Chiropractic Management of Performance Related Musculoskeletal Disorder in a Career Violist.
BACKGROUND Music performance is a highly stressful activity, requiring skilled neuromuscular dexterity. A lack of reported strategies for musicians suffering performance-related musculoskeletal disorders (PRMDs) exists. Papers investigating the role that postural distortions or spinal structural anomalies that could play a role in setting the stage for PRMD do not exist. The purpose of this paper was to provide a description and discussion of the use of a specialized upper cervical manual correction at the cranio-cervical junction (CCJ) to treat a violist who had disabling pain in her wrists, arms, neck, and hip. Differential diagnoses are required regarding possible confounding elements within the cervical spine. CASE REPORT After 40 years of music performance, a violist experienced severe pain while attempting to play the simplest student musical pieces. Early retirement seemed imminent. To determine appropriate chiropractic approach, the patient's clinical assessment included active range of motion, chiropractic tests, palpation, and radiographic study. Postural distortions, hypertonic muscles, joint pain, arthritis, and ponticulus posticus (PP) were noted. Upper cervical spine orthogonal radiographic series were used to develop a correction strategy. These images identified excursion of the cervical spine away from the vertical axis and C0-C1-C2 misalignments. After performing low-velocity, low-force manual correction to the CCJ, the patient experienced immediate relief of wrist pain. Over a 9-month follow-up period, the patient reported gradual decrease of pain and increased stamina while performing. Upon completing chiropractic care, the violist's career was restored. CONCLUSIONS This case supports the hypothesis that evaluating and correcting spinal structures proximal to painful extremities may represent an efficient and long-lasting solution for PRMD.


Retinal pigment epithelium damage enhances expression of chemoattractants and migration of bone marrow-derived stem cells.
To characterize chemoattractants expressed by the retinal pigment epithelium (RPE) after sodium iodate (NaIO3)-induced damage and to investigate whether ocular-committed stem cells preexist in the bone marrow (BM) and migrate in response to the chemoattractive signals expressed by the damaged RPE. C57/BL6 mice were treated with a single intravenous injection of NaIO3 (50 mg/kg) to create RPE damage. At different time points real-time RT-PCR, ELISA, and immunohistochemistry were used to identify chemoattractants secreted in the subretinal space. Conditioned medium from NaIO3-treated mouse RPE was used in an in vitro assay to assess chemotaxis of stem cell antigen-1 positive (Sca-1+) BM mononuclear cells (MNCs). The expression of early ocular markers (MITF, Pax-6, Six-3, Otx) in migrated cells and in MNCs isolated from granulocyte colony-stimulating factor (G-CSF) and Flt3 ligand (FL)-mobilized and nonmobilized peripheral blood (PB) was analyzed by real-time RT-PCR. mRNA for stromal cell-derived factor-1 (SDF-1), C3, hepatocyte growth factor (HGF), and leukemia inhibitory factor (LIF) was significantly increased, and higher SDF-1 and C3 protein secretion from the RPE was found after NaIO3 treatment. A higher number of BMMNCs expressing early ocular markers migrated to conditioned medium from damaged retina. There was also increased expression of early ocular markers in PBMNCs after mobilization. Damaged RPE secretes cytokines that have been shown to serve as chemoattractants for BM-derived stem cells (BMSCs). Retina-committed stem cells appear to reside in the BM and can be mobilized into the PB by G-CSF and FL. These stem cells may have the potential to serve as an endogenous source for tissue regeneration after RPE damage.


Predilection of otosclerotic foci related to the bone turnover in the otic capsule.
Using multiple fluorochrome tagging of eight mongrel dogs and a newly established methodology of measuring bone turnover (BTO) in the otic capsule, it has previously been demonstrated that BTO in the canine otic capsule is highly reduced close to the perilymphatic spaces (PLS) compared to the normal level of BTO in the periphery. Reanalysis of these data shows that this inhibition of BTO is far more pronounced around the cochlea and vestibule than around the semicircular canals. Similar tendencies are seen for the numerical density and mean label area of the bone remodelling units. With increasing distance to the PLS, these patterns are weakened, but still recognizable. In otosclerosis, foci of abnormal bone deposition are particularly frequent around the oval and round windows and in the cochlear capsule, i.e. where inhibition of bone remodelling is most prominent. A surpassing (or failure) of this pronounced inhibition must precede the tumultuous but delimited osteogenesis of otosclerosis. Otosclerosis may be a deviation of the normal BTO process in an osteometabolically abnormal site, perhaps initiated as an osteogenetic response to abnormal stress exposure.


Rebuilding the lid region from conformational and dynamic features to engineering applications of lipase in foods: Current status and future prospects.
The applications of lipases in esterification, amidation, and transesterification have broadened their potential in the production of fine compounds with high cumulative values. Mostly, the catalytic triad of lipases is covered by either one or two mobile peptides called the "lid" that control the substrate channel to the catalytic center. The lid holds unique conformational allostery via interfacial activation to regulate the dynamics and catalytic functions of lipases, thereby highlighting its importance in redesigning these enzymes for industrial applications. The structural characteristic of lipase, the dynamics of lids, and the roles of lid in lipase catalysis were summarized, providing opportunities for rebuilding lid region by biotechniques (e.g., metagenomic technology and protein engineering) and enzyme immobilization. The review focused on the advantages and disadvantages of strategies rebuilding the lid region. The main shortcomings of biotechnologies on lid rebuilding were discussed such as negative effects on lipase (e.g., a decrease of activity). Additionally, the main shortcomings (e.g., enzyme desorption at high temperatre) in immobilization on hydrophobic supports via interfacial action were presented. Solutions to the mentioned problems were proposed by combinations of computational design with biotechnologies, and improvements of lipase immobilization (e.g., immobilization protocols and support design). Finally, the review provides future perspectives about designing hyperfunctional lipases as biocatalysts in the food industry based on lid conformation and dynamics.


Validation of a four items version of the Functional Remission of General Schizophrenia scale (the mini-FROGS) to capture the functional benefits of clinical remission.
We previously developed the Functional Remission Of General Schizophrenia (FROGS) scale demonstrating first, reliable assessment in a cross-sectional study and second, good time-stability. The purpose of the present analysis was to propose a shorter version (mini-FROGS), more compatible with the limited time available in a psychiatric visit, focusing on the functional domains that have higher likelihood of being improved with higher and/or longer symptomatic remission in different cultural backgrounds. We used multiple regressions to find the most informative items explaining increased length of symptomatic remission, using prospective data from a national observational multicenter survey. Then, the mini-FROGS was used in different European countries to test its between-center reliability, compared to other scales. Four domains were retained as capturing the maximum of symptomatic remission, namely (1) travel and communication, (2) management of illness and treatment, (3) self-esteem and sense of independence and (4) respect of biological rhythms. First, the mini-FROG was evaluated in 443 French patients with clinical remission and 22 without, and 12/18 months later in 140 patients still in clinical remission and 23 in relapse. In Europe, 295 schizophrenia patients were assessed with the mini-FROGS and other scales devoted to functional remission, allowing comparisons. The mini-FROGS showed good correlations with other scales in different countries and demonstrated good psychometric properties. These results give evidence that a 4 items-only version of the FROGS scale may be useful to assess important aspects of functional remission, tightly linked to the length of clinical remission.


Active immunotherapy combined with blockade of a coinhibitory pathway achieves regression of large tumor masses in cancer-prone mice.
Vaccines that aim to expand tumor-specific CD8(+) T cells have yielded disappointing results in cancer patients although they showed efficacy in transplantable tumor mouse models. Using a system that more faithfully mimics a progressing cancer and its immunoinhibitory microenvironment, we here show that in transgenic mice, which gradually develop adenocarcinomas due to expression of HPV-16 E7 within their thyroid, a highly immunogenic vaccine expressing E7 only induces low E7-specific CD8(+) T-cell responses, which fail to affect the size of the tumors. In contrast, the same type of vaccine expressing E7 fused to herpes simplex virus (HSV)-1 glycoprotein D (gD), an antagonist of the coinhibitory B- and T-lymphocyte attenuator (BTLA)/CD160-herpes virus entry mediator (HVEM) pathways, stimulates potent E7-specific CD8(+) T-cell responses, which can be augmented by repeated vaccination, resulting in initial regression of even large tumor masses in all mice with sustained regression in more than half of them. These results indicate that active immunization concomitantly with blockade of the immunoinhibitory HVEM-BTLA/CD160 pathways through HSV-1 gD may result in sustained tumor regression.


Data and tools to integrate climate and environmental information into public health.
During the last 30 years, the development of geographical information systems and satellites for Earth observation has made important progress in the monitoring of the weather, climate, environmental and anthropogenic factors that influence the reduction or the reemergence of vector-borne diseases. Analyses resulting from the combination of geographical information systems (GIS) and remote sensing have improved knowledge of climatic, environmental, and biodiversity factors influencing vector-borne diseases (VBDs) such as malaria, visceral leishmaniasis, dengue, Rift Valley fever, schistosomiasis, Chagas disease and leptospirosis. These knowledge and products developed using remotely sensed data helped and continue to help decision makers to better allocate limited resources in the fight against VBDs. Because VBDs are linked to climate and environment, we present here our experience during the last four years working with the projects under the, World Health Organization (WHO)/ The Special Programme for Research and Training in Tropical Diseases (TDR)-International Development Research Centre (IDRC) Research Initiative on VBDs and Climate Change to integrate climate and environmental information into research and decision-making processes. The following sections present the methodology we have developed, which uses remote sensing to monitor climate variability, environmental conditions, and their impacts on the dynamics of infectious diseases. We then show how remotely sensed data can be accessed and evaluated and how they can be integrated into research and decision-making processes for mapping risks, and creating Early Warning Systems, using two examples from the WHO TDR projects based on schistosomiasis analysis in South Africa and Trypanosomiasis in Tanzania. The tools presented in this article have been successfully used by the projects under the WHO/TDR-IDRC Research Initiative on VBDs and Climate Change. Combined with capacity building, they are an important piece of work which can significantly contribute to the goals of WHO Global Vector Control Response and to the Sustainable Development Goals especially those on health and climate action.


Models of speciation: where are we now?
Theory building is an integral part of biological research, in general, and of speciation research, in particular. Here, I review the modeling work on speciation done in the last 10 years or so, assessing the progress made and identifying areas where additional effort is required. Specific topics considered include evolutionary dynamics of genetic incompatibilities, spatial and temporal patterns of speciation, links to neutral theory of biodiversity, effects of multidimensionality of phenotype, sympatric and parapatric speciation, adaptive radiation, speciation by sexual conflict, and models tailored for specific biological systems. Particularly challenging questions for future theoretical research identified here are 1) incorporating gene regulatory networks in models describing accumulation of genetic incompatibilities; 2) integrating models of community ecology with those developed in speciation theory; 3) building models providing better insights on the dynamics of parapatric speciation; 4) modeling speciation in multidimensional ecological niches with mating preferences based on multidimensional mating cues and sexual characters; 5) linking microevolutionary processes with macroevolutionary patterns as observed in adaptive radiations and paleontological record; 6) modeling speciation in specific systems studied by empirical biologists; and 7) modeling human origins. The insights from dynamic models of speciation should be useful in developing statistical tools that would enable empiricists to infer the history of past evolutionary divergence and speciation from genomic data.


Canine scabies in humans: a case report and review of the literature.
Sarcoptes scabiei causes mange in many domestic and wild mammals, and it has been reported to be transmitted from animals to humans. Canine scabies is known to infest humans, as well. We report a 27-year-old woman who presented with severe pruritic papules on the trunk and arms. The patient reported that she had just bought a puppy which was also itchy. Direct microscopy from the dog showed scabies mites. The patient was treated by 5% permethrin which accomplished full recovery. Canine scabies in humans is a challenging disease to diagnose since mites are hard to find on skin scrapings of dogs and the burrows that are the hallmark of scabies are absent. Dermatological examination of the lesions in our patient did not show any burrows or a specific dermoscopic image of scabies. Instead, we observed curvilinear crusts on most of the papules. To our knowledge, dermoscopic appearance of canine scabies in humans has not been described before. We think this special pattern of excoriations is the result of superficially dug tunnels that had been torn leaving vacant curved linear remnants behind, and this may provide a good support for the diagnosis of canine scabies contributing to the spectrum of entodermoscopy.


The influence of personal care and assistive devices on the measurement of disability.
The goal of all long-term care arrangements is to reduce the disabling effects of physical impairments and functional limitations. However, the means with which individuals cope with disability may not be equivalent and these differences may influence self-reports of disability in surveys. This paper examines assistive devices and personal care as factors in the measurement of disability among persons aged 70 and older in the community using the 1994 Survey of Asset and Health Dynamics of the Oldest Old (AHEAD) in the US. The use of assistive technology differs from personal care on a fundamental level. It does not require the ongoing cooperation or coordination of other people and therefore increases the sense of independence with which a disabled individual can meet their long-term care needs. Results indicate that older individuals can expect to spend most of their remaining years in good functional health, but up to two-thirds of disabled years will be spent with unmet ADL needs. Among those who are disabled, those who use only equipment and no personal care report less residual difficulty with mobility than those who use personal assistance (either alone or in combination with equipment) but the use of equipment alone is most effective for those with the least severe limitations.


Radiographic alveolar bone assessment in correlation with primary implant stability: A systematic review and meta-analysis.
The radiographic examination of alveolar bone using 3D radiographic examination is essential in dental implant treatment planning. Our study aimed to systematically review and quantitatively analyze the correlation between alveolar bone parameters, specifically bone density and cortical bone thickness, assessed using cone beam computed tomography (CBCT) and/or multidetector computed tomography (MDCT); and primary implant stability (PIS) determined using implant stability quotient (ISQ), Periotest® value (PTV), and insertion torque value (ITV). This review was registered in the PROSPERO database (registration number CRD42022307245). An electronic literature search was conducted on the PubMed, SCOPUS, and Web of Science databases for papers published until February 2022. The Quality Assessment in Prognostic Studies (QUIPS) tool was used to assess risk of bias. Meta-analyses were conducted to calculate the estimated average correlation coefficient based on a multilevel random-effects model, followed by subgroup analysis. Twenty-six studies were included in this review, consisting of 17 prospective cohort studies, eight retrospective cohort studies, and one nonrandomized controlled trial. A total of 3109 implants placed in 1171 subjects were analyzed. Twenty-three studies were evaluated using meta-analysis. The alveolar bone condition was significantly correlated with ISQ (r = 0.60; p < .001), IT (r = 0.52; p < .001), and PTV (r = -0.42; p < .05). Alveolar bone condition is significantly associated with PIS. Low bone density and thin cortical bone can lead to low PIS; therefore, modification of treatment planning and surgical procedures might be needed to avoid poor osseointegration.


Self-reported patient psychosocial needs in integrated primary health care: A role for social work in interdisciplinary teams.
Despite being identified as significant determinants of health, depression and anxiety continue to be underdiagnosed and undertreated in primary care settings. This study examined the psychosocial health needs of patients at four urban interdisciplinary primary health teams. Quantitative analysis revealed that nearly 80% of patients reported anxiety and/or depression. Self-reported anxiety and depression was correlated with poor social relationships, compromised health status and underdeveloped problem-solving skills. These findings suggest that social workers have a vital role to play within interdisciplinary primary health teams in the amelioration of factors associated with anxiety and depression.


[A case of gastric adenocarcinoma presenting as portal hypertension].
Portal vein thrombus has been detected in patients with liver cirrhosis, pancreatitis, ulcerative colitis, septicemia, myeloproliferative disorder, and neoplasm. The formation of portal tumor thrombus by hepatocellular carcinoma is well recognized, because of its high incidence, and subsequent development of portal hypertension such as rupture of varices, ascites and liver failure indicates the poor prognosis. In gastric cancer, portal hypertension as an initial presentation is extremely rare. Herein we report a case presenting as portal hypertension caused by tumor thrombus without invasion of liver parenchyma. It is presumed to be intraluminal tumor thrombus originating from primary foci of gastric adenocarcinoma. Tumor thrombus in the portal vein is demonstrated on the PET-CT.


A retrospective and prospective study of megaesophagus in the parma wallaby (Macropus parma) at the San Diego Zoo, California, USA.
At the San Diego Zoo (California, USA), 22 cases of megaesophagus were diagnosed in the parma wallaby (Macropus parma), yielding a prevalence of 21.1%. Parma wallabies often have no clinical signs until severe and chronic dilation of the esophagus is present. Clinical signs of advanced disease include weight loss, swelling of the cervical region, regurgitation without reswallowing of ingesta, short flight distance, depression, collapse, dyspnea, and sudden death. Retrospective and prospective studies at the San Diego Zoo and a multi-institutional survey in the United States were used to try to determine the cause of megaesophagus. The retrospective study did not identify an etiology. The prospective study revealed megaesophagus and severely delayed esophageal transit time in eight of eight animals. Myasthenia gravis, lead toxicosis, toxoplasmosis, and thyroid disease were eliminated as possible causes. Of 286 living and dead parma wallabies surveyed at other institutions, three cases of esophageal diverticulum and one case of megaesophagus were reported. The cause of megaesophagus in parma wallabies was not determined.


Use of an endoscope in minimally invasive lesion biopsy and removal within the skull and cranial vault in two dogs and one cat.
CASE DESCRIPTION- 2 dogs and 1 cat underwent endoscopic-assisted intracranial procedures for lesion biopsy (1 dog and 1 cat) and definitive lesion removal (1 dog). CLINICAL FINDINGS- 1 cat was treated for an interhemispheric, pedunculated meningioma with an associated arachnoid cyst. Two dogs underwent endoscopic surgery procedures; 1 dog underwent removal of an intranasal dermoid cyst with extension to the olfactory bulb dura, and the other underwent lesion biopsy for histologic confirmation of suspected intracranial granular cell tumor. TREATMENT AND OUTCOME- Minimally invasive intracranial procedures were achieved by use of an endoscope to aid in lesion biopsy in a dog and a cat with neoplasia and complete lesion removal in 1 dog with a dermoid cyst. No obvious morbidity from the use of the endoscope was observed. Rapid recovery from surgery was seen in all 3 animals, and hospitalization times were a few days. CLINICAL RELEVANCE- In human and veterinary neurosurgery, minimally invasive surgical approaches for diagnosis and treatment are gaining in popularity. Minimally invasive techniques are used to achieve a decrease in surgical time, minimize brain exposure, and decrease postoperative recovery times. Keyhole and minimally invasive approaches require some degree of dexterity and knowledge of where the endoscope is in a 3-dimensional orientation and its relationship to the topography of an anatomic region. Anticipation of complications should allow for potential conversion to an open craniotomy. Use of the endoscope in minimally invasive procedures is associated with a steep learning curve to understand orientation, topography, and normal versus abnormal anatomy.


[The role of nurses in the introduction of home parenteral nutrition (HPN)].
HPN makes it possible for patients, who otherwise must remain hospitalized, to be discharged and contributes to improve their QOL. We report 3 patients for whom HPN was introduced and could either stay out or to be discharged. Both strong will to be discharged and self-confidence acquired after a test stay out led the patients to HPN. It was important to design the contents of instruction, the methods, and the periods according to the comprehension, will and abilities of the patients. Since the HPN equipment weighs over 2 kg, it was hard for patients in a terminal stage and senile patients to carry them. All 3 patients had the cooperation of their families and the nurses to design various additional devices and thus continue the therapy at home. The nurses should participate in the renovation of the transfer equipment in order to improve the QOL of the patients. Moreover, it is important to promote the will of patients though active information and to suggest a management plan suitable to their lifestyles.


Personality disorder: a disease in disguise.
Personality disorders (PDs) can be described as the manifestation of extreme personality traits that interfere with everyday life and contribute to significant suffering, functional limitations, or both. They are common and are frequently encountered in virtually all forms of health care. PDs are associated with an inferior quality of life (QoL), poor health, and premature mortality. The aetiology of PDs is complex and is influenced by genetic and environmental factors. The clinical expression varies between different PD types; the most common and core aspect is related to an inability to build and maintain healthy interpersonal relationships. This aspect has a negative impact on the interaction between health-care professionals and patients with a PD. From being discrete and categorical disease entities in previous classification systems, the current concept of PD, reflected in the newly proposed ICD-11, is a dimensional description based on the severity of the disturbed functioning rather than on the type of clinical presentation. Insight about the characteristics of PDs among medical practitioners is limited, which is partly because persons do not seek health care for their PD, but instead for other medical issues which are obscured by their underlying personality problems. What needs to be emphasized is that PDs affect both the clinical presentation of other medical problems, and the outcome of these, in a negative manner and that the integrated effects of having a PD are a shortened life expectancy. Accordingly, PDs need to be recognized in clinical practice to a greater extent than previously.


Islet Endothelial Cells Induce Glycosylation and Increase Cell-surface Expression of Integrin β1 in β Cells.
The co-culturing of insulinoma and islet-derived endothelial cell (iEC) lines results in the spontaneous formation of free-floating pseudoislets (PIs). We previously showed that iEC-induced PIs display improved insulin expression and secretion in response to glucose stimulation. This improvement was associated with a de novo deposition of extracellular matrix (ECM) proteins by iECs in and around the PIs. Here, iEC-induced PIs were used to study the expression and posttranslational modification of the ECM receptor integrin β1. A wide array of integrin β subunits was detected in βTC3 and NIT-1 insulinomas as well as in primary islets, with integrin β1 mRNA and protein detected in all three cell types. Interestingly, the formation of iEC-induced PIs altered the glycosylation patterns of integrin β1, resulting in a higher molecular weight form of the receptor. This form was found in native pancreas but was completely absent in monolayer β-cells. Fluorescence-activated cell sorting analysis of monolayers and PIs revealed a higher expression of integrin β1 in PIs. Antibody-mediated blocking of integrin β1 led to alterations in β-cell morphology, reduced insulin gene expression, and enhanced glucose secretion under baseline conditions. These results suggest that iEC-induced PI formation may alter integrin β1 expression and posttranslational modification by enhancing glycosylation, thereby providing a more physiological culture system for studying integrin-ECM interactions in β cells.


PPARγ activation reduces ischemia/reperfusion-induced metastasis in a murine model of hepatocellular carcinoma.
Ischemia/reperfusion (I/R) injury during liver resection or transplantation for the treatment of hepatocellular carcinoma (HCC) may increase the risk of metastasis. Peroxisome proliferator-activated receptor-γ (PPARγ) activation has been observed to exert a protective effect against hepatic I/R injury. However, whether PPARγ activation exerts a protective effect against I/R-associated liver metastasis remains unknown. Therefore, the present study aimed to investigate the effects of the PPAR agonist rosiglitazone and the specific PPARγ antagonist GW9662 on tumor metastasis following hepatic I/R. An experimental mouse model of hepatic I/R-induced HCC metastasis was designed in order to determine the effects of I/R on tumor metastasis in the liver. Four groups were established: Sham, control (I/R), rosiglitazone (Ro) and rosiglitazone with GW9662 (Ro + GW) groups. In the latter two groups, the treatments were administered intravenously 1 h prior to the induction of ischemia. Tumor load was measured 12 days after the procedure. Furthermore, tissue analyses were conducted to determine the expression levels of alanine aminotransferase, myeloperoxidase (MPO), matrix metalloproteinase (MMP)-9, vascular cell adhesion molecule (VCAM)-1, nuclear factor (NF)-κB and PPARγ. Rosiglitazone pretreatment appeared to significantly mitigate hepatic I/R injury, as indicated by serological and histological analysis. The levels of VCAM-1, MPO and MMP-9 expression in the Ro group were significantly reduced at 8 h following ischemia compared with those in the control and Ro + GW groups. In addition, rosiglitazone inhibited the I/R-induced activation of NF-κB, and GW9662 attenuated the inhibitory effect. To the best of our knowledge, the present study is the first to report on the expression and the functional roles of PPARγ in I/R-associated metastasis. Short-term treatment of mice with rosiglitazone, a potent PPARγ agonist, confers protective effects against hepatic I/R-associated metastasis. Thus, PPARγ may be a potential therapeutic target for the protection of the liver against I/R-associated metastasis.


Feasibility of Self-administered Neuromodulation for Neurogenic Bladder in Spinal Cord Injury.
To determine if self-administered transcutaneous tibial nerve stimulation (TTNS) is a feasible treatment option for neurogenic bladder among people with spinal cord injury (SCI) who utilize intermittent catheterization for bladder management. Four-week observational trial in chronic SCI subjects performing intermittent catheterization with incontinence episodes using TTNS at home daily for 30 minutes. Those using anticholinergic bladder medications were given a weaning schedule to begin at week 2. Primary outcomes were compliance and satisfaction. Secondary outcomes included change in bladder medications, efficacy based on bladder diary, adverse events, and incontinence quality of life (I-QoL) survey. All 16 subjects who started the study completed the 4-week trial rating TTNS with high satisfaction and easy to use, without discomfort. Twelve of 14 patients (86%) using anticholinergic bladder medications reduced their dosage and maintained similar frequency and volumes of bladder catheterization and incontinence episodes. Bladder medication reduced by approximately 3.2 mg weekly (95% confidence interval, -5.9 to -0.4) and anticholinergic side effects of dry mouth and drowsiness decreased more than 1 level of severity from baseline (P=0.027, P=0.015, respectively). At 4 weeks, total I-QoL score improved by an average of 3.2 points compared to baseline in all domains. This pilot trial suggests TTNS is feasible to be performed at home in people with chronic SCI. Participants were able to reduce anticholinergic medication dosage and anticholinergic side effects while maintaining continence, subsequently improving QoL scores. These results advocate for further randomized, controlled trials with longer duration and urodynamic evaluation to assess long-term efficacy.


Creating your own line - reflections of early-career scientists.
The changing landscape of academia can be difficult to navigate for anyone at any point throughout their career. One thing is certainly clear - effective mentorship is key to ensuring success, fueling scientific curiosity, and creating a sense of community. This manuscript is a collection of personal reflections and stories, offering advice directed to aspiring and junior graduate trainees - written by PhD students, Post-Doctoral researchers, early-stage Assistant Professors, and life-long educators. The objective of this article is to inform, empower, and inspire the next generation of physiologists.


Comparing Outcomes of HIV-Infected Chinese Adults on Antiretroviral Therapy by CD4 Count at Treatment Initiation: A Nationwide Retrospective Observational Cohort Study, 2012-2014.
The chief concerns for antiretroviral therapy (ART) programs considering removal of CD4+ cell count thresholds for treatment are the increased incidence of ART-related adverse events. A nationwide observational cohort study was conducted among patients who initiated ART in 2012. We divided the eligible patients into three groups: an early ART group with a baseline CD4+ cell count of 500 cells/μL or greater, a standard ART group with a baseline CD4+ cell count between 350 and 499 cells/μL, and a late ART group with a baseline CD4+ cell count between 200 and 349 cells/μL. These patients were followed up to December 31, 2014 and observed for three outcomes: virological failure, treatment nonretention, or time to death. Patients who met the eligibility criteria numbered at 26,752. Out of all study participants, 20,827 participants were in late ART group, 4336 were in standard ART group, and 1589 were in early ART group. Patients in late ART group were more likely to become virally suppressed 12 and 24 months after treatment initiation than patients in early ART group [adjusted odds ratio (aOR) 0.81; 95% CI, 0.69-0.95 and aOR, 0.78; 95% CI, 0.65-0.94]. Treatment nonretention was also less likely to occur among patients in late ART group than early ART group 12 months after treatment initiation (aOR, 0.85; 95% CI, 0.75-0.96). Compared with early ART group, neither standard ART group nor late ART group had a statistically significant difference in the time-to-death analysis. Late ART initiates were more likely to be virally suppressed and retained on treatment than early ART initiates. The importance of treatment retention and adherence should be emphasized for high CD4+ patients newly initiated to ART therapy through education and counseling programs.


Coregulation of extracellular vesicle production and fluconazole susceptibility in Cryptococcus neoformans.
Resistance to fluconazole (FLC), the most widely used antifungal drug, is typically achieved by altering the azole drug target and/or drug efflux pumps. Recent reports have suggested a link between vesicular trafficking and antifungal resistance. Here, we identified novel Cryptococcus neoformans regulators of extracellular vesicle (EV) biogenesis that impact FLC resistance. In particular, the transcription factor Hap2 does not affect the expression of the drug target or efflux pumps, yet it impacts the cellular sterol profile. Subinhibitory FLC concentrations also downregulate EV production. Moreover, in vitro spontaneous FLC-resistant colonies showed altered EV production, and the acquisition of FLC resistance was associated with decreased EV production in clinical isolates. Finally, the reversion of FLC resistance was associated with increased EV production. These data suggest a model in which fungal cells can regulate EV production in place of regulating the drug target gene expression as a first line of defense against antifungal assault in this fungal pathogen. IMPORTANCE Extracellular vesicles (EVs) are membrane-enveloped particles that are released by cells into the extracellular space. Fungal EVs can mediate community interactions and biofilm formation, but their functions remain poorly understood. Here, we report the identification of the first regulators of EV production in the major fungal pathogen Cryptococcus neoformans. Surprisingly, we uncover a novel role of EVs in modulating antifungal drug resistance. Disruption of EV production was associated with altered lipid composition and changes in fluconazole susceptibility. Spontaneous azole-resistant mutants were deficient in EV production, while loss of resistance restored initial EV production levels. These findings were recapitulated in C. neoformans clinical isolates, indicating that azole resistance and EV production are coregulated in diverse strains. Our study reveals a new mechanism of drug resistance in which cells adapt to azole stress by modulating EV production.


Cutaneous leishmaniasis in Basrah Villages, South Iraq.
CL in Iraq is caused by both Leishmania major and Leishmania tropica. Marshes Villages of Basrah province south Iraq are regarded as a rural area. A total of 35 cutaneous leishmaniasis cases 12 (34.28%) females and 23(65.71%) males were clinically registered from April 2013 to March 2014 in Health Care Center of Basrah Marshes Villages, South of Iraq are reported and investigated. All patients were parasitologically confirmed by stained smears and culture, the main clinical features were ulcerations. Number of cutaneous lesions per patients ranged from 1 to 5 with different lesions' size from 3x3 mm to 25x25 mm in diameter. Amastigotes form were detected in all cases 35 (100%), while promastigotes from were found in culture sample of 29 (82.8%) cases. The results were analyzed and evaluated. Cutaneous leishmaniasis in Basrah marshes villages may differ from other regions because of the difference of the Leishmania strains, people life style, behaviors and difference in vectors and reservoir hosts.


Ligand-based electronic effects on the electrocatalytic hydrogen production by thiosemicarbazone nickel complexes.
This work reports on the synthesis and characterization of a series of mononuclear thiosemicarbazone nickel complexes that display significant catalytic activity for hydrogen production in DMF using trifluoroacetic acid as the proton source. The ligand framework was chemically modified by varying the electron-donating abilities of the para substituents on the phenyl rings, which was expected to impact the capability of the resulting complexes to reduce protons into hydrogen. Over the four nickel complexes that were obtained, the one with the thiomethyl substituent, NiSCH3, was found to overtake the catalytic performances of the parent complex NiOCH3 featuring lower overpotential values and similar maximum turnover frequencies. These results confirm the electronic effects of the ligand on HER when using thiosemicarbazone nickel complexes and support that chemical modifications can tune the catalytic performances of such systems.


Diffusion equation modeling for sound energy flow analysis in multi domain structures.
This study investigates reliable models and methods to be applied in sound field analysis of multi-domain structures. The case structures are two monuments, namely, Süleymaniye Mosque and Hagia Sophia in İstanbul. These are both multi-volume spaces with many smaller sub-volumes coupled to each other by coupling apertures in form of arches. A key concern of the study is to examine energy flow decays and understand the mechanism of multi-slope sound energy decays. The methodology involves diffusion equation model (DEM) application in a finite-element scheme for sound energy flow analysis. Energy flow decays, energy flow dips, and spatial flow vectors are examined for single versus multi-domain DEM solutions. It is concluded that specification of different domains with individual diffusion coefficients is a critical setting such that, if not assigned correctly, may mislead the results. The energy flow vector analysis has enabled us to comprehend the architectural features in relation to such energy flow decay dip occurrence. The computational efficiency of DEM is also discussed. The DEM application in this study has proved to be a powerful and practical method in room acoustics applications, specifically for multi-rate decay investigations.


The toll-like receptor 3 ligand, poly(I:C), improves immunosuppressive function and therapeutic effect of mesenchymal stem cells on sepsis via inhibiting MiR-143.
Mesenchymal stem cells (MSCs) are attractive candidates for clinical therapeutic applications. Recent studies indicate MSCs express active Toll-like receptors (TLRs), but their effect on MSCs and the underlying mechanisms remain unclear. In this study, we found that, after treating human umbilical cord MSCs with various TLR ligands, only TLR3 ligand, poly(I:C), could significantly increase the expression of cyclooxygenase-2 (COX-2). Furthermore, poly(I:C) could enhance MSCs' anti-inflammatory effect on macrophages. Next, we focused on the regulatory roles of microRNAs (miRNAs) in the process of poly(I:C) activating MSCs. Our experiments indicated that miR-143 expression was significantly decreased in MSCs with poly(I:C) treatment, and the expression level of miR-143 could regulate the effect of poly(I:C) on MSCs' immunosuppressive function. Subsequent results showed that the reporter genes with putative miR-143 binding sites from the transforming growth factor-β-activated kinase-1 (TAK1) and COX-2 3' untranslated regions were downregulated in the presence of miR-143. In addition, mRNA and protein expression of TAK1 and COX-2 in MSCs was also downregulated with miR-143 overexpression, suggesting that TAK1 and COX-2 are target genes of miR-143 in MSCs. Consistent with miR-143 overexpression, TAK1 interference also attenuated MSCs' immunosuppressive function enhanced by poly(I:C). Additionally, it was shown that TLR3-activated MSCs could improve survival in cecal ligation and puncture (CLP)-induced sepsis, while miR-143 overexpression reduced the effectiveness of this therapy. These results proved that poly(I:C) improved the immunosuppressive abilities of MSCs, revealed the regulatory role of miRNAs in the process, and may provide an opportunity for potential novel therapies for sepsis.


Multiple myeloma in the elderly: when to treat, when to go to transplant.
Until recently, standard treatment of multiple myeloma (MM) in elderly patients who were not candidates for autologous stem cell transplantation was with the combination of melphalan plus prednisone (MP). Novel agents (thalidomide, lenalidomide, bortezomib) are dramatically changing frontline therapy of MM. Randomized studies have shown the superiority of adding one novel agent to MP, either thalidomide (MPT) or bortezomib (MPV). The combination of lenalidomide with low doses of dexamethasone is another attractive alternative. Recent results show that maintenance therapy with low-dose lenalidomide may prolong progression-free survival. The objective of these improved treatment regimens should be to achieve complete response, as in younger patients. However, toxicity is a significant concern, and doses of thalidomide and of myelotoxic agents should be reduced in patients who are older than 75 years or who have poor performance status. Weekly bortezomib appears to induce severe peripheral neuropathy less frequently than the same agent administered twice weekly. Autologous stem cell transplantation is feasible in selected fit patients over 65 years of age, and its results are improved by the addition of novel agents before and after high-dose therapy. However, considering the progress in non-intensive therapy, autologous transplantation should not currently be offered to elderly patients outside of a clinical trial.


Pseudomonas aeruginosa recognizes carbohydrate chains containing type 1 (Gal beta 1-3GlcNAc) or type 2 (Gal beta 1-4GlcNAc) disaccharide units.
The adhesion of Pseudomonas aeruginosa to type 1 (Gal beta 1-3GlcNAc) and type 2 (Gal beta 1-4GlcNAc) disaccharide determinants was studied in a microtiter adhesion assay and a thin-layer chromatography bacterial overlay assay. The oligosaccharides were prepared from human breast milk and human urine and were conjugated to hexadecylaniline to form neoglycolipids that were used in were used in the assays. Both the mucoid and the nonmucoid strains that were studied recognized the disaccharide determinants Sialylation of the oligosaccharides did not suppress binding in the thin-layer chromatography assay, but alpha 2-6-linked sialic acid blocked binding in the microtiter assay. The use of bovine serum albumin instead of gelatin as a blocking agent against nonspecific binding completely suppressed binding in the thin-layer chromatography assay. Isogenic nonpiliated mutants of nonmucoid strains constructed by interrupting the pilin gene retained their adhesive capacity for the disaccharide units, indicating that binding to the disaccharides was mediated by a nonpilus adhesin(s). Furthermore, two monoclonal antibodies that recognize the type 2 disaccharide determinant (Gal beta 1-4GlcNAc) partially inhibited adhesion of a pair of piliated and nonpiliated isogenic strains to mucin. This study suggests that P. aeruginosa utilizes a nonpilus adhesin(s) to bind to disaccharide units commonly found in mucins, in addition to pili and alginate, two previously described adhesins.


The expression of cannabinoid type 1 receptor and 2-arachidonoyl glycerol synthesizing/degrading enzymes is altered in basal ganglia during the active phase of levodopa-induced dyskinesia.
Management of levodopa-induced dyskinesias (LID) is one of the main challenges in the treatment of Parkinson's disease patients. Mechanisms involved in the appearance of these involuntary movements are not well known but modifications in the activity of different neurotransmitter pathways seem to play an important role. The objective of this study was to determine differences in the expression levels of the endocannabinoid system (ECS) elements that would support a role in LID. The basal ganglia nuclei, putamen, external segment of the globus pallidus (GPe), internal segment of the globus pallidus (GPi), subthalamic nucleus (STN) and substantia nigra (SN) were dissected out from cryostat sections obtained from two groups of parkinsonian monkeys treated with levodopa to induce dyskinesias. One group of dyskinetic animals was sacrificed under the effect of levodopa, during the active phase of LID, and the other group 24 h after the last levodopa dose (OFF levodopa). Biochemical analysis by real-time PCR for ECS elements was performed. CB1 receptor expression was upregulated in the putamen, GPe and STN during the active phase of dyskinesia and downregulated in the same nuclei and in the SN when dyskinetic animals were OFF levodopa. Changes in the 2-arachidonoyl glycerol (2-AG) synthesizing/degrading enzymes affecting the pallidal-subthalamic projections in dyskinetic animals OFF levodopa would suggest that 2-AG may play a role in LID. Anandamide (AEA) synthesizing/degrading enzymes were altered specifically in the GPe of untreated parkinsonian monkeys, suggesting that increased AEA levels may be a compensatory mechanism. These results indicate that the expression of the ECS elements is influenced by alterations in dopaminergic neurotransmission. On one hand, changes in CB1 receptor expression and in the 2-AG synthesizing/degrading enzymes suggest that they could be a therapeutic target for the active phase of LID. On the other hand, AEA metabolism could provide a non-dopaminergic target for symptomatic relief. However, further research is needed to unravel the mechanism of action of the ECS and how they could be modulated for a therapeutic purpose.


Photonic approach for multiple-frequency-component measurement using spectrally sliced incoherent source.
A photonic approach to the instantaneous measurement of multiple frequency components using a spectrally sliced incoherent source (SSIS) is proposed. In the proposed system, a broadband incoherent source is spectrally sliced using an etalon to generate an SSIS. Each channel of the SSIS is externally modulated by a microwave signal containing multiple frequency components. The modulated SSIS is then sent to a second etalon. Thanks to the difference between the free spectral ranges of the two etalons, multiple frequency components are simultaneously estimated from the power distribution at the output channels of the second etalon. Compared with the use of a laser source array, the use of an SSIS provides a simpler way to perform multiple-frequency-component measurement.


[Corneal complications of traditional local ocular treatment in the Democratic Republic of the Congo].
The purpose of this retrospective study was to determine the relationship between the use of local traditional eye medicine and the occurrence of corneal ulcers. The study population included 53 patients who consulted from January 1998 to October 1999 at two hospitals in Kinshasa, Democratic Republic of the Congo, after visiting a traditional healer. Clinical examination of the eye was performed in all cases and bacteriological tests in most. Local traditional eye medicine is used in both urban and rural areas. Factors associated with the use of local traditional eye medicine include level of education and social class. A cause-and-effect relationship was found between the use of local traditional eye medicines and development or worsening of corneal ulcers. Peripheral corneal ulcers were the most common. Corneal perforation was more frequent in association with peripheral ulcers. Use of traditional eye medicine often leads to corneal ulcers with perforation and destruction of the eye in most cases. For this reason these practice must be curtailed. However further study is needed to identify the active agents in plants used by traditional healers as well as to determine their efficacy and toxicity for the eye.


TGFβ2 Induces the Soluble Isoform of CTLA-4 - Implications for CTLA-4 Based Checkpoint Inhibitor Antibodies in Malignant Melanoma.
Malignant melanoma is an aggressive form of cancer, which can be treated with anti-CTLA-4 and anti-PD-1 checkpoint inhibitor antibodies but while anti-CTLA-4 antibodies have clear benefits for some patients with melanoma, productive responses are difficult to predict and often associated with serious immune related adverse events. Antibodies specific to CTLA-4 bind two major isoforms of CTLA-4 in humans, the receptor isoform and a second naturally secretable, soluble isoform - sCTLA-4. The primary aim here was to examine the effect of selectively blocking the function of sCTLA-4 on in vitro immune responses from volunteer healthy or melanoma patient PBMC samples. Addition of recombinant sCTLA-4 to healthy PBMC samples demonstrated sCTLA-4 to have immunosuppressive capacity comparable to recombinant CTLA4-Ig, partially reversible upon antibody blockade. Further, we identified a mechanistic relationship where melanoma patient TGFβ2 serum levels correlated with sCTLA-4 levels and provided the basis for a novel protocol to enhance sCTLA-4 production and secretion by T cells with TGFβ2. Finally, a comparison of selective antibody blockade of sCTLA-4 demonstrated that both healthy and melanoma patient effector cytokine responses can be significantly increased. Overall, the data support the notion that sCTLA-4 is a contributory factor in cancer immune evasion.


Whole-body MR imaging: evaluation of patients for metastases.
To compare the results of whole-body magnetic resonance (MR) imaging with staging based on computed tomographic (CT), dedicated MR imaging, and nuclear scintigraphic results as standard of reference. Fifty-one patients with known malignant tumors were included in the study. Patients were placed on a rolling table platform capable of moving the patient rapidly through the isocenter of the magnet bore. The thorax and the abdomen were imaged by using fast breath-hold T2-weighted sequences in the transverse plane. After intravenous administration of a paramagnetic contrast agent, three-dimensional gradient-echo data sets were collected in five stations and covered the body from the skull to the knees. Location and size of cerebral, pulmonary, hepatic, and osseous metastases were documented by two experienced radiologists. Whole-body MR imaging findings were compared with results obtained at skeletal scintigraphy, CT, and dedicated MR imaging. The mean examination time for whole-body MR imaging was 14.5 minutes. All cerebral, pulmonary, and hepatic metastases greater than 6 mm in diameter could be identified with whole-body MR imaging. Small pulmonary metastases were missed with MR imaging, which did not change therapeutic strategies, but MR imaging depicted a single hepatic metastasis that was missed with CT. Skeletal scintigraphy depicted osseous metastases in 21 patients, whereas whole-body MR imaging revealed osseous metastases in 24 patients. The additional osseous metastases seen with MR imaging were confirmed at follow-up examinations but did not result in a change in therapy. Whole-body MR imaging performed on a per-patient basis revealed sensitivity and specificity values of 100%. Whole-body MR imaging for the evaluation of metastases compared well with the reference techniques for cerebral, pulmonary, and hepatic lesions. Whole-body MR imaging was more sensitive in the detection of hepatic and osseous metastases than were the reference techniques.


Growth hormone does not attenuate the inhibitory effects of sepsis on wound healing.
Chronic abdominal sepsis is associated with impaired tissue repair. Treatment of burn patients with growth hormone results in improved healing of skin graft donor sites. The goal of this study was to determine whether administration of growth hormone could attenuate the inhibitory effects of sepsis on cutaneous wound healing. Four groups of male Sprague Dawley rats were studied: control, control + growth hormone, sepsis, and sepsis + growth hormone. Sepsis was caused by implantation of a bacterial focus in the peritoneal cavity. Control animals underwent sham laparotomy, and polyvinyl alcohol sponge implants were placed in subdermal pockets in all animals. Saline or growth hormone (400 microg) was injected subcutaneously every 12 hours. On day 5, the incisional wounds and polyvinyl alcohol sponge implants were harvested. The breaking strength of abdominal incisions was measured. Granulation tissue penetration and quality were determined by scoring polyvinyl alcohol sponge implant histology from 1 to 4 in a blinded fashion. Collagen deposition in polyvinyl alcohol sponge implants was quantitated by hydroxyproline assay. Septic mortality was not altered by growth hormone administration. Septic animals showed a reduction in food consumption for 2 days after surgery (p < 0.05 vs. controls), which was not affected by growth hormone administration. The breaking strength of incisional wounds and hydroxyproline content of polyvinyl alcohol sponge implants was reduced in septic rats (p < 0.001 vs. controls) but administration of growth hormone for 5 days did not improve breaking strength or collagen deposition in either group. We conclude that the administration of growth hormone for 5 days did not improve collagen deposition or breaking strength in cutaneous wounds from control or septic animals. The results suggest that growth hormone treatment is unlikely to improve tissue repair in sepsis-induced catabolic illness.


The state and civil society in disaster response: post-tsunami experiences in Tamil Nadu.
This paper, based on the report "The State and Civil Society in Disaster Response: An Analysis of the Tamil Nadu Tsunami Experience," (Srinivasan, Nagaraj, & Venkatesh, 2005) is essentially an empirical analysis of state and civil society responses in Tamil Nadu (India) to the tsunami of December 26, 2004. It examines interventions by state and non-state agencies, as well as people's experiences in the relief and rehabilitation phases to identify factors influencing both positive and negative outcomes of the tsunami response. Issues related to vulnerability and exclusion, equity, transparency and accountability in different sectors of disaster intervention are explored to highlight themes revolving around reach and efficacy of relief and recovery processes. These analyses bring out some interesting lessons with regard to the importance of institutional autonomy, non-politicized decision-making, and synergetic state-civil society interfaces in fostering inclusive, transparent and accountable rehabilitation processes. The roles played by institutional responsiveness and flexibility in shaping an effective disaster response also emerge very clearly from this study of the Tamil Nadu experience. Another crucial finding points to the need for detailed, reliable and disaggregated geo-demographic and socioeconomic records as a resource base for informing relief and rehabilitation interventions. The study draws extensively from the experiences and insights of people affected by, and involved in tsunami response, and from secondary knowledge resources available on the disaster.


Depression and anxiety in child and adolescents with follow-up celiac disease and in their families.
Earlier research has indicated a positive association between Celiac disease and some mental disorders in both adults and children. The aim of this study was to explore the diet compliance and depression and anxiety levels of pediatric celiac children and their families after a gluten-free diet. A total of 30 celiac pediatric patients (17 children [57%] and 13 adolescents [43%]) were enrolled in the study, and 20 healthy controls (11 children [55%] and 9 adolescents [45%]) were studied as controls. Depression was assessed with the Children's Depression Inventory (CDI) form, and anxiety was assessed with the Screen for Child Anxiety Related Disorders (SCARED) form. Diet compliance was measured with a diet compliance form, and the families were asked to complete the Beck Depression Measurement (BDI) form for depression and the State-Trait Anxiety Inventory I-II (STAI-I and STAI-II) forms for anxiety. There was no significant difference in depression and anxiety between pediatric celiac patients consuming a gluten-free diet and the healthy control group. We observed no difference in depression and anxiety in the Celiac CD group patients. Diet compliance was 73.3% in the study group. The depression and anxiety levels of pediatric celiac patients and their parents did not differ from those in the healthy group.


Edaravone-Encapsulated Agonistic Micelles Rescue Ischemic Brain Tissue by Tuning Blood-Brain Barrier Permeability.
Thrombolysis has been a standard treatment for ischemic stroke. However, only 2-7% patients benefit from it because the thrombolytic agent has to be injected within 4.5 h after the onset of symptoms to avoid the increasing risk of intracerebral hemorrhage. As the only clinically approved neuroprotective drug, edaravone (EDV) rescues ischemic brain tissues by eradicating over-produced reactive oxygen species (ROS) without the limitation of therapeutic time-window. However, EDV's short circulation half-life and inadequate cerebral uptake attenuate its therapeutic efficacy. Here we developed an EDV-encapsulated agonistic micelle (EDV-AM) to specifically deliver EDV into brain ischemia by actively tuning blood-brain barrier (BBB) permeability. The EDV-AM actively up-regulated endothelial monolayer permeability in vitro. HPLC studies showed that EDV-AM delivered more EDV into brain ischemia than free EDV after intravenous injection. Magnetic resonance imaging also demonstrated that EDV-AM more rapidly salvaged ischemic tissue than free EDV. Diffusion tensor imaging indicated the highest efficiency of EDV-AM in accelerating axonal remodeling in the ipsilesional white matter and improving functional behaviors of ischemic stroke models. The agonistic micelle holds promise to improve the therapeutic efficiency of ischemic stroke patients who miss the thrombolytic treatment.


[Effect of pharmacological agents on the development of heat stroke].
The effect of drugs on the development of excitation, thermal shock and animal survival was studied. The alpha-adrenoblockers aminazin and phentolamine, the sympatholytic dopegit, and antidepressants sapilent, teperin and nuredal prolonged the time of the onset of excitation and thermal shock, and prevented the animals' death in 50-87% of experiments. It is assumed that the sympathetic nervous system plays the leading role in the development of thermal shock. Aminazin, dopegit, sapilent, teperin and nuredal can be recommended as protectors on body exposure to high temperatures.


Biochemical-markers for the diagnosis of bone metastasis: a clinical review.
The preferential metastasis of cancer cells to skeleton not only disrupts the process of bone remodeling and influences the therapeutic decision, but also results in severe complications. Although the current diagnosis of bone metastases (BM) relies on bone imaging techniques, they are not sensitive enough for early detection as well as they are invasive and expensive to use. Since factors derived from bone metabolism are potentially useful to diagnose metastatic bone disease in cancer patients, a number of clinical trials have been carried out on this area. Results suggest that higher levels of bone biomarkers are associated with an increased risk of BM. As a result, biochemical-markers are showing prospects in early diagnosis of BM. This review summarizes the available evidence on the clinical use of biochemical-markers in the diagnosis of various cancers with high incidence of BM including breast, prostate and lung.


[Natural products with antimycotic activity].
In the past few decades, a worldwide increase in the incidence of fungal infections has been observed and the resistance of some species of fungus to different fungicidals used in medical practice has also risen. This has led to the search for new antimycotics, particularly those obtained from natural sources such as plants, insects, and land and marine microorganisms. In these natural sources, a series of molecules with antifungal activity against different species of fungus of great clinical importance for humans has been found, and these substances have become an alternative for the development and formulation of new antifungals with fewer side effects, a greater spectrum of action and lower cost than those in current use. In this article, we review the main sources of molecules with antimycotic activity obtained from natural sources.


Insights Regarding the Article "Exploring Transthyretin Amyloid Cardiomyopathy: A Comprehensive Review of the Disease and Upcoming Treatments".
Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly important but under-recognized cause of heart failure in persons over 60 years of age. Transthyretin amyloid cardiomyopathy (ATTR-CM) occurs when the disease affects the heart with or without the involvement of a more extensive systemic disorder. Both ATTRwt and less frequently hATTR are possibilities. Advances in diagnostics have identified specific populations in whom ATTR-CM is clinically important. The recent emergence of effective therapies that slow disease progression and improve clinical outcomes promises to render ATTR-CM a treatable disease. For such therapies to be most effective, early identification of affected individuals is critical. Treatments have been limited to supportive care, with no guideline-recommended treatment. In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. This commentary aims to afford providers the tools required to facilitate earlier diagnosis of ATTR-CM and delineate management strategies.


Mitochondrial fusion proteins and human diseases.
Mitochondria are highly dynamic, complex organelles that continuously alter their shape, ranging between two opposite processes, fission and fusion, in response to several stimuli and the metabolic demands of the cell. Alterations in mitochondrial dynamics due to mutations in proteins involved in the fusion-fission machinery represent an important pathogenic mechanism of human diseases. The most relevant proteins involved in the mitochondrial fusion process are three GTPase dynamin-like proteins: mitofusin 1 (MFN1) and 2 (MFN2), located in the outer mitochondrial membrane, and optic atrophy protein 1 (OPA1), in the inner membrane. An expanding number of degenerative disorders are associated with mutations in the genes encoding MFN2 and OPA1, including Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy. While these disorders can still be considered rare, defective mitochondrial dynamics seem to play a significant role in the molecular and cellular pathogenesis of more common neurodegenerative diseases, for example, Alzheimer's and Parkinson's diseases. This review provides an overview of the basic molecular mechanisms involved in mitochondrial fusion and focuses on the alteration in mitochondrial DNA amount resulting from impairment of mitochondrial dynamics. We also review the literature describing the main disorders associated with the disruption of mitochondrial fusion.


Competitive sports participation in high school and subsequent substance use in young adulthood: Assessing differences based on level of contact.
The objective of this analysis is to examine how participation in different types of competitive sports (based on level of contact) during high school is associated with substance use 1 to 4 years after the 12th grade. The analysis uses nationally representative samples of 12th graders from the Monitoring the Future Study who were followed 1 to 4 years after the 12th grade. The longitudinal sample consisted of 970 12th graders from six recent cohorts (2006-2011). The analyses found that respondents who participated in at least one competitive sport during the 12th grade had greater odds of binge drinking during the past two weeks (AOR = 2.04; 95% CI = 1.43, 2.90) 1 to 4 years after the 12th grade, when compared to their peers who did not participate in sports during their 12th grade year. Moreover, respondents who participated in high-contact sports (i.e., football, ice hockey, lacrosse, and wrestling) had greater odds of binge drinking (AOR = 1.80; 95% CI = 1.18, 2.72) and engaging in marijuana use during the past 30 days (AOR = 1.81; 95% CI = 1.12, 2.93) 1 to 4 years after the 12th grade when compared to their peers who did not participate in these types of sports during their 12th grade year. Accordingly, the findings indicate important distinctions in sport participation experiences on long-term substance use risk that can help inform potential interventions among young athletes.


Adverse Childhood Experiences and BMI: Lifecourse Associations in a Black-White U.S. Women Cohort.
Although adverse childhood experiences (ACEs) have been positively associated with adiposity, few studies have examined long-term race-specific ACE-BMI relationships. A Black and White all-women cohort (N=611; 48.6% Black) was followed between 1987 and 1997 from childhood (ages 9-10 years) through adolescence (ages 19-20 years) to midlife (ages 36-43 years, between 2015 and 2019). In these 2020-2022 analyses, the interaction between race and individual ACE exposures (physical abuse, sexual abuse, household substance abuse, multiple ACEs) on continuous BMI at ages 19-20 years and midlife was evaluated individually through multivariable linear regression models. Stratification by race followed as warranted at α=0.15. Race only modified ACE-BMI associations for sexual abuse. Among Black women, sexual abuse was significantly associated with BMI (Badjusted=3.24, 95% CI=0.92, 5.57) at ages 19-20 years and marginally associated at midlife (Badjusted=2.37, 95% CI= -0.62, 5.35); among White women, corresponding associations were null. Overall, having ≥2 ACEs was significantly associated with adolescent BMI (Badjusted=1.47, 95% CI=0.13, 2.80) and was marginally associated at midlife (Badjusted=1.45, 95% CI= -0.31, 3.22). This was similarly observed for physical abuse (adolescent BMI: Badjusted=1.23, 95% CI= -0.08, 2.54; midlife BMI: Badjusted=1.03, 95% CI= -0.71, 2.78), but not for substance abuse. Direct exposure to certain severe ACEs is associated with increased BMI among Black and White women. It is important to consider race, ACE type, and life stage to gain a more sophisticated understanding of ACE-BMI relationships. This knowledge can help strengthen intervention, prevention, and policy efforts aiming to mitigate the impacts of social adversities and trauma on persistent cardiometabolic health disparities over the lifecourse.


From sarcomeres to whole muscles.
The series connection of sarcomeres in a muscle raises the possibility of instabilities due to some sarcomeres being capable of greater isometric tension than others, due to non-uniform activation, cross-sectional area or sarcomere length. Such instabilities are heavily damped by the force-velocity curve and stabilized by passive tension. The variation of active tension with sarcomere length may act to stabilize or destabilize the situation. Such instabilities can affect tension in a complex manner, causing both increases and decreases in different situations. Some examples of situations where sarcomere nonuniformities have been observed or inferred are given, and their mode of action explained.


Study of attentional deficits (unilateral spatial neglect) in Moroccan adolescents attending school-Rabat Sale Kenitra region.
Attention is an essential part of cognitive functions for all learning in the school environment. The screening of attentional deficits constitutes an important field of research, given its relationship with other cognitive functions and the neurocognitive profiling of Moroccan adolescents in school. A study was conducted over 3 months. A comparative and predictive method is used, the Bells test, to assess the state of neglect of these students, as well as the detection of attention deficit. Two hundred and fifty students participated, including 152 girls [60.4%] and 98 boys [39.6%], the average age is 16.77 ± 1.23 years, range: 14-21, divided into three school levels: Common core (TC) 27.6%, 1st-year baccalaureate 50.8%, and 2nd-year baccalaureate 21.6%. This study found that 18.4% of the students had attentional deficits and 4% had a unilateral spatial neglect pattern in young adolescents in school. The Bells Test is a useful screening tool to detect these attentional deficits. This implies that attentional disorders negatively influence the academic and motor performance of the subjects. This implies that attentional disorders negatively influence the academic and motor performance of the subjects and, therefore, increase the percentage of school failure.


In vivo imaging of acute cardiac rejection in human patients using (99m)technetium labeled annexin V.
Annexin V binds phosphatidylserine moieties on apoptotic cells. This study reports the initial experience at Stanford University Medical Center with 99mTc-labeled annexin V imaging as a noninvasive measure of apoptosis in acute cardiac rejection. Ten cardiac transplant patients had 99mTc Annexin V imaging and endomyocardial biopsy (EMB) performed within 24 h. No complications related to 99mTc annexin V administration occurred. Eight patients had ISHLT grade of acute rejection of 1A or less. Five patients had two or more areas of uptake noted in the right ventricle on imaging studies. Two of these patients had positive biopsies: one patient had grade 2 rejection with two focal uptake areas and another had grade 3A rejection with three foci. An additional five patients had either one or zero hot spot areas and corresponding negative EMBs. 99mTc-annexin V appears to be well tolerated and may identify patients with acute cardiac rejection.


Hour-glass behavior of the circadian clock controlling eclosion of the silkmoth Antheraea pernyi.
The emergence of the Pernyi silkmoth from the pupal exuviae is dictated by a brain-centered, photosensitive clock. In continuous darkness the clock displays a persistent free-running rhythm. In photoperiod regimens the interaction of the clock with the daily lightdark cycle produces a characteristic time of eclosion. But, in the majority of regimens (from 23L:1D to 4L:20D), the eclosion clock undergoes a discontinuous "hourglass" behavior. Thus, during each daily cycle, the onset of darkness initiates a free-running cycle of the clock. The next "lights-on" interrupts this cycle and the clock comes to a stop late in the photophase. The moment when the Pernyi clock stops signals the release of an eclosion-stimulating hormone and is demonstrated to be a function of the time when the free-running cycle is interrupted by lights-on. Moreover, the width (duration) of the eclosion peak in a photoperiod is shown to be dependent upon the length of the dark phase, and, consequently, upon the amount of the free-running cycle that is completed. This relationship demonstrates that the free-running cycle may be divided into two parts. The attainment of maximal accuracy (and thus the narrowest eclosion peak) is dependent upon the completion of only the first 2 hr of the free-running cycle. The completion of succeeding portions of the cycle, while having an effect upon the time of eclosion, no longer affects the accuracy of the clock. A mechanistic model of the eclosion clock is presented.


ACTH 1-24 inhibits proliferation of adrenocortical tumors in vivo.
Although several lines of evidence suggest that the overall effects of the ACTH receptor, melanocortin 2 receptor (MC2-R), mediated signal transduction on adrenocortical growth and tumorigenesis are anti-proliferative, activation of MC2-R induces mitogens like jun, fos, and myc and activates the MAPK pathway. In vivo, potential effects of endogenous ACTH on adrenal tumori-genesis can not be separated from effects of other POMC derived peptides. Murine adrenocortical tumor cells that lack MC2-R expression (Y6(pcDNA)) and Y6 cells stablely transfected with MC2-R (Y6(MC2-R)) were generated. Presence of functional MC2-R was demonstrated by RT-PCR and Western blot using an antibody for phosphorylated CREB. As a syngenic tumor model, LaHeF1/J mice simultaneously received 10(7) Y6(MC2-R) and Y6(pcDNA) subcutaneously, giving rise to MC2-R positive and negative tumors within the same animal. Animals were treated for 3 weeks in groups of 12 according to the following schedule: group A, control animals receiving saline injection; group B, animals receiving 5.7 ng/injection of a slow release formula of ACTH 1-24 administered i.p. three times a week (aiming at a low physiologic dose); and group C, animals receiving 57 ng/injection of ACTH 1-24 (high physiological dose). Twenty days of ACTH 1-24 treatment did not significantly affect corticosterone levels, endogenous ACTH levels or adrenal and thymus weight compared with saline injection. However, ACTH 1-24 treatment of group B and C mice significantly reduced tumor weight in MC2-R positive tumors in a dose dependent manner (P = 0.03), while no significant difference in tumor mass was observed in MC2-R negative tumors. PCNA and TUNEL staining, together with morphological characterization, demonstrated that these in vivo effects were due to reduced proliferation, while apoptosis and cellular hypertrophy within the tumor remained unchanged. MC2-R expression is associated with a less aggressive adrenal tumor phenotype and anti-proliferative effects can be amplified through stimulation with physiological doses of ACTH.


Brain white matter integrity and cortisol in older men: the Lothian Birth Cohort 1936.
Elevated glucocorticoid (GC) levels are hypothesized to be deleterious to some brain regions, including white matter (WM). Older age is accompanied by increased between-participant variation in GC levels, yet relationships between WM integrity and cortisol levels in older humans are underexplored. Moreover, it is unclear whether GC-WM associations might be general or pathway specific. We analyzed relationships between salivary cortisol (diurnal and reactive) and general measures of brain WM hyperintensity (WMH) volume, fractional anisotropy (gFA), and mean diffusivity (gMD) in 90 males, aged 73 years. Significant associations were predominantly found between cortisol measures and WMHs and gMD but not gFA. Higher cortisol at the start of a mild cognitive stressor was associated with higher WMH and gMD. Higher cortisol at the end was associated with greater WMHs. A constant or increasing cortisol level during cognitive testing was associated with lower gMD. Tract-specific bases of these associations implicated anterior thalamic radiation, uncinate, and arcuate and inferior longitudinal fasciculi. The cognitive sequelae of these relationships, above other covariates, are a priority for future study.


[Studies on the biomechanics of the human clavicle (author's transl)].
64 non preserved and 35 preserved clavicles were fractured in three defined positions in a bending test by a tension testing machine with electronic measurement of force. 30 non preserved bones were fractured in an axial infraction test. Force-deflection-diagrams were registered, and the values of maximum load, breaking load, ultimate deflection and energy were correlated to cross section and thickness of compacta. The significantly greater non preserved male clavicles are loadable at a higher level (medium breaking load about 1200 N) than female bones (medium breaking load abut 800 N). The breaking energy of the more flexible female clavicles is about 30% lower than those of males whereas elastic modulus of female clavicles is significant greater. Preservation has a significant influence on biomechanical properties of bones: ultimate deflection decreases; breaking energy, ultimate stress and elastic modulus increase. Breaking load is greatest in the middle portion of the clavicle, while deflection is greatest in the sternal portion. Removal of periosteum causes lower breaking load, deflection, ultimate stress and elastic modulus as well. With axial load clavicle fractures occur most frequently between middle and sternal third.


Functionalized Carbon Nanotube and Graphene Oxide Embedded Electrically Conductive Hydrogel Synergistically Stimulates Nerve Cell Differentiation.
Nerve regeneration after injury is a critical medical issue. In previous work, we have developed an oligo(poly(ethylene glycol) fumarate) (OPF) hydrogel incorporated with positive charges as a promising nerve conduit. In this study, we introduced cross-linkable bonds to graphene oxide and carbon nanotube to obtain the functionalized graphene oxide acrylate (GOa) and carbon nanotube poly(ethylene glycol) acrylate (CNTpega). An electrically conductive hydrogel was then fabricated by covalently embedding GOa and CNTpega within OPF hydrogel through chemical cross-linking followed by in situ reduction of GOa in l-ascorbic acid solution. Positive charges were incorporated by 2-(methacryloyloxy)ethyltrimethylammonium chloride (MTAC) to obtain rGOaCNTpega-OPF-MTAC composite hydrogel with both surface charge and electrical conductivity. The distribution of CNTpega and GOa in the hydrogels was substantiated by transmission electron microscopy (TEM), and strengthened electrical conductivities were determined. Excellent biocompatibility was demonstrated for the carbon embedded composite hydrogels. Biological evaluation showed enhanced proliferation and spreading of PC12 cells on the conductive hydrogels. After induced differentiation using nerve growth factor (NGF), cells on the conductive hydrogels were effectively stimulated to have robust neurite development as observed by confocal microscope. A synergistic effect of electrical conductivity and positive charges on nerve cells was also observed in this study. Using a glass mold method, the composite hydrogel was successfully fabricated into conductive nerve conduits with surficial positive charges. These results suggest that rGOa-CNTpega-OPF-MTAC composite hydrogel holds great potential as conduits for neural tissue engineering.


Early vs. delayed cerebral infarction after aneurysm repair after subarachnoid hemorrhage.
Cerebral infarction is a major contributor to poor outcome after subarachnoid hemorrhage (SAH). Although usually considered a complication of delayed cerebral ischemia, infarcts may also occur early, in relation to initial brain injury or aneurysm-securing procedures. We analyzed the relative frequency and volume of early vs delayed infarcts after SAH and their relationship to hospital outcome. Retrospective review of consecutive patients admitted with aneurysmal SAH over 4 years who had follow-up brain imaging 7 days or later after admission. Imaging 24 to 48-hours after aneurysm-securing procedures was reviewed to classify infarcts seen on final imaging as early or delayed. Infarct volumes were measured by perimeter tracing and infarct burden calculated for each patient. Of 250 eligible patients, 205 had follow-up imaging; infarcts were present in 61 patients. Of these, 29 had early infarcts, 16 had delayed infarcts, and 5 had both early and delayed infarcts. Eleven patients with infarcts did not undergo postprocedure computed tomography; these were presumptively classified as having late infarcts. Early and delayed infarcts contributed equally to infarct burden. Early infarcts were associated with aneurysm clipping (odds ratio: 4.2, 95% confidence interval: 1.8-9.5 compared with coiling), whereas delayed infarcts were almost always seen in association with angiographic vasospasm (odds ratio: 3.3, 95% confidence interval: 1.5-7.3). Patients with early as well as late infarcts, especially those with infarct burden more than 30 cm had worse hospital discharge disposition. Early infarction occurs frequently after SAH and contributes as much as delayed cerebral ischemia to infarct burden and hospital outcome. Efforts to better understand and modify contributors to early infarction appear warranted.


Autistic people's perspectives on stereotypes: An interpretative phenomenological analysis.
Autism stereotypes can often portray autistic people in a negative way. However, few studies have looked at how autistic people think they are perceived by others, and none have specifically asked autistic people what they think the autistic stereotypes are. Semi-structured interviews with 12 autistic adults (aged between 20 and 63 years) were conducted. Using interpretative phenomenological analysis, three main themes emerged from the data. These were as follows: (1) the primary stereotype is that autistic people are 'weird'; (2) autistic stereotypes have negative effects and consequences; and (3) autistic people are heterogeneous. This study makes an important and novel contribution to understanding the experience of being autistic by exploring how autistic people feel they are perceived by others and identifying some of the ways in which negative stereotypes are believed to have negative consequences for autistic people.


PATHOLOGY OF NORTHERN FULMARS (FULMARUS GLACIALIS) AND SHEARWATERS BEACHED ON SABLE ISLAND, NOVA SCOTIA, CANADA.
Marine birds are frequently found dead on beaches, either from natural or from anthropogenic causes. Complete necropsies of those carcasses can provide valuable information, particularly for pelagic species, such as Northern Fulmars (Fulmarus glacialis) and shearwaters, which come to land only to breed and for which information on diseases that may affect them is, therefore, sparse. Between 2000 and 2012, 315 carcasses of four species of Procellariiformes (173 Northern Fulmars, 89 Great Shearwaters [Ardenna gravis], 50 Sooty Shearwaters [Ardenna grisea], and three Cory's Shearwaters [Calonectris diomedea]) were collected on Sable Island, Nova Scotia, Canada, an isolated island near the edge of the continental shelf. A complete necropsy, including examination for the presence of ingested plastic, was performed on all carcasses. Most (70%) of these birds were immature. The cause of death was undetermined in 22% (n=70) of the birds: 36% (62/173) of the Northern Fulmars, 4% (4/89) of the Great Shearwaters, 6% (3/50) of the Sooty Shearwaters, and 33% (1/3) of the Cory's Shearwaters. Emaciation was considered the primary cause of death in 91% of the remaining 245 birds: 87% (97/111) of the Northern Fulmars, 92% (78/85) of the Great Shearwaters, 100% (47/47) of the Sooty Shearwaters, and 100% (2/2) of the Cory's Shearwaters. Notable primary causes of death other than emaciation included mycobacteriosis and neoplasia in Northern Fulmars and transmural parasitic proventriculitis in Great Shearwaters. For Northern Fulmars, nutritional condition (as determined semiquantitatively) was compared with other parameters. Birds in good nutritional condition had heavier body mass and flight muscle mass than those in poor nutritional condition (P<0.01). More adults were in poor nutritional condition than expected by chance (91%; χ2=8.23, P<0.01), whereas only 57% of immature birds were in poor condition. There was no relationship between nutritional condition and sex or mass of ingested plastic. Our study provides information on some previously unsuspected health threats in Procellariiformes.


Quantitative characterizations of visual fibrousness in meat analogues using automated image analysis.
A desirable quality of plant-based meat analogues is to resemble the fibrous structure of cooked muscle meat. While texture analysis can characterize fibrous structures mechanically, assessment of visual fibrous structures remains subjective. Quantitative assessment of visual fibrous structures of meat analogues relies on expert knowledge, is resource-intensive, and time-consuming. In this study, a novel image-based method (Fiberlyzer) is developed to provide automated, quantitative, and standardized assessment of visual fibrousness of meat analogues. The Fiberlyzer method segments fibrous regions from 2D images and extracts fiber shape features to characterize the fibrous structure of meat analogues made from mung bean, soy, and pea protein. The computed fiber scores (the ratio between fiber length and width) demonstrate a strong correlation with expert panel evaluations, particularly on a per-formulation basis (r2 = 0.93). Additionally, the Fiberlyzer method generates fiber shape features including fiber score, fiber area, and the number of fiber branches, facilitating comparisons of structural similarity between meat analogue samples and cooked chicken meat as a benchmark. With a simple measurement setup and user-friendly interface, the Fiberlyzer method can become a standard tool integrated into formulation development, quality control, and production routines of plant-based meat analogue. This method offers rapid, cheap, and standardized quantification of visual fibrousness, minimizing the need for expert knowledge in the process of quality control.


Active Crossfire Between Cyanobacteria and Cyanophages in Phototrophic Mat Communities Within Hot Springs.
Cyanophages are viruses with a wide distribution in aquatic ecosystems, that specifically infect Cyanobacteria. These viruses can be readily isolated from marine and fresh waters environments; however, their presence in cosmopolitan thermophilic phototrophic mats remains largely unknown. This study investigates the morphological diversity (TEM), taxonomic composition (metagenomics), and active infectivity (metatranscriptomics) of viral communities over a thermal gradient in hot spring phototrophic mats from Northern Patagonia (Chile). The mats were dominated (up to 53%) by cosmopolitan thermophilic filamentous true-branching cyanobacteria from the genus Mastigocladus, the associated viral community was predominantly composed of Caudovirales (70%), with most of the active infections driven by cyanophages (up to 90% of Caudovirales transcripts). Metagenomic assembly lead to the first full genome description of a T7-like Thermophilic Cyanophage recovered from a hot spring (Porcelana Hot Spring, Chile), with a temperature of 58°C (TC-CHP58). This could potentially represent a world-wide thermophilic lineage of podoviruses that infect cyanobacteria. In the hot spring, TC-CHP58 was active over a temperature gradient from 48 to 66°C, showing a high population variability represented by 1979 single nucleotide variants (SNVs). TC-CHP58 was associated to the Mastigocladus spp. by CRISPR spacers. Marked differences in metagenomic CRISPR loci number and spacers diversity, as well as SNVs, in the TC-CHP58 proto-spacers at different temperatures, reinforce the theory of co-evolution between natural virus populations and cyanobacterial hosts. Considering the importance of cyanobacteria in hot spring biogeochemical cycles, the description of this new cyanopodovirus lineage may have global implications for the functioning of these extreme ecosystems.


[Localization of tryptophan residues in Ca2+-ATPase from sarcoplasmic reticulum].
By the methods of spectroscopy, fluorimetry and chemical modification of tryptophane residues with N-bromsuccinimide, the sarcoplasmic reticulum of rabbit sceletal muscle was shown to contain 18 +/- 1 tryptophane residues per Ca2+-ATPase molecule, 6 of which were, probably, inside the protein globule, in its hydrophobic region, and thus unavailable for modifier, while the rest 12 +/- 1 were easily transformed to the 6-oxyindole chromophore being the main source of the intrinsic fluorescence of the enzyme. The quantum yield for the rest four residues was equal to 0.015. Four tryptophane residues are located at the distance of less than 14 A from the ATP-binding site of the enzyme. The quantum yields of fluorescence for 8 of the tryptophane residues of Ca2+-ATPase were similar and equal to 0.03.


Chapter 14: Acute severe asthma (status asthmaticus).
Acute severe asthma, formerly known as status asthmaticus, is defined as severe asthma unresponsive to repeated courses of beta-agonist therapy such as inhaled albuterol, levalbuterol, or subcutaneous epinephrine. It is a medical emergency that requires immediate recognition and treatment. Oral or parenteral corticosteroids should be administered to all patients with acute severe asthma as early as possible because clinical benefits may not occur for a minimum of 6-12 hours. Approximately 50% of episodes are attributable to upper respiratory infections, and other causes include medical nonadherence, nonsteroidal anti-inflammatory exposure in aspirin-allergic patients, allergen exposure (especially pets) in severely atopic individuals, irritant inhalation (smoke, paint, etc.), exercise, and insufficient use of inhaled or oral corticosteroids. The patient history should be focused on acute severe asthma including current use of oral or inhaled corticosteroids, number of hospitalizations, emergency room visits, intensive-care unit admissions and intubations, the frequency of albuterol use, the presence of nighttime symptoms, exercise intolerance, current medications or illicit drug use, exposure to allergens, and other significant medical conditions. Severe airflow obstruction may be predicted by accessory muscle use, pulsus paradoxus, refusal to recline below 30°, a pulse >120 beats/min, and decreased breath sounds. Physicians' subjective assessments of airway obstruction are often inaccurate. More objective measures of airway obstruction via peak flow (or forced expiratory volume in 1 second) and pulse oximetry before oxygen administration usually are helpful. Pulse oximetry values >90% are less commonly associated with problems although CO(2) retention and a low Pao(2) may be missed.


Tubular mitochondrial pyruvate carrier disruption elicits redox adaptations that protect from acute kidney injury.
Energy-intensive kidney reabsorption processes essential for normal whole-body function are maintained by tubular epithelial cell metabolism. Although tubular metabolism changes markedly following acute kidney injury (AKI), it remains unclear which metabolic alterations are beneficial or detrimental. By analyzing large-scale, publicly available datasets, we observed that AKI consistently leads to downregulation of the mitochondrial pyruvate carrier (MPC). This investigation aimed to understand the contribution of the tubular MPC to kidney function, metabolism, and acute injury severity. We generated tubular epithelial cell-specific Mpc1 knockout (MPC TubKO) mice and employed renal function tests, in vivo renal 13C-glucose tracing, mechanistic enzyme activity assays, and tests of injury and survival in an established rhabdomyolysis model of AKI. MPC TubKO mice retained normal kidney function, displayed unchanged markers of kidney injury, but exhibited coordinately increased enzyme activities of the pentose phosphate pathway and the glutathione and thioredoxin oxidant defense systems. Following rhabdomyolysis-induced AKI, compared to WT control mice, MPC TubKO mice showed increased glycolysis, decreased kidney injury and oxidative stress markers, and strikingly increased survival. Our findings suggest that decreased renal tubular mitochondrial pyruvate uptake hormetically upregulates oxidant defense systems before AKI and is a beneficial adaptive response after rhabdomyolysis-induced AKI. This raises the possibility of therapeutically modulating the MPC to attenuate AKI severity.


Immunohistochemical localization of GABA(B) receptors in the rat central nervous system.
The recent cloning of two gamma-aminobutyric acid(B) (GABA(B)) receptor isoforms (GABA(B)R1a/b), which are probably splice variants of the same gene transcript, allowed us to develop an antiserum that recognized the receptors in fixed tissue and to map their distribution in the rat central nervous system (CNS). We also investigated whether GABA(B)R1 colocalizes with glutamic acid decarboxylase (GAD), a marker of GABAergic cell bodies and terminals. Although GABA(B)R1-like immunoreactivity (GABA(B)R1-LI) was distributed throughout the CNS, several distinct distribution patterns emerged: (1) all monoaminergic brainstem cell groups appeared to contain very high levels of GABA(B)R1, (2) a very high intensity of GABA(B)R1-LI was observed in the majority of the cholinergic regions in the CNS, with exception of motoneurons of the third through sixth cranial nerve nuclei, and (3) a low density of the receptor was observed in most of the nuclei that contain cell bodies of GABAergic projection neurons. The highest GABA(B)R1 labeling was observed in the thalamus, interpeduncular nucleus and medial habenula. Cell bodies were labeled throughout the neuroaxis. We also observed dense neuropil labeling in many regions, suggesting that this receptor is localized in dendrites and/or axon terminals. However, in immunofluorescent double-labeling experiments for GABA(B)R1 and GAD, we never observed GABA(B)R1-LI in GAD-positive axon terminals; this result suggests that the GABA(B)R1 may not function as an autoreceptor. Double labeling was observed in the cell bodies of Purkinje neurons and in some interneurons. In general, the immunohistochemical localization of the GABA(B)R1 correlates well with physiologic and autoradiographic data on the distribution of GABA(B) receptors, but some critical differences were noted. Thus, it is likely that additional GABA(B) receptor subtypes remain to be identified.


A Physical Model Suggests That Hip-Localized Balance Sense in Birds Improves State Estimation in Perching: Implications for Bipedal Robots.
In addition to a vestibular system, birds uniquely have a balance-sensing organ within the pelvis, called the lumbosacral organ (LSO). The LSO is well developed in terrestrial birds, possibly to facilitate balance control in perching and terrestrial locomotion. No previous studies have quantified the functional benefits of the LSO for balance. We suggest two main benefits of hip-localized balance sense: reduced sensorimotor delay and improved estimation of foot-ground acceleration. We used system identification to test the hypothesis that hip-localized balance sense improves estimates of foot acceleration compared to a head-localized sense, due to closer proximity to the feet. We built a physical model of a standing guinea fowl perched on a platform, and used 3D accelerometers at the hip and head to replicate balance sense by the LSO and vestibular systems. The horizontal platform was attached to the end effector of a 6 DOF robotic arm, allowing us to apply perturbations to the platform analogous to motions of a compliant branch. We also compared state estimation between models with low and high neck stiffness. Cross-correlations revealed that foot-to-hip sensing delays were shorter than foot-to-head, as expected. We used multi-variable output error state-space (MOESP) system identification to estimate foot-ground acceleration as a function of hip- and head-localized sensing, individually and combined. Hip-localized sensors alone provided the best state estimates, which were not improved when fused with head-localized sensors. However, estimates from head-localized sensors improved with higher neck stiffness. Our findings support the hypothesis that hip-localized balance sense improves the speed and accuracy of foot state estimation compared to head-localized sense. The findings also suggest a role of neck muscles for active sensing for balance control: increased neck stiffness through muscle co-contraction can improve the utility of vestibular signals. Our engineering approach provides, to our knowledge, the first quantitative evidence for functional benefits of the LSO balance sense in birds. The findings support notions of control modularity in birds, with preferential vestibular sense for head stability and gaze, and LSO for body balance control,respectively. The findings also suggest advantages for distributed and active sensing for agile locomotion in compliant bipedal robots.


[Mechanism of polyene antibiotic inactivation. Possible ways for levorin stabilization].
Various means for levorin isolation were studied with the EPR method and approaches to stabilization of the antibiotic on storage under natural conditions were discussed. It was shown that formation of the radicals begins already at the first stage of the antibiotic isolation, i.e. during extraction from the mycelium. Treatment of the solvents with an inert gas or addition of antioxidants decreased the number of free radicals in a freshly isolated product. The antibiotic inactivation rate depended on the initial concentration of the free radicals and conditions of natural storage. The levorin stability increased when oxygen was thoroughly removed from the solvents at all isolation stages and the antibiotic was subsequently stored under conditions preventing any access of the air. The stabilizing effect was also observed when the oxidative effect of the amino sugar moiety on destruction of the polyenic chromophore during the antibiotic complex formation with respect to the amino group was decreased.