclear proteins to each of the mutant sites is disrupted to a variable extent. There appears to be some, although reduced, protein binding to all of the mutant oligonucleotides apart from the -26 mutant. In vitro transcription assays have shown that each of the mutations reduces the global proximal promoter activity by approximately 40%. Two double mutant promoters did not show any additional downregulation in the in vitro transcription assay. In experiments designed to assess the relative transcriptional activity mediated from each of the five sites independently, we have tested artificial homopolymer promoters of each site in the in vitro transcription assay. These studies show that sites 4 and 5 are the strongest activators and that transactivation from site 5 is further enhanced by the albumin D site-binding protein. In summary, these investigations show deleterious effects of each of the Leyden mutations tested on the binding of trans-acting factors and also show disruption of transcriptional activation in a functional in vitro transcription assay. Our results also show that cis-acting elements 4 and 5 are the principal activators of this locus.


On the reaction of a uranium atom with a nitrogen molecule: a theoretical attempt.
An attempt has been made to study the reaction between a uranium atom and a nitrogen molecule theoretically using multiconfigurational wave functions. The C2v part of the reaction surface has been computed for several electronic states of various spin mulltiplicities. The system proceeds from a neutral uranium atom in its (5f)3(6d)(7s)2, 5L ground state to the linear molecule NUN, which has a 1sigma(+)g ground state and uranium in a formal U(VI) oxidation state. The effect of spin-orbit coupling has been estimated at crucial points along the reaction. These preliminary results shows that the system proceeds from a quintet state for U + N2, via a triplet transition state to the final closed shell molecule. An eventual energy barrier for the insertion reaction is caused by the spin orbit coupling energy.


Membrane associated Ca2+ buffers in the heart.
Ca2+ is a universal signalling molecule that affects a variety of cellular processes including cardiac development. The majority of intracellular Ca2+ is stored in the endoplasmic and sarcoplasmic reticulum of muscle and non-muscle cells. Calreticulin is a well studied Ca2+-buffering protein in the endoplasmic reticulum, and calreticulin deficiency is embryonic lethal due to impaired cardiac development. Despite calsequestrin being the most abundant Ca2+-buffering protein in the sarcoplasmic reticulum, viability is maintained in embryos without calsequestrin and normal Ca2+ release and contractile function is observed. The Ca2+ homeostasis regulated by the endoplasmic and sarcoplasmic reticulum is critical for the development and proper function of the heart.


Space-time covid-19 Bayesian SIR modeling in South Carolina.
The Covid-19 pandemic has spread across the world since the beginning of 2020. Many regions have experienced its effects. The state of South Carolina in the USA has seen cases since early March 2020 and a primary peak in early April 2020. A lockdown was imposed on April 6th but lifting of restrictions started on April 24th. The daily case and death data as reported by NCHS (deaths) via the New York Times GitHUB repository have been analyzed and approaches to modeling of the data are presented. Prediction is also considered and the role of asymptomatic transmission is assessed as a latent unobserved effect. Two different time periods are examined and one step prediction is provided. The results suggest that both socio-economic disadvantage, asymptomatic transmission and spatial confounding are important ingredients in any model pertaining to county level case dynamics.


Normobaric Hypoxia Reduces V˙O2 at Different Intensities in Highly Trained Runners.
We sought to determine the effect of low and moderate normobaric hypoxia on oxygen consumption and anaerobic contribution during interval running at different exercise intensities. Eight runners (age, 25 ± 7 yr, V˙O2max: 72.1 ± 5.6 mL·kg·min) completed three separate interval sessions at threshold (4 × 5 min, 2-min recovery), V˙O2max (8 × 90 s, 90-s recovery), and race pace (10 × 45 s, 1 min 45 s recovery) in each of; normoxia (elevation: 580 m, FiO2: 0.21), low (1400 m, 0.195) or moderate (2100 m, 0.18) normobaric hypoxia. The absolute running speed for each intensity was kept the same at each altitude to evaluate the effect of FiO2 on physiological responses. Expired gas was collected throughout each session, with total V˙O2 and accumulated oxygen deficit calculated. Data were compared using repeated-measures ANOVA. There were significant differences between training sessions for peak and total V˙O2, and anaerobic contribution (P < 0.001, P = 0.01 respectively), with race pace sessions eliciting the lowest and highest responses respectively. Compared to 580 m, total V˙O2 at 2100 m was significantly lower (P < 0.05), and anaerobic contribution significantly higher (P < 0.05) during both threshold and V˙O2max sessions. No significant differences were observed between altitudes for race pace sessions. To maintain oxygen flux, completing acute exercise at threshold and V˙O2max intensity at 1400 m simulated altitude appears more beneficial compared with 2100 m. However, remaining at moderate altitude is a suitable when increasing the anaerobic contribution to exercise is a targeted response to training.


Artificial Domicile Use by Bumble Bees (Bombus; Hymenoptera: Apidae) in Ontario, Canada.
Bumble bees are an important group of pollinating insects that are of increasing conservation concern due to relatively recent and dramatic species-specific declines. Nesting ecology can vary significantly between species, and nest site selection may be affected by many factors, including heredity, individual experience, and habitat availability. Data on bumble bee nesting ecology are inherently difficult to collect in the wild as nests are often cryptic. Artificial domiciles (nest boxes) can be a useful tool for gathering information on species-specific nesting behavior to inform conservation management of native pollinator populations. The aim of this study was to examine the use of three different domicile designs for monitoring bumble bees: aboveground, underground, and false underground, while collecting information on occupying species identity and richness to compare with sampling with traditional netting survey methods. Across Ontario, the majority of sites had at least one domicile occupied, with the aboveground installation method proving most successful whereas no false-underground domiciles were occupied. Occupied domiciles appeared to preferentially sample certain species compared to netting surveys, and rarefied species richness of both methods was similar. Given that some bumble bees did occupy artificial domiciles, and species richness relative to sample size was high, with further refinement, this method may be useful for bumble bee research and monitoring: filling in nesting ecology knowledge gaps and potentially as a conservation management tool.


Immune reactivity to type VII collagen: implications for gene therapy of recessive dystrophic epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe genodermatosis caused by loss-of-function mutations in COL7A1 encoding type VII collagen, the component of anchoring fibrils. As exogenous type VII collagen may elicit a deleterious immune response in RDEB patients during upcoming clinical trials of gene therapies or protein replacement therapies, we developed enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunosorbent spot (ELISPOT) assays to analyze B- and T-cell responses, to the full-length type VII collagen. The ELISA was highly sensitive and specific when tested against sera from 41 patients with epidermolysis bullosa acquisita (EBA), and the IFN-gamma ELISPOT detected a cellular response that correlated with ongoing EBA manifestations. Both tests were next applied to assess the risk of an immune response to type VII collagen in seven RDEB patients with a range of type VII collagen expression profiles. Immune responses against type VII collagen were dependent on the expression of type VII collagen protein, and consequently on the nature and position of the respective COL7A1 mutations. These immunologic tests will be helpful for the selection of RDEB patients for future clinical trials aiming at restoring type VII collagen expression, and in monitoring their immune response to type VII collagen after treatment.


Association among an autocrine parameter (EGF-R) and endocrine parameters (ER and PR) in locoregional breast cancer.
Sixty-three locoregional breast cancer biopsies were examined for association among epidermal growth factor receptors (as parameter of autocrine growth control), and estrogen and progesterone receptors (as endocrine parameters of estrogen responsiveness). In the tumor group with similar steroid receptor levels, low (0-50 fmol/mg), medium (50-100 fmol/mg) and high (above 100 fmol/mg), an inverse quantitative correlation between epidermal growth factor receptors and progesterone receptors was obtained (p < 0.05). In the tumor groups where estrogen receptor levels were higher or lower than progesterone receptor levels, epidermal growth factor receptors were correlated neither with estrogen nor with progesterone receptors (p > 0.05). It seemed that inverse correlation between endocrine and autocrine parameters obtained in previous studies might not be a common behaviour of all breast tumors.


[Validation of a Spanish version of the Edinburgh Postnatal Depression Scale].
The objective of this study is to validate a version in Spanish of the Edinburgh Postnatal Depression Scale (EPDS) in Peruvian women with less than 1 year of delivery. We administered the EPDS and the SCID section for diagnosis of major depression according to DSM-IV criteria to 321 women within the first year of postpartum. We found that the optimum cut-off score of the EPDS for the studied population was 13.5. With this value the sensitivity was 84.21% and the specificity 79.47% for diagnosis of major depression. No woman with score lower than 7.5 had major depression (sensitivity and negative predictive value were 100%). The correlation coefficient between the EPDS score and the number of criterion A symptoms for major depression according to DSM-IV was 0.4478. The Cronbach's alpha coefficient was 0.7043. The items that had more predictive power for postpartum depression were those regarding worries, ability to cope, panic, cry and optimism. The version in Spanish of the EPDS performed adequately in Peruvian women.


Surgical pulmonary valve insertion--when, how, and why.
Relief of right ventricular outflow tract obstruction in tetralogy of Fallot or similar physiology often results in pulmonary regurgitation. The resultant chronic volume overload can lead to right ventricular dilatation, biventricular dysfunction, heart failure symptoms, arrhythmias, and sudden death. Although pulmonary valve replacement can lead to improvement in functional class and a substantial decrease or normalisation of right ventricular volumes, the optimal timing of pulmonary valve replacement is not well defined. Benefits of pulmonary valve replacement have to be weighed against the risks of this procedure, including subsequent reoperation. This article will review the benefits and risks of pulmonary valve replacement, options for pulmonary valve substitute, and timing of pulmonary valve replacement in patients with chronic pulmonary regurgitation after relief of right ventricular outflow tract obstruction.


A Review of the Clinical, Radiological and Biochemical Characteristics and Genetic Causes of High Bone Mass Disorders.
High bone mass (HBM) disorders are a group of clinically and genetically heterogeneous bone diseases characterized by increased bone density on radiographs, due to progressive bone overgrowth or impaired bone resorption, or both. Some HBM cases are secondary to other diseases, such as chronic hepatitis C virus infection. Despite the great advance in gene diagnostic technology, the majority of HBM individuals remain undiagnosed. In this review, we will summarize the clinical, radiological and biochemical characteristics of HBM cases due to varying etiologies, since these features are helpful in the differential diagnosis of HBM. Each subgroup of HBM cases shows distinctive clinical, radiological and biochemical characteristics. HBM, due to bone overgrowth, was designated as sclerosteosis, as a result of mutations located in genes critically involved in the Wnt/beta-catenin signal pathway. Mutations in genes encoding factors relevant to the differentiation and maturation of osteoclasts, or critical for the acidification and resorption of osteoclasts may lead to osteopetrosis. Hepatitis C associated osteosclerosis is characterized by a generalized increase in bone mass and markedly elevated serum levels of bone specific alkaline phosphatase. The clarification of the etiologies of HBM may have a breakthrough role in understanding the molecular mechanisms involved in bone metabolism and may provide new pathways for the intervention of osteoporosis.


[Current status of drug therapy in chronic polyarthritis].
This review covers the differential indications of oral and topical non-steroidal antiinflammatory drugs, as well as oral and intra-articular corticosteroids. The so-called "disease modifying" drugs, such as chloroquine, sulfasalazine, gold compounds and penicillamine have been surpassed by low-dose pulses of methotrexate, due to its lower short-time toxicity and higher response rate. Parenteral cyclophosphamide or corticosteroid pulses should be reserved for cases with vasculitis or refractoriness to conventional drugs. Combined treatments by several "disease modifying" drugs or immunosuppressives have not yet proved their safety or higher efficacy. Selective immunosuppressives, such as cyclosporin A, have proved to be of limited efficacy but await comparison with more established drugs. Looking to the future, cytokines, e.g. interferon gamma, and monoclonal antibodies are discussed.


Functioning Pituitary Adenomas - Current Treatment Options and Emerging Medical Therapies.
Pituitary adenomas are benign tumours comprising approximately 16% of all primary cranial neoplasms. Functioning pituitary adenomas (prolactinomas, somatotroph, corticotroph, thyrotroph and rarely gonadotroph adenomas) cause complex clinical syndromes and require prompt treatment to reduce associated morbidity and mortality. Treatment approaches include transsphenoidal surgery, medical therapy and radiation. Medical therapy is the primary therapy for prolactinomas, and surgery by a skilled neurosurgeon is the first-line approach for other functioning pituitary adenomas. A multimodal treatment is frequently necessary to achieve biochemical and clinical control, especially, when surgery is not curative or when medical therapy fails. Several emerging, novel, medical treatments for acromegaly, Cushing's disease and prolactinomas are in phase II and III clinical trials and may become effective additions to the current drug armamentarium. The availability of various management options will allow an individualised treatment approach based on the unique tumour type, clinical situation and patient preference.


Successful management of hepatic artery pseudoaneurysm complicating chronic pancreatitis by stenting.
A 41-year old alchoholic male with a history of chronic pancreatitis was admitted for nausea, vomiting and weight loss. Angiogram was performed and demonstrated an aneurysmal sac with a narrow neck originating from the inferior aspect of the distal portion of the proper hepatic artery. The origin of the pseudoaneurysm was covered with a 5 mm multiply 2.5 cm Viabahn cover stent (Gore). A repeat angiogram showed some leak and a second stent (6 mm multiply 2.3 cm) was deployed and overlapped with the first stent by 3 mm. Contrast was injected and a repeat angiogram demonstrated complete exclusion of the aneurysm. A repeat computerized axial tomography (CAT) scan of the abdomen after 24 h showed successful stenting. The patient had an uneventful post-operative course.


[Laparotomy in Hodgkin's disease: significance of splenic involvement].
We retrospectively reviewed 224 cases of Hodgkin's disease, in 120 of which staging laparotomy was performed. The surgical findings in cases of clinical stage I or II disease with supradiaphragmatic presentation or clinical stage III disease did not influence the treatment plans. Of the 64 patients with positive results of laparotomy (splenic or lymph node involvement or both) 51 had splenic involvement; their 5-year survival rate, 57%, was similar to that of the patients with clinical or pathological stage III disease - 58% and 54% respectively. At laparotomy 11 patients with pathological stage III disease were found to have isolated splenic involvement; their 5-year survival rate, 64%, was not appreciably different from that of the patients with clinical stage II disease, 70%; both groups were treated with radiotherapy only. From this study we can conclude that splenic involvement in Hodgkin's disease has no deleterious effect on survival and that splenic irradiation seems to be as effective as splenectomy in controlling the disease.


Value of Antibody Drug Conjugates for Gynecological Cancers: A Modern Appraisal Following Recent FDA Approvals.
Antibody drug conjugates (ADCs) are a new class of targeted anti-cancer therapies that combine a monoclonal tumor surface receptor-targeting antibody with a highly cytotoxic molecule payload. They enable delivery of cytotoxic therapy more directly to tumor cells and minimize delivery to healthy tissues. This review summarizes the existing literature about ADC therapies approved for use in gynecologic malignancies, relevant preclinical studies, as well as ongoing clinical trials.


Investigation of osteosarcoma genomics and its impact on targeted therapy: an international collaboration to conquer human osteosarcoma.
Osteosarcoma is a genetically unstable malignancy that most frequently occurs in children and young adults. The lack of progress in managing this devastating disease in the clinic has prompted international researchers to collaborate to profile key genomic alterations that define osteosarcoma. A team of researchers and clinicians from China, Finland, and the United States investigated human osteosarcoma by integrating transcriptome sequencing (RNA-seq), high-density genome-wide array comparative genomic hybridization (aCGH), fluorescence in situ hybridization (FISH), reverse transcription-polymerase chain reaction (RT-PCR), Sanger sequencing, cell culture, and molecular biological approaches. Systematic analysis of genetic/genomic alterations and further functional studies have led to several important findings, including novel rearrangement hotspots, osteosarcoma-specific LRP1-SNRNP25 and KCNMB4-CCND3 fusion genes, VEGF and Wnt signaling pathway alterations, deletion of the WWOX gene, and amplification of the APEX1 and RUNX2 genes. Importantly, these genetic events associate significantly with pathogenesis, prognosis, progression, and therapeutic activity in osteosarcoma, suggesting their potential impact on improved managements of human osteosarcoma. This international initiative provides opportunities for developing new treatment modalities to conquer osteosarcoma.


Adaptive responses to environmental chemicals.
Adaption to chemical agents in the environment is a fundamental part of the evolutionary process and a large number of genes have evolved to specifically detoxify potentially harmful chemical agents. These genes can act at various levels within cells and determine circulating chemical or toxin concentrations, and uptake and efflux rates as well as intracellular detoxification enzymes, such as the cytochrome P-450-dependent mono-oxygenases and glutathione S-transferases. These multigene families of proteins play a central role in chemical and drug detoxification and their polymorphic expression may well be a factor in disease susceptibility.


The path to student-centered teaching in gerontology and geriatrics.
Student- or learner-centered teaching has an historical context--it is old and new. This article traces the path that has brought us full circle to once again concentrating on student learning instead of teacher teaching--from the era of learning being restricted to the wealthy and privileged, to today where learning institutions are inclusive. Three pressures are identified and discussed that have been the catalysts for reevaluating teaching methods in higher education: assessment of teaching and learning at the institutional level, generational differences between instructor and student, and a better understanding of how students learn. The rubric is examined as a method of assessing student progress in a student-centered environment. These are then related to the teaching of gerontology and geriatrics where students and teachers alike have a distinct edge over other content areas where the practicum experience is not part of the educational fabric.


[Selective expression of a mutation of the rad 201 radiosensitivity gene in Drosophila embryogenesis].
Embryonic sensitivity to the lethal effect of gamma-irradiation was compared in a radiosensitive mutant strain rad201G1 and a control radioresistant strain of Drosophila during the first 9 h of embryonic development. Embryonic radiosensitivity was analyzed with regard to the physiological age of embryos at the time of exposure to radiation. In the wild-type embryos, age-dependent variations of radiosensitivity were shown to be closely associated with genetically determined alterations in mitotic cycle structure, synchronism, and duration of separate phases. The rad201 gene mutation, which disrupts repair of chromosome damage in female germ cells and somatic cells of Drosophila, is expressed selectively during the period studied. The mutation had no effect on lethality at the stages of cleavage division, which represent alternations of S and M phases of the cell cycle. However, it caused an increase in lethality at the stage of postblastodermal mitotic divisions, whose onset is associated with a transformation of the organization and functions of genetic material and the appearance of G2 in the cell cycle. This transformation seems to be required for the functioning of the repair system affected by rad201.


MRGPRX2 and Adverse Drug Reactions.
Many adverse reactions to therapeutic drugs appear to be allergic in nature, and are thought to be triggered by patient-specific Immunoglobulin E (IgE) antibodies that recognize the drug molecules and form complexes with them that activate mast cells. However, in recent years another mechanism has been proposed, in which some drugs closely associated with allergic-type events can bypass the antibody-mediated pathway and trigger mast cell degranulation directly by activating a mast cell-specific receptor called Mas-related G protein-coupled receptor X2 (MRGPRX2). This would result in symptoms similar to IgE-mediated events, but would not require immune priming. This review will cover the frequency, severity, and dose-responsiveness of allergic-type events for several drugs shown to have MRGPRX2 agonist activity. Surprisingly, the analysis shows that mild-to-moderate events are far more common than currently appreciated. A comparison with plasma drug levels suggests that MRGPRX2 mediates many of these mild-to-moderate events. For some of these drugs, then, MRGPRX2 activation may be considered a regular and predictable feature after administration of high doses.


Systemic control of nodule formation by plant nitrogen demand requires autoregulation-dependent and independent mechanisms.
In legumes interacting with rhizobia, the formation of symbiotic organs involved in the acquisition of atmospheric nitrogen gas (N2) is dependent on the plant nitrogen (N) demand. We used Medicago truncatula plants cultivated in split-root systems to discriminate between responses to local and systemic N signaling. We evidenced a strong control of nodule formation by systemic N signaling but obtained no clear evidence of a local control by mineral nitrogen. Systemic signaling of the plant N demand controls numerous transcripts involved in root transcriptome reprogramming associated with early rhizobia interaction and nodule formation. SUPER NUMERIC NODULES (SUNN) has an important role in this control, but we found that major systemic N signaling responses remained active in the sunn mutant. Genes involved in the activation of nitrogen fixation are regulated by systemic N signaling in the mutant, explaining why its hypernodulation phenotype is not associated with higher nitrogen fixation of the whole plant. We show that the control of transcriptome reprogramming of nodule formation by systemic N signaling requires other pathway(s) that parallel the SUNN/CLE (CLAVATA3/EMBRYO SURROUNDING REGION-LIKE PEPTIDES) pathway.


Considerations on the new nevirapine: switching patients from twice-daily to once-daily.
Nevirapine (NVP) was the first nonnucleoside reverse transcriptase inhibitor (NNRTI) approved for the treatment of HIV infection. NVP can provide safe and efficacious viral suppression for treatment-naive patients and for virologically controlled patients "switching" from other NNRTI or protease inhibitor-based regimens. Formulations allowing once-daily dosing of antiretrovirals can significantly improve regimen adherence, which is important for maintaining virologic control, especially for NNRTI-based regimens with low barriers for genetic resistance. Randomized and controlled clinical trials have established the clinical non inferiority of a new, extended-release formulation (XR) of NVP, in both treatment-naive (VERxVE) and treatment-experienced patients (TRANxITION), where patients already stable on the immediate-release formulation of NVP were safely transitioned directly to NVP XR. As a potentially more convenient once-daily option, NVP XR may improve adherence and reduce the risk of mutant viruses, attendant virologic failure, and the spread of drug resistance.


Comparison of shape-matching and docking as virtual screening tools.
Ligand docking is a widely used approach in virtual screening. In recent years a large number of publications have appeared in which docking tools are compared and evaluated for their effectiveness in virtual screening against a wide variety of protein targets. These studies have shown that the effectiveness of docking in virtual screening is highly variable due to a large number of possible confounding factors. Another class of method that has shown promise in virtual screening is the shape-based, ligand-centric approach. Several direct comparisons of docking with the shape-based tool ROCS have been conducted using data sets from some of these recent docking publications. The results show that a shape-based, ligand-centric approach is more consistent than, and often superior to, the protein-centric approach taken by docking.


Synthesis and behaviour of small RNA species of CHO cells submitted to a heat chick.
Incubation of Chinese hamster ovary (CHO) cells for 1 hour at 43 degrees C results in an inhibition of high molecular weight RNA synthesis while most of the ow molecular weight RNAs are still synthesized. In cells returned to 37 degrees C, the transcription of high molecular weight RNA is reinitiated after 7 h recovery. The synthesis of snRNA A, C, D which are transcribed by RNA polymerase B (II) is inhibited in cells incubated at 43 degrees C while the synthesis of 4S, 5S, L and K components is not affected. During the recovery period the synthesis of low molecular weight RNA is increased variously according to the components relative to control cells : x 1.5 for 5S RNA to x 8 for snK. After 9 h recovery at 37 degrees C, snA and SnD are again synthesized but newly synthesized snC does not appear in the nucleus while a putative preC component accumulates in the cytoplasm. On the other hand, the distribution of all the pre-existing low molecular weight RNAs is not affected by the heat shock.


[The fifth metastasis route of gastric cancer and the third principle of radical operation].
The local-regional recurrence is the most important failure reason of D2 radical operation for curative advanced gastric cancer. Another way of metastasis, which exists in the mesogastrium and separates apart from the primary tumor, blood vessels and lymph nodes, appears to be responsible for the local-regional recurrence partly. We call it as the fifth route of metastasis. The mesogastrium is surrounded by proper fascia completely and covered partly by serosa. We suggest that D2 radical operation should not only include the resection of primary tumor and lymphadenectomy, but also add the complete mesogastric excision (CME) as the third principle in gastric cancer radical operations to cut down the fifth metastasis route of gastric cancer, to prevent the fifth metastasis scattered on the field of operation which may induce the local-regional recurrence.


Mechanisms of airway protection during retching, vomiting, and swallowing.
We investigated the mechanisms of airway protection and bolus transport during retching and vomiting by recording responses of the pharyngeal, laryngeal, and hyoid muscles and comparing them with responses during swallowing and responses of the gastrointestinal tract. Five dogs were chronically instrumented with electrodes on the striated muscles and strain gauges on smooth muscles. Retching and vomiting were stimulated by apomorphine (5-10 ug/kg iv). During retching, the hyoid and thyroid descending and laryngeal abductor muscles were activated; between retches, the hyoid, thyroid, and pharyngeal elevating, and laryngeal adductor muscles were activated. Vomiting always occurred during the ascending phase of retching and consisted of three sequential phases of hyoid and pharyngeal muscle activation culminating in simultaneous activation of all recorded elevating and descending laryngeal, hyoid, and pharyngeal muscles. Retrograde activation of esophagus and pharyngeal muscles occurred during the later phases, and laryngeal adductor was maximally activated in all phases of the vomit. During swallowing, the laryngeal adductor activation was followed immediately by brief activation of the laryngeal abductor. We concluded that retching functions to mix gastric contents with refluxed intestinal secretions and to impart an orad momentum to the bolus before vomiting. During retches, the airway is protected by glottal closure, and between retches, it is protected by ascent of the larynx and closure of the upper esophageal sphincter. The airway is protected by maximum glottal closure during vomiting. During swallowing, the airway is protected by laryngeal elevation and glottal closure followed by brief opening of the glottis, which may release subglottal pressure expelling material from the laryngeal vestibule.


Antileishmanial and cytotoxic activities of a new limonoid and a new phenyl alkene from the stem bark of Trichilia gilgiana (Meliaceae).
One new limonoid, trigilgianin (1), one new phenyl alkene, epoxy gilgialkene (2), together with five known compounds: scopoletin (3), sitosteryl-6'-O-undecanoate-β-D-glucoside (4), sitosteryl-O-β-D-glucopyranoside (5), cinchonain A (6) and cinchonain B (7) were isolated from the stem bark of Trichilia gilgiana Harms. (Meliaceae). All compounds were isolated for the first time from this species. The structures were elucidated on the basis of spectral studies and by comparison of these data with those from the literature. Compounds 1, 2, 3, 6 and 7 were tested for in vitro antileishmanial activity against visceral leishmaniasis parasite Leishmania donovani and cytotoxicity against macrophage RAW 264.7 cell line. Compounds 1 and 3 showed the highest antileishmanial activity (IC50 values of 6.044 and 6.804 µg/mL, respectively) with low cytotoxicity (CC50 values of >200 and 47.47 µg/mL, respectively), while compound 2 was moderately active on L. donovani promastigotes (IC50 56.81 µg/mL).


Sequences of two kinetoplast minicircle DNAs of Trypanosoma (Nannomonas) congolense.
Random minicircle DNA molecules were released from isolated kinetoplast network DNA of Trypanosoma congolense by BamHI digestion and cloned into plasmid pUC19. The sequences of two cloned minicircles (958 bp and 964 bp) were determined. Both minicircles contain the 13 bp sequence, 5'-GGGGTTGGTGTAA-3', thought to be the replication origin of minicircles in other trypanosomatids. The two minicircles have extensive homology in the 120 bp preceeding, and the 20 bp following, this 13-mer but only scattered homology elsewhere. Both possess tandem repeats downstream of the 13-mer. Comparison of these minicircles with minicircle sequences from other trypanosomatids reveals that they have the same general sequence organization as the others although only the 13-mer and its flanking regions are homologous.


Plio-Pleistocene facies environments from the KBS Member, Koobi Fora Formation: implications for climate controls on the development of lake-margin hominin habitats in the northeast Turkana Basin (northwest Kenya).
Climate change is hypothesized as a cause of major events of Plio-Pleistocene East African hominin evolution, but the vertically discontinuous and laterally confined nature of the relevant geological records has led to difficulties with assessing probable links between the two. High-resolution sedimentary sequences from lacustrine settings can provide comprehensive data of environmental changes and detailed correlations with well-established orbital and marine records of climate. Hominin-bearing deposits from Koobi Fora Ridge localities in the northeast Turkana Basin of Kenya are an archive of Plio-Pleistocene lake-margin sedimentation though significant developmental junctures of northern African climates, East African environments, and hominin evolution. This study examines alluvial channel and floodplain, nearshore lacustrine, and offshore lacustrine facies environments for the approximately 136-m-thick KBS Member (Koobi Fora Formation) exposed at the Koobi Fora Ridge. Aspects of the facies environments record information on the changing hydrosedimentary dynamics of the lake margin and give insights into potential climatic controls. Seasonal/yearly climate changes are represented by the varve-like laminations in offshore mudstones and the slickensides, dish-shaped fractures, and other paleosol features overprinted on floodplain strata. Vertical shifts between facies environments, however, are interpreted to indicate lake-level fluctuations deriving from longer-term, dry-wet periods in monsoonal rainfall. Recurrence periods for the inferred lake-level changes range from about 10,000 to 50,000 years, and several are consistent with the average estimated timescales of orbital precession ( approximately 20,000 years) and obliquity ( approximately 40,000 years). KBS Member facies environments from the Koobi Fora Ridge document the development of lake-margin hominin habitats in the northeast Turkana Basin. Environmental changes in these habitats may be a result of monsoonal rainfall variations that derive from orbital insolation and/or glacial forcing.


Evidence for photoinduced cross-linkage, in situ, of 30S ribosomal proteins to 16S rRNA.
The effects of ultraviolet radiation on the 30S ribosomal subunit of Escherichia coli were studied. Irradiation in aqueous solution under anaerobic conditions resulted in a dose-dependent decrease in the separability of the rRNA and protein components of the 30S ribosomal subunit in 4 M urea-3 M LiC1. The results of gel filtration studies of the irradiated ribosomes before and after treatment with pancreatic ribonuclease indicated that the decrease in separability of the ribosome components was a result of the photoinduced formation of covalent RNA-protein cross-links. The number of covalent cross-links was estimated to correspond to less than 3 per 10,000 daltons of ribosomal proteins. One-dimensional gel electrophoresis studies of the course of the photoinduced cross-linkage reaction indicated that cross-linkage of individual 30S ribosomal proteins to the 16S rRNA proceeds in two dose-dependent steps. The first step requires an input of 1 X 10(20) quanta of 253.7 -nm radiation and results in the cross-linkage of at least five ribosomal proteins to the 16S rRNA. The second step requires a total input of 2 X 10(20) quanta of 253.7 -nm radiation, and results in the cross-linkage of most of the remaining 30S ribosomal proteins to the 16S rRNA.


Beyond Respiratory Depression and Constipation: Adverse Effects of Opioids.
The numbers of opioid presciptions have skyrocketed over the last two decades. Adverse effects of opioids are difficult to diagnose because the usual presenting complaints is persistence of severe pain and decreases function leading to chronic usage of medication with minimal benefit to patients. This concise review discusses the adverse effects of opioids to appropriately diagnose and treat patients on opioid therapy. We emphasize less commonly known adverse effects and the controversial use of opioids in non-cancer pain.


Comparison of refractometer and biuret methods for total protein measurement in body cavity fluids.
Most hand-held medical refractometers have internal scales that limit protein measurement to results >/=2.5 g/dL. Tables for conversion of refraction (r) to protein concentration for values as low as 0.1 g/dL were published in the 1960s, but their accuracy for use on body fluids has not been established. The purpose of this study was to assess the reliability of body cavity fluid protein determination by refractometry. We compared the protein concentration of 25 body cavity fluids as determined by 2 Goldberg type hand-held refractometers with results obtained by the biuret method. Published charts converting refraction (r) to protein concentration were used to determine protein concentration in samples with protein <2.5 g/dL. Higher protein values were read directly from the instruments. The range of comparison was limited to >/=0.6 g/dL, the lowest concentration of the biuret method's standard curve. Twenty-one peritoneal fluid, 2 pleural fluid and 2 pericardial fluid samples from 16 horses, 5 cattle, 3 dogs, 2 llamas and 1 cat were tested. The results obtained by the two refractometers were closely and linearly related to biuret results (P<.001), with slopes by linear regression analysis close to 1, and correlation coefficients >0.977. Based on this study, the range for quantification of body cavity fluid protein concentration by refractometry can be extended below 2.5 g/dL, allowing for quantitative assessment of most clinical samples.


Troubleshooting Programming of Conduction System Pacing.
Conduction system pacing (CSP) comprises His bundle pacing and left bundle branch area pacing and is rapidly gaining widespread adoption. Effective CSP not only depends on successful system implantation but also on proper device programming. Current implantable impulse generators are not specifically designed for CSP. Either single chamber, dual chamber or CRT devices can be used for CSP depending on the underlying heart rhythm (sinus rhythm or permanent atrial arrhythmia) and the aim of pacing. Different programming issues may arise depending on the device configuration. This article aims to provide an update on practical considerations for His bundle and left bundle branch area pacing programming and follow-up.


Aquatic effects of aerial spraying for mosquito control over an urban area.
In an effort to combat West Nile Virus, planes dispersed insecticide over Sacramento, CA, treating nearly 50,000 hectares with pyrethrins and the synergist piperonyl butoxide (PBO). Widespread dispersal of insecticide over a metropolitan area, coupled with extensive pretreatment data on the area's urban creeks, provided a unique opportunity to study effects of mosquito control agents on aquatic habitats within an urban setting. There was no evidence of aquatic toxicity from the two active ingredients in the product applied. However, PBO concentrations were high enough to enhance toxicity of pyrethroids already existing in creek sediments from general urban pesticide use. PBO concentrations of 2-4 microg/L were high enough to nearly double the toxicity of sediments to the amphipod Hyalella azteca. Though the increase in toxicity was modest, it was unexpected to find environmental synergy at all. Risk assessments for mosquito control agents have focused on the active ingredients but have failed to recognize the potential for interactions with pesticides previously existing in the environment, which in this case appeared to represent a risk to aquatic life greater than that of the active ingredients themselves.


Structural aspects of the reversal phase of alveolar bone remodelling.
The ultrastructure of the reversal line during alveolar bone remodelling was investigated in the rat. Surface bone remodelling along the periosteum of the mandible was induced by the extraction of opposing maxillary molars. With transmission EM the reversal line was seen to be composed of a superficial electron-dense amorphous layer and a deep filamentous layer at 7 d after extraction. The reversal line exhibited strong alkaline phosphatase activity and contained acid mucopolysaccharide. Scanning EM of the surface of the line, exposed by sonication in distilled water, showed papillary structures, the surface of which appeared granular and exhibited a crystalline appearance. The tips of collagen fibrils of new bone were attached to the top of the papillae in the front area of bone formation. It is suggested that the reversal line is involved in the coupling of bone resorption and formation.


Concurrent urinary tract infection and stone disease: pathogenesis, diagnosis and management.
Urinary tract stones and urinary tract infection are strongly associated. Infection is implicated as the cause of stones in about 15% of stone formers, and the development of infection can complicate the management of pre-existing stones. Left untreated, both situations can result in loss of kidney function, and can, on occasion, be life threatening. The underlying pathophysiology of infection stones is generally well understood, but factors dictating why a particular individual should be affected are less clear, although obstruction is a uniformly recognized risk factor. Surgery is the mainstay of treatment for infection calculi: stone clearance is the goal and a range of minimally invasive treatments is available. Systemic sepsis remains the most serious complication of treatment, and, although rare, still occurs despite antibiotic prophylaxis. Once the stone and the causative infection have been removed, various strategies can be employed to minimize the risk of recurrence. When infection complicates pre-existing stone disease, the primary aim of management is to treat the infective episode and delay definitive stone management until the infection has cleared. In such cases where obstruction is also present, prompt drainage of the affected kidney is likely to prevent permanent renal damage, and may be life saving.


NiII formate complexes with bi- and tridentate nitrogen-donor ligands: synthesis, characterization, and magnetic and thermal properties.
The synthesis of four NiII formate complexes of the type [Ni(N∩N)n][O2CH]2 (2, adduct with 3/4 EtOH, N∩N = en, e[combining low line]thylen[combining low line]ediamine, n = 3; 4, N∩N = dien, N,N',N''-d[combining low line]i[combining low line]e[combining low line]thylen[combining low line]etriamine, n = 2), [Ni2(O2CH)4(H2O)(tmeda)2] (3, tmeda = N,N,N',N'-t[combining low line]etram[combining low line]ethyle[combining low line]thylened[combining low line]ia[combining low line]mine) and [{Ni(O2CH)2(pmdta)}2·H2O] (5, pmdta = N,N',N',N'',N''-p[combining low line]entam[combining low line]ethyld[combining low line]iethylenet[combining low line]ria[combining low line]mine) by a reaction of [{Ni(O2CH)2}·2H2O] (1) with the respective N-donor bases is reported. The structures of 2-5 in the solid state were determined by single X-ray structure analysis, revealing a discrete dinuclear structure of 3 and the formation of polymeric networks in the case of 2, 4 and 5 due to intermolecular hydrogen bonding. SQUID and ESR measurements of 3 evidenced a weak antiferromagnetic coupling between the NiII ions and an easy plane magnetic anisotropy. Accompanying quantum chemical studies of the magnetic properties and IR characteristics of 3 were performed to strengthen the conclusions drawn from experimentally obtained data. The thermal decomposition temperatures of 2-5 were determined by TG (thermogravimetry) and obtained residues were analyzed by PXRD (powder X-ray diffraction) measurements. The decomposition processes were completed at 207 (3), 215 (5), 250 (2) and 273 °C (4) and are shown to result in the formation of pure metallic nickel.


Study protocol: safety and efficacy of propranolol 0.2% eye drops in newborns with a precocious stage of retinopathy of prematurity (DROP-ROP-0.2%): a multicenter, open-label, single arm, phase II trial.
Retinopathy of prematurity (ROP) still represents one of the leading causes of visual impairment in childhood. Systemic propranolol has proven to be effective in reducing ROP progression in preterm newborns, although safety was not sufficiently guaranteed. On the contrary, topical treatment with propranolol eye micro-drops at a concentration of 0.1% had an optimal safety profile in preterm newborns with ROP, but was not sufficiently effective in reducing the disease progression if administered at an advanced stage (during stage 2). The aim of the present protocol is to evaluate the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns at a more precocious stage of ROP (stage 1). A multicenter, open-label, phase II, clinical trial, planned according to the Simon optimal two-stage design, will be performed to analyze the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns with stage 1 ROP. Preterm newborns with a gestational age of 23-32 weeks, with a stage 1 ROP will receive propranolol 0.2% eye micro-drops treatment until retinal vascularization has been completed, but for no longer than 90 days. Hemodynamic and respiratory parameters will be continuously monitored. Blood samplings checking metabolic, renal and liver functions, as well as electrocardiogram and echocardiogram, will be periodically performed to investigate treatment safety. Additionally, propranolol plasma levels will be measured at the steady state, on the 10th day of treatment. To assess the efficacy of topical treatment, the ROP progression from stage 1 ROP to stage 2 or 3 with plus will be evaluated by serial ophthalmologic examinations. Propranolol eye micro-drops could represent an ideal strategy in counteracting ROP, because it is definitely safer than oral administration, inexpensive and an easily affordable treatment. Establishing the optimal dosage and treatment schedule is to date a crucial issue. ClinicalTrials.gov Identifier NCT02504944, registered on July 19, 2015, updated July 12, 2016. EudraCT Number 2014-005472-29.


Inhibitors of the interaction of a thyroid hormone receptor and coactivators: preliminary structure-activity relationships.
The modulation of gene regulation by blocking the interaction between the thyroid receptor (TR) and obligate coregulators has been reported recently with the discovery of the lead compound 3-(dimethylamino)-1-(4-hexylphenyl)propan-1-one). Herein we report studies aimed at optimization of this initial hit to determine the basic parameters of the structure-activity relationships and clarify the mechanism of action. These studies provided new insights, showing that activity and TRbeta isoform selectivity is highly correlated with the structural composition of these covalent inhibitors.


Treatment of traumatic dental injuries in children.
The major emphasis of this review rests on articles written within the past 12 months. Many of these papers comprise comprehensive surveys of treatment of various aspects of dental trauma in the primary and permanent dentition, as well as epidemiologic studies. There have also been some very good experimental studies that have attempted to standardize luxation injuries as well as tooth replantation in order to study pulpal and periodontal healing in reproducible animal models. However, it can been seen from the reference list that 1 year's production in dental traumatology would not suffice to cover the scope of the treatment needs nor to adequately orient the reader to the progress made with respect to our present knowledge of wound healing following injury and the most recent developments in the restoration of the traumatized dentition. To present an overall view of the philosophy that has evolved concerning wound healing in the dental pulp and periodontium following injury as well as innovations in the treatment of acute dental trauma, this review must of necessity delve back into the mid-1980s and probe forward into publications that are on the way in 1991.


Evaluating Gait Stability and Muscle Activation in Different Hand Holding Conditions Using the Robotic Walker-mTPAD.
While walkers are used as mobility aids for different gait impairments, little is known about the factors that affect the performance of such aids. Therefore, we investigated the impact of arm-holding conditions on gait stability and muscle activation. We used surface electromyography (sEMG) sensors on specific arm and leg muscles while the users took laps with a robotic walker, the mobile Tethered Pelvic Assist Device (mTPAD), on an instrumented mat. Eleven participants without gait disorders walked with and without a 10% body weight (BW) force applied on the pelvis in the following three configurations: (i) while gripping the walker's frame, (ii) while using an armrest with their arms at a 90∘ angle, and (iii) while using an armrest with their arms at a 130∘ angle for 5 min each. Our results showed that when applying a force, the users changed their gait to increase stability. We also discovered differences in muscle activation based on the user's specific arm conditions. Specifically, the 130∘ condition required the least muscle activation, while gripping the walker's frame increased specific muscle activation compared to 90∘ and 130∘. This study is the first to evaluate how arm-holding and external loading conditions alter gait and muscle activations using the mTPAD.


The use of a three-dimensional dynamic arm support prevents the development of muscle fatigue during repetitive manual tasks in healthy individuals.
Work-related upper extremity disorders are costly to society due to resulting medical costs, presenteeism and absenteeism. Although their aetiology is likely multifactorial, physical workplace factors are known to play an important role in their development. Promising options for preventing work-related upper extremity disorders include assistive technologies such as dynamic arm supports designed to follow the movement of the arm while compensating for its weight. The objective of this study was to assess the effects of a dynamic arm support on perceived exertion, muscle activity and movement patterns of the upper limb during repetitive manual tasks in healthy individuals. Thirty healthy right-handed individuals were allocated either a static or a dynamic task to perform with and without a dynamic arm support. During the task, surface electromyographic activity (anterior and middle deltoid, upper trapezius) and upper limb kinematics (elbow, shoulder, sternoclavicular) were measured using surface EMG and inertial sensors. Results showed that the dynamic arm support significantly reduced perceived exertion during the tasks and limited the development of muscular fatigue of the anterior and middle deltoid as demonstrated by EMG signal mean epoch amplitudes and median frequency of the EMG power spectrum. The dynamic arm support also prevented a decrease in shoulder elevation and an increase in total shoulder joint excursion during static and dynamic task, respectively. These results denote the potential benefits of dynamic arm supports in work environments. Further studies should focus on their efficacy, acceptability and implementability in work settings.


Anti-Stokes Emission from Hot Carriers in Gold Nanorods.
The origin of light emission from plasmonic nanoparticles has been strongly debated lately. It is present as the background of surface-enhanced Raman scattering and, despite the low yield, has been used for novel sensing and imaging applications because of its photostability. Although the role of surface plasmons as an enhancing antenna is widely accepted, the main controversy regarding the mechanism of the emission is its assignment to either radiative recombination of hot carriers (photoluminescence) or electronic Raman scattering (inelastic light scattering). We have previously interpreted the Stokes-shifted emission from gold nanorods as the Purcell effect enhanced radiative recombination of hot carriers. Here we specifically focused on the anti-Stokes emission from single gold nanorods of varying aspect ratios with excitation wavelengths below and above the interband transition threshold while still employing continuous wave lasers. Analysis of the intensity ratios between Stokes and anti-Stokes emission yields temperatures that can only be interpreted as originating from the excited electron distribution and not a thermally equilibrated phonon population despite not using pulsed laser excitation. Consistent with this result as well as previous emission studies using ultrafast lasers, the power-dependence of the upconverted emission is nonlinear and gives the average number of participating photons as a function of emission wavelength. Our findings thus show that hot carriers and photoluminescence play a major role in the upconverted emission.


Atypical mycobacteriosis caused by Mycobacterium haemophilum in an immunocompromised patient: diagnosis by (18)F-FDG PET/CT.
We report a rare case of atypical mycobacteriosis diagnosed by F-FDG PET/CT. A 28-year-old man with a history of kidney transplantation presented with fever, painful nodular skin lesions, and elevated inflammatory markers. FDG PET/CT demonstrated multiple subcutaneous, cutaneous, and osseous areas of increased tracer uptake. Histopathologic and microbiological evaluation revealed disseminated infection with Mycobacterium haemophilum. FDG PET/CT is a valuable tool for early and correct diagnosis of occult sources of infection in immunocompromised patients.


Effects of Auditory Training in Older Adults.
This study examines the effects of an auditory training program on the auditory and cognitive abilities of older adults. Auditory rehabilitation programs are generally designed for hearing aid users, and studies have demonstrated benefits for them. In this study, we seek to understand whether such a training program can also benefit older adults who do not wear hearing aids. We also examined if cognitive benefits can indeed be observed as a result of the training. Sixty-four older adults were recruited and assigned into three groups: the experimental group (n = 20), the active control group (n = 21), and the no-training control group (n = 23). The experimental group underwent an auditory training program (Listening and Communication Enhancement [LACE]) during the training phase. Meanwhile, the active control group listened to short audio clips and the no-training control group did not participate in any program. An auditory test (Quick Speech-in-Noise [QuickSIN]) and a battery of cognitive tests were conducted before and after the training to examine the participants' performance on auditory ability, short-term memory, and attention. The results showed improvements in auditory and cognitive abilities during the training period. When assessing the training effects by comparing the pre- and the posttraining performances, a significant improvement on the QuickSIN task was found in the training group but not in the other two groups. However, other cognitive tests did not show any significant improvement. That is, the LACE training did not benefit short-term memory and attention. The improved performance on short-term memory during the training was not maintained in the posttraining session. Overall, the study has extended the auditory benefit from the LACE training to the typical aging population in terms of improved communication ability, but the effect of training on auditory abilities did not transfer to gains in cognitive abilities.


Excretion of tryptophan metabolites in Friedreich's ataxia.
The overnight urinary excretions of the tryptophan metabolites 5-hydroxy indole acetic acid (5HIAA), indole acetic acid (IAA), indoxyl sulphate, and kynurenine were determined in 10 cases of Friedreich's ataxia and in 11 controls. Levels of 5HIAA and IAA were slightly lower and of indoxyl sulphate higher than in the controls but within normal limits; kynurenine was normal.A tryptophan load test subsequently given to four patients and three controls showed no significant abnormality in IAA, 5HIAA, indoxyl sulphate, and kynurenine.A specific abnormality in tryptophan metabolism in Friedreich's ataxia suggested by other workers was not observed.


Internal jugular vein thrombosis due to ovarian hyper-stimulation syndrome.
Internal jugular vein thrombosis from non-otological causes is not well documented in the otolaryngology literature. The authors report a case of left internal jugular vein thrombosis due to severe ovarian hyperstimulation syndrome. Causes, investigations and treatment of internal jugular vein thrombosis from non-otological causes are discussed.


Aicardi syndrome in a Nigerian female child: A case report and literature review of a rare neuro-developmental disorder from North-Western Nigeria.
Aicardi syndrome is a very rare neurodevelopmental disorder, inherited as an X-linked dominant condition with a triad of infantile spasm, partial or complete agenesis of the corpus callosum, and chorio-retinal "lacunae." We report a case of a female infant with the classical triad of Aicardi syndrome. A female infant presented to the Paediatric Neurology Clinic of the Federal Medical Centre Birnin-Kebbi, North-western Nigeria, at the age of two months with complaints of recurrent afebrile convulsions typical for infantile spasms. The patient was delivered at term with normal Apgar scores and anthropometry. Examination revealed an infant with no dysmorphic features and normal systemic examination. Magnetic Resonance Imaging (MRI) of the brain however, showed complete agenesis of the corpus callosum and dilatation of the posterior horn of the lateral and third ventricles. Fundoscopy showed multiple yellowish spots along the vascular arcades in the right eye. The left eye had a one-disc diameter lacuna in the superior nasal quadrant adjacent to the optic disc with multiple yellowish spots. A diagnosis of Aicardi syndrome was made. The child was placed on oral phenobarbital and followed up. At the age of 18 months, the child can only sit without support, hold an object in each hand, smile socially, and babble. The frequency of the seizures had also reduced from >100 episodes per day to 2-3 episodes per day, but the child had developed right-sided spastic hemiparesis. The patient was commenced on physiotherapy and the anti-epileptic drugs were maintained. We recommend clinicians consider Aicardi syndrome in the differential diagnosis of any child presenting with infantile spasms.


Serum levels of follicle stimulating hormone, luteinizing hormone, prolactin, testosterone, 5 alpha-dihydrotestosterone, 5 alpha-androstane-3 alpha, 17 beta-diol, 5 alpha-androstane-3 beta, 17 beta-diol, and 17 beta-estradiol from male beagles with spontaneous or induced benign prostatic hyperplasia.
The serum concentration of testosterone (T) 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol), 5 alpha-androstane-3 beta , 17 beta-diol (3 beta-diol), luteinizing hormone (LH), follicle stimulating hormone (FSH), and prolactin in young (less than 40 months) beagles with spontaneous benign prostatic hyperplasia (BPH) were not significantly (P greater than 0.25) different from serum hormone levels of age matched controls, or old (greater than 60 months) beagles with BPH. However, the serum hormone levels of age matched controls, or with BPH (2.46 +/- 0.51 pg per ml) was significantly (P less than 0.05) lower than that of age matched controls (3.93 +/- 0.35 pg per ml) and of old beagles with BPH is not associated with increased serum concentrations of androgens, or changes in serum levels of gonadotropins, but may be related to some change in estrogen biosynthesis or metabolism. In the second part of the experiment, castrate and intact beagles were treated for 4 months with three weekly injections of T, DHT, 3 alpha-diol, estradiol, T + estradiol, DHT + estradiol, or 3 alpha-diol + estradiol. As expected, the serum concentration of T, DHT, 3 alpha-diol, estradiol, LH, and FSH varied dramatically depending on the steroid regimen used. Analysis of these results showed that prostate weight was increased by steroid treatments which elevated the serum DHT concentration. However, glandular hyperplasia, indistinguishable from that seen in dogs with BPH, occurred only when estradiol was added to those steroid treatments which caused elevated serum DHT concentration.


Phase I trial of recombinant interleukin-2 and recombinant beta-interferon in refractory neoplastic diseases.
Interleukin-2 (IL-2) and beta-interferon (beta-IFN) are cytokines with profound immunobiological effects on T-cell and natural killer (NK) cell activity; IL-2 also induces lymphokine-activated killer (LAK) cell cytotoxicity in humans. Both lymphokines induce antineoplastic activity against several refractory tumors. This Phase I study of 50 patients assessed the toxicities, maximally tolerated dose (MTD), effects on certain immune effector cells, pharmacokinetics of IL-2, and development of antibodies to the combination of subcutaneously administered IL-2 and intravenously administered beta-IFN. Fever was common. Indomethacin reduced the incidence and severity of fever and was necessary to prevent it from becoming dose-limiting. Hypotension occurred but never required pressors or produced complications. Constitutional symptoms, local skin toxicity at the site of IL-2 injection, generalized desquamation, eosinophilia, nausea, and vomiting were also observed. One patient had reversible renal dysfunction. Two patients experienced drug-related dyspnea without evidence of capillary leak syndrome; neither required intubation. Fluid retention and cardiotoxicity were not observed. The MTD was 5 x 10(6) U/m2 s.c. of IL-2 and 2 x 10(6) U/m2 i.v. of beta-IFN when given in combination. Enhancement of in vivo NK cell cytotoxicity and proliferation of T4+, T8+, and NK cells occurred. In vivo induction of LAK cell cytotoxicity was observed in three patients. Four patients developed nonneutralizing anti-IL-2 IgG antibodies, but none developed antibodies to beta-IFN. Peak IL-2 serum levels typically occurred 4 h following drug administration. Serum levels were within a factor of 3 of the peak level in the period studied, 1-6 h postinjection. No complete responses occurred. One patient with rectal cancer and one with transitional cell carcinoma each had a partial response, and 13 other patients (5 with renal cell, 4 with colorectal, and 4 other cancers) had stable disease. Induction of NK cell cytotoxicity was seen more commonly in patients with stable disease than in those with progressive disease. Combined administration of these agents is feasible with acceptable toxicity, and Phase II trials are warranted.


The Effect of Thymus vulgaris on Hepatic Enzymes Activity and Apoptosis-Related Gene Expression in Streptozotocin-Induced Diabetic Rats.
Many diseases, including diabetes, are involved in the development of liver disorders through changes in the expression of genes such as apoptosis-related genes. In the present study, the effect of Thymus vulgaris (T. vulgaris) on hepatic enzyme activity and apoptosis-related gene expression in streptozotocin (STZ)-induced diabetic rats was examined. In this study, 50 adult male Wistar rats weighing approximately 200-220 g were divided into five groups. Diabetes was induced by an intraperitoneal injection of STZ (60 mg/kg). Following 18 days, all the animals in different groups were weighed and blood samples were taken from their cardiac veins. Gas chromatography-mass spectrometry (GC-MS) analysis revealed 45 different compounds in the T. vulgaris, including thymol (39.1%), p-cymene (20.63%), and γ-terpinene (14.85%). The results showed a significant increase in liver enzymes (aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP)) in diabetic or STZ mice compared to the control group (healthy mice) (P < 0.0001). The levels of AST, ALT, and ALP in rats treated with 200 mg/kg and 400 mg/kg of T. vulgaris extract showed a significant decrease in these enzymes in comparison with diabetic rats (P < 0.0001). The expression of caspase 3 and 9 genes in the groups treated with thyme significantly decreased compared to diabetic mice (P < 0.0001), and the expression of B-cell lymphoma-2 (Bcl-2) in the group receiving 400 mg/kg of thyme significantly increased compared to diabetic mice (P < 0.0001). Due to its antioxidant compounds, thyme improves the liver tissue cells in STZ-induced diabetic mice by reducing caspases 3 and 9 as well as increasing Bcl-2.


An autoclavable ventilation failure alarm.
A small ventilation failure alarm which can be used with all types of lung ventilator is described. The entire patient circuit can be removed and autoclaved easily. Activation of the unit is by a removable key, a mains failure warning is provided, and alarm may be muted during aspiration of secretions from the tracheobronchial tree.


Phenotypic and Functional Diversities of Myeloid-Derived Suppressor Cells in Autoimmune Diseases.
Myeloid-derived suppressor cells (MDSCs) are identified as a heterogeneous population of cells with the function to suppress innate as well as adaptive immune responses. The initial studies of MDSCs were primarily focused on the field of animal tumor models or cancer patients. In cancer, MDSCs play the deleterious role to inhibit tumor immunity and to promote tumor development. Over the past few years, an increasing number of studies have investigated the role of MDSCs in autoimmune diseases. The beneficial effects of MDSCs in autoimmunity have been reported by some studies, and thus, immunosuppressive MDSCs may be a novel therapeutic target in autoimmune diseases. There are some controversial findings as well. Many questions such as the activation, differentiation, and suppressive functions of MDSCs and their roles in autoimmune diseases remain unclear. In this review, we have discussed the current understanding of MDSCs in autoimmune diseases.


The result of a baseline survey on drink driving in Nanning and Liuzhou of Guangxi Province, China.
Because the official data in China on drink-driving accidents as well as related fatalities and injuries are much lower than many of the developed and developing countries in the world, the Global Road Safety Partnership (GRSP) decided to conduct a baseline survey to understand the prevalence of drink driving and related accidents in Nanning and Liuzhou, both in Guangxi Province, in order to develop targeted interventions. The baseline survey included a roadside survey and an accident survey. Motor vehicle (including motorcycles) drivers were randomly stopped for a breath test and interview in the roadside survey. In the accident survey, all drivers involved in a road accident resulting in at least 1 person killed or seriously injured were requested to provide a blood sample. A total of 10,685 drivers accepted the random breath test and 10,666 drivers were interviewed in the roadside survey. An examination of the raw (unweighted) breath alcohol readings reveals that of the 10,685 breath-tested drivers, 730 (6.8%) had positive blood alcohol concentrations (BACs); 245 of these drivers (2.3% of all drivers) had BACs below 20 mg/100 mL; 415 (3.9% of all drivers) were driving under the influence (DUI; 20 mg/100 mL-80 mg/100 mL); and 70 (0.7% of all drivers) were driving while intoxicated (DWI; ≥0.80 mg/100 mL). Overall, 4.6 percent of the drivers had BACs over 20 mg/100 mL (the lowest legal BAC limit in China). Among the 10,666 interviewed drivers, only 4.8 percent were aware of the lowest national BAC limit (20 mg/100 mL); 24.9 percent had been discouraged by other people from driving after drinking; 78 percent had never been stopped by the traffic police for a BAC check during the last 2 years (during 2005-2006), and only 0.3 percent had been punished for drink driving. The accident survey results revealed that an average of 34.1 percent of road accidents (Nanning: 25.7%; Liuzhou: 48%) were alcohol related; the mean BAC level of the drivers in the accidents was 156.7 mg/100 mL and the highest was 310 mg/100 mL. Valuable information was obtained from the baseline survey to provide a better understanding of the drink driving situation in Nanning and Liuzhou. From the survey data it can be seen that drinking and driving was a major issue in both cities. A drink driving intervention was developed with both components of public education/social marketing and enforcement activities after the survey, which was conducted in 2008. However, this article will focus on the methodology and results of the baseline survey, not the activities and outcome of the intervention.


[Cardiovascular diseases in nocturnal disorders of respiratory regulation].
Sleep related disorders of respiratory regulation can result, through various mechanisms, in impairment of the hemodynamics of the heart and the systemic and pulmonary circulations. The group of patients with sleep apnea has been most thoroughly investigated thus far. The patients frequently develop essential and/or pulmonary hypertension. In sleep all forms of cardiac arrhythmia may occur, and thus the patients are at high risk for nocturnal sudden cardiac death. Responsibility for most hemodynamic alterations is attributed to apnea-induced hypoxia and hypercapnia and the intrathoracic pressure fluctuations observed in obstructive apnea. However, we are still short of detailed knowledge regarding the individual pathologic mechanisms. The hemodynamic changes observed in patients with sleep related disorders of respiratory regulation lead in the long run to cardiac failure. Early diagnosis and care of these patients is therefore urgently necessary to render timely therapeutic action possible.


Effects of environmental exposure to diazepam on the reproductive behavior of fathead minnow, Pimephales promelas.
Pharmaceutical drugs are continuously discharged into the aquatic environment primarily through wastewater discharge; therefore, their possible effects on wildlife is a reason of concern. Diazepam is a widely prescribed benzodiazepine drug used to treat insomnia and anxiety disorders, and it has been found in wastewater effluents worldwide. The present study tested the effects of diazepam on fecundity and the reproductive behavior of the fathead minnow, Pimephales promelas, a fish that exhibits male parental care. Sexually mature fathead minnows were housed at a ratio of one male and two females per tank and exposed to nominal (measured) concentrations of 0, 0.1 (0.14 ± 0.06), 1.0 (1.04 ± 0.15), 10 (13.4 ± 1.5) µg L(-1) for 21 days. Fish receiving the low diazepam treatment had significantly larger clutches than fish receiving the highest concentration but neither were different from controls. Diazepam exposure was not associated with a significant change in fertilization rate, hatchability or time to hatch, but a trend toward a higher number of eggs/day was observed in fish exposed to the low diazepam concentration relative to those exposed to the medium concentration. There were no significant differences in any of the behaviors analyzed when responses were averaged over time. The results showed that exposure to diazepam at concentrations as high as 13 µg L(-1) did not significantly impact the reproductive behavior of fathead minnow.


Lipid abnormalities in stable liver transplant recipients--effects of cyclosporin, tacrolimus, and steroids.
Dyslipidemia is common after liver transplantation, but the underlying mechanisms are largely unknown. We studied the lipid profile of 27 liver transplant recipients randomized to received either cyclosporin (CyA, n = 14) or tacrolimus (n = 13) and compared them with 20 healthy, matched controls. Before transplantation, patients presented low total and low-density lipoprotein (LDL) cholesterol (as compared to controls) that increased shortly, i.e., 3 months, after transplantation. Eighteen months post-transplantation, total and LDL cholesterol levels decreased to pre-transplant values but tended to remain higher in CyA-treated patients. However, at that time, prednisone treatment was more prevalent among CyA-treated than tacrolimus-treated patients and fully accounted for the difference in cholesterol levels. Indeed, regardless of therapy, patients not receiving prednisone exhibited lower cholesterol levels than prednisone-treated patients and controls. We conclude that prednisone therapy, rather than CyA or tacrolimus immunosuppression, seems to be the major determinant of increased cholesterol levels.


[Outcomes and the role of adjuvant therapy of limited stage small cell lung cancer undergoing surgical treatment].
Objective: To investigate the outcomes of limited stage small cell lung cancer (L-SCLC) undergoing surgical therapy and to explore the value of adjuvant therapy for those patients. Methods: A retrospective analysis was initialed for the L-SCLC patients who underwent the surgical treatment in the Zhongnan Hospital of Wuhan University from January 2012 to December 2018. The median disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier method. Cox regression was used to explore the prognostic factors. Results: A total of 44 patients were included in our study. The median DFS was 25 months, 1- and 2-year DFS rate were 70.2% and 51.9%, respectively. The median OS was 41 months, 1- and 2- year OS rate were 88.4% and 69.9%, respectively. Multivariate analysis showed male (RR=6.56, P=0.03), T3-4 (RR=6.23, P=0.01), pathological lymph node metastasis (RR=6.52, P=0.03) and adjuvant radiotherapy (RR=0.13, P=0.002) were associated with disease relapse significantly. Moreover, pathological lymph node metastasis (RR=3.62, P=0.01) coupled with sufficient adjuvant chemotherapy (≥4 cycles) (RR=0.12, P=0.01) were independent prognostic factors of OS. Conclusions: Surgical therapy may be an alternative primary treatment for L-SCLC. Additional adjuvant radiotherapy can reduce the risk of recurrence. Giving sufficient course of adjuvant chemotherapy can improve OS.


Sexual Dysfunctions among Veterans with and without PTSD.
Research on the relationship between posttraumatic stress disorder (PTSD) and sexual dysfunctions (SD) has clearly recognized the association among these conditions. The main objective of this research was to compare the levels of the overall and the level of certain domains of sexual functioning among veterans with and those without PTSD. Two hundred and fifty veterans with PTSD and 187 veterans without PTSD were included in the comparative study. The following assessments were conducted: LEC-5, PCL-5, ITQ, IIEF, PEDT, and MINI. Veterans with PTSD had significantly higher levels of all types of SD in the PTSD group compared with the non-PTSD veterans. Veterans with PTSD more frequently experienced psychiatric and somatic comorbidities and use of medication that may contribute to the occurrence and severity of SD. The present study emphasized that SDs are an important issue among patients with PTSD. The study comprehensively accounted for conditions that may contribute to the occurrence and severity of SD among veterans with PTSD. Future directions of the research that could further improve the healthcare of the patients were indicated.


High-fat diet affects skeletal muscle mitochondria comparable to pressure overload-induced heart failure.
In heart failure, high-fat diet (HFD) may exert beneficial effects on cardiac mitochondria and contractility. Skeletal muscle mitochondrial dysfunction in heart failure is associated with myopathy. However, it is not clear if HFD affects skeletal muscle mitochondria in heart failure as well. To induce heart failure, we used pressure overload (PO) in rats fed normal chow or HFD. Interfibrillar mitochondria (IFM) and subsarcolemmal mitochondria (SSM) from gastrocnemius were isolated and functionally characterized. With PO heart failure, maximal respiratory capacity was impaired in IFM but increased in SSM of gastrocnemius. Unexpectedly, HFD affected mitochondria comparably to PO. In combination, PO and HFD showed additive effects on mitochondrial subpopulations which were reflected by isolated complex activities. While PO impaired diastolic as well as systolic cardiac function and increased glucose tolerance, HFD did not affect cardiac function but decreased glucose tolerance. We conclude that HFD and PO heart failure have comparable effects leading to more severe impairment of IFM. Glucose tolerance seems not causally related to skeletal muscle mitochondrial dysfunction. The additive effects of HFD and PO may suggest accelerated skeletal muscle mitochondrial dysfunction when heart failure is accompanied with a diet containing high fat.


Electrochemical analysis in a liposome suspension using lapachol as a hydrophobic electro active species.
This study demonstrated that the electro-chemical analysis of hydrophobic quinones can be performed in liposome suspension systems. We prepared and analyzed liposome suspensions containing lapachol, which is a quinone-based anti-tumor activity compound. In this suspension system, a simple one redox couple of lapachol is observed. These results are quite different from those obtained in organic solvents. In addition, the pH dependence of redox behaviors of lapachol could be observed in multilamellar vesicle (MLV) suspension system. This MLV suspension system method may approximate the electrochemical behavior of hydrophobic compounds in aqueous conditions. A benefit of this liposome suspension system for electrochemical analysis is that it enables to observe water-insoluble compounds without using organic solvents.


Aldosterone acts via an ATP autocrine/paracrine system: the Edelman ATP hypothesis revisited.
Aldosterone, the most important sodium-retaining hormone, was first characterized >50 years ago. However, despite numerous studies including the classical work of Isidore S. "Izzy" Edelman showing that aldosterone action depended on ATP production, the mechanism by which it activates sodium reabsorption via the epithelial sodium channel remains unclear. Here, we report experiments that suggest that one of the key steps in aldosterone action is via an autocrine/paracrine system. The hormone stimulates ATP release from the basolateral side of the target kidney cell. Prevention of ATP accumulation or its removal blocks aldosterone action. ATP then acts via a purinergic mechanism to produce contraction of small groups of adjacent epithelial cells. Patch clamping demonstrates that it is these contracted cells that have channel activity. With progressive recruitment of contracting cells, there is then a parallel increase in transepithelial electrical conductance. In common with other stimuli of sodium transport, this pathway involves phosphatidylinositol 3-kinase. Inhibition of phosphatidylinositol 3-kinase blocks both cell contraction and conductance. We put forward the hypothesis that redistribution of the cell volume caused by the lateral contraction results in apical swelling and that this change, in turn, disrupts the epithelial sodium channel interaction with the F-actin cytoskeleton, opening the channel and hence increasing sodium transport.


Angiopoietin-like 8 (Angptl8) controls adipocyte lipolysis and phospholipid composition.
Angiopoietin-like 8 (Angptl8) inhibits lipolysis in the circulation together with Angplt3 and controls post-prandial fat storage in white adipose tissue (WAT). It is strongly induced by insulin in vivo in WAT and in vitro in adipocytes. In this study we addressed the function of Angptl8 in adipocytes by its stable lentivirus-mediated knock-down in 3T3-L1 cells, followed by analyses of triglyceride (TG) storage, lipid droplet (LD) morphology, the cellular lipidome, lipolysis, and gene expression. Depletion of Angptl8 did not drastically affect the adipocyte differentiation of 3T3-L1 cells but resulted in a moderate (18-19%) reduction of stored TGs. The lipidome analysis revealed a reduction of alkyl- phosphatidylcholines (PCs) and phosphatidylethanolamine (PE) plasmalogens, as well as saturated PCs and PEs. Importantly, the Angptl8 depleted cells displayed enhanced lipolysis as measured by release of non-esterified fatty acids (NEFAs). Consistently, mRNAs encoding Angptl4 and Leptin, which facilitate lipolysis, as well as Cpt1a, Cpt1b, and Pgc-1α involved in FA oxidation, were elevated. The Angptl8 mRNA itself was suppressed by pharmacologic treatments inducing lipolysis: stimulation with the β-adrenergic agonist isoproterenol or with the adenylate cyclase activator forskolin. To conclude, knock-down of Angptl8 in adipocytes suggests that the protein acts to inhibit intracellular lipolysis, analogous to its activity in the circulation. Depletion of Angptl8 results in an altered cellular phospholipid composition. The findings identify Angptl8 as a central insulin-regulated controller of adipocyte lipid metabolism.


Wechsler Adult Intelligence Scale and Wechsler Adult Intelligence Scale-Revised in a neurologically impaired population.
Compared Verbal, Performance, and Full Scale IQ scores from two groups of neurologically impaired patients (N = 114) similar in age, years of education, occupation, race, sex, and etiology and location of cerebral dysfunction. One group had been given the WAIS and the other the WAIS-R. All three IQ scores were higher for the WAIS group, with Full Scale and Verbal scores significantly (p less than .05) higher. Changes in item content and standardization sample cohort effects are offered as partial possible explanation for the results. The IQ scores from the two tests cannot be considered as interchangeable for neurological patients.


Effects of plant density on recombinant hemagglutinin yields in an Agrobacterium-mediated transient gene expression system using Nicotiana benthamiana plants.
Agrobacterium-mediated transient expression systems enable plants to rapidly produce a wide range of recombinant proteins. To achieve economically feasible upstream production and downstream processing, it is beneficial to obtain high levels of two yield-related quantities of upstream production: recombinant protein content per fresh mass of harvested biomass (g gFM-1 ) and recombinant protein productivity per unit area-time (g m-2 /month). Here, we report that the density of Nicotiana benthamiana plants during upstream production had significant impacts on the yield-related quantities of recombinant hemagglutinin (HA). The two quantities were smaller at a high plant density of 400 plants m-2 than at a low plant density of 100 plants m-2 . The smaller quantities at the high plant density were attributed to: (i) a lower HA content in young leaves, which usually have high HA accumulation potentials; (ii) a lower biomass allocation to the young leaves; and (iii) a high area-time requirement for plants. Thus, plant density is a key factor for improving upstream production in Agrobacterium-mediated transient expression systems. Biotechnol. Bioeng. 2017;114: 1762-1770. © 2017 Wiley Periodicals, Inc.


Possible recruitment of peripheral blood CXCR3+ CD27+ CD19+ B cells to the liver of chronic hepatitis C patients.
It has been suggested that hepatitis C virus (HCV) infects not only hepatocytes but also immune cells, including B cells. HCV infection of B cells is the likely cause of B-cell dysregulation disorders such as mixed cryoglobulinemia, rheumatoid factor production, and B-cell lymphoproliferative disorders that may evolve into non-Hodgkin's lymphoma. To clarify the effects of chronic HCV infection on B-cell dynamics, peripheral B cells from chronic hepatitis C patients (CHC) were characterized. We found that the frequency of CD27(+) B cells, that is memory phenotype, was significantly reduced in the peripheral blood of CHC. At the same time, the amount of IFN-gamma-inducible protein-10 (IP-10), a CXCR3 ligand, was markedly elevated in the plasma of CHC. Furthermore, the CD27(+) B-cell population was found to highly express CXCR3 in CHC, thus suggesting that the CD27(+) B-cell population was recruited from peripheral blood to the inflammatory site of the liver of CHC, where IP-10 is produced. Immunohistochemical analyses of intrahepatic lymphocytes indicated that CXCR3(+) B cells were infiltrated in the liver of CHC. Our results thus offer new insight into the role of memory B cells in the HCV pathogenesis.