Prediction of human pharmacokinetics from preclinical information: comparative accuracy of quantitative prediction approaches.
Quantitative prediction of human pharmacokinetics is critical in assessing the viability of drug candidates and in determining first-in-human dosing. Numerous prediction methodologies, incorporating both in vitro and preclinical in vivo data, have been developed in recent years, each with advantages and disadvantages. However, the lack of a comprehensive data set, both preclinical and clinical, has limited efforts to evaluate the optimal strategy (or strategies) that results in quantitative predictions of human pharmacokinetics. To address this issue, the authors conducted a retrospective analysis using 50 proprietary compounds for which in vitro, preclinical pharmacokinetic data and oral single-dose human pharmacokinetic data were available. Five predictive strategies, involving either allometry or use of unbound intrinsic clearance from microsomes or hepatocytes, were then compared for their ability to predict human oral clearance, half-life through predictions of systemic clearance, volume of distribution, and bioavailability. Use of a single-species scaling approach with rat, dog, or monkey was as accurate as or more accurate than using multiple-species allometry. For those compounds cleared almost exclusively by P450-mediated pathways, scaling from human liver microsomes was as predictive as single-species scaling of clearance based on data from rat, dog, or monkey. These data suggest that use of predictive methods involving either single-species in vivo data or in vitro human liver microsomes can quantitatively predict human in vivo pharmacokinetics and suggest the possibility of streamlining the predictive methodology through use of a single species or use only of human in vitro microsomal preparations.


Cell-cell junctions: a target of acoustic overstimulation in the sensory epithelium of the cochlea.
Exposure to intense noise causes the excessive movement of the organ of Corti, stretching the organ and compromising sensory cell functions. We recently revealed changes in the transcriptional expression of multiple adhesion-related genes during the acute phases of cochlear damage, suggesting that the disruption of cell-cell junctions is an early event in the process of cochlear pathogenesis. However, the functional state of cell junctions in the sensory epithelium is not clear. Here, we employed graded dextran-FITC, a macromolecule tracer that is impermeable to the organ of Corti under physiological conditions, to evaluate the barrier function of cell junctions in normal and noise-traumatized cochlear sensory epithelia. Exposure to an impulse noise of 155 dB (peak sound pressure level) caused a site-specific disruption in the intercellular junctions within the sensory epithelium of the chinchilla cochlea. The most vulnerable sites were the junctions among the Hensen cells and between the Hensen and Deiters cells within the outer zone of the sensory epithelium. The junction clefts that formed in the reticular lamina were permeable to 40 and 500 but not 2,000 kDa dextran-FITC macromolecules. Moreover, this study showed that the interruption of junction integrity occurred in the reticular lamina and also in the basilar membrane, a site that had been considered to be resistant to acoustic injury. Finally, our study revealed a general spatial correlation between the site of sensory cell damage and the site of junction disruption. However, the two events lacked a strict one-to-one correlation, suggesting that the disruption of cell-cell junctions is a contributing, but not the sole, factor for initiating acute sensory cell death. Impulse noise causes the functional disruption of intercellular junctions in the sensory epithelium of the chinchilla cochlea. This disruption occurs at an early phase of cochlear damage. Understanding the role of this disruption in cochlear pathogenesis will require future study.


An ambulatory bile reflux monitoring system: an in vitro appraisal.
Assessment of duodenogastric bile reflux has hitherto been unsatisfactory. An ambulatory system which utilizes the optical properties of bilirubin is examined. Test readings are correlated with the laboratory values for bilirubin in each of a number of physiological solutions. For dilutions of pure bile there was a linear correlation between absorbance and bilirubin concentration (r = 0.93, p < 0.001). In the more acidic environment of gastric juice there was also a linear correlation between absorbance and bilirubin concentration (r = 0.65, p < 0.001), but absorbance values were significantly higher than those of pure bile solutions (F ratio = 130, p < 0.0001). Normal gastric secretions and saliva give low absorbance values (0.02-0.04). Common foodstuffs such as soups, tea and coffee give higher readings and may interfere with bile reflux assessment in a clinical setting. Bilitec 2000 has potential for use as an ambulatory bile reflux monitoring system but consideration should be given to a standard diet or attention must focus on the fasting period.


Preparation and visible light induced photocatalytic activity of C-NaTaO3 and C-NaTaO3-Cl-TiO2 composite.
A nice visible light responsive C-doped NaTaO3 (C-NaTaO3) particle has been successfully prepared by a facile solvothermal method using water-ethylene glycol mixed solutions as solvent. The results presented that the carbon could be easily incorporated in NaTaO3 from ethylene glycol during a solvothermal reaction, finally leading to excellent visible light absorption. The as-synthesized C-NaTaO3 showed excellent visible light induced photocatalytic activity superior to those of pure NaTaO3 and commercial P25. In addition, in order to further improve the visible light driven photocatalytic performance of C-NaTaO3, a new C-doped NaTaO3-Cl-doped TiO2 (C-NaTaO3-Cl-TiO2) core-shell type of composite was also fabricated. After coupling C-NaTaO3 with Cl-TiO2, the visible light induced NOx gas destruction ability of C-NaTaO3-Cl-TiO2 composite was significantly enhanced as compared to those of sole C-NaTaO3 and Cl-TiO2, probably due to the hindrance of the recombination rate of photogenerated electron-hole pairs. The C-NaTaO3 particle and C-NaTaO3-Cl-TiO2 composite prepared in this work would probably provide a new way to prepare high performance of visible light induced perovskite-type NaTaO3 based photocatalysts.


Changes in DNase and DNA-polymerase activities in different tissues of chick with age.
The presence of acid and alkaline DNases in nuclei of chick brain cells has been demonstrated. The activities of these two DNases along with those of DNA-polymerases were assessed in chicken tissues with known varied cell proliferative capacities (eg., spleen, kidney and brain) at different ages. The results indicate that the acid and alkaline DNases are probably the 'house keeping' enzymes with a constitutive role in DNA repair process, the former with a DNA-repair process that is linked to cell proliferation (DNA synthesis) while the latter with the basal DNA-repair operations that must go on at all times without any regard to the cell division process. Chicken brain, unlike that of rat, possesses significant levels of aphidicolin sensitive DNA-polymerase(s) that are considered to be more replication oriented enzymes suggesting that the replication potential of adult and old avian brain cells may be different from that of a mammalian brain.


[Changes in basic fibroblast growth factor in lung injury induced by combined injury].
In this study, we have investigated the changes of basic fibroblast growth factor after lung injury. Acute lung injury was produced by combination injury (burn and blast injury). Basic fibroblast growth factor was isolated from lung tissue. Mitogenic activity was determined by measuring the incorporation of 3H-thymidine into DNA by confluent cultures of 3T3 cells. The result revealed that the level of basic fibroblast growth factor was elevated significantly in 1, 3, 5 days after lung injury. On 7th days after injury, the basic fibroblast growth factor was not detected. The findings suggest that basic fibroblast growth factor takes an important role in lung injury and repair. The mechanism of elevation of basic fibroblast growth factor in the lung after injury was discussed.


Different brain areas mediate the analgesic and epileptic properties of enkephalin.
Single injections of 120 micrograms of methionine-enkephalin were made into various midbrain and forebrain structures in the rat. Analgesia was observed after injections into or near the ventral, caudal midbrain periaqueductal gray matter. Seizures and other pathological electroencephalogram (EEG) changes were seen with injections into or near the forebrain dorsomedial nucleus of the thalamus. No animals with midbrain injection sites showed EEG changes, and none with forebrain injection sites were analgesic. These data, taken together with other lines of evidence, suggest that enkephalin-induced analgesia and enkephalin-induced seizures are mediated by opiate receptors that are located in different brain areas and that are pharmacologically different.


A hybrid neurogenetic approach for stock forecasting.
In this paper, we propose a hybrid neurogenetic system for stock trading. A recurrent neural network (NN) having one hidden layer is used for the prediction model. The input features are generated from a number of technical indicators being used by financial experts. The genetic algorithm (GA) optimizes the NN's weights under a 2-D encoding and crossover. We devised a context-based ensemble method of NNs which dynamically changes on the basis of the test day's context. To reduce the time in processing mass data, we parallelized the GA on a Linux cluster system using message passing interface. We tested the proposed method with 36 companies in NYSE and NASDAQ for 13 years from 1992 to 2004. The neurogenetic hybrid showed notable improvement on the average over the buy-and-hold strategy and the context-based ensemble further improved the results. We also observed that some companies were more predictable than others, which implies that the proposed neurogenetic hybrid can be used for financial portfolio construction.


Diterpenoid alkaloids from Delphinium trichophorum.
Three new hetisine type C20-diterpenoid alkaloids, named as trichophorines A-C (1-3), were isolated from Delphinium trichophorum, together with nine known alkaloids (4-12). Their structures were elucidated on the basis of spectroscopic data (1D, 2D NMR, single-crystal X-ray, and HR-ESI-MS). All compounds were evaluated for the inhibitory activities against LPS induced NO production in RAW 264.7 macrophage cells, and none of them showed considerable inhibitory activity.


Deaths among female patients with carcinoma of the breast treated by a surgical procedure only.
The postoperative mortality from carcinoma of the breast is low, and it appears to be getting lower. Mortality is highest for the women in the older age group and for those with the most advanced stage of disease. Surgeons who generally consider these factors in deciding whether or not to perform an operation may wish to review their own experience in light of these data. In general, while surgical mortality for carcinoma of the breast is not zero, it certainly is low. The historical data collected in the Surveillance, Epidemiology and End Results Program do not contain details on the extent of the operations actually performed, and this should influence the mortality. With proper safeguards for protecting the confidentiality of the medical records, it may be possible for qualified persons interested in surgical research to review a sample of the detailed records that contributed to the series reported herein to determine the exact extent of the operation and the curative or palliative purpose, and to help elucidate the actual causes and patterns of early deaths.


Optimizing Chemicals Management in the United States and Canada through the Essential-Use Approach.
Chemicals have improved the functionality and convenience of industrial and consumer products, but sometimes at the expense of human or ecological health. Existing regulatory systems have proven to be inadequate for assessing and managing the tens of thousands of chemicals in commerce. A different approach is urgently needed to minimize ongoing production, use, and exposures to hazardous chemicals. The premise of the essential-use approach is that chemicals of concern should be used only in cases in which their function in specific products is necessary for health, safety, or the functioning of society and when feasible alternatives are unavailable. To optimize the essential-use approach for broader implementation in the United States and Canada, we recommend that governments and businesses (1) identify chemicals of concern for essentiality assessments based on a broad range of hazard traits, going beyond toxicity; (2) expedite decision-making by avoiding unnecessary assessments and strategically asking up to three questions to determine whether the use of the chemical in the product is essential; (3) apply the essential-use approach as early as possible in the process of developing and assessing chemicals; and (4) engage diverse experts in identifying chemical uses and functions, assessing alternatives, and making essentiality determinations and share such information broadly. If optimized and expanded into regulatory systems in the United States and Canada, other policymaking bodies, and businesses, the essential-use approach can improve chemicals management and shift the market toward safer chemistries that benefit human and ecological health.


Amelioration of lupus nephritis by serum amyloid P component gene therapy with distinct mechanisms varied from different stage of the disease.
Our previous study revealed that administration of syngeneic female BALB/c mice with excessive self activated lymphocyte-derived DNA (ALD-DNA) could induce systemic lupus erythematosus (SLE) disease, indicating that overload of self-DNA might exceed normal clearance ability and comprise the major source of autoantigens in lupus mice. Serum amyloid P component (SAP), an acute-phase serum protein with binding reactivity to DNA in mice, was proved to promote the clearance of free DNA and prevent mice against self-antigen induced autoimmune response. It is reasonable to hypothesize that SAP treatment might contribute to alleviation of SLE disease, whereas its role in ALD-DNA-induced lupus nephritis is not fully understood. The ratios of SAP to DNA significantly decreased and were negatively correlated with the titers of anti-dsDNA antibodies in ALD-DNA-induced lupus mice, indicating SAP was relatively insufficient in lupus mice. Herein a pcDNA3-SAP plasmid (pSAP) was genetically constructed and intramuscularly injected into BALB/c mice. It was found that SAP protein purified from the serum of pSAP-treated mice bound efficiently to ALD-DNA and inhibited ALD-DNA-mediated innate immune response in vitro. Treatment of ALD-DNA-induced lupus mice with pSAP in the early stage of SLE disease with the onset of proteinuria reversed lupus nephritis via decreasing anti-dsDNA autoantibody production and immune complex (IC) deposition. Further administration of pSAP in the late stage of SLE disease that had established lupus nephritis alleviated proteinuria and ameliorated lupus nephritis. This therapeutic effect of SAP was not only attributable to the decreased levels of anti-dsDNA autoantibodies, but also associated with the decreased infiltration of lymphocytes and the reduced production of inflammatory markers. These results suggest that SAP administration could effectively alleviated lupus nephritis via modulating anti-dsDNA antibody production and the inflammation followed IC deposition, and SAP-based intervening strategy may provide new approaches for treating SLE disease.


Pronounced differences in signal processing and synaptic plasticity between piriform-hippocampal network stages: a prominent role for adenosine.
Extended trains of theta rhythm afferent activity lead to a biphasic response facilitation in field CA1 but not in the lateral perforant path input to the dentate gyrus. Processes that reverse long-term potentiation in field CA1 are not operative in the lateral perforant path: multiple lines of evidence indicate that this reflects differences in adenosine signalling. Adenosine A1 receptors modulate baseline synaptic transmission in the lateral olfactory tract but not the associational afferents of the piriform cortex. Levels of ecto-5'-nucleotidase (CD73), an enzyme that converts extracellular ATP into adenosine, are markedly different between regions and correlate with adenosine signalling and the efficacy of theta pulse stimulation in reversing long-term potentiation. Variations in transmitter mobilization, CD73 levels, and afferent divergence result in multivariate differences in signal processing through nodes in the cortico-hippocampal network. The present study evaluated learning-related synaptic operations across the serial stages of the olfactory cortex-hippocampus network. Theta frequency stimulation produced very different time-varying responses in the Schaffer-commissural projections than in the lateral perforant path (LPP), an effect associated with distinctions in transmitter mobilization. Long-term potentiation (LTP) had a higher threshold in LPP field potential studies but not in voltage clamped neurons; coupled with input/output relationships, these results suggest that LTP threshold differences reflect the degree of input divergence. Theta pulse stimulation erased LTP in CA1 but not in the dentate gyrus (DG), although adenosine eliminated potentiation in both areas, suggesting that theta increases extracellular adenosine to a greater degree in CA1. Moreover, adenosine A1 receptor antagonism had larger effects on theta responses in CA1 than in the DG, and concentrations of ecto-5'-nucleotidase (CD73) were much higher in CA1. Input/output curves for two connections in the piriform cortex were similar to those for the LPP, whereas adenosine modulation again correlated with levels of CD73. In sum, multiple relays in a network extending from the piriform cortex through the hippocampus can be differentiated along three dimensions (input divergence, transmitter mobilization, adenosine modulation) that potently influence throughput and plasticity. A model that incorporates the regional differences, supplemented with data for three additional links, suggests that network output goes through three transitions during the processing of theta input. It is proposed that individuated relays allow the circuit to deal with different types of behavioural problems.


Identification of SFRP1 as a candidate mediator of stromal-to-epithelial signaling in prostate cancer.
Genetic changes in epithelial cells initiate the development of prostatic adenocarcinomas. As nascent tumors grow and undergo progression, epithelial tumor cells are intimately associated with stromal cells. Stromal cells within the tumor microenvironment acquire new properties, including the capacity to promote phenotypic and genetic progression in adjacent epithelial cells. Affymetrix microarrays were used to identify 119 genes differentially expressed between normal-derived and carcinoma-derived prostatic stromal cells. These included 31 genes encoding extracellular proteins that may act as stromal-to-epithelial paracrine signals. Further investigation of one of these genes, secreted frizzled related protein 1 (SFRP1), revealed that its expression parallels prostatic growth with high expression during prostatic development, low expression in the adult prostate, and elevated expression in prostatic tumor stroma. In addition, as prostatic epithelial cells progressed to a tumorigenic state under the influence of tumor stroma, SFRP1 became overexpressed in the progressed epithelial cells. To further understand the roles of SFRP1 in the prostate, we tested the affects of increased SFRP1 levels on prostatic tissues and cells. Treatment of developing prostates with SFRP1 in culture led to increased organ growth. Treatment of a human prostatic epithelial cell line with SFRP1 led to increased proliferation, decreased apoptosis, and decreased signaling through the Wnt/beta-catenin pathway in vitro and increased proliferation in vivo. These data suggest that overexpression of SFRP1 by prostatic tumor stroma may account for the previously reported capacity of prostatic tumor stroma to provide a pro-proliferative paracrine signal to adjacent epithelial cells.


A Biopsychosocial Framework to Examine Risk for Type 2 Diabetes in Asian Pacific Islander Immigrants.
There is large disparity in the incidence of Type 2 diabetes (T2D) for Asian Pacific Islanders (APIs), one of the fastest growing minority populations in the United States. It is critical to examine biopsychosocial pathways and vulnerability factors that intensify risk for T2D in API. Increasing evidence links chronic stress to poor health outcomes and accelerated development and progression of diseases of aging, such as diabetes. Immigrant populations face unique life stressors, including the challenges associated with the process of adapting to a new environment, new language, and cultural differences. In addition, immigrants experience high levels of psychological distress related to changes of identity and values, loss of support, discrimination, and disempowerment. The purpose of this article is to propose a biopsychosocial framework to explicate potential mechanistic pathways that link cumulative life stress to risk for T2D in the API immigrant population. Unique to the proposed framework is the emphasis on inflammatory processes and accelerated cellular aging (telomere biology). A deeper understanding of biopsychosocial pathways can lead to tailored and targeted interventions to reduce the incidence of T2D in the API immigrant population.


Pulmonary alveolar proteinosis.
Pulmonary alveolar proteinosis (PAP) is a disease of alveolar accumulation of phospholipoproteinaceous material that results in gas exchange impairment leading to dyspnea and alveolar infiltrates. There are three forms of PAP: congenital, acquired and idiopathic; of which the latter two are predominant in the adult population. Previous case studies have found that the acquired form can be secondary to various autoimmune, infectious, malignant and environmental etiologies. Recent advances in the understanding of the pathophysiology of PAP demonstrate that the idiopathic form is due to antigranulocyte macrophage-colony stimulating factor antibodies. Therapeutic targets that replace granulocyte macrophage colony stimulating factor or remove these antibodies are being actively developed. The current standard of care is to perform whole lung lavage on these patients to clear the alveolar space to help improve respiratory physiology. A case of PAP is reported, followed by a literature review on the diagnosis and management of this rare condition with the aim of increasing awareness among physicians when treating patients who present with alveolar infiltrates.


Promoting Participation in Daily Activities Through Reablement: A Qualitative Study.
A well-known prediction is that the growing elderly population will place a strain on our healthcare systems. At the same time, healthcare is becoming increasingly patient-centered and individualized, with the patient becoming an active participant rather than a mere object of healthcare. The need for change may be met by using a reablement service, utilizing the rehabilitation mindset through home-based services. Rehabilitation and reablement aim to provide opportunities for individuals to participate to a maximum of their potential. This study is part of a larger research project exploring different aspects of reablement in municipalities. It aims to describe how older adults engage in daily activities within the context of reablement and to explore participation in daily activities. A qualitative design was chosen, and the study is explorative in nature due to limited research on participants' experience with reablement. Ten older adults age 70 to 94 years old were recruited and interviewed. The interviews were transcribed verbatim and analyzed using systematic text condensation (STC) strategies. This study provides insights on how older adults experience participation in daily activities and important aspects for performing these activities and living independently as long as possible. Based on the older adults' experiences, three main themes were identified when receiving reablement. First, what to achieve with reablement and feeling a sense of security to participate in daily activities. Second, how to carry out wanted activities using different skills and last, how the social network is important for enabling active living. This calls for healthcare workers to address and facilitate these in reablement. Our findings show the importance of collaborating with the social network and strengthening participation in daily activities to establish and develop existing reablement services.


Haromyia, a new genus of long-legged flies from Dominica (Diptera: Dolichopodidae).
The new micro-dolichopodid genus Haromyia gen. nov. and the type species H. iviei sp. nov. are described from the island of Dominica in the Lesser Antilles. Males and females of Haromyia are distinguished by the large setae on a bulging clypeus, minute size, and wing veins that are nearly straight and evenly diverging from wing base. Haromyia does not fit readily into any contemporary dolichopodid subfamily, although it superficially resembles the Enliniinae and Achalcinae. Haromyia should be regarded as incertae sedis until the dolichopodid subfamilies can be refined, particularly to better incorporate the tropical diversity of this large family.


Multiplicity-dependent replication of varicella-zoster virus in interferon-treated cells.
The inhibitory effects of interferon (IF) on the replication of varicella-zoster (VZ) virus in human foreskin fibroblast (HFF) cultures inoculated with infected cells or with cell-free virus were assayed by measuring (1) yields of infected cells, (2) plaques, (3) microfoci and (4) cytopathic effects. More IF was needed to reduce yields of infected cells at high input multiplicities of challenge than at low input multiplicites, and still more IF was needed to prevent cytopathology due to VZ virus. A cell-free virus inoculum was more sensitive to the inhibitory effects of IF than an inoculum of infected cells. With the latter, but not with cell-free virus, the continuous presence of IF in the medium was necessary for it to express its maximum antiviral activity. To explain these results, it is suggested that some herpesviruses may establish "reservoirs' of infectivity and thus provide a prolonged challenge to IF-treated cells which are not uniformly resistant to infection.


Virulence of Toxoplasma gondii is associated with distinct dendritic cell responses and reduced numbers of activated CD8+ T cells.
The Toxoplasma gondii population consists of multiple strains, defined by genotype and virulence. Previous studies have established that protective immunity to this organism is mediated by IL-12, which drives T cells to produce IFN-gamma. Paradoxically, although type I and type II strains of T. gondii both induce IL-12 and IFN-gamma in the mouse, type I parasites are lethal, whereas type II strains establish chronic infection. The cellular basis for these strain-dependent differences remains unclear. To better understand these events, the CD8(+) T cell and dendritic cell (DC) responses to transgenic, OVA-expressing type I RH (RH OVA) and type II Prugniuad (Pru OVA) parasites were examined. Pru OVA-infected mice developed a robust DC response at the site of infection and the draining lymph node and generated a population of endogenous OVA-specific CD8(+) T cells. In contrast, RH OVA-infected mice had fewer DCs and OVA-specific CD8(+) T cells. RH OVA-infected mice given preactivated OVA-specific CD8(+) T cells were protected, suggesting that reduced DC-derived signals contributed to the low OVA-specific CD8(+) T cell numbers observed during type I infection. Indeed, DC depletion prior to Pru OVA infection resulted in a failure to generate activated OVA-specific CD8(+) T cells, and IL-12p70 treatment during RH OVA infection modestly increased the number of Ag-specific cells. Together, these data are consistent with a model of immunity to T. gondii in which strain-dependent DC responses shape the generation of Ag-specific CD8(+) T cells and determine the outcome of infection.


Assistive listening devices drive neuroplasticity in children with dyslexia.
Children with dyslexia often exhibit increased variability in sensory and cognitive aspects of hearing relative to typically developing peers. Assistive listening devices (classroom FM systems) may reduce auditory processing variability by enhancing acoustic clarity and attention. We assessed the impact of classroom FM system use for 1 year on auditory neurophysiology and reading skills in children with dyslexia. FM system use reduced the variability of subcortical responses to sound, and this improvement was linked to concomitant increases in reading and phonological awareness. Moreover, response consistency before FM system use predicted gains in phonological awareness. A matched control group of children with dyslexia attending the same schools who did not use the FM system did not show these effects. Assistive listening devices can improve the neural representation of speech and impact reading-related skills by enhancing acoustic clarity and attention, reducing variability in auditory processing.


The laminar organization of the Drosophila ellipsoid body is semaphorin-dependent and prevents the formation of ectopic synaptic connections.
The ellipsoid body (EB) in the Drosophila brain is a central complex (CX) substructure that harbors circumferentially laminated ring (R) neuron axons and mediates multifaceted sensory integration and motor coordination functions. However, what regulates R axon lamination and how lamination affects R neuron function remain unknown. We show here that the EB is sequentially innervated by small-field and large-field neurons and that early developing EB neurons play an important regulatory role in EB laminae formation. The transmembrane proteins semaphorin-1a (Sema-1a) and plexin A function together to regulate R axon lamination. R neurons recruit both GABA and GABA-A receptors to their axon terminals in the EB, and optogenetic stimulation coupled with electrophysiological recordings show that Sema-1a-dependent R axon lamination is required for preventing the spread of synaptic inhibition between adjacent EB lamina. These results provide direct evidence that EB lamination is critical for local pre-synaptic inhibitory circuit organization.


[Diagnostic methods in the bulbus duodeni. Agreement and disagreement between endoscopic, roentgenological and histological examinations (author's transl)].
In a collective of 1012 patients (700 m., 312 f.), 346 (268 m., 78 f.) had pathological endoscopic findings in the bulbus. Diseases of the bulbus appeared in women about 10 years later than in men. In comparison to the endoscopic findings, roentgen findings showed disagreement in about 35% which mainly arose from contradictions in the assessment of cicatricial changes in the bulbus. False negative ulcer findings amounted to about 21%, the false positive to 19%. Endoscopic and histologically confirmed malignancies were not overlooked in a single case.


[Selection of a drainage operation in obstruction of the common bile duct].
Drainage operations were accomplished on extrahepatic bile ducts in 194 patients. It is the authors' opinion that in emergency surgery the operative procedure may be terminated by external drainage only in relative blockade of bile outflow in the duodenal lumen, while in unrelieved complete blockade of bile outflow such drainage seems to be permissible only in patients with an extremely high operative risk. Biliodigestive anastomoses were constructed in 96 patients. In persistant cholemia, cholangitis, signs of hepatic insufficiency the authors construct biliodigestive anastomoses and simultaneously accomplish provisional external drainage of bile ducts.


Family caregivers' experiences of relinquishing the care of a person with dementia to a nursing home: insights from a meta-ethnographic study.
Many people with dementia are cared for in their homes by family caregivers. As the dementia progresses, admission of the family member to a nursing home becomes inevitable. The aim of this meta-ethnographic study was to describe caregivers' experiences of relinquishing the care of a family member with dementia to a nursing home. A systematic literature search of PubMed, Cinahl and PsychInfo, between the years 1992 and 2012, was performed, and 10 qualitative articles, based on 180 family caregivers' experiences, were included. The family caregivers' described their experiences as a process that went from being responsible for the decision, through living with the decision, adjusting to a new caring role and having changed relationships. They felt unprepared and lonely with these changes. They experienced loss, guilt and shame, but also feelings of relief. Their roles in the nursing home environment were to make sure that the individual needs of the person with dementia were respected and to monitor the quality of care. They wished to maintain their relationship with the person with dementia and to establish meaningful relationships with caring staff. The process of relinquishing care is similar to a crisis process, which starts with a turning point, followed by a coping face and finally the outcome of the process. The adaption to the new situation can be facilitated if the family caregivers are recognised as partners in the care of the person with dementia. The family caregivers' unique knowledge of their relatives' previous life story should be acknowledged in both care planning and daily care. Welcoming family caregivers to regular meetings with staff can contribute to increase the feeling of partnership. Offering staff clinical supervision could be one way of preparing them to deal with the emotional strain reported by family caregivers.


The Dilution of Diversity: Ironic Effects of Broadening Diversity.
Diversity is one of the buzzwords of the 21st century. But who counts as diverse? We coded diversity statements to examine how organizations typically define diversity and whether oppressed-group members perceive some definitions as diluting diversity, or detracting from the original intention of diversity initiatives. Organizations most commonly opted for a broad definition of diversity (38%) that focused on diversity in perspectives and skills, with no mention of demographic group identities (e.g., race; Study 1). In Studies 2 and 3, people of color perceived broad statements as diluting diversity more than other diversity statements. They were also less interested in working at those organizations, and broad statements led sexual minorities to be less willing to disclose their sexual identity (Study 4). Thus, broadening the definition of diversity to include individual characteristics and skills may backfire, unless the importance of demographic diversity is also acknowledged.


The conserved RIC-3 coiled-coil domain mediates receptor-specific interactions with nicotinic acetylcholine receptors.
RIC-3 belongs to a conserved family of proteins influencing nicotinic acetylcholine receptor (nAChR) maturation. RIC-3 proteins are integral membrane proteins residing in the endoplasmic reticulum (ER), and containing a C-terminal coiled-coil domain (CC-I). Conservation of CC-I in all RIC-3 family members indicates its importance; however, previous studies could not show its function. To examine the role of CC-I, we studied effects of its deletion on Caenorhabditis elegans nAChRs in vivo. Presence of CC-I promoted maturation of particular nAChRs expressed in body-wall muscle, whereas it was not required for other nAChR subtypes expressed in neurons or pharyngeal muscles. This effect is receptor-specific, because it could be reproduced after heterologous expression. Consistently, coimmunoprecipitation analysis showed that CC-I enhances the interaction of RIC-3 with a nAChR that requires CC-I in vivo; thus CC-I appears to enhance affinity of RIC-3 to specific nAChRs. However, we found that this function of CC-I is redundant with functions of sequences downstream to CC-I, potentially a second coiled-coil. Alternative splicing in both vertebrates and invertebrates generates RIC-3 transcripts that lack the entire C-terminus, or only CC-I. Thus, our results suggest that RIC-3 alternative splicing enables subtype specific regulation of nAChR maturation.


Hereditary angioedema and pregnancy.
Hereditary angioedema is a relatively uncommon disease that may affect women during their reproductive years. A case report of a pregnancy complicated by hereditary angioedema, followed by a review of the literature, is presented. Although the disease usually follows a benign course, maternal mortality has been noted. Features unique to pregnancy are discussed. Knowledge of the pathophysiology and possible complications is essential for the proper management of the pregnancy.


What are GPs' preferences for financial and non-financial incentives in cancer screening? Evidence for breast, cervical, and colorectal cancers.
General practitioners (GPs) play a key role in the delivery of preventive and screening services for breast, cervical, and colorectal cancers. In practice, GPs' involvement varies considerably across types of cancer and among GPs, raising important questions about the determinants of GPs' implication in screening activities: what is the relative impact of financial and non-financial incentives? Are GPs' preferences for financial and non-financial incentives cancer-specific? Is there preference heterogeneity and how much does it differ according to the screening context? This study investigates the determinants of GPs' involvement in cancer screening activities using the discrete choice experiment (DCE) methodology. A representative sample of 402 GPs' was recruited in France between March and April 2014. Marginal rates of substitution were used to compare GPs' preferences for being involved in screening activities across three types of cancers: breast, cervical, and colorectal. Variability of preferences was investigated using Hierarchical Bayes mixed logit models. The results indicate that GPs are sensitive to both financial and non-financial incentives, such as a compensated training and systematic transmission of information about screened patients, aimed to facilitate communication between doctors and patients. There is also evidence that the level and variability of preferences differ across screening contexts, although the variations are not statistically significant on average. GPs appear to be relatively more sensitive to financial incentives for being involved in colorectal cancer screening, whereas they have higher and more heterogeneous preferences for non-financial incentives in breast and cervical cancers. Our study provides new findings for policymakers interested in prioritizing levers to increase the supply of cancer screening services in general practice.


The missing link: mothers' neural response to infant cry related to infant attachment behaviors.
This study addresses a gap in the attachment literature by investigating maternal neural response to cry related to infant attachment classifications and behaviors. Twenty-two primiparous mothers and their 18-month old infants completed the Strange Situation (SS) procedure to elicit attachment behaviors. During a separate functional MRI session, mothers were exposed to their own infant's cry sound, as well as an unfamiliar infant's cry and control sound. Maternal neural response to own infant cry related to both overall attachment security and specific infant behaviors. Mothers of less secure infants maintained greater activation to their cry in left parahippocampal and amygdala regions and the right posterior insula consistent with a negative schematic response bias. Mothers of infants exhibiting more avoidant or contact maintaining behaviors during the SS showed diminished response across left prefrontal, parietal, and cerebellar areas involved in attentional processing and cognitive control. Mothers of infants exhibiting more disorganized behavior showed reduced response in bilateral temporal and subcallosal areas relevant to social cognition and emotion regulation. No differences by attachment classification were found. Implications for attachment transmission models are discussed.


The mechanism of action of lymphokines. VIII. Lymphokine-enhanced spontaneous hydrogen peroxide production by macrophages.
Oil-elicited guinea-pig peritoneal macrophages (MPs) cultured for 2-3 days in medium containing supernatant of concanavalin A-activated lymphocytes (lymphokine, LK) generated large amounts of hydrogen peroxide (H2O2), as detected by the horseradish peroxidase (HRP)-dependent oxidation of phenol red, in the absence of further stimulation. H2O2 production increased with the duration of exposure to LK and was evident at high dilutions of supernatant (1/64). Parallel cultures of MPs in medium or a supernatant of non-activated lymphocytes also increased their H2O2 production during culture but levels at all time intervals were significantly lower than those measured in LK treated cultures. The marked increase in H2O2 production was associated with only a moderate increment in superoxide (O-2) liberation and this was not specific for LK treated cells. Detection of LK-dependent H2O2 production was dependent on ongoing pinocytosis during the assay. This and other arguments suggest that the HRP-phenol red assay, as applied here, detects H2O2 generation occurring at the level of intracellular vesicles and it is concluded that LK elicits H2O2 production that is limited to the intracellular compartment. H2O2 is, apparently, derived by non-enzymatic dismutation of O-2 taking place within the cell; LK treatment of MPs also resulted in a significant reduction in catalase activity.


Nurses' smoking behaviour related to cessation practice.
To examine the smoking behaviour, knowledge and attitudes of nurses, their willingness to provide smoking cessation support to patients, the accessibility of training in this area and their willingness to undertake future training in this area. A randomised sample of qualified nurses (n = 1,074) in statutory, private and voluntary sectors and across a variety of specialties were surveyed by postal questionnaire. Four focus groups were conducted in various settings before and after the survey. Of those who took part in the survey, 55% had never smoked, 19% were ex-smokers and 26% were smokers. Most agreed that nurses have a responsibility to help those who want to quit smoking. However, nurses who smoked rated their ability to help patients and their effectiveness as a role model lower than nurses who were ex-smokers or non-smokers. Smoking prevalence among nurses is no greater than in the general female population. Nurses who smoke are less motivated to provide cessation support for patients, have less positive attitudes to the value of smoking cessation, are less likely to have received smoking cessation training and are less likely to want further training. These results have implications for nurses' own smoking status, as well as their attitudes to cessation training, health promotion practice and future research.


Bovine humoral immune response to Cryptosporidium parvum.
Cryptosporidiosis is a diarrheal disease predominantly affecting cattle and humans. Sera from experimentally infected calves and calves of various ages with no histories of exposure were evaluated for immunoglobulin G to Cryptosporidium parvum. An age-associated increase in immunoglobulin G was present in experimental calves and in calves with no histories of infection from 1 to 3, but not > 3, months of age.


Phorbol esters induce differentiation of human CD34+ hemopoietic progenitors to dendritic cells: evidence for protein kinase C-mediated signaling.
The intracellular signals that mediate the differentiation of pluripotent hemopoietic progenitors to dendritic cells (DC) are largely undefined. We have found that the phorbol ester PMA by itself induced 47% +/- 8.7% of input human CD34+ hemopoietic progenitors to differentiate into cells with morphology and surface Ag phenotype characteristic of DC by day 7 of culture. Functionally, PMA-generated DC processed and presented whole soluble Ag and also induced resting T cell proliferation and Ag-specific CTL effector function. Unlike cytokine-driven DC differentiation, PMA suppressed proliferation and induced cell death (in part via apoptosis) in cells that did not differentiate to DC. The effects of PMA were blocked by inhibitors of protein kinase C activation, suggesting a central role for this signaling molecule. PMA-mediated signaling also induced expression of the RelB transcription factor, an NF-kappaB family member implicated in DC differentiation. These findings suggest that phorbol esters activate protein kinase C, which then initiates the terminal component of an intracellular signaling pathway(s) involved in the DC differentiation of CD34+ hemopoietic progenitors.


Use of Antibiotic Prophylaxis for Tooth Extractions, Dental Implants, and Periodontal Surgical Procedures.
Guidelines for antibiotics prior to dental procedures for patients with specific cardiac conditions and prosthetic joints have changed, reducing indications for antibiotic prophylaxis. In addition to guidelines focused on patient comorbidities, systematic reviews specific to dental extractions and implants support preprocedure antibiotics for all patients. However, data on dentist adherence to these recommendations are scarce. This was a cross-sectional study of veterans undergoing tooth extractions, dental implants, and periodontal procedures. Patients receiving antibiotics for oral or nonoral infections were excluded. Data were collected through manual review of the health record. Of 183 veterans (mean age, 62 years; 94.5% male) undergoing the included procedures, 82.5% received antibiotic prophylaxis (mean duration, 7.1 ± 1.6 days). Amoxicillin (71.3% of antibiotics) and clindamycin (23.8%) were prescribed most frequently; 44.7% of patients prescribed clindamycin were not labeled as penicillin allergic. Of those who received prophylaxis, 92.1% received postprocedure antibiotics only, 2.6% received preprocedural antibiotics only, and 5.3% received pre- and postprocedure antibiotics. When prophylaxis was indicated, 87.3% of patients received an antibiotic. However, 84.9% received postprocedure antibiotics when preprocedure administration was indicated. While the majority of antibiotics were indicated, only 8.2% of patients received antibiotics appropriately. The primary reason was secondary to prolonged duration. Three months postprocedure, there were no occurrences of Clostridium difficile infection, infective endocarditis, prosthetic joint infections, or postprocedure oral infections. The majority of patients undergoing a dental procedure received antibiotic prophylaxis as indicated. Although patients for whom antibiotic prophylaxis was indicated should have received a single preprocedure dose, most antibiotics were prescribed postprocedure. Dental stewardship efforts should ensure appropriate antibiotic timing, indication, and duration.


Upper extremity bypass grafting. A 15-year experience.
To analyze the perioperative morbidity and mortality, long-term patient survival, and patency characteristics of arterial bypass related to upper extremity ischemia. This is a retrospective review of sequential patients undergoing upper extremity arterial bypass during a 15-year period at a single tertiary-care teaching hospital. Data are expressed in a 5-year life-table format and interpreted using log-rank analysis. Seventy-four patients with upper extremity ischemia undergoing arterial bypass, which included 95 separate operations. Operative morbidity and mortality, life-table survival, life-table bypass graft patency, and limb salvage are reported. There was no operative mortality, and there was a single major amputation. Survival rate was 86% at 5 years, and overall patency rate was 61.2% at 5 years, with autogenous conduits superior at all sites compared with prosthesis (70.9% vs 37.7%). Secondary operation was inferior to primary bypass (66% vs 48%) and associated with higher morbidity (22% vs 5%). All far distal forearm prosthetic bypass grafts failed within 1 year. Primary upper extremity bypass with venous conduit is a safe, durable procedure, after which prolonged patient survival can be expected.


Valorization of Apple Pomace by Extraction of Valuable Compounds.
Apple pomace is a promising source of carbohydrates, proteins, amino acids, fatty acids, phenolic compounds, vitamins, and other compounds with a vast range of food applications. This review focuses on the valorization of apple pomace towards the recovery of the main compounds, namely pectin and polyphenols. Applications, advantages, and drawbacks of conventional extraction (acidic medium under high temperatures) compared with novel extraction technologies are presented. The comparison is based on an extensive literature review of research on extraction of valuable compounds from plant matrixes, particularly apple pomace. Novel extraction techniques involving enzymes, electric field, ultrasound, microwave heating, pressurized liquid, and super/subcritical fluid are also discussed. These techniques offer several advantages, including shorter extraction time, increased yield, reduction-or suppression-of solvents, and minimization of the environmental impact. This paper may help researchers and food industry professionals on the scaling-up and optimization of eco-friendly extractions of pectin and phenolic compounds.


Mapping of a dominant rust resistance gene revealed two R genes around the major Rust_QTL in cultivated peanut (Arachis hypogaea L.).
A consensus rust QTL was identified within a 1.25 cM map interval of A03 chromosome in cultivated peanut. This map interval contains a TIR-NB-LRR R gene and four pathogenesis-related genes. Disease resistance in plants is manifested due to the specific interaction between the R gene product and its cognate avirulence gene product (AVR) in the pathogen. Puccinia arachidis Speg. causes rust disease and inflicts economic damages to peanut. Till now, no experimental evidence is known for the action of R gene in peanut for rust resistance. A fine mapping approach towards the development of closely linked markers for rust resistance gene was undertaken in this study. Phenotyping of an RIL population at five environments for field rust score and subsequent QTL analysis has identified a 1.25 cM map interval that harbored a consensus major Rust_QTL in A03 chromosome. This Rust_QTL is flanked by two SSR markers: FRS72 and SSR_GO340445. Both the markers clearly identified strong association of the mapped region with rust reaction in both resistant and susceptible genotypes from a collection of 95 cultivated peanut germplasm. This 1.25 cM map interval contained 331.7 kb in the physical map of A. duranensis and had a TIR-NB-LRR category R gene (Aradu.Z87JB) and four glucan endo-1,3 β glucosidase genes (Aradu.RKA6 M, Aradu.T44NR, Aradu.IWV86 and Aradu.VG51Q). Another resistance gene analog was also found in the vicinity of mapped Rust_QTL. The sequence between SSR markers, FRS72 and FRS49, contains an LRR-PK (Aradu.JG217) which is equivalent to RHG4 in soybean. Probably, the protein kinase domain in AhRHG4 acts as an integrated decoy for the cognate AVR from Puccinia arachidis and helps the TIR-NB-LRR R-protein to initiate a controlled program cell death in resistant peanut plants.


DeePKS + ABACUS as a Bridge between Expensive Quantum Mechanical Models and Machine Learning Potentials.
Recently, the development of machine learning (ML) potentials has made it possible to perform large-scale and long-time molecular simulations with the accuracy of quantum mechanical (QM) models. However, for different levels of QM methods, such as density functional theory (DFT) at the meta-GGA level and/or with exact exchange, quantum Monte Carlo, etc., generating a sufficient amount of data for training an ML potential has remained computationally challenging due to their high cost. In this work, we demonstrate that this issue can be largely alleviated with Deep Kohn-Sham (DeePKS), an ML-based DFT model. DeePKS employs a computationally efficient neural network-based functional model to construct a correction term added upon a cheap DFT model. Upon training, DeePKS offers closely matched energies and forces compared with high-level QM method, but the number of training data required is orders of magnitude less than that required for training a reliable ML potential. As such, DeePKS can serve as a bridge between expensive QM models and ML potentials: one can generate a decent amount of high-accuracy QM data to train a DeePKS model and then use the DeePKS model to label a much larger amount of configurations to train an ML potential. This scheme for periodic systems is implemented in a DFT package ABACUS, which is open source and ready for use in various applications.


Compressed sensing for high-resolution nonlipid suppressed 1 H FID MRSI of the human brain at 9.4T.
The aim of this study was to apply compressed sensing to accelerate the acquisition of high resolution metabolite maps of the human brain using a nonlipid suppressed ultra-short TR and TE 1 H FID MRSI sequence at 9.4T. X-t sparse compressed sensing reconstruction was optimized for nonlipid suppressed 1 H FID MRSI data. Coil-by-coil x-t sparse reconstruction was compared with SENSE x-t sparse and low rank reconstruction. The effect of matrix size and spatial resolution on the achievable acceleration factor was studied. Finally, in vivo metabolite maps with different acceleration factors of 2, 4, 5, and 10 were acquired and compared. Coil-by-coil x-t sparse compressed sensing reconstruction was not able to reliably recover the nonlipid suppressed data, rather a combination of parallel and sparse reconstruction was necessary (SENSE x-t sparse). For acceleration factors of up to 5, both the low-rank and the compressed sensing methods were able to reconstruct the data comparably well (root mean squared errors [RMSEs] ≤ 10.5% for Cre). However, the reconstruction time of the low rank algorithm was drastically longer than compressed sensing. Using the optimized compressed sensing reconstruction, acceleration factors of 4 or 5 could be reached for the MRSI data with a matrix size of 64 × 64. For lower spatial resolutions, an acceleration factor of up to R∼4 was successfully achieved. By tailoring the reconstruction scheme to the nonlipid suppressed data through parameter optimization and performance evaluation, we present high resolution (97 µL voxel size) accelerated in vivo metabolite maps of the human brain acquired at 9.4T within scan times of 3 to 3.75 min.


Genus-Wide Characterization of Bumblebee Genomes Provides Insights into Their Evolution and Variation in Ecological and Behavioral Traits.
Bumblebees are a diverse group of globally important pollinators in natural ecosystems and for agricultural food production. With both eusocial and solitary life-cycle phases, and some social parasite species, they are especially interesting models to understand social evolution, behavior, and ecology. Reports of many species in decline point to pathogen transmission, habitat loss, pesticide usage, and global climate change, as interconnected causes. These threats to bumblebee diversity make our reliance on a handful of well-studied species for agricultural pollination particularly precarious. To broadly sample bumblebee genomic and phenotypic diversity, we de novo sequenced and assembled the genomes of 17 species, representing all 15 subgenera, producing the first genus-wide quantification of genetic and genomic variation potentially underlying key ecological and behavioral traits. The species phylogeny resolves subgenera relationships, whereas incomplete lineage sorting likely drives high levels of gene tree discordance. Five chromosome-level assemblies show a stable 18-chromosome karyotype, with major rearrangements creating 25 chromosomes in social parasites. Differential transposable element activity drives changes in genome sizes, with putative domestications of repetitive sequences influencing gene coding and regulatory potential. Dynamically evolving gene families and signatures of positive selection point to genus-wide variation in processes linked to foraging, diet and metabolism, immunity and detoxification, as well as adaptations for life at high altitudes. Our study reveals how bumblebee genes and genomes have evolved across the Bombus phylogeny and identifies variations potentially linked to key ecological and behavioral traits of these important pollinators.


A Comparison of Weight-Related Behaviors of Hispanic Mothers and Children by Acculturation Level.
Hispanic mothers and children in the United States experience a high prevalence of obesity, which may be affected by maternal acculturation level. Little is known about the association of acculturation on weight-related behaviors. This study describes differences in weight-related behaviors by acculturation level of Hispanic mothers residing in the U.S. and compares them to behaviors of White mothers. Acculturation level was determined using personal acculturation and acculturation environment variables. Cluster analysis of acculturation variables identified three groups of Hispanic mothers: low personal and environmental acculturation (n = 46), high personal and low environmental acculturation (n = 65), and high personal and environmental acculturation (n = 38). Results indicate that, compared to White mothers (n = 340), the least acculturated cluster of Hispanic mothers tended to model physical activity less often and the most acculturated exerted more pressure on children to eat. Mothers in the least acculturated cluster tended to rate children's health status lower, indicate that children had greater fruit juice and less milk intakes, have more meals in locations associated with less healthy meals, and have the least space and supports for physical activity. Findings highlight relationships between maternal acculturation level and weight-related behaviors and suggest strategies for helping acculturating Hispanic mothers create healthier lifestyles and home environments.


[Variability in Spanish National Health System hospital emergency services utilization].
The aims of this study were to estimate the rate of hospital emergency services (HES) visits per health area, the associated percentage of admissions and the standardized HES utilization ratio, and to analyze their relationship with hospital resources. We performed an ecological study that combined information from distinct sources (Survey of Health Care Hospitalization Establishments 2006 and Minimum Data Set 2006) to estimate the rate of HES visits and the percentage of associated emergency admissions in 164 health areas in 14 autonomous communities (AC). Among 35.3 million inhabitants in the 164 areas examined, there were 16.2 million visits to the HES (45.75 per 100 inhabitants); more than 2 million (12.6%) were hospitalized. Excluding 5% of extreme areas, rates oscillated between 31.60 and 78.69 HES visits/100 inhabitants, and the percentage of admissions was between 7.6% and 27.9%. These differences were not attenuated after standardization. The AC factor explained 29% of variance in HES visits and 82% of variance in admissions. The rate of visits was not associated with the number of beds or staff physicians but did correlate with the number HES doctors, and smaller and non-teaching hospitals. There is wide variability in the rates of HES visits and emergency admissions in the different areas of the Spanish National Health System. This variability seems to be associated with a differential use for minor problems.


Activation of bacterial channel MscL in mechanically stimulated droplet interface bilayers.
MscL, a stretch-activated channel, saves bacteria experiencing hypo-osmotic shocks from lysis. Its high conductance and controllable activation makes it a strong candidate to serve as a transducer in stimuli-responsive biomolecular materials. Droplet interface bilayers (DIBs), flexible insulating scaffolds for such materials, can be used as a new platform for incorporation and activation of MscL. Here, we report the first reconstitution and activation of the low-threshold V23T mutant of MscL in a DIB as a response to axial compressions of the droplets. Gating occurs near maximum compression of both droplets where tension in the membrane is maximal. The observed 0.1-3 nS conductance levels correspond to the V23T-MscL sub-conductive and fully open states recorded in native bacterial membranes or liposomes. Geometrical analysis of droplets during compression indicates that both contact angle and total area of the water-oil interfaces contribute to the generation of tension in the bilayer. The measured expansion of the interfaces by 2.5% is predicted to generate a 4-6 mN/m tension in the bilayer, just sufficient for gating. This work clarifies the principles of interconversion between bulk and surface forces in the DIB, facilitates the measurements of fundamental membrane properties, and improves our understanding of MscL response to membrane tension.


An open access database for the evaluation of respiratory sound classification algorithms.
Over the last few decades, there has been significant interest in the automatic analysis of respiratory sounds. However, currently there are no publicly available large databases with which new algorithms can be evaluated and compared. Further developments in the field are dependent on the creation of such databases. This paper describes a public respiratory sound database, which was compiled for an international competition, the first scientific challenge of the IFMBE's International Conference on Biomedical and Health Informatics. The database includes 920 recordings acquired from 126 participants and two sets of annotations. One set contains 6898 annotated respiratory cycles, some including crackles, wheezes, or a combination of both, and some with no adventitious respiratory sounds. In the other set, precise locations of 10 775 events of crackles and wheezes were annotated. The best system that participated in the challenge achieved an average score of 52.5% with the respiratory cycle annotations and an average score of 91.2% with the event annotations. The creation and public release of this database will be useful to the research community and could bring attention to the respiratory sound classification problem.


Mutations in the SOD2 promoter reveal a molecular basis for an activating protein 2-dependent dysregulation of manganese superoxide dismutase expression in cancer cells.
A primary antioxidant enzyme in mitochondria, manganese superoxide dismutase (MnSOD), plays a critical role in the survival of aerobic life. It is well documented that, compared with normal cell counterparts, MnSOD level is decreased in neoplastic transformed cells but is increased in aggressive cancers. However, the underlying mechanism for the observed dysregulation of MnSOD in cancer is unknown. We have identified previously a unique set of mutations located in the promoter region of the SOD2 gene in several types of cancer cells. We found that a C-to-T transition at -102 and an insertion of A at -93 down-regulate MnSOD transcription by interrupting the formation of a single-stranded loop that is essential for a high level of promoter activity. Here, we show that the additional downstream mutation, C-to-G transversion at -38, creates a binding site for the transcription factors specificity protein 1 (Sp1) and activating protein 2 (AP-2). The promoter function is regulated by the relative levels of Sp1 and AP-2. In cytokine-induced expression of the SOD2 gene, Sp1 cooperates with a transcriptional complex containing nuclear factor-kappaB and nucleophosmin. The presence of AP-2 attenuates this induction. Our results suggest that the high level of MnSOD observed in aggressive cancer cells may be due, in part, to the absence of AP-2 transcriptional repression.


Mitochondria damage in the pathogenesis of diabetic retinopathy and in the metabolic memory associated with its continued progression.
Diabetic retinopathy is the leading cause of blindness in young adults, and with the incidence of diabetes increasing at a frightening rate, retinopathy is estimated to threaten vision for almost 51 million patients worldwide. In diabetes, mitochondria structure, function and DNA (mtDNA) are damaged in the retina and its vasculature, and the mtDNA repair machinery and biogenesis are compromised. Proteins encoded by mtDNA become subnormal contributing to dysfunctional electron transport system, and the transport of proteins that are important in mtDNA biogenesis and function, but are encoded by nuclear DNA, is impaired. These diabetes-induced abnormalities in mitochondria continue even when hyperglycemic insult is terminated, and are implicated in the metabolic memory phenomenon associated with the continued progression of diabetic retinopathy. Diabetes also facilitates epigenetic modifications-the changes in histones and DNA methylation in response to cells changing environmental stimuli, which the cell can memorize and pass to the next generation. Epigenetic modifications contribute to the mitochondria damage, and are postulated in the development of diabetic retinopathy, and also to the metabolic memory phenomenon. Thus, strategies targeting mitochondria homeostasis and/or enzymes important for histone and DNA methylation could serve as potential therapies to halt the development and progression of diabetic retinopathy.


The activities of acyl-CoA:1-acyl-lysophospholipid acyltransferase(s) in human platelets.
The activities of acyl-CoA:1-acyl-lysophospholipid acyltransferases (EC 220.127.116.11) have been studied in human platelet lysates by using endogenously formed [14C]acyl-CoA from [14C]fatty acid, ATP and CoA in the presence of 1-acyl-lysophosphatidyl-choline (lysoPC), -ethanolamine (lysoPE), -serine (lysoPS) or -inositol (lysoPI). Linoleic acid as fatty acid substrate had the highest affinity to acyl-CoA:1-acyl-lysophospholipid acyltransferase with lysoPC as variable substrate, followed by eicosapentaenoic acid (EPA) and arachidonic acid (AA). The activity at optimal conditions was 7.4, 7.3 and 7.2 nmol/min per 10(9) platelets with lysoPC as substrate, with linoleic acid, AA and EPA respectively. EPA and AA were incorporated into all lyso-forms. Linoleic acid was also incorporated into lysoPE at a high rate, but less into lysoPS and lysoPI. DHA was incorporated into lysoPC and lysoPE, but only slightly into lysoPI and lysoPS. Whereas incorporation of all fatty acids tested was maximal for lysoPC and lysoPI at 200 and 80 microM respectively, maximal incorporation needed over 500 microM for lysoPE and lysoPS. The optimal concentration for [14C]fatty acid substrates was in the range 15-150 microM for all lysophospholipids. Competition experiments with equimolar concentrations of either lysoPC and lysoPI or lysoPE resulted in formation of [14C]PC almost as if lysoPI or lysoPE were not added to the assay medium.


[Epidemiological study of cerebrovascular disease in the Taiwan area: current status].
We reviewed the reported epidemiological studies on cerebrovascular disease in the Taiwan area and discussed the following advantages and drawbacks of different approaches to data acquisition and analysis of the results. 1) Analysis of the data from vital statistics is readily available, and gives adequate information for secular trends, but the reliability of death certificate and the accuracy of subtypes of cerebrovascular disease must be taken into consideration. 2) A series of patients based on hospital registration can provide detailed data about the clinical manifestation and subtypes of stroke; whereas selection bias among hospitals may distort some clinical profile, and patients who have not visited the hospital are not included. 3) A community survey can obtain representative distribution of diseases in a community, but it takes much manpower and cost. The diagnosis of stroke is not very reliable because of limited usage of computed tomography and insufficient participation by qualified neurologists. 4) A community based hospital study has the advantage of combining a hospital registry and a community survey. It is difficult to conduct this type of study in the current medical environment in Taiwan since the referral system has not been well established. 5) A study of the survivalship of stroke can provide valuable information about the natural course of cerebrovascular disease.


Serum myo-inositol and valine improve metabolomic-based estimated glomerular filtration rate among kidney transplant recipients.
Close monitoring of glomerular filtration rate (GFR) is essential for the management of patients post kidney transplantation. Measured GFR (mGFR), the gold standard, is not readily accessible in most centers. Furthermore, the performance of new estimated GFR (eGFR) equations based upon creatinine and/or cystatin C have not been validated in kidney transplant patients. Here we evaluate a recently published eGFR equation using cystatin C, creatinine, myo-inositol and valine as measured by nuclear magnetic resonance (eGFRNMR). Residual sera was obtained from a cohort of patients with clinically ordered iothalamate renal clearance mGFR (n = 602). Kidney transplant recipients accounted for 220 (37%) of participants. Compared to mGFR, there was no significant bias for eGFRcr or eGFRNMR, while eGFRcr-cys significantly underestimated mGFR. P30 values were similar for all eGFR. P15 was significantly higher for eGFRNMR compared to eGFRcr, while the P15 for eGFRcr-cys only improved among patients without a kidney transplant. Agreement with mGFR CKD stages of <15, 30, 45, 60, and 90 ml/min/1.73 m2 was identical for eGFRcr and eGFRcr-cys (61.8%, both cases) while eGFRNMR was significantly higher (66.4%) among patients with a kidney transplant. The 2021 CKD-EPI eGFRcr and eGFRcr-cys have similar bias, P15, and agreement while eGFRNMR more closely matched mGFR with the strongest improvement among kidney transplant recipients.


Dispositional and ideological factor correlate of conspiracy thinking and beliefs.
This study explored how the Big Five personality traits, as well as measures of personality disorders, are related to two different measures of conspiracy theories (CTs)The two measures correlated r = .58 and were applied to examine generalisability of findings. We also measured participants (N = 397) general knowledge levels and ideology in the form of religious and political beliefs. Results show that the Big Five and ideology are related to CTs but these relationships are generally wiped out by the stronger effects of the personality disorder scales. Two personality disorder clusters (A and B) were significant correlates of both CT measures, in both cases accounting for similar amounts of variance (20%). The personality disorders most predictive of conspiracy theories were related to the A cluster, characterized by schizotypal symptoms such as oddities of thinking and loose associations. These findings were corroborated by an additional analysis using Latent Semantic Analysis (LSA). LSA demonstrated that the items measuring schizotypal and related symptoms are cognitively related to both our measures of CTs. The implications for the studying of CTs is discussed, and limitations are acknowledged.


Promising prevention approaches: tenofovir gel and prophylactic use of antiretroviral medications.
Thirty years into the global HIV epidemic, the need for effective prevention strategies remains critical. In July 2010, the CAPRISA-004 study demonstrated that topical administration of a gel containing the antiretroviral agent tenofovir decreased the risk of HIV acquisition among at-risk heterosexual women. Subsequently, the iPrEx study reported that prophylactic use of a daily oral tablet containing tenofovir and emtricitabine reduced the risk of HIV acquisition among high-risk men who have sex with men. These studies illustrate the promise of antiretroviral pre-exposure chemoprophylaxis (PrEP) as an innovative prevention approach. This review discusses the rationale for chemoprophylaxis, compares the advantages of topical and oral delivery, outlines recommended safety monitoring, offers principles to guide selection of antiretroviral agents, and highlights potential unintended consequences of PrEP use. If future studies confirm the safety and efficacy of tenofovir gel and oral PrEP, successful implementation of these strategies could significantly impact the HIV epidemic.


Volume changes and whole cell membrane currents activated during gradual osmolarity decrease in C6 glioma cells: contribution of two types of K+ channels.
Volume changes and whole cell ionic currents activated by gradual osmolarity reductions (GOR) of 1.8 mosM/min were characterized in C6 glioma cells. Cells swell less in GOR than after sudden osmolarity reductions (SOR), the extent of swelling being partly Ca(2+) dependent. In nominally Ca(2+)-free conditions, GOR activated predominantly whole cell outward currents. Cells depolarized from the initial -79 mV to a steady state of -54 mV reached at 18% osmolarity reduction [hyposmolarity of -18% (H-18%)]. Recordings of Cl(-) and K(+) currents showed activation at H-3% of an outwardly rectifying Cl(-) current, with conductance of 1.6 nS, sensitive to niflumic acid and 5-nitro-2-(3-phenylpropylamino)benzoic acid, followed at H-18% by an outwardly rectifying K(+) current with conductance of 4.1 nS, inhibited by clofilium but insensitive to the typical K(+) channel blockers. With 200 nM Ca(2+) in the patch pipette, whole cell currents activated at H-3% and at H-13% cells depolarized from -77 to -63 mV. A K(+) current activated at H-1%, showing a rapid increase in conductance, suppressed by charybdotoxin and insensitive to clofilium. These results show the operation of two different K(+) channels in response to GOR in the same cell type, activated by Ca(2+) and osmolarity and with different osmolarity activation thresholds. Taurine and glutamate efflux, monitored by labeled tracers, showed delayed osmolarity thresholds of H-39 and H-33%, respectively. This observation clearly separates the Cl(-) and amino acid osmosensitive pathways. The delayed amino acid efflux may contribute to counteract swelling at more stringent osmolarity reductions.


Rat embryo cells immortalized with transfected oncogenes are transformed by gamma irradiation.
Cesium-137 gamma rays were used to transform rat embryo cells (REC) which were first transfected with activated c-myc or c-Ha-ras oncogenes to produce immortal cell lines (REC:myc and REC:ras). When exposed to 6 Gy of 137Cs gamma rays, some cells became morphologically transformed with focus formation frequencies of approximately 3 x 10(-4) for REC:myc and approximately 1 x 10(-4) for REC:ras, respectively. Cells isolated from foci of gamma-ray-transformed REC:myc (REC:myc:gamma) formed anchorage-independent colonies and were tumorigenic in nude mice, but foci from gamma-ray-transformed REC:ras (REC:ras:gamma) did not exhibit either of these criteria of transformation. Similar to the results with gamma irradiation, we observed a sequence-dependent phenomenon when myc and ras were transfected into REC, one at a time. REC immortalized by ras transfection were not converted to a tumorigenic phenotype by secondary transfection with myc, but REC transfected with myc were very susceptible to transformation by subsequent ras transfection. This suggests that myc-immortalized cells are more permissive to transformation via secondary treatments. In sequentially transfected REC, myc expression was high whether it was transfected first or second, whereas ras expression was highest when the ras gene was transfected secondarily into myc-containing REC. Molecular analysis of REC:ras:gamma transformants showed no alterations in structure of the transfected ras or of the endogenous ras, myc, p53, or fos genes. The expression of ras and p53 was increased in some isolates of REC:ras:gamma, but myc and fos expression were not affected. Similarly, REC:myc:gamma transformants did not demonstrate rearrangement or amplification of the transfected or the endogenous myc genes, or of the potentially cooperating Ha-, Ki-, or N-ras genes. Northern hybridization analysis revealed increased expression of N-ras in two isolates, REC:myc:gamma 33 and gamma 41, but no alterations in the expression of myc, raf, Ha-ras, or Ki-ras genes in any REC:myc transformant. DNA from several transformed REC:myc:gamma cell lines induced focus formation in recipient C3H 10T1/2 and NIH 3T3 cells. The NIH 3T3 foci tested positive when hybridized to a probe for rat repetitive DNA. A detailed analysis of the NIH 3T3 transformants generated from REC:myc:gamma 33 and gamma 41 DNA failed to detect Ha-ras, Ki-ras, raf, neu, trk, abl, fms, or src oncogenes of rat origin.(ABSTRACT TRUNCATED AT 400 WORDS)


Primary Tumor Location as a Prognostic and Predictive Marker in Metastatic Colorectal Cancer (mCRC).
Clinico-pathological differences between adenocarcinoma in the right and left colo-rectum play a role in determining the prognosis and response to treatment. Studies suggest that primary tumor location is more relevant as the disease progresses and reflects a possible difference in biology and response to therapy. This review aims to explore the clinico-pathological features of right and left colo-rectum and the impact of primary tumor location on prognosis of CRC as well as discuss the available clinical data on tumor sidedness in metastatic colorectal cancer. In so far as the clinical data of tumor sidedness is concerned, very few reviews have discussed the clinical implications of sidedness in heavily pre-treated metastatic colorectal cancer (second and subsequent lines of therapy in metastatic disease). This review aims to fill the current gap in this setting.


Comparison of pharmacokinetic profiles of seven major bioactive components in normal and non-alcoholic fatty liver disease (NAFLD) rats after oral administration of Ling-Gui-Zhu-Gan decoction by UPLC-MS/MS.
A sensitive and rapid ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was hereby developed for the determination of seven components, namely, glycyrrhizic acid, glycyrrhetinic acid, dehydrotumulosic acid, isoliquiritin, liquiritin, atractylenolide III, and cinnamic acid, in the plasma of rats after the oral administration of Ling-Gui-Zhu-Gan decoction (LGZGD). Besides, this very method was methodologically validated for specificity, linearity, inter-day and intra-day precision, accuracy, matrix effect, extraction recovery, and stability. It was also successfully used for the first time to compare the pharmacokinetic characteristics of the seven components after oral administration of LGZGD to normal rats and non-alcoholic fatty liver disease (NAFLD) rats. The results indicated significant differences between the pharmacokinetic characteristics of normal and NAFLD rats. To further reveal the different pharmacokinetic behaviors, the expressions of enzymes and transporters in the liver of normal and NAFLD rats were detected using UPLC-MS/MS. In the NAFLD rats, UDP-glucuronosyltransferase 1-1 (UGT1A1) and nine transporters were significantly inhibited and a positive correlation was observed between them and the AUC of the major components. The present results indicate that the pharmacokinetic differences between the normal and NAFLD rats might be attributed to the significant lower expression levels of both the metabolic enzyme UGT1A1 and nine transporter proteins in the NAFLD rats than in the normal rats. Meanwhile, UGT1A1 and the nine transporter proteins might be used as potential biomarkers to assess the ameliorative effect of LGZGD on NAFLD, which could provide useful information to guide the clinical application of LGZGD.


Neuroimaging abnormalities, neurocognitive function, and fatigue in patients with hepatitis C.
This study examined neurologic abnormalities (as measured by proton magnetic resonance spectroscopy imaging and diffusion tensor imaging), neurocognitive performance, and fatigue among a sample of adults with hepatitis C virus (HCV). We hypothesized that HCV+ individuals would demonstrate structural brain abnormalities and neurocognitive compromise consistent with frontostriatal dysfunction as well as increased fatigue compared to controls. Participants were 76 individuals diagnosed with HCV and 20 controls who underwent a comprehensive neurocognitive evaluation and clinical assessments. A subset of the HCV+ participants (n = 29) and all controls underwent MRI. Individuals diagnosed with chronic HCV infection demonstrated greater fractional anisotropy in the striatum as well as greater mean diffusivity in the fronto-occiptal fasciculus and external capsule compared to HCV- controls. HCV+ participants also demonstrated lower levels of N-acetylaspartate in bilateral parietal white matter and elevations in myo-inosital (mI) in bilateral frontal white matter compared to HCV- controls (all p values < 0.05). HCV+ participants also demonstrated significantly poorer neuropsychological performance, particularly in processing speed and verbal fluency. HCV+ patients reported higher levels of fatigue than controls, and fatigue was significantly correlated with diffusivity in the superior fronto-occipital fasciculus, elevations in mI in frontal white matter, and overall cognitive performance. Our results suggest that HCV-associated neurologic complications disrupt frontostriatal structures, which may result in increased fatigue and poorer cognitive performance, particularly in those cognitive domains regulated by frontostriatal regions.


Effect of Physical Exercise-Based Rehabilitation on Long COVID: A Systematic Review and Meta-analysis.
The number of persons living with post-coronavirus disease 2019 (COVID-19) conditions or long COVID continues to rise worldwide; however, the etiology and treatment of long COVID remain nebulous. Therefore, efficient, feasible, and cost-effective therapeutic strategies for a large population with long COVID remain warranted. Physical exercise-based rehabilitation is a promising strategy for long COVID, although its therapeutic effects remain to be determined. This systematic review and meta-analysis aimed to examine the effects of physical exercise-based rehabilitation on long COVID. The electronic databases Medline, Embase, Global Health (Ovid), CINAHL (EBSCO), Web of Science, WHO Global Research Database on COVID-19, LitCovid, and Google Scholar were searched from their inception to November 2022. The identified articles were independently screened by three reviewers, and a random-effects model was utilized to determine the mean differences in the meta-analysis. Twenty-three studies involving 1,579 individuals who had COVID-19 (752 women) were included. Physical exercise-based rehabilitation showed beneficial effects on long COVID-related symptoms characterized by dyspnea, fatigue, and depression, as well as on the 6-minute walk test, forced expiratory volume in 1 second/forced vital capacity, and quality of life in people who had COVID-19. Physical exercise-based rehabilitation is a potential therapeutic strategy against long COVID and can be applied as a routine clinical practice in people who have recovered from COVID-19. However, customized physical exercise-based rehabilitation programs and their effects on specific types of long COVID require future large-scale studies.


Miocene Climate and Habitat Change Drove Diversification in Bicyclus, Africa's Largest Radiation of Satyrine Butterflies.
Compared to other regions, the drivers of diversification in Africa are poorly understood. We studied a radiation of insects with over 100 species occurring in a wide range of habitats across the Afrotropics to investigate the fundamental evolutionary processes and geological events that generate and maintain patterns of species richness on the continent. By investigating the evolutionary history of Bicyclus butterflies within a phylogenetic framework, we inferred the group's origin at the Oligo-Miocene boundary from ancestors in the Congolian rainforests of central Africa. Abrupt climatic fluctuations during the Miocene (ca. 19-17 Ma) likely fragmented ancestral populations, resulting in at least eight early-divergent lineages. Only one of these lineages appears to have diversified during the drastic climate and biome changes of the early Miocene, radiating into the largest group of extant species. The other seven lineages diversified in forest ecosystems during the late Miocene and Pleistocene when climatic conditions were more favorable-warmer and wetter. Our results suggest changing Neogene climate, uplift of eastern African orogens, and biotic interactions have had different effects on the various subclades of Bicyclus, producing one of the most spectacular butterfly radiations in Africa. [Afrotropics; biodiversity; biome; biotic interactions; Court Jester; extinction; grasslands; paleoclimates; Red Queen; refugia forests; dependent-diversification; speciation.].


Disclaimer labels on fashion magazine advertisements: Does timing of digital alteration information matter?
The study aimed to investigate whether a message informing readers about digital alteration read before exposure to thin ideal advertisements would enhance the effectiveness of disclaimer labels. Participants were 280 female undergraduate students who viewed eleven thin ideal fashion magazine advertisements. Half viewed the advertisements in their original format, and half viewed the same advertisements with a digital alteration disclaimer label. Prior to viewing the advertisements, participants read either a brief message informing them that advertisements are commonly digitally altered, or a control message. Irrespective of experimental condition, exposure to the thin ideal advertisements led to increased body dissatisfaction, with social comparison predicting this increase. Neither the disclaimer label nor the pre-exposure message, nor their combination, led to reductions in perceived realism, social comparison, or body dissatisfaction. However, trait appearance comparison moderated the effect of pre-exposure message on perceived realism, such that women high on trait appearance comparison in the digital alteration pre-exposure message condition rated the models as relatively more realistic than did women low on this trait. It was concluded that more research is needed to identify brief and easy-to-implement universal prevention strategies that can reduce the negative effects of thin ideal media imagery on women's body image.


Cecal perforation and adrenocortical adenoma in a dog.
Cecal perforation was diagnosed in a dog with a history of acute vomiting. The dog also had an adrenocortical adenoma. Intestinal perforation can be a serious complication of cortico-steroid treatment in the dog, but has not been attributable to hyperadrenocorticism. Fever and an inflammatory CBC were not observed, which could have been secondary to adrenal-dependent hyperadrenocorticism. The acute abdominal crisis associated with peritonitis required quick resolution in an attempt to save the dog, but also precluded any further diagnostic procedures for possible hyperadrenocorticism. The signs that suggested hyper-adrenocorticism in this dog included alopecia, lymphopenia, eosinopenia, high liver enzyme activities, hypercholesterolemia, and one large and one small adrenal gland. This latter finding presumably indicated negative feedback suppression and atrophy attributable to a functional adrenocortical adenoma.


Rapamycin selectively inhibits expression of an inducible keratin (K6a) in human keratinocytes and improves symptoms in pachyonychia congenita patients.
The macrolide sirolimus (rapamycin) selectively blocks translation of mRNAs containing a terminal 5' oligopyrimidine (TOP) tract by altering the activity of mammalian target of rapamycin (mTOR) and inhibiting downstream mTOR pathway components involved in TOP mRNA translation. The skin disorder pachyonychia congenita (PC) is caused by mutations in the inducible keratins (K) including K6a, K6b, K16 and K17. Published sequence data suggest the 5' untranslated regions of K6a and K6b mRNAs contain 5' TOP motifs and therefore may be sensitive to rapamycin treatment. Determine if mTOR inhibitors (rapamycin, temsirolimus or everolimus) are viable drug candidates for treatment of PC and other disorders caused by inappropriate expression of K6a and K6b. 5' RACE analysis was used to map the transcriptional start sites for K5, K6a, K6b, K14, K16 and K17. The sensitivity of these keratins to mTOR inhibitors was determined by Western and qPCR analysis following treatment of a human HaCaT keratinocyte cell line with rapamycin, temsirolimus or everolimus. A small off-label study was undertaken using orally administered rapamycin in three PC patients and the effects were monitored by clinical examination, photography, a validated Dermatology Life Quality Index (DLQI) and a pain and activity diary. Sequence comparison and 5' RACE analysis of the 5' untranslated regions of K6a and K6b revealed putative TOP regulatory elements. Treatment of a human HaCaT keratinocyte cell line with mTOR inhibitors (rapamycin, temsirolimus or everolimus) resulted in selective K6a repression. Furthermore, treatment of this HaCaT cell line with siRNAs targeting components of the mTOR pathway altered the levels of K6a expression. To test the ability of rapamycin to ameliorate PC symptoms, an off-label study was conducted. PC patient clinical responses to oral rapamycin showed a therapeutic response in callus character as well as subjective improvement. Of particular note, rapamycin greatly reduced the presence of painful cutaneous thromboses after reaching therapeutic serum levels. The well-known rapamycin side effects led to the early withdrawal of all of the patients from the study. Rapamycin selectively blocks K6a expression in human keratinocytes. The improvement of symptoms in PC patients following rapamycin treatment suggests rapamycin (or rapamycin analogs) may be a therapeutic option, particularly if topical formulations can be developed that avoid the side effects associated with systemic administration.


[The participation of the GABAergic system of the brain in shaping the breathing rhythm].
I.v. administration of sodium hydroxybutyrate induced periodic apneustic breathing with inspiratory arrests in anesthetised cats. Bilateral vagotomy did not change respiratory or circulatory parameters under these conditions. Administration of the same agent into both nuclei tractus solitarii induced similar effects, as well as administration of the GABA agonist baclofen. The data obtained suggest that the medullary GABA-ergic system takes an active part in generation of the respiration rhythm.


Holding Out and Protected Titles - Issues for Non-registrant Complementary and Alternative Health Practitioners.
The regulation of registered health practitioners in Australia focuses upon holding out provisions rather than statutory scope of practice provisions. One concern for non-registrant complementary and alternative medicine practitioners and other non-registrants is whether these holding out provisions are breached by simply providing a modality which may also be applied by a registered health practitioner (such as the use of Chinese Massage) and when does a breach of the holding out occur when they use particular words that might in the context of when they are used may be deemed to constitute a holding out. This article will analyse the relevant provisions of the National Law and case law to determine some guidelines for practitioners to avoid liability.


Description of the targeted water supply and hygiene response strategy implemented during the cholera outbreak of 2017-2018 in Kinshasa, DRC.
Rapid control of cholera outbreaks is a significant challenge in overpopulated urban areas. During late-2017, Kinshasa, the capital of the Democratic Republic of the Congo, experienced a cholera outbreak that showed potential to spread throughout the city. A novel targeted water and hygiene response strategy was implemented to quickly stem the outbreak. We describe the first implementation of the cluster grid response strategy carried out in the community during the cholera outbreak in Kinshasa, in which response activities targeted cholera case clusters using a grid approach. Interventions focused on emergency water supply, household water treatment and safe storage, home disinfection and hygiene promotion. We also performed a preliminary community trial study to assess the temporal pattern of the outbreak before and after response interventions were implemented. Cholera surveillance databases from the Ministry of Health were analyzed to assess the spatiotemporal dynamics of the outbreak using epidemic curves and maps. From January 2017 to November 2018, a total of 1712 suspected cholera cases were reported in Kinshasa. During this period, the most affected health zones included Binza Météo, Limeté, Kokolo, Kintambo and Kingabwa. Following implementation of the response strategy, the weekly cholera case numbers in Binza Météo, Kintambo and Limeté decreased by an average of 57% after 2 weeks and 86% after 4 weeks. The total weekly case numbers throughout Kinshasa Province dropped by 71% 4 weeks after the peak of the outbreak. During the 2017-2018 period, Kinshasa experienced a sharp increase in cholera case numbers. To contain the outbreak, water supply and hygiene response interventions targeted case households, nearby neighbors and public areas in case clusters using a grid approach. Following implementation of the response, the outbreak in Kinshasa was quickly brought under control. A similar approach may be adapted to quickly interrupt cholera transmission in other urban settings.


The Role of Biofilms in the Development and Dissemination of Microbial Resistance within the Food Industry.
Biofilms are multicellular sessile microbial communities embedded in hydrated extracellular polymeric matrices. Their formation is common in microbial life in most environments, while those formed on food-processing surfaces are of considerable interest in the context of food hygiene. Biofilm cells express properties that are distinct from planktonic ones, in particular, notorious resistance to antimicrobial agents. Thus, a special feature of biofilms is that, once they have been developed, they are hard to eradicate, even when careful sanitization procedures are regularly applied. A great deal of ongoing research has investigated how and why surface-attached microbial communities develop such resistance, and several mechanisms are to be acknowledged (e.g., heterogeneous metabolic activity, cell adaptive responses, diffusion limitations, genetic and functional diversification, and microbial interactions). The articles contained in this Special Issue deal with biofilms of some important food-related bacteria (including common pathogens such as Salmonella enterica, Listeria monocytogenes, and Staphylococcus aureus, as well as spoilage-causing spore-forming bacilli), providing novel insights on their resistance mechanisms and implications, together with novel methods (e.g., use of protective biofilms formed by beneficial bacteria, enzymes) that could be used to overcome such resistance and thus improve the safety of our food supply and protect public health.


All the little pieces. -Regulation of mitochondrial fusion and fission by ubiquitin and small ubiquitin-like modifer and their potential relevance in the heart.-.
Mitochondria are dynamic organelles that undergo a constant cycle of division and fusion to maintain their function. The process of mitochondrial fusion has the effect of mixing their content, allowing complementation of protein components, mtDNA repair, and distribution of metabolic intermediates. Fission, on the other hand, enables mitochondria to increase in number and capacity, and to segregate mitochondria for autophagy by the lysosome ("mitophagy"). Disruption of these protein quality control mechanisms has recently been identified in multiple cardiac diseases, including cardiac hypertrophy, heart failure, dilated cardiomyopathy, and ischemic heart disease, and is intimately tied to mitochondrial control of apoptosis. Proteins that regulate mitochondrial fusion and fission have been discovered, including Mfn1, Mfn2, and Opa1 (fusion) and Drp1 and Fis1 (fission). In this review, we discuss how these proteins are regulated by post-translational modification with ubiquitin and SUMO (small ubiquitin-like modifier). We then present what is known about the ubiquitin and SUMO ligases that regulate these post-translational modifications and regulation of mitochondrial fusion and fission, exploring their potential as therapeutic targets of cardiac disease.