Value of 18FDG PET scan in staging of ocular adnexal lymphomas: a large single-center experience.
Fluorine 18 deoxyglucose positron emission tomography ((18)FDG PET) is widely used in staging of non-Hodgkin's lymphomas (NHL), but very few studies have focused on its role in the initial staging of patients with ocular adnexal lymphoma (OAL). The aim of this study was therefore to evaluate the role of (18)FDG PET in the diagnosis of ophthalmologic lymphoma. A retrospective review of all imaging records, including computed tomography (CT), magnetic resonance imaging (MRI), and FDG PET, was performed. Forty-one OAL patients were included in the study. A pathologic review according to the World Health Organization classification showed 32 low-grade lymphoma patients (78%), including 26 mucosa-associated lymphoid tissue lymphomas (63%). Ophthalmologic sites were intra-orbital + lacrimal gland in 24 patients (59%), conjunctival in 13 patients (32%), multiple in 4 cases, and bilateral in 6 patients. (18)FDG PET was positive in orbital and conjunctival sites in 68 and 35% of cases, respectively. (18)FDG PET positivity was correlated with pathologic sites detected by MRI in 22/30 patients (73%); (18)FDG PET positivity was correlated with pathologic sites detected by CT in 25/34 patients (73%). This study shows that (18)FDG PET has a lower sensitivity than MRI to detect ophthalmologic lymphoma, particularly in non-conjunctival sites.


Espin cross-links cause the elongation of microvillus-type parallel actin bundles in vivo.
The espin actin-bundling proteins, which are the target of the jerker deafness mutation, caused a dramatic, concentration-dependent lengthening of LLC-PK1-CL4 cell microvilli and their parallel actin bundles. Espin level was also positively correlated with stereocilium length in hair cells. Villin, but not fascin or fimbrin, also produced noticeable lengthening. The espin COOH-terminal peptide, which contains the actin-bundling module, was necessary and sufficient for lengthening. Lengthening was blocked by 100 nM cytochalasin D. Espin cross-links slowed actin depolymerization in vitro less than twofold. Elimination of an actin monomer-binding WASP homology 2 domain and a profilin-binding proline-rich domain from espin did not decrease lengthening, but made it possible to demonstrate that actin incorporation was restricted to the microvillar tip and that bundles continued to undergo actin treadmilling at approximately 1.5 s-1 during and after lengthening. Thus, through relatively subtle effects on actin polymerization/depolymerization reactions in a treadmilling parallel actin bundle, espin cross-links cause pronounced barbed-end elongation and, thereby, make a longer bundle without joining shorter modules.


Allosterically regulated supramolecular catalysis of acyl transfer reactions for signal amplification and detection of small molecules.
The advent of methods for the construction of supramolecular assemblies provides a route to exploring the benefits of artificial allosteric catalysts. To expand our ability to control reactions using supramolecular catalysts capable of changing shape in response to chemical input signals, we report the development and high yield syntheses of multidomain modular supramolecular catalysts. These structures can be chemically interconverted between relatively inactive and catalytically active states depending on their shape. Furthermore, this class of supramolecular catalysts can be made to respond to a range of analytes via the introduction of specific structure control elements responsible for binding analyte molecules. Herein, we describe several of these catalysts and their ability to regulate acyl transfer reactions allosterically. In addition, the generality of this approach to signal amplification and detection is examined by incorporating the acyl transfer reaction into a small molecule detection scheme consisting of (i) analyte binding to structure control sites of the catalytic supramolecular assemblies, (ii) enhanced catalytic activity turned on by the resulting shape change, thereby allowing for signal amplification of the binding event, and (iii) signal detection by analysis of the products of the catalytic reaction.


Issues Associated With the Management and Governance of Sensor Data and Information to Assist Aging in Place: Focus Group Study With Health Care Professionals.
Smart home and telemonitoring technologies have often been suggested to assist health care workers in supporting older people to age in place. However, there is limited research examining diverse information needs of different groups of health care workers and their access to appropriate information technologies. The aim of this study was to investigate the issues associated with using technologies that connect older people to their health care providers to support aging in place and enhance older people's health and well-being. Seven focus group discussions were conducted comprising 44 health care professionals who provided clinic-based or in-home services to community-dwelling older people. Participants were asked about their information needs and how technology could help them support older people to age in place. The recordings of the sessions were transcribed and thematically analyzed. The perspectives varied between the respondents who worked in primary care clinics and those who worked in community-based services. Three overarching themes were identified. The first theme was "access to technology and systems," which examined the different levels of technology in use and the problems that various groups of health care professionals had in accessing information about their patients. Primary care professionals had access to good internal information systems but they experienced poor integration with other health care providers. The community-based teams had poor access to technology. The second theme was "collecting and sharing of information," which focused on how technology might be used to provide them with more information about their patients. Primary care teams were interested in telemonitoring for specific clinical indicators but they wanted the information to be preprocessed. Community-based teams were more concerned about gaining information on the patients' social environment. The third theme was that all respondents identified similar "barriers to uptake": cost and funding issues, usability of systems by older people, and information security and privacy concerns. The participants perceived the potential benefits of technologies, but they were concerned that the information they received should be preprocessed and integrated with current information systems and tailored to the older people's unique and changing situations. Several management and governance issues were identified, which needed to be resolved to enable the widespread integration of these technologies into the health care system. The disconnected nature of the current information architecture means that there is no clear way for sensor data from telemonitoring and smart home devices to be integrated with other patient information. Furthermore, cost, privacy, security, and usability barriers also need to be resolved. This study highlights the importance and the complexity of management and governance of systems to collect and disseminate such information. Further research into the requirements of all stakeholder groups and how the information can be processed and disseminated is required.


Detection of HBeAg in the lymphocytes of sero-HBeAg negative patients with chronic hepatitis B and primary hepatocellular carcinoma.
HBeAg has been detected in the peripheral lymphocytes of chronic hepatitis B patients who were seronegative for HBeAg. Nearly 50% of these patients (males, aged 41-66) had histology confirmed hepatocellular carcinoma while the normal carriers (males, aged 22-37) showed histological changes of chronic persistent or chronic active hepatitis. The HBeAg was also demonstrated in the lymphocytes of eight voluntary blood donors who were found to be seropositive for HBsAg and HBeAg. The lymphocyte HBeAg exists in two subentities; a soluble and a particulate form. These observations suggest that the peripheral blood lymphocytes are hosts for HBV replication and production of infectious virus particles. Such processes may lead to an impaired immune defence mechanism, and explain the chronicity of the disease, and hepatic oncogenesis.


The effect of vitamin D3 and ketoconazole combination on VDR-mediated P-gp expression and function in human colon adenocarcinoma cells: implications in drug disposition and resistance.
The vitamin D3 metabolite 1,25-dihydroxycholecalciferol (DHC) and analogues derived from it are being investigated as potential agents for the treatment of cancer. Combining ketoconazole (KTZ) with DHC has been recommended to enhance the anticancer activity of DHC. DHC exerts its biological activities through the vitamin D receptor (VDR). VDR is recognized to be a regulator of P-glycoprotein (P-gp), a member of the ABC transporter family well known for its role in multidrug resistance in cancer chemotherapy. We have investigated the effect of DHC and adding KTZ together with DHC on P-gp and VDR expression and the functional consequences of P-gp induction in intestinal human colonic adenocarcinoma cells LS174T cells. DHC increased P-gp expression by two times, and the addition of KTZ further increased the expression to four times. The combination of DHC + KTZ also significantly increased VDR expression, consistent with the enhanced increase in P-gp expression by this combination. The increase in P-gp expression was accompanied by increased P-gp function, as measured by decreased Rh123 accumulation in the LS174T cells. In addition, DHC significantly decreased colchicine cytotoxicity in a dose-sensitive manner, and the addition of KTZ further decreased the colchicine cytotoxicity, indicating the chemo-protective effect of DHC is enhanced by KTZ, consistent with the enhanced expression of P-gp. The results of this study raise the possibility that DHC and the addition of KTZ to DHC treatment may decrease the effectiveness of cancer chemotherapy by promoting P-gp-mediated drug resistance.


Evolution of an X-Linked miRNA Family Predominantly Expressed in Mammalian Male Germ Cells.
MicroRNAs (miRNAs) are important posttranscriptional regulators of gene expression. However, comprehensive expression profiles of miRNAs during mammalian spermatogenesis are lacking. Herein, we sequenced small RNAs in highly purified mouse spermatogenic cells at different stages. We found that a family of X-linked miRNAs named spermatogenesis-related miRNAs (spermiRs) is predominantly expressed in the early meiotic phases and has a conserved testis-specific high expression pattern in different mammals. We identified one spermiR homolog in opossum; this homolog might originate from THER1, a retrotransposon that is active in marsupials but extinct in current placental mammals. SpermiRs have expanded rapidly with mammalian evolution and are diverged into two clades, spermiR-L and spermiR-R, which are likely to have been generated at least in part by tandem duplication mediated by flanking retrotransposable elements. Notably, despite having undergone highly frequent lineage-specific duplication events, the sequences encoding all spermiR family members are strictly located between two protein-coding genes, Slitrk2 and Fmr1. Moreover, spermiR-Ls and spermiR-Rs have evolved different expression patterns during spermatogenesis in different mammals. Intriguingly, the seed sequences of spermiRs, which are critical for the recognition of target genes, are highly divergent within and among mammals, whereas spermiR target genes largely overlap. When miR-741, the most highly expressed spermiR, is knocked out in cultured mouse spermatogonial stem cells (SSCs), another spermiR, miR-465a-5p, is dramatically upregulated and becomes the most abundant miRNA. Notably, miR-741-/- SSCs grow normally, and the genome-wide expression levels of mRNAs remain unchanged. All these observations indicate functional compensation between spermiR family members and strong coevolution between spermiRs and their targets.


The molecular basis of skeletal metastases.
Metastasis is the culmination of numerous highly regulated sequences of steps that results in the proliferation and migration of cells from the primary site to a distant location. The biologic consequence of skeletal metastasis is focal bone sclerosis or osteolysis that leads to pain, pathologic fracture, and biochemical derangement. The difficulty in determining a point of control for clinical application has been because of the numerous systems, substrates, ligands, receptors, factors, and pathways that exist. These may be grouped into functional mechanisms identifiable by their relevance to the metastatic process. These include cell-cell or cell-matrix adhesion, invasion and migration, interactions with endothelial cells, growth factor regulation, proteolysis, and stimulation of differentiated osteoblast and osteoclast function. The challenge for cancer therapy will be to identify means to prevent metastasis or reduce its effect once it occurred. This review examines recent advances in the study of molecular processes of metastasis, which have identified potential sites and substrates for targeting with novel therapies and agents.


Advanced DNA Nanopore Technologies.
Diverse nanopore-based technologies have substantially expanded the toolbox for label-free single-molecule sensing and sequencing applications. Biological protein pores, lithographically fabricated solid-state and graphene nanopores, and hybrid pores are in widespread use and have proven to be feasible devices for detecting amino acids, polynucleotides, and their specific conformations. However, despite the indisputable and remarkable advantages in technological exploration and commercialization of such equipment, the commonly used methods may lack modularity and specificity in characterization of particular phenomena or in development of nanopore-based devices. In this review, we discuss DNA nanopore techniques that harness the extreme addressability, precision, and modularity of DNA nanostructures that can be incorporated as customized gates or plugs into for example lipid membranes, solid-state pores, and nanocapillaries, thus forming advanced hybrid instruments. In addition to these, there exist a number of diverse DNA-assisted nanopore-based detection and analysis methods. Here, we introduce different types of DNA nanostructure-based pore designs and their intriguing properties as well as summarize the extensive collection of current and future technologies and applications that can be realized through combining DNA nanotechnology with common nanopore approaches.


Agouti C57BL/6N embryonic stem cells for mouse genetic resources.
We report the characterization of a highly germline competent C57BL/6N mouse embryonic stem cell line, JM8. To simplify breeding schemes, the dominant agouti coat color gene was restored in JM8 cells by targeted repair of the C57BL/6 nonagouti mutation. These cells provide a robust foundation for large-scale mouse knockout programs that aim to provide a public resource of targeted mutations in the C57BL/6 genetic background.


Nitric oxide has little effect on acute pulmonary hypertension and right ventricular function during acute respiratory distress syndrome.
To evaluate the effect of nitric oxide (NO) on acute pulmonary hypertension and right ventricular function in patients with acute respiratory distress syndrome. A prospective clinical study. Ten patients in the respiratory and surgical intensive care units were used. They met the criteria for acute respiratory distress syndrome and were significantly hypoxic. They were all ventilator-dependent at the time of the study. NO was delivered to the patients in 5, 10, 20 and 30 ppm doses for 30 minutes at each concentration. The dosing was not randomised. The general and central haemodynamics were measured. Right ventricular function and interaction with the pulmonary artery impedance (Ea) were quantified with the ratio of right ventricular stroke work index/Ea. NO did not decrease the raised pulmonary artery pressure found in all of the patients. Right ventricular coupling to the circulation did not improve during the administration of NO. NO did not relieve the acute pulmonary artery hypertension associated with acute respiratory distress syndrome. As a consequence of this, right ventricular function failed to improve during the administration of NO.


Isolation and characterization of bacteriophages infecting the fish pathogen Flavobacterium psychrophilum.
Flavobacterium psychrophilum is a serious pathogen in trout aquaculture, responsible for the diseases rainbow trout fry syndrome (RTFS) and cold water disease (CWD). Bacteriophage control of F. psychrophilum may constitute a realistic approach in the treatment of these diseases; however, a detailed understanding of the phage-host interactions is needed to evaluate the potential of F. psychrophilum bacteriophages for that purpose. Twenty-two F. psychrophilum phages from Danish rainbow trout farms were isolated and characterized. The phage genome sizes differed considerably and fell into three major size classes (8.5 to 12 kb, 48 kb, and 90 kb). The phage host ranges comprised from 5 to 23 of the 28 tested F. psychrophilum strains, and 18 of the phage isolates showed unique host ranges. Each bacterial strain had a unique pattern of susceptibility to the 22 phages, and individual strains also showed large variations (up to 10(7)-fold differences) in susceptibility to specific phages. Phage burst size (7 to 162 phages infected cell(-1)) and latency period (4 to 6 h) also showed pronounced differences both between phages and, for a specific phage, between host strains. In general, the characterization documented the presence of diverse F. psychrophilum phage communities in Danish trout farms, with highly variable patterns of infectivity. The discovery and characterization of broad-host-range phages with strong lytic potential against numerous pathogenic F. psychrophilum host strains thus provided the foundation for future exploration of the potential of phages in the treatment of RTFS and CWD.


The Current State of Gender Discrimination and Sexual Harassment in the Radiology Workplace: A Survey.
Our objectives were (1) to determine the extent to which gender discrimination and sexual harassment are experienced by female radiologists and trainees; (2) to examine whether experiencing harassment or discrimination influences perceptions of gender parity; and (3) to explore whether the existence of either formal institutional policies or the number of women in the workplace and/or in leadership positions influences perceptions of having achieved gender equity. An online anonymous questionnaire, developed through an Association of University Radiologists (AUR) - affiliated 2019-2020 Task Force, was used to assess participant demographics, perceptions of gender parity, and experiences of gender discrimination and sexual harassment. A total of 375 complete responses were collected. All respondents were female with most practices consisting of fewer than 25% female radiologists. The majority of respondents reported having been a victim of sexual harassment (n = 226, 60.3%) and gender discrimination (n = 318, 84.8%) in the workplace. Approximately 87.5% of participants believed workplace gender parity would take longer than 10 years to achieve; 26.9% responded that it will never happen. Experiencing gender discrimination or harassment in the workplace was significantly associated with a negative outlook on achieving gender parity. Conversely, the presence and number of adequate formal institutional policies to address workplace gender equity and harassment were significantly associated with optimistic views on achieving gender parity. Higher percentages of women in one's practice as well as number of women in leadership positions were also significantly associated with more optimistic expectations. Gender discrimination and sexual harassment are common in the field of radiology and influence victims' outlook on achieving gender parity in the workplace. Perceptions can be improved by implementing adequate institutional training policies on harassment and increasing the representation of female radiologists.


Evaluation of Patient-Reported Delays and Affordability-Related Barriers to Care in Head and Neck Cancer.
To examine the prevalence and predictors of patient-reported barriers to care among survivors of head and neck squamous cell carcinoma and the association with health-related quality of life (HRQOL) outcomes. Retrospective cohort study. Outpatient oncology clinic at an academic tertiary care center. Data were obtained from the UNC Health Registry/Cancer Survivorship Cohort. Barriers to care included self-reported delays in care and inability to obtain needed care due to cost. HRQOL was measured with validated questionnaires: general (PROMIS) and cancer specific (FACT-GP). The sample included 202 patients with head and neck squamous cell carcinoma with a mean age of 59.6 years (SD, 10.0). Eighty-two percent were male and 87% were White. Sixty-two patients (31%) reported at least 1 barrier to care. Significant predictors of a barrier to care in unadjusted analysis included age ≤60 years (P = .007), female sex (P = .020), being unmarried (P = .016), being uninsured (P = .047), and Medicaid insurance (P = .022). Patients reporting barriers to care had significantly worse physical and mental HRQOL on the PROMIS questionnaires (P < .001 and P = .002, respectively) and lower cancer-specific HRQOL on the FACT-GP questionnaire (P < .001), which persisted across physical, social, emotional, and functional domains. There was no difference in 5-year OS (75.3% vs 84.1%, P = .177) or 5-year CSS (81.6% vs 85.4%, P = .542) in patients with and without barriers to care. Delay- and affordability-related barriers are common among survivors of head and neck cancer and appear to be associated with significantly worse HRQOL outcomes. Certain sociodemographic groups appear to be more at risk of patient-reported barriers to care.


Caffeine does not influence persistent inward current contribution to motoneuron firing.
The purpose of this study was to investigate whether caffeine consumption would change persistent inward current (PIC) contribution to motoneuron firing at increased contraction intensities and after repetitive sustained maximal contractions. Before and after the consumption of 6 mg·kg-1 of caffeine or placebo, 16 individuals performed isometric triangular-shaped ramp dorsiflexion contractions (to 20% and 40% of peak torque), followed by four maximal contractions sustained until torque production dropped to 60% of maximum, and consecutive 20% triangular-shaped contractions. Tibialis anterior motor unit firing frequencies were analyzed from high-density surface electromyograms. PIC contribution to motor unit firing was estimated by calculating the delta frequency (ΔF) using the paired motor unit technique. Motoneuron peak firing frequencies at 20% and 40% contractions and total torque-time integral during the repetitive sustained maximal contractions were also assessed. ΔF increased 0.69 peaks per second (pps) (95% CI = -0.98, -0.405; d = -0.87) from 20% to 40% contraction intensities and reduced 0.85 pps (95% CI = 0.66, 1.05; d = 0.99) after the repetitive sustained maximal contractions, regardless of caffeine consumption. Participants produced 337 Nm·s (95% CI = 49.9, 624; d = 0.63) more torque integral during the repetitive sustained maximal contractions after caffeine consumption. A strong repeated-measures correlation (r = 0.61; 95% CI = 0.49, 0.69) was observed between reductions of ΔF and peak firing frequencies after the repetitive sustained maximal contractions. PIC contribution to motoneuron firing increases from 20% to 40% contraction intensities, with no effect of caffeine (on rested tibialis anterior). Repetitive sustained maximal contractions reduced PIC contribution to motoneuron firing, regardless of caffeine or placebo consumption, evidencing that changes in intrinsic motoneuron properties contributed to performance loss. Caffeine-attenuated reduction of torque production capacity was unlikely mediated by PICs.NEW & NOTEWORTHY Persistent inward current (PIC) contribution to motoneuron firing increases with contraction intensities and is reduced after repetitive sustained maximal contractions, regardless of caffeine consumption. Reductions of PIC contribution to motoneuron firing and peak firing frequencies were largely associated, evidencing a novel mechanism underpinning decrements in maximal torque production capacity following repetitive sustained maximal contractions. Caffeine consumption attenuated neuromuscular performance reductions-allowing higher time-torque integral production during repetitive sustained maximal contractions. This was unlikely mediated by PIC.


Immunology of hearing: experiments of nature.
Cellular and humoral immune reactions may play a role in the ethiopathogenesis of an audiovestibular dysfunction. Immune-mediated inner ear disorders can be of cochlear and retrocochlear origin. Autoimmunity plays occasionally a role, but is certainly not obligatory.


Enterococcus faecalis shifts macrophage polarization toward M1-like phenotype with an altered cytokine profile.
Background: The macrophage is an innate immune defense cell involved in pathogen recognition and clearance. Aim: In view of the diversity of the macrophage phenotype and function, the present study investigated how Enterococcus faecalis infection affects the differentiation, phenotype and cytokine profile of macrophages. Methods: Murine bone marrow-derived stem cells were co-cultured with E. faecalis before and after differentiation. Macrophage M0 polarization towards M1 or M2 was initiated at day 6 by addition of LPS and INF-γ, or IL-4 and IL-13, respectively. Results: E. faecalis did not inhibit macrophage differentiation and were identified within macrophages. Viability of the macrophages infected with E. faecalis prior to differentiation was enhanced, evidenced by apoptosis inhibition, as was expression of CD38 and IRF5 proteins, indicators of M1-like polarization. These M1-like macrophages expressed an aberrant cytokine mRNA profile, with reduction in inflammatory cytokines IL-1β and IL-12 and increase in regulatory cytokine IL-10. No changes in TNF-α or TGF-β1 were detected, compared with the control groups. This atypical M1-like phenotype was retained even upon stimulation with growth factors that normally trigger their development into M2 macrophages. Conclusions: These findings suggested that E. faecalis infection of bone marrow-derived stem cells during differentiation into macrophages induces an atypical M1-like phenotype associated with intracellular bacterial survival.


The X-linked gene G4.5 is responsible for different infantile dilated cardiomyopathies.
Barth syndrome (BTHS) is an X-linked disorder characterized clinically by the associated features of cardiac and skeletal myopathy, short stature, and neutropenia. The clinical manifestations of the disease are, in general, quite variable, but cardiac failure as a consequence of cardiac dilatation and hypertrophy is a constant finding and is the most common cause of death in the first months of life. X-linked cardiomyopathies with clinical manifestations similar to BTHS have been reported, and it has been proposed that they may be allelic. We have recently identified the gene responsible for BTHS, in one of the Xq28 genes, G4.5. In this paper we report the sequence analysis of 11 additional familial cases: 8 were diagnosed as possibly affected with BTHS, and 3 were affected with X-linked dilated cardiomyopathies. Mutations in the G4.5 gene were found in nine of the patients analyzed. The molecular studies have linked together what were formerly considered different conditions and have shown that the G4.5 gene is responsible for BTHS (OMIM 302060), X-linked endocardial fibroelastosis (OMIM 305300), and severe X-linked cardiomyopathy (OMIM 300069). Our results also suggest that very severe phenotypes may be associated with null mutations in the gene, whereas mutations in alternative portions or missense mutations may give a "less severe" phenotype.


Uncoupling protein-1 is not leaky.
The activity of uncoupling protein-1 (UCP1) is rate-limiting for nonshivering thermogenesis and diet-induced thermogenesis. Characteristically, this activity is inhibited by GDP experimentally and presumably mainly by cytosolic ATP within brown-fat cells. The issue as to whether UCP1 has a residual proton conductance even when fully saturated with GDP/ATP (as has recently been suggested) has not only scientific but also applied interest, since a residual proton conductance would make overexpressed UCP1 weight-reducing even without physiological/pharmacological activation. To examine this question, we have here established optimal conditions for studying the bioenergetics of wild-type and UCP1-/- brown-fat mitochondria, analysing UCP1-mediated differences in parallel preparations of brown-fat mitochondria from both genotypes. Comparing different substrates, we find that pyruvate (or palmitoyl-L-carnitine) shows the largest relative coupling by GDP. Comparing albumin concentrations, we find the range 0.1-0.6% optimal; higher concentrations are inhibitory. Comparing basic medium composition, we find 125 mM sucrose optimal; an ionic medium (50-100 mM KCl) functions for wild-type but is detrimental for UCP1-/- mitochondria. Using optimal conditions, we find no evidence for a residual proton conductance (not a higher post-GDP respiration, a lower membrane potential or an altered proton leak at highest common potential) with either pyruvate or glycerol-3-phosphate as substrates, nor by a 3-4-fold alteration of the amount of UCP1. We could demonstrate that certain experimental conditions, due to respiratoty inhibition, could lead to the suggestion that UCP1 possesses a residual proton conductance but find that under optimal conditions our experiments concur with implications from physiological observations that in the presence of inhibitory nucleotides, UCP1 is not leaky.


Infiltrative nonamyloidotic monoclonal immunoglobulin light chain cardiomyopathy: an underappreciated manifestation of plasma cell dyscrasias.
Infiltrative cardiomyopathies are characterized by diastolic dysfunction. In monoclonal plasma cell dyscrasias, organ compromise may be produced by tissue deposition of monoclonal immunoglobulins or their constituent peptides independently of the effects of unbridled plasma cell proliferation. The deposits may be fibrillar, as in light chain amyloid (AL) or nonfibrillar, as in light chain deposition disease (LCDD). AL disease of the heart is a restrictive cardiomyopathy. We hypothesized that, despite differences in physical properties, nonamyloidotic light chain deposition in the myocardium could produce similar clinical and physiological abnormalities. Cardiac tissue from five patients with LCDD and cardiac dysfunction was examined by immunohistochemical and electron microscopic techniques. Hospital charts, electrocardiograms, echocardiograms and cardiac catheterization results were reviewed. In two cases, the original echocardiograms were reanalyzed. The five patients with nonamyloidotic light chain deposits in the myocardium had either mechanical or electrocardiographic abnormalities. In four with adequate clinical documentation, the diastolic dysfunction and conduction abnormalities were similar or identical to that described in cardiac AL disease. Although nonamyloidotic immunoglobulin light chain deposits in the myocardium differ in distribution and ultrastructural organization from the fibrillar deposits of AL disease, an analogous pattern of diastolic dysfunction and conduction disturbances results. The diagnosis should be considered in patients with a plasmacytic dyscrasia and restrictive cardiomyopathy in whom Congo red staining of endomyocardial biopsy tissue is negative. The diagnosis can be established by using the appropriate immunohistochemical and ultrastructural tissue examinations.


Dynorphin A inhibits NMDA receptors through a pH-dependent mechanism.
Dynorphin A (DynA), an endogenous agonist of kappa-opioid receptors, has also been reported to directly interact with the NMDA receptor. DynA inhibition of NMDA receptor function has been suggested to be involved in its neuroprotective action during ischemic and acidic conditions. However, the effect of external pH on DynA inhibition of the NMDA receptor has not been reported. Here, we show that DynA inhibition of the NMDA receptor is dependent on extracellular pH over the range of pH 6.7-8.3, and the inhibition by 10 microM DynA increases at low pH by three- to four-fold in hippocampal neurons and in Xenopus oocytes expressing NR1-1a/2B subunits. Molecular studies showed that the interacting site for DynA on the NMDA receptor is distinct from that of proton or redox sites. Peptide mapping demonstrated important contributions of positively charged residues and specific structural organization of the peptide to the potency of DynA inhibition. Thus, DynA inhibits NMDA receptors through an allosteric mechanism, which is pH dependent and involves the specific structural features of the peptide.


Ophthalmia in turkeys infected with Pasteurella multocida.
Blepharoconjunctivitis and hypopyon were observed in eyes of turkeys infected during 2 epornitics of fowl cholera. Blepharoconjunctivitis, hypopyon, anterior synechiae, and panophthalmitis were observed sporadically in turkeys experimentally exposed to Pasteurella multocida via drinking water. P. multocida was isolated from these lesions.


Double-barreled chloride channels of collecting duct basolateral membrane.
Microelectrode studies have shown that the basolateral membrane of the principal cells (PC) of the rabbit cortical collecting duct (CCD) contains Cl(-)-conductive pathways. To determine the properties of single Cl- channels we prepared the basolateral membrane for patch clamping by incubating the CCD in collagenase and/or tearing the basement membrane with a fine needle. When high concentrations of collagenase were used, only a small nonselective channel was observed. In low concentrations or the absence of collagenase, however, we identified a Cl- channel (g46) in both cell-attached and excised patches. The Cl- channel gated rapidly between three equally spaced substates of 0 (S0), 23 (S1), and 46 pS (S2) and slowly between states C (inactive) and S0. The conductance of each substate was not voltage dependent between pipette potentials from -60 to +60 mV (cell attached). The probability that the channel gated from C to S0 increased with hyperpolarizing potentials, but the probability that g46 was in substate S0 increased with depolarizing patch potentials. This channel was similar to that described by Miller for the nonexcitable membrane of the electric organ of Torpedo californica. Because g46 was the most frequently observed basolateral membrane channel and was voltage dependent at physiological potentials, it is probably the channel responsible for the dominant Cl- conductance of PC.


[Malaria vaccines--which vaccines to whom?].
More than a third of the world's population is at risk of contracting malaria. It is estimated that 200 people, primarily children in Africa, die of malaria every hour of every day all year round. Malaria is one of the main obstacles to socio-economic development in Africa. Vaccines against malaria are considered to be the control tool most in need of development. Fundamentally there are three types of malaria vaccines: vaccines against the invading sporozoite or the parasite's development in the liver cells, vaccines directed against the parasite's invasion of and development in the red blood cells; vaccines directed against the fertilisation process in the mosquito. Each malaria vaccine has its own area of application. In spite of promising results in animals it has been difficult to reproduce the results in clinical trials in humans. Recently, however, an experimental vaccine containing a sporozoite protein coupled to a hepatitis B surface molecule with a new adjuvant has been tested in Gambia. The results of these tests are promising, but it is unlikely that the vaccine will be of use in endemic areas. Increased focus on one of the world's biggest health problems has to a certain extent promoted the funding of development work on malaria vaccines. Despite minimal interest from the pharmaceutical industry, a number of experimental vaccines for clinical phase I trials are on their way. However, it will take a huge increase in public financial resources to secure effective and safe malaria vaccines for those most in need of them: people in developing countries and particularly in Sub-Saharan Africa.


Breech deliveries and cesarean section.
Breech presentation is the most common malpresentation, with about 3-4% of singleton fetuses presenting breech at delivery. Management of breech presentation has been a contentious issue with a lowering threshold for cesarean section in recent years. Perinatal mortality and morbidity are estimated to be three times that of comparable infants with vertex presentation. Breech presentation is commonly associated with certain adverse maternal and fetal factors which inherently give rise to increased perinatal morbidity and mortality. At present, most obstetricians favor cesarean delivery for uncomplicated pre-term breech. Controlled prospective studies have shown that the outcome of breech fetuses weighing more than 1500 g was not dependent on the mode of delivery. A more recent review from the Cochrane database by Grant does not justify a policy of elective cesarean section for pre-term breech. Vaginal delivery is preferred if the following criteria are met: frank breech only, estimated fetal weight of 2500-3500 g, adequate pelvimetry without hyperextended head, normal progression of labor, no evidence of fetal hypoxia under continuous fetal monitoring, and maternal weight under 90 kg. Vaginal delivery of frank breech at term may be just as safe as cesarean section when careful selection criteria are used. If these criteria are not fulfilled, or fetal monitoring cannot be performed, cesarean section is advisable.


Early detection of stroke at the sudden sensorineural hearing loss stage.
Sudden sensorineural hearing loss (SSNHL) can be a prodromal symptom of ischemic stroke, especially posterior circulation strokes in the anterior inferior cerebellar artery (AICA) area. Early diagnosis and optimal treatment for vascular SSNHL provide an opportunity to prevent more extensive area infarction. The objective of our research was to find clues that suggest stroke at the stage of isolated sudden hearing loss. We retrospectively investigated the medical records of patients who received an initial diagnosis of sudden sensorineural hearing loss upon admission from January 2017 to December 2022 at Capital Medical University Affiliated Beijing Tiantan Hospital. Among these patients, 30 individuals who developed acute ischemic stroke during their hospital stay were enrolled as the case group. To create a control group, we matched individuals from the nonstroke idiopathic SSNHL patients to the case group in terms of age (±3 years old) at a ratio of 1:4. We collected the clinical characteristics, pure tone hearing threshold test results, and imaging information for all patients included in the study. Three models were constructed to simulate different clinical situations and to identify vascular sudden sensorineural hearing loss (SSNHL). The results revealed that patients with SSNHL who had three or more stroke risk factors, bilateral hearing loss, moderately severe to total hearing loss, and any intracranial large artery stenosis and occlusion (≥50%) were at a higher risk of developing ischemic stroke during hospitalization. Consistent with previous studies, the presence of vertigo at onset also played a significant role in the early detection of upcoming stroke. Clinicians should be alert to SSNHL patients with bilateral hearing loss, moderately severe to total hearing loss and other aforementioned features. Early pure tone audiometric hearing assessment and vascular assessment are necessary for high-risk patients with SSNHL.


Hyponatraemia and neurological complications in children admitted with bronchiolitis.
Hyponatraemia occurs during bronchiolitis, sometimes with neurological manifestations. The prevalence of the latter differs widely and little is known about the time of occurrence and associated factors. This study was undertaken to investigate these complications. This was a retrospective observational chart review of a cohort of 233 infants under 2 years of age admitted with bronchiolitis to a teaching hospital in the United Arab Emirates. Hyponatraemia (serum sodium <135 mmol/L) occurred in 105 infants (45%, 95% CI 38-51). Hyponatraemia was present on admission in 84 infants (80%) with 90% of cases occurring within 6 days of the onset of illness. It was mild (130-135) in 100 infants (95%) and severe (<130) in five (5%). It was not significantly associated with age, duration of illness before admission, viral aetiology, white cell count or serum C-reactive protein concentrations, or the volume of administered intravenous fluid or use of 0.18% sodium chloride (NaCl). Neurological manifestations occurred in a 29-day-old child with a serum sodium level of 123 mmol/L while receiving two-thirds intravenous maintenance fluids (0.18% NaCl). His developmental milestones remained normal on follow-up to the age of 5 years. Hyponatraemia is common in infants with bronchiolitis and occurs in the majority within 6 days of onset of symptoms. There was a significant association between the presence of fever (>38°C) on admission and the duration of hospitalisation.


Adaptive strategies of high-flying migratory hoverflies in response to wind currents.
Large migrating insects, flying at high altitude, often exhibit complex behaviour. They frequently elect to fly on winds with directions quite different from the prevailing direction, and they show a degree of common orientation, both of which facilitate transport in seasonally beneficial directions. Much less is known about the migration behaviour of smaller (10-70 mg) insects. To address this issue, we used radar to examine the high-altitude flight of hoverflies (Diptera: Syrphidae), a group of day-active, medium-sized insects commonly migrating over the UK. We found that autumn migrants, which must move south, did indeed show migration timings and orientation responses that would take them in this direction, despite the unfavourability of the prevailing winds. Evidently, these hoverfly migrants must have a compass (probably a time-compensated solar mechanism), and a means of sensing the wind direction (which may be determined with sufficient accuracy at ground level, before take-off). By contrast, hoverflies arriving in the UK in spring showed weaker orientation tendencies, and did not correct for wind drift away from their seasonally adaptive direction (northwards). However, the spring migrants necessarily come from the south (on warm southerly winds), so we surmise that complex orientation behaviour may not be so crucial for the spring movements.


Severe Bleeding During Orthognathic Surgery for a Noonan Syndrome Patient.
Noonan syndrome (NS) is a genetic disorder characterized by craniofacial dysmorphism, chest deformities, congenital heart defects, and bleeding disorders. Although patients with NS have a high prevalence of orofacial deformity, few reports are available on their anesthetic management during orthognathic surgery. This case report describes a 31-year-old female with NS, anemia, hypertrophic cardiomyopathy, and mild mitral valve regurgitation who experienced severe bleeding during orthognathic surgery. After treating her anemia with oral iron therapy and subcutaneous epoetin β, 4 units of autologous blood was deposited prior to surgery. General anesthesia was induced with remifentanil and propofol and maintained with sevoflurane, remifentanil, and fentanyl. Despite mild hypotensive anesthesia (targeted mean arterial pressure of 65 mm Hg) with nitroglycerine and intravenous tranexamic acid for bleeding, adequate hemostasis was difficult to achieve and led to severe blood loss (1442 mL). Therefore, the 4 units of autologous blood and 2 units of packed red blood cells were transfused. Her postoperative course proceeded uneventfully without abnormal postoperative bleeding. Because patients with NS can have difficulty with hemostasis, vascular malformations, and fragile blood vessels, extensive hematologic evaluation and thorough preparation for unexpected bleeding are crucial to accomplish orthognathic surgery.


[Cataplexy in type C Niemann-Pick disease].
Cataplexy usually occurs as a part of the tetrad of clinical phenomena of idiopathic narcolepsy. Symptomatic cases are rare. A 4 years old girl from consangineous parents had recurrent loss of muscle tone and fell to the ground, when she laughed. The EEG was normal. Prolonged neonatal jaundice with cholestasis, hepatosplenomegaly, mental regression, supranuclear ophthalmoplegia, and foam cells led to the diagnosis of Niemann-Pick disease type C with symptomatic cataplexy. Symptomatic forms of the narcolepsy-cataplexy complex should be considered, when there is an early onset before puberty, cataplectic attacks predominate the narcoleptic attacks, and when additional neurological symptoms occur. Symptomatic cataplexy occurs in Niemann-Pick disease type C. It is considered to be the result of lesions of the pontine reticular formation.


Lewis (y) antigen overexpression increases the expression of MMP-2 and MMP-9 and invasion of human ovarian cancer cells.
Lewis (y) antigen is a difucosylated oligosaccharide present on the plasma membrane, and its overexpression is frequently found in human cancers and has been shown to be associated with poor prognosis. Our previous studies have shown that Lewis (y) antigen plays a positive role in the process of invasion and metastasis of ovarian cancer cells. However, the mechanisms by which Lewis (y) antigen enhances the invasion and tumor metastasis are still unknown. In this study, we established a stable cell line constitutively expressing Lewis (y) antigen (RMG-1-hFUT) by transfecting the cDNA encoding part of the human α1,2-fucosyltransferase (α1,2-FUT) gene into the ovarian cancer cell line RMG-1, and investigated whether Lewis (y) antigen regulates the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, and tissue inhibitors of metalloproteinases (TIMP-1) and TIMP-2. We found that RMG-1-hFUT cells exhibited higher invasive capacities than their control cells. In addition, expression of TIMP-1 and TIMP-2 was down-regulated and expression of MMP-2 and MMP-9 was up-regulated. Anti-Lewis (y) antigen antibody treatment significantly reversed the expression of TIMP-1, TIMP-2, MMP-2 and MMP-9. Taken together, we provide the first evidence that down-regulation of TIMP-1 and TIMP-2 and up-regulation of MMP-2 and MMP-9 represents one of the mechanisms by which Lewis (y) antigen promotes cell invasion.


Electroacupuncture induces c-Fos expression in the rostral ventrolateral medulla and periaqueductal gray in cats: relation to opioid containing neurons.
Our previous studies have shown that electroacupuncture (EA) at the Neiguan-Jianshi (P5-P6) acupoints inhibits sympathetic outflow and attenuates excitatory visceral cardiovascular reflexes through enkephalin- or beta-endorphin-related opioid receptors in the rostral ventrolateral medulla (rVLM). It is not known whether EA at these acupoints activates neurons containing enkephalin or beta-endorphin in the rVLM as well as in the periaqueductal gray (PAG) that are involved in EA-mediated central neural regulation of sympathetic activity. The present study evaluated activated neurons in the rVLM and PAG by detecting c-Fos immunoreactivity, and identified the relationship between c-Fos nuclei and neuronal structures containing enkephalin or beta-endorphin in these regions. To enhance the detection of cell bodies containing enkephalin or beta-endorphin, colchicine (90-100 microg/kg) was injected into the subarachnoid space in anesthetized cats 28-30 h prior to EA or the sham-operated control for EA. Following bilateral barodenervation and cervical vagotomy, EA (1-4 mA, 2 Hz, 0.5 ms) was performed at the P5-P6 acupoints (overlying median nerve; n=7) for 30 min. Identical procedures, with the exception of electrical stimulation, were carried out in five control animals. EA decreased blood pressure (BP) in four of seven cats (5-15 mm Hg) while the sham procedure for EA produced no responses. Perikarya containing enkephalin were found in the rVLM and rarely in the PAG, while no cell bodies labeled with beta-endorphin were identified in either region. Compared to animals in the control group, more c-Fos immunoreactivity, located principally in close proximity to fibers containing enkephalin or beta-endorphin, was observed in the rVLM and ventrolateral PAG (vlPAG) in EA-treated cats. Moreover, neurons double-labeled with c-Fos and enkephalin in the rVLM were significantly increased in cats following EA stimulation (P<0.05). These data indicate that EA at the P5-P6 acupoints activates neurons in the rVLM and vlPAG. These activated neurons contain enkephalin in the rVLM, and most likely interact with nerve fibers containing enkephalin or beta-endorphin in both the rVLM and vlPAG. The results from this study provide the first anatomical evidence showing that EA at the P5-P6 acupoints has the potential to influence neuronal structures (perikarya, axons and/or dendrites) containing enkephalin or beta-endorphin in specific regions of the brain stem. These neurons likely form the substrate for EA's influence on sympathoexcitatory cardiovascular reflexes.


The generation of piezoelectricity and flexoelectricity in graphene by breaking the materials symmetries.
Graphene is a non-piezoelectric material. Engineering the piezoelectricity in graphene is possible with the help of impurities, defects and structural modifications. This study reports the mechanism of strain induced polarization and the estimation of piezoelectric and flexoelectric coefficients for graphene system. The combination of charge-dipole potential and the strong many-body potential is employed for describing the inter-atomic interactions. The breaking of symmetry in graphene material is utilized to generate the polarization. Pristine graphene, graphene with circular defect, graphene with triangular defect and trapezium-shaped graphene are considered. Molecular dynamics simulations are performed for straining the graphene atomic systems. The optimization of charge-dipole potential functions measure the polarization for these systems. Pristine and circular defect graphene systems show a constant polarization with strain. The polarization is varying with strain for a triangular defected and trapezium-shaped graphene system. The local atomic deformation produces a change in polarization with respect to the strain gradient. Estimated piezo and flexo coefficients motivate the usage of graphene in electro-mechanical devices.


The cost of accessing infant HIV medications and health services in Uganda.
Patient costs are a critical barrier to the elimination of mother to child HIV transmission. Despite the Ugandan government providing free public HIV services, infant antiretroviral (ARV) prophylaxis coverage remains low (25%). To understand costs mothers incur in accessing ARV prophylaxis for their infants, we conducted a mixed methods study to quantify and identify their direct costs. We used cross-sectional survey data and focus group discussions from 49 HIV-positive mothers in Uganda. Means and standard deviations were calculated for the direct costs (e.g., transportation, caretaker, services/medications) involved in accessing infant HIV services. The direct cost of attending HIV clinic visits averaged $3.71 (SD = $3.52). Focus group discussions identified two costs hindering access to infant HIV services: transportation costs and informal service charges. All participants reported significant costs associated with accessing infant HIV services - the equivalent of 2-3 days' income. To address transportation costs, community and home care models should be explored. Additionally, stricter policies and oversight should be implemented to prevent informal HIV service charges.


Lessons from anti-thalassemia campaigns in Italy, before prenatal diagnosis.
The essay reconstructs the antithalassemia campaign carried out by means of population screening and pre-marriage counseling for about twenty years in Italy, immediately after the relationship between microcythemia and Cooley's anemia had been established, as well as its genetic bases. We examine the Italian contributions to the understanding of the genetics and of the clinical treatment of thalassemic disorders, and analyze the approaches to prevention as well as the results obtained by the first campaign against a genetic disease, conceived and largely implemented in Italy by Ezio Silvestroni and Ida Bianco. We discuss the resistances met by the antithalassemia campaign due to the cultural and organizational backwardness of the Italian medical community and of the public health system. Moreover we analyze the explanations and interpretations of the problematic results of these experiences in terms of morbidity reduction. It will be pointed out that the objective of genetic counselling practised in that context assumed the concept of disease prevention at the population level, and it was far from the idea, emerged in the 1970s, of non directive genetic counselling.


[Surgical strategy for wound to the neck under conditions of medical institutions in peace time].
The work is based on a clinical-statistical analysis of results of treatment of 316 wounded with injuries to the neck got in different situations in St. Petersburg and admitted to the clinic of field surgery and other medical institutions of the city. It was found that unfavorable outcomes of treatment of neck wounds of peace time depend on the character of the neck wound, adequacy of medical aid at the pre-hospital period, the decision on the medico-diagnostic strategy. The decision on the medico-diagnostic strategy for wounded to the neck must depend on the diagnostic resources of the medical institution and the succession and volume of the medico-diagnostic measures must be chosen depending on the general state, life-threatening consequences of the neck wound and severe associated injuries of other anatomical areas.


Segmental expression of an engrailed-class gene during early development and neurogenesis in an annelid.
ht-en protein, an annelid homolog of the Drosophila engrailed protein, is expressed during both early development and neurogenesis in embryos of the leech, Helobdella triserialis. In Helobdella as in Drosophila, early expression is in segmentally iterated stripes of cells within the posterior portion of the segment and later expression is in cells of the segmental ganglia. These findings suggest that dual expression of an en-class gene was present in a common ancestor of annelids and arthropods.


Scalable co-cured polyimide/poly(p-phenylene benzobisoxazole) all-organic composites enabling improved energy storage density, low leakage current and long-term cycling stability.
The all-organic high-temperature polymer dielectrics with promising scale-up potential have witnessed much progress in the energy storage area, etc. However, the electron suppression trap mechanisms behind many all-organic dielectrics are still unclear, especially for high temperature resistant poly(p-phenylene benzobisoxazole) (PBO) polymers. To resolve this tough issue, we herein innovatively prepared PBO-based all-organic thin films containing sulfone-based polyimide (P(DSDA-ODA)) functioning as an electron trap phase using a facile and scalable co-curing method. The great linear dielectric properties of the prepared P(DSDA-ODA)/PBO films hold high dielectric thermal stability over the temperature range from 25 °C to 200 °C. The 60 wt% P(DSDA-ODA) systems yield the lowest leakage current (3.8 × 10-8 A cm-2). The tight structure and reduced leakage current enable an enhanced breakdown strength of 60 wt% P(DSDA-ODA)/PBO (470 kV mm-1), which is 1.7 times that of pure PBO. Meanwhile, it can reach 4.16 J cm-3 of energy density, which is 257% higher than that for pure PBO thin films while concurrently maintaining a long stable charge-discharge cycle (at least 5000 times) and high charge-discharge efficiency at 85.10%. Moreover, P(DSDA-ODA)/PBO still exhibits excellent energy storage performance at high temperature compared to PBO. This innovative strategy is further verified by replacing P(DSDA-ODA) with P(6FDA-ODA), and therefore lays a solid foundation for more investigation on scalable all-organic dielectrics.


A scoping review on HIV early infant diagnosis among HIV exposed infants, ART use and adherence in Tanzania.
HIV Early Infant Diagnosis (HEID) is critical for the timely initiation of HIV treatments and improved health outcomes among HIV-infected infants. However, the uptake of HEID remains largely low in Tanzania. This descriptive scoping review of evidence on HEID among HIV-exposed infants in Tanzania seeks to understand the dynamics of HEID, ART use and adherence to inform targeted interventions and promote its uptake. The Arksey and O'Malley's methodological framework guided this scoping review. We searched for peer-published articles on HEID in Tanzania through PubMed and Google Scholar with full-text retrieval from HINAR. We included only English language articles published between 2013 and 2022. Further searches for the materials on the reference lists of the publications yielded additional relevant articles. We carried out an inductive thematic analysis to analyze and synthesize the data. In all, nine articles met the inclusion criteria and, hence, qualified for the review. The variations in the uptake of HEID in the empirical literature reviewed indicate an upward trend. HEID increased from 77.2% in 2009 to 97.8% in 2011 in Kilimanjaro, Mbeya and Tanga and from 53.2% in 2014 to 69.2% in 2016 in Dar es Salaam. The median age at the initial test ranged from 5.6 weeks in Kilimanjaro to 8.6 weeks in Mbeya. The uptake of HEID was necessitated by individual, household and health facility factors. Unknown HIV status at conception, low level of education of the household head, and large household size negatively affected uptake of HEID. The health facility factors such as unavailability of the test kits, long distances to the facility and transport costs negatively influenced HEID uptake. The percentage of HIV-positive infants on ART ranged from 52.7 to 61%, and loss to follow ranged from 31 to 61%. The uptake of HEID varied among regions depending on individual, household and health facility factors. Multifaced efforts are needed to address these factors for accelerated uptake of HEID and improved health outcomes and survival among this strategic population group.


Proteotoxic stress and the ubiquitin proteasome system.
The ubiquitin proteasome system maintains protein homeostasis by regulating the breakdown of misfolded proteins, thereby preventing misfolded protein aggregates. The efficient elimination is vital for preventing damage to the cell by misfolded proteins, known as proteotoxic stress. Proteotoxic stress can lead to the collapse of protein homeostasis and can alter the function of the ubiquitin proteasome system. Conversely, impairment of the ubiquitin proteasome system can also cause proteotoxic stress and disrupt protein homeostasis. This review examines two impacts of proteotoxic stress, 1) disruptions to ubiquitin homeostasis (ubiquitin stress) and 2) disruptions to proteasome homeostasis (proteasome stress). Here, we provide a mechanistic description of the relationship between proteotoxic stress and the ubiquitin proteasome system. This relationship is illustrated by findings from several protein misfolding diseases, mainly neurodegenerative diseases, as well as from basic biology discoveries from yeast to mammals. In addition, we explore the importance of the ubiquitin proteasome system in endoplasmic reticulum quality control, and how proteotoxic stress at this organelle is alleviated. Finally, we highlight how cells utilize the ubiquitin proteasome system to adapt to proteotoxic stress and how the ubiquitin proteasome system can be genetically and pharmacologically manipulated to maintain protein homeostasis.


HDAC-inhibition counteracts everolimus resistance in renal cell carcinoma in vitro by diminishing cdk2 and cyclin A.
Targeted therapies have improved therapeutic options of treating renal cell carcinoma (RCC). However, drug response is temporary due to resistance development. Functional and molecular changes in RCC Caki-1 cells, after acquired resistance to the mammalian target of rapamycin (mTOR)-inhibitor everolimus (Cakires), were investigated with and without additional application of the histone deacetylase (HDAC)-inhibitor valproic acid (VPA). Cell growth was evaluated by MTT assay, cell cycle progression and apoptosis by flow cytometry. Target molecules of everolimus and VPA, apoptotic and cell cycle regulating proteins were investigated by western blotting. siRNA blockade was performed to evaluate the functional relevance of the proteins. Everolimus resistance was accompanied by significant increases in the percentage of G2/M-phase cells and in the IC50. Akt and p70S6K, targets of everolimus, were activated in Cakires compared to drug sensitive cells. The most prominent change in Cakires cells was an increase in the cell cycle activating proteins cdk2 and cyclin A. Knock-down of cdk2 and cyclin A caused significant growth inhibition in the Cakires cells. The HDAC-inhibitor, VPA, counteracted everolimus resistance in Cakires, evidenced by a significant decrease in tumor growth and cdk2/cyclin A. It is concluded that non-response to everolimus is characterized by increased cdk2/cyclin A, driving RCC cells into the G2/M-phase. VPA hinders everolimus non-response by diminishing cdk2/cyclin A. Therefore, treatment with HDAC-inhibitors might be an option for patients with advanced renal cell carcinoma and acquired everolimus resistance.


Effect of fluorescein dye concentration in oral cancer tissue: Statistical and spectroscopic analysis.
Oral cancer screening with exogenous agents is highly demanding due to high sensitivity, as the early diagnosis plays a vital role in achieving favorable outcomes for oral squamous cell carcinomas (OSCC) by facilitating prompt detection and comprehensive surgical removal. Optical techniques utilizing the local application of fluorescein dye or fluorescence-guided surgery offer potential for early OSCC detection. The use of fluorescein dye in oral cancer is significantly less, and there is a need to inspect the local application of fluorescein dye in oral cancer patients. Concentration-based investigations of the dye with OSCC patients are essential to ensure accurate fluorescence-guided surgery and screening with fluorescein labeling and to mitigate possible adverse effects. Additionally, analyzing the dye distribution within OSCC tissues can provide insights into their heterogeneity, a critical indicator of malignancy. The present study includes a concentration-based statistical and spectroscopic analysis of fluorescein dye in ex-vivo and in-vivo OSCC patients. In the ex-vivo examination of OSCC tissues, five concentrations (18.66 ± 0.06, 9.51 ± 0.02, 6.38 ± 0.01, 4.80 ± 0.004, and 3.85 ± 0.002 millimolar) are employed for optical analysis. The ex-vivo OSCC tissues are analyzed for multiple statistical parameters at all concentrations, and the results are thoroughly described. Additionally, spectroscopic analysis is conducted on all concentrations for a comprehensive evaluation. Following optical analysis of all five concentrations in the ex-vivo study, two concentrations, 6.38 ± 0.01 and 4.80 ± 0.004 millimolar, are identified as suitable for conducting in-vivo investigations of oral cancer. A detailed spectroscopic and statistical study of OSCC tissues in-vivo has been done using these two concentrations.


Human mutation in the anti-apoptotic heat shock protein 20 abrogates its cardioprotective effects.
The small heat shock protein Hsp20 protects cardiomyocytes against apoptosis, and phosphorylation at its Ser16 site enhances its cardioprotection. To determine whether genetic variants exist in human Hsp20, which may modify these beneficial effects, we sequenced the coding region of the Hsp20 gene in 1347 patients suffering from dilated cardiomyopathy and 744 subjects with no heart disease. We identified a C59T substitution in the human Hsp20 gene in one patient and three individuals without heart disease. All subjects were heterozygous for this mutation, which changes a fully conserved proline residue into leucine at position 20 (P20L), resulting in secondary structural alterations. To examine the potential functional significance of the P20L-Hsp20 human variant, adult rat cardiomyocytes were infected with Ad.GFP (where Ad is adenovirus and GFP is green fluorescent protein), Ad.WT-Hsp20 (where WT is wild-type), and Ad.P20L-Hsp20 and subjected to simulated ischemia/reperfusion injury. Expression of WT-Hsp20 resulted in significant attenuation of apoptosis compared with the GFP control. However, the P20L-Hsp20 mutant showed no protection against apoptosis, assessed by Hoechst staining and DNA fragmentation. The loss of cardioprotection by the mutant Hsp20 was associated with its diminished phosphorylation at Ser16 compared with WT-Hsp20. Furthermore, maximal stimulation of cardiomyocytes with isoproterenol or protein kinase A-mediated phosphorylation in vitro confirmed the impaired ability of the mutant Hsp20 to become phosphorylated at Ser16. In conclusion, we have identified a P20L substitution in human Hsp20, which is associated with diminished phosphorylation at Ser16 and complete abrogation of the Hsp20 cardioprotective effects which may adversely affect the ability of human carriers to cope with cellular stress.


Positive criminology in practice.
The discourse regarding offender rehabilitation has been criticized by various scholars who have claimed that reducing negative causes and managing risk will not automatically prompt positive human development and elements that are associated with desistance. Positive criminology is an innovative concept that challenges the common preoccupation with negative elements, by placing emphasis on human encounters and forces of inclusion that are experienced positively by target individuals and that can promote crime desistance. However, as the concept is relatively new, there are still no guiding principles for the practice of positive criminology that could direct research and the criminal justice system. This article attempts to fill that gap by providing principles that could be practiced by criminal justice personnel and examples of different interventions that reflect positive criminology. The article also provides ideological explanations for adopting the concept of positive criminology in practice.


Effects of beta-lipotropin and beta-lipotropin-derived peptides on aldosterone production in the rat adrenal gland.
To investigate the role of non-ACTH pituitary peptides on steroidogenesis, we studied the effects of synthetic beta-lipotropin, beta-melanotropin, and beta-endorphin on aldosterone and corticosterone stimulation using rat adrenal collagenase-dispersed capsular and decapsular cells. beta-lipotropin induced a significant aldosterone stimulation in a dose-dependent fashion (10 nM-1 muM). beta-endorphin, which is the carboxyterminal fragment of beta-lipotropin, did not stimulate aldosterone production at the doses used (3 nM-6 muM). beta-melanotropin, which is the middle fragment of beta-lipotropin, showed comparable effects on aldosterone stimulation. beta-lipotropin and beta-melanotropin did not affect corticosterone production in decapsular cells. Although ACTH(1-24) caused a significant increase in cyclic AMP production in capsular cells in a dose-dependent fashion (1 nM-1 muM), beta-lipotropin and beta-melanotropin did not induce an increase in cyclic AMP production at the doses used (1 nM-1 muM). The beta-melanotropin analogue (glycine[Gly](10)-beta-melanotropin) inhibited aldosterone production induced by beta-lipotropin or beta-melanotropin, but did not inhibit aldosterone production induced by ACTH(1-24) or angiotensin II. Corticotropin-inhibiting peptide (ACTH(7-38)) inhibited not only ACTH(1-24) action but also beta-lipotropin or beta-melanotropin action; however it did not affect angiotensin II-induced aldosterone production. (saralasin [Sar](1); alanine [Ala](8))-Angiotensin II inhibited the actions of beta-lipotropin and beta-melanotropin as well as angiotensin II. These results indicate that (a) beta-lipotropin and beta-melanotropin cause a significant stimulation of aldosterone production in capsular cells, (b) beta-lipotropin and beta-melanotropin have a preferential effect on zona glomerulosa cells, (c) beta-melanotropin contains the active peptide core necessary for aldosterone stimulation, (d) the effects of these peptides on aldosterone production may be independent of cyclic AMP, and (e) the receptors for beta-lipotropin or beta-melanotropin may be different from those for ACTH or angiotensin II.


Two Groups of Thellungiella salsuginea RAVs Exhibit Distinct Responses and Sensitivity to Salt and ABA in Transgenic Arabidopsis.
Containing both AP2 domain and B3 domain, RAV (Related to ABI3/VP1) transcription factors are involved in diverse functions in higher plants. A total of eight TsRAV genes were isolated from the genome of Thellungiella salsuginea and could be divided into two groups (A- and B-group) based on their sequence similarity. The mRNA abundance of all Thellungiella salsuginea TsRAVs followed a gradual decline during seed germination. In Thellungiella salsuginea seedling, transcripts of TsRAVs in the group A (A-TsRAVs) were gradually and moderately reduced by salt treatment but rapidly and severely repressed by ABA treatment. In comparison, with a barely detectable constitutive expression, the transcriptional level of TsRAVs in the group B (B-TsRAVs) exhibited a moderate induction in cotyledons when confronted with ABA. We then produced the "gain-of-function" transgenic Arabidopsis plants for each TsRAV gene and found that only 35S:A-TsRAVs showed weak growth retardation including reduced root elongation, suggesting their roles in negatively controlling plant growth. Under normal conditions, the germination process of all TsRAVs overexpressing transgenic seeds was inhibited with a stronger effect observed in 35S:A-TsRAVs seeds than in 35S:B-TsRAVs seeds. With the presence of NaCl, seed germination and seedling root elongation of all plants including wild type and 35S:TsRAVs plants were retarded and a more severe inhibition occurred to the 35S:A-TsRAV transgenic plants. ABA treatment only negatively affected the germination rates of 35S:A-TsRAV transgenic seeds but not those of 35S:B-TsRAV transgenic seeds. All 35S:TsRAVs transgenic plants showed a similar degree of reduction in root growth compared with untreated seedlings in the presence of ABA. Furthermore, the cotyledon greening/expansion was more severely inhibited 35S:A-TsRAVs than in 35S:B-TsRAVs seedlings. Upon water deficiency, with a wider opening of stomata, 35S:A-TsRAVs plants experienced a faster transpirational water loss than wild type and 35S:B-TsRAVs lines. Taken together, our results suggest that two groups of TsRAVs perform distinct regulating roles during plant growth and abiotic defense including drought and salt, and A-TsRAVs are more likely than B-TsRAVs to act as negative regulators in the above-mentioned biological processes.


Peroxisomal peripheral membrane protein YlInp1p is required for peroxisome inheritance and influences the dimorphic transition in the yeast Yarrowia lipolytica.
Eukaryotic cells have evolved molecular mechanisms to ensure the faithful inheritance of organelles by daughter cells in order to maintain the benefits afforded by the compartmentalization of biochemical functions. Little is known about the inheritance of peroxisomes, organelles of lipid metabolism. We have analyzed peroxisome dynamics and inheritance in the dimorphic yeast Yarrowia lipolytica. Most peroxisomes are anchored at the periphery of cells of Y. lipolytica. In vivo video microscopy showed that at cell division, approximately half of the anchored peroxisomes in the mother cell are dislodged individually from their static positions and transported to the bud. Peroxisome motility is dependent on the actin cytoskeleton. YlInp1p is a peripheral peroxisomal membrane protein that affects the partitioning of peroxisomes between mother cell and bud in Y. lipolytica. In cells lacking YlInp1p, most peroxisomes were transferred to the bud, with only a few remaining in the mother cell, while in cells overexpressing YlInp1p, peroxisomes were preferentially retained in the mother cell, resulting in buds nearly devoid of peroxisomes. Our results are consistent with a role for YlInp1p in anchoring peroxisomes in cells. YlInp1p has a role in the dimorphic transition in Y. lipolytica, as cells lacking the YlINP1 gene more readily convert from the yeast to the mycelial form in oleic acid-containing medium, the metabolism of which requires peroxisomal activity, than does the wild-type strain. This study reports the first analysis of organelle inheritance in a true dimorphic yeast and identifies the first protein required for peroxisome inheritance in Y. lipolytica.


2-Acetyl-5,8-dihydro-6-(4-methyl-3-pentenyl)-1,4-naphthohydroquinone-Derived Chalcones as Potential Anticancer Agents.
Based on previous results with benzoindazolequinone (BIZQ) and 3-methylnaphtho [2,3-d]isoxazole-4,9-quinone (NIQ) derivatives, a novel series of chalcone-1,4-naphthoquinone/benzohydroquinone (CNQ and CBHQ) compounds were synthesized from 2-acetyl-5,8-dihydro-6-(4-methyl-3-pentenyl)-1,4-naphthohydroquinone. Their structures were elucidated via spectroscopy. These hybrids were assessed in vivo for their antiproliferative activity on MCF-7 breast adenocarcinoma and HT-29 colorectal carcinoma cells, revealing cytotoxicity with IC50 values between 6.0 and 110.5 µM. CBHQ hybrids 5e and 5f displayed enhanced cytotoxicity against both cell lines, whereas CNQ hybrids 6a-c and 6e exhibited higher cytotoxic activity against MCF-7 cells. Docking studies showed strong binding energies (ΔGbin) of CNQs to kinase proteins involved in carcinogenic pathways. Furthermore, our in silico analysis of drug absorption, distribution, metabolism, and excretion (ADME) properties suggests their potential as candidates for cancer pre-clinical assays.


Folding propensities of synthetic peptide fragments covering the entire sequence of phage 434 Cro protein.
The phage 434 Cro protein, the N-terminal domain of its repressor (R1-69) and that of phage lambda (lambda6-85) constitute a group of small, monomeric, single-domain folding units consisting of five helices with striking structural similarity. The intrinsic helix stabilities in lambda6-85 have been correlated to its rapid folding behavior, and a residual hydrophobic cluster found in R1-69 in 7 M urea has been proposed as a folding initiation site. To understand the early events in the folding of 434 Cro, and for comparison with R1-69 and lambda6-85, we examined the conformational behavior of five peptides covering the entire 434 Cro sequence in water, 40% (by volume) TFE/water, and 7 M urea solutions using CD and NMR. Each peptide corresponds to a helix and adjacent residues as identified in the native 434 Cro NMR and crystal structures. All are soluble and monomeric in the solution conditions examined except for the peptide corresponding to the 434 Cro helix 4, which has low water solubility. Helix formation is observed for the 434 Cro helix 1 and helix 2 peptides in water, for all the peptides in 40% TFE and for none in 7 M urea. NMR data indicate that the helix limits in the peptides are similar to those in the native protein helices. The number of side-chain NOEs in water and TFE correlates with the helix content, and essentially none are observed in 7 M urea for any peptide, except that for helix 5, where a hydrophobic cluster may be present. The low intrinsic folding propensities of the five helices could account for the observed stability and folding behavior of 434 Cro and is, at least qualitatively, in accord with the results of the recently described diffusion-collision model incorporating intrinsic helix propensities.


Same-day Versus Split-dose Bowel Preparation Before Colonoscopy: A Meta-analysis.
Split-dose regimens (SpDs) were recommended as a first choice for bowel preparation, whereas same-day regimens (SaDs) were recommended as an alternative; however, randomized trials compared them with mixed results. The meta-analysis was aimed at clarifying efficacy level between the 2 regimens. We used MEDLINE/PubMed, EMBASE, Scopus, CINAHL, Cochrane Library, and Web of Science to identify randomized trials published from 1990 to 2016, comparing SaDs to SpDs in adults. The pooled odds ratios (ORs) were calculated for preparation quality, cecal intubation rate (CIR), adenoma detection rate (ADR), and any other adverse effects. Fourteen trials were included. The proportion of individuals receiving SaDs and SpDs with adequate preparation in the pooled analysis were 79.4% and 81.7%, respectively, with no significant difference [OR=0.92; 95% confidence interval (CI), 0.62-1.36] in 11 trials. Subgroup analysis revealed that the odds of adequate preparation for SaDs with bisacodyl were 2.45 times that for SpDs without bisacodyl (95% CI, 1.45-4.51, in favor of SaDs with bisacodyl). Subjects received SaDs experienced better sleep. SaDs were comparable with SpDs in terms of bowel cleanliness, CIR, and ADR, and could also outperform SpDs in preparation quality with bisacodyl. SaDs also offered better sleep the previous night than SpDs did, which suggests that SaDs might serve as a superior alternative to SpDs. The heterogenous regimens and measurements likely account for the low rates of optimal bowl preparations in both arms. Further studies are needed to validate these results and determine the optimal purgatives and dosages.


A double-blind, placebo-controlled trial of topiramate for the treatment of comorbid cocaine and alcohol dependence.
Topiramate increases GABAergic activity and antagonizes the AMPA/kainate subtype of glutamate receptors. Through these mechanisms of action, topiramate may reduce alcohol and cocaine reward and may reduce alcohol and cocaine craving. Topiramate has been shown to reduce drinking in persons with alcohol dependence, and reduce relapse in stimulant-dependent patients. The current trial was intended to test the ability of topiramate to promote cocaine and alcohol abstinence among patients addicted to both drugs. The study was a double-blind, placebo-controlled, 13-week trial involving 170 cocaine and alcohol dependent subjects. After achieving a period of cocaine and alcohol abstinence, subjects were randomized to topiramate, 300 mg daily, or identical placebo capsules. In addition, subjects received weekly individual psychotherapy. Primary outcome measures included self-reported alcohol and cocaine use, and thrice weekly urine drug screens. Secondary outcome measures included cocaine and alcohol craving, Addiction Severity Index results, cocaine withdrawal symptoms, and clinical global improvement ratings. Topiramate was not better than placebo in reducing cocaine use on the a priori primary outcome measure, or in reducing alcohol use. Topiramate was not better than placebo in reducing cocaine craving. Topiramate-treated subjects, compared to placebo-treated subjects, were more likely to be retained in treatment and more likely to be abstinent from cocaine during the last three weeks of the trial. Subjects who entered treatment with more severe cocaine withdrawal symptoms responded better to topiramate. Topiramate plus cognitive behavioral therapy may reduce cocaine use for some patients with comorbid cocaine and alcohol dependence.


Physician accuracy in interpreting potential ST-segment elevation myocardial infarction electrocardiograms.
With adoption of telemedicine, physicians are increasingly asked to diagnose ST-segment elevation myocardial infarctions (STEMIs) based on electrocardiograms (ECGs) with minimal associated clinical information. We sought to determine physicians' diagnostic agreement and accuracy when interpreting potential STEMI ECGs. A cross-sectional survey was performed consisting of 36 deidentified ECGs that had previously resulted in putative STEMI diagnoses. Emergency physicians, cardiologists, and interventional cardiologists participated in the survey. For each ECG, physicians were asked, "based on the ECG above, is there a blocked coronary artery present causing a STEMI?" The reference standard for ascertaining the STEMI diagnosis was subsequent emergent coronary arteriography. Responses were analyzed with generalized estimating equations to account for nested and repeated measures. One hundred twenty-four physicians interpreted a total of 4392 ECGs. Among all physicians, interreader agreement (kappa) for ECG interpretation was 0.33, reflecting poor agreement. The sensitivity to identify "true" STEMIs was 65% (95% CI: 63 to 67) and the specificity was 79% (95% CI: 77 to 81). There was a 6% increase in the odds of accurate ECG interpretation for every 5 years of experience since medical school graduation (OR 1.06, 95% CI: 1.02 to 1.10, P = 0.01). After adjusting for experience, there was no significant difference in the odds of accurate interpretation by specialty-Emergency Medicine (reference), General Cardiology (AOR 0.97, 95% CI: 0.79 to 1.2, P = 0.80), or Interventional Cardiology physicians (AOR 1.24, 95% CI: 0.93 to 1.7, P = 0.15). There is significant physician disagreement in interpreting ECGs with features concerning for STEMI. Such ECGs lack the necessary sensitivity and specificity to act as a suitable "stand-alone" diagnostic test.


Expression of Brassica napus TTG2, a regulator of trichome development, increases plant sensitivity to salt stress by suppressing the expression of auxin biosynthesis genes.
WRKY transcription factors (TFs) are plant specific and play important roles in regulating diverse biological processes. To identify TFs with broad-spectrum effects on various stress responses in Brassica napus, an important oil crop grown across diverse ecological regions worldwide, we functionally characterized Bna.TTG2 genes, which are homologous to the Arabidopsis AtTTG2 (WRKY44) gene. Four Bna.TTG2 genes were capable of rescuing the trichome phenotypes of Arabidopsis ttg2 mutants. Overexpressing one Bna.TTG2 family member, BnaA.TTG2.a.1, remarkably increased trichome numbers in Arabidopsis and B. napus plants. Interestingly, the BnaA.TTG2.a.1-overexpressing plants of both species exhibited increased sensitivity to salt stress. In BnaA.TTG2.a.1-overexpressing Arabidopsis under salt stress, the endogenous indole-3-acetic acid (IAA) content was reduced, and the expression of two auxin biosynthesis genes, TRYPTOPHAN BIOSYNTHESIS 5 (TRP5) and YUCCA2 (YUC2), was downregulated. The results from yeast one-hybrid, electrophoretic mobility shift, and dual-luciferase reporter assays revealed that BnaA.TTG2.a.1 is able to bind to the promoters of TRP5 and YUC2. These data indicated that BnaA.TTG2.a.1 confers salt sensitivity to overexpressing plants by suppressing the expression of IAA synthesis genes and thus lowering IAA levels. Transgenic Arabidopsis plants with an N-terminus-deleted BnaA.TTG2.a.1 no longer showed hypersensitivity to salt stress, suggesting that the N terminus of BnaA.TTG2.a.1 plays a critical role in salt stress responses. Therefore, in addition to its classical function in trichome development, our study reveals a novel role for Bna.TTG2 genes in salt stress responses.


A study of cutaneous tuberculosis in children.
Sixty-three children out of a total of 199 patients seen with cutaneous tuberculosis during a 7-year period were included in this study. Culture was positive in only four, and the diagnosis was based on clinical examination, tuberculin reaction, histopathology, and response to antitubercular therapy. Forty had lupus vulgaris (LV) and 23 scrofuloderma (SD). The lower half of the body was predominantly affected in those with LV, and keratotic and hypertrophic forms were frequently encountered. LV planus mainly affected the face. Ulcerative and atrophic types of LV were infrequent. Extensive lesions in three children led to disfiguring scars and contractures. Scrofuloderma often involved the cervical group of lymph nodes followed by the inguinal, submandibular, and axillary groups. As compared to skin tuberculosis in adults, regional lymph node involvement in LV was more common, and a combination of both LV and SD was less frequent in children. No difference in clinical presentation could be detected between the BCG vaccinated and unvaccinated children. Tuberculous infection either in the lungs or the bones was present in eight children. An HIV test done in five patients with widespread lesions was negative. Irregular therapy or late diagnosis leading to serious complications, inadequate parental or community support, and lack of awareness among practitioners are the problems to be remedied.


[Geometrical motives in the Tetraodontiformes fishes morphology].
Analysis of features of the Ostraciontidae (boxfishes) and Diodontidae (porcupinefishes) families revealed their morphological dualism, also known in combinatorial geometry and crystallography as the dualism of the Dirichlet tiling and that of Delaunay. If we take bases of spines on the body of Diodontidae for the Delaunay points (R, r)-system, the respective Dirichlet tiling will reveal the surface of an Ostraciontidae species being divided into polygonal osseous blades. This fact corroborates taxonomic relationship of the Ostraciontidae and Diodontidae families within the Tetraodontiformes order and indicates the principles of purposefulness in nature, which manifest both in mineral and biological structures. In the course of the present research four specimens of Diodon holocanthus (Diodontidae) were studied and characteristics of the Dirichlet tiling for the surfaces of their bodies were determined.


Glucocorticoid cytosol binding in exercise-induced sparing of muscle atrophy.
Female rats were initially divided into a sedentary or an exercise group that was trained by treadmill running to a final work rate of 31 m/min, 100 min/day, for 13-18 wk. During the last 12 days of training each of these groups were further subdivided into groups that received daily subcutaneous injections of cortisol acetate (CA) (100 mg/kg body wt) or the vehicle (1% carboxymethyl cellulose). Exercise prevented approximately 40% of the gastrocnemius muscle weight loss due to CA treatment. Training did not influence glucocorticoid cytosol-receptor binding concentrations, using [3H]triamcinolone acetonide (TA) as the labeled glucocorticoid in any of the skeletal muscle types investigated. TA-receptor binding capacities were depleted by the multiple injections but were higher in the red fiber types of the CA-treated trained than those in the CA-treated sedentary animals. In a second series of experiments in which receptor depletion and repletion rates were studied using a single injection of cortisol, TA binding capacities 2 h after the cortisol injection were higher in slow-twitch red soleus muscles of trained as compared with sedentary rats (36.4 +/- 2.0 vs. 26.8 +/- 2.5 fmol/mg protein). Similar patterns of TA binding were also observed at 2 h between trained and sedentary animals in the fast-twitch red muscle types, whereas no training related differences were observed in white muscle types. Total and free serum cortisol concentrations also returned to base-line values faster in the trained animals following the single injection protocol.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of alpha-tocopherol on metmyoglobin formation and reduction in beef from cattle fed soybean or cottonseed meal diets.
Hereford-Angus crossbred heifers were fed a cottonseed meal-based diet containing gossypol (14 mg free gossypol x kg body wt(-1) x d(-1); CSM), a soybean meal-based diet (SBM), or alpha-tocopherol-supplemented diets (4,036 IU vitamin E x heifer(-1) x d(-1) for 90 d; CSM+E and SBM+E). The effects of diet on color stability and aerobic metmyoglobin reducing ability of beef longissimus lumborum (LL) and psoas major (PM) were evaluated. The CSM containing gossypol did not affect alpha-tocopherol concentration, a* value, or hue angle value of beef muscles obtained from control or vitamin E-supplemented cattle compared to their SBM counterparts. Vitamin E supplementation increased endogenous alpha-tocopherol concentrations and color stability in LL and PM muscles compared with controls from either diet (P < .05). In the aerobic metmyoglobin reducing ability study, LL and PM muscles were stored in 1% O2:99% N2 (a pigment-oxidizing atmosphere) for 48 h and subsequently stored aerobically for an additional 48 h. Within the LL, alpha-tocopherol supplementation delayed metmyoglobin formation in LL exposed to 1% O2 (P < .05). Within the PM, no differences in metmyoglobin formation were found between controls and vitamin E treatments in SBM or CSM diets. Relative aerobic metmyoglobin reduction was the same (P > .05) in LL and PM muscles within SBM or CSM diets for control and vitamin E treatments. Alpha-tocopherol did not seem to affect metmyoglobin aerobic reducing ability in LL and PM muscles.


KLF5 promotes esophageal squamous cell cancer through the transcriptional activation of FGFBP1.
Krüpple-like factor 5 (KLF5) is a zinc-finger-containing transcription factor implicated in several human malignancies, but its potential regulatory mechanisms implicated in esophageal squamous cell carcinoma (ESCC) remain elusive. Here, we show that KLF5 is upregulated in ESCC, where its level was significantly associated with tumor differentiation and lymph node metastasis status. Upregulated KLF5 expression promoted the proliferation, migration, and invasion of ESCC cells. Reduced KLF5 showed the opposite effects. Mechanistically, KLF5 exerts its tumor promotion effect by up-regulating fibroblast growth factor binding protein 1 (FGF-BP1) and snail family transcriptional repressor 2 (SNAIL2). KLF5 binds to the promoter regions of FGF-BP1 and transcriptionally activates its expression. Our study indicated that KLF5 could promote esophageal squamous cell cancer proliferation, migration, and invasion by upregulating FGF-BP1/SNAIL2 signaling. Our work suggests that KLF5 might be a proto-oncogene in ESCC and implicated in ESCC metastasis.


A nonrandomized controlled trial: long-term outcomes of LATG/LAPG for cStage I gastric cancer: Japan Clinical Oncology Group Study JCOG1401.
A previous report confirmed the safety of laparoscopy-assisted total and proximal gastrectomies (LATG and LAPG) (JCOG1401). This report demonstrates the 5-year relapse-free survival (RFS) and overall survival (OS) after long-term follow-up to confirm the efficacy of these surgical methods as key secondary endpoints for cStage I gastric cancer. This study enrolled patients who had histologically proven gastric adenocarcinoma and were diagnosed with clinical T1N0, T1N(+), or T2N0 tumors according to the 14th edition of the Japanese Classification of Gastric Carcinoma (3rd English edition). Between April 2015 and February 2017, 246 patients were enrolled, although one patient was excluded because of misregistration. Meticulous follow-up was continued for > 5 years for each patient, and the data were analyzed in March 2022. The 5-year RFS was 90.0% (95% confidence interval [CI] 85.5-93.2%), and the 5-year OS was 91.2% (95% CI 86.9-94.2%) in all enrolled patients. Grade 3 or 4 late postoperative complications were detected in 12.7% of patients. This single-arm study showed that the long-term outcomes of LATG/LAPG for cStage I gastric cancer were acceptable, which is considered one of the standard treatments when performed by experienced surgeons. Trail registration UMIN000017155 ( http://www.umin.ac.jp/ctr/ ).


DNA and S-phase representation in human growth hormone producing pituitary adenomas.
The DNA contents of 33 pituitary adenomas from patients with acromegaly were analysed with flow-cytofluorometry. Degrees of ploidy and the proliferation rate, expressed as percentage of cells in S-phase, were determined. The aim was to compare these morphological and functional tumour properties with clinical and laboratory parameters to establish a possible relation and to further elucidate the characteristics of these tumours. In 15 tumours (45%) diploid DNA pattern were found, while 18 (55%) showed varying degrees of aneuploidy. The frequency of cells in S-phase showed wide variations and were equally distributed in diploid and aneuploid tumours. Duration of symptoms, age at diagnosis, preoperative growth hormone (GH)- and prolactin (Prl)-levels, tumour size and grade of invasive tumour growth as determined by radiological estimations, did not correlate to ploidy or grade of proliferation. The lack of correlation between DNA pattern and proliferation rate in relation to clinical, laboratory and radiological parameters in tumours causing acromegaly contrasts to the documented relation between the degree of ploidy, cells in proliferation and grade of malignancy reported in tumours of other sites. The 55% aneuploid GH producing tumours indicate a certain malignant transformation. The high frequency of cells in S-phase in several GH secreting tumours completes the malignant morphological and functional cell properties. The benign character of tumours causing acromegaly is therefore in contrast to these findings. The lack of clinical significance of the DNA pattern and the frequency of cells in proliferation in GH producing tumours and the benign character despite malignant cell properties in most of these tumours are difficult to explain.(ABSTRACT TRUNCATED AT 250 WORDS)


Myosin light chain kinases and myosin phosphorylation in skeletal muscle.
Myosin light chain kinases appear to exist as a family of tissue- and species-specific isozymes. The skeletal muscle kinases, although differing widely in molecular weight among vertebrate species, are catalytically similar and antigenically related. The smooth muscle kinases are catalytically and antigenically distinct from the skeletal muscle kinases. The functional basis for the existence of myosin light chain kinase isozymes has not been determined. Phosphorylation of fast-twitch skeletal muscle myosin P-light chain occurs at physiologically relevant contraction frequencies and durations, and the extent of P-light chain phosphorylation correlates with enhancement of isometric twitch tension in fast-twitch muscle under a variety of experimental conditions. Phosphorylation of myosin P-light chain in vertebrate fast-twitch skeletal muscle may play a modulatory role in calcium regulation of muscle contractility.


[Increased activity of stress-regulating systems in Alzheimer disease].
Behavioral, i.e. non-cognitive, disturbances, such as anxiety, agitation, sleep disturbances and depression occur in the majority of Alzheimer's disease (AD) patients, but their neurobiological basis is unknown. Disturbance of stress regulating systems, like the locus coeruleus, could play an important role. The locus coeruleus, the main production site of noradrenaline in the central nervous system, is involved in phenomena like attention, arousal and the response to the environment. In Alzheimer's disease, there is a marked reduction of noradrenergic neurons in the locus coeruleus. We studied the activity in the remaining locus coeruleus neurons and found an inverse relationship between the number of remaining neurons and the noradrenergic activity. This could indicate compensatory activity and loss of flexibility of this system. Clinically, the loss of flexibility could result in an impairment to focus attention and to respond to the environment. These results can be related to another stress related system, the hypothalamo-pituitary-adrenal-(HPA)axis. This means that further evaluation of both of these systems is necessary.


Competing for a desired reward in the Stroop task: when attentional control is unconscious but effective versus conscious but ineffective.
Recent studies using Stroop's paradigm have shown that word recognition processes can be controlled when the local context of the task is manipulated. In the present study, factors related to the participants' broader context (i.e., presence vs. absence of a competitor and of a desired reward) were manipulated. The results (1) support the conclusion that control of semantic-level activation can be unconscious but effective versus conscious but ineffective, (2) suggest that unconscious control alone operates on line (i.e., when the participant is responding), and (3) clarify the impact of socio-contextual factors that have been confounded in past research. Taken together, these findings strengthen the view that word recognition processes are controllable and offer new reasons to pay constant attention to the social environment of cognition.