Sub-threshold mental illness in adolescents: within and beyond DSM's boundaries.
As researchers, clinicians and health systems strive to understand and improve mental health and well-being in youth, the parameters by which mental illness itself is defined have increasingly become the topic of inquiry. In the March 2015 issue of SPPE, Roberts et al. (Soc Psychiatry Psychiatr Epidemiol 50(3):397-406, 2015) integrate DSM diagnostic criteria with impairment in adolescents, showing that the latter is more frequent in full-syndrome disorders but still relevant for sub-threshold conditions, which have higher overall prevalence. These findings shift the focus away from specific diagnostic criteria and thresholds, and towards the backdrop of distress and impairment in young people. They also have implications for staging models and clinical services for youth mental health, particularly for prevention and early intervention efforts.


Relationship of vancomycin minimum inhibitory concentration to mortality in patients with methicillin-resistant Staphylococcus aureus hospital-acquired, ventilator-associated, or health-care-associated pneumonia.
Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and health-care-associated pneumonia (HCAP). These infections are associated with significant morbidity, mortality, and cost. The impact of vancomycin minimum inhibitory concentration (MIC) on mortality for patients with MRSA pneumonia has not been determined. Adult patients in ICUs with a diagnosis of MRSA HAP, VAP, or HCAP were entered in the study. Clinical and laboratory information were prospectively collected. Vancomycin MIC and heteroresistance were determined for each MRSA isolate. Data were collected from February 2006 through August 2007. The primary outcome variable was all-cause mortality at day 28. A propensity score approach was used to adjust for confounding variables. The study sample consisted of 158 patients. All-cause mortality at day 28 was 32.3%. The majority of MRSA isolates had a vancomycin MIC ≥ 1.5 mg/mL (115/158, 72.8%). Propensity score analysis demonstrated an increase in 28-day mortality as vancomycin MIC increased from 0.75 to 3 mg/mL (P ≤ .001). Heteroresistance to vancomycin, demonstrated in 21.5% isolates, was not associated with mortality. Mortality in patients with MRSA HAP, VAP, and HCAP increases as a function of the vancomycin MIC, even for strains with MIC values within the susceptible range. Evaluation of vancomycin MICs should be contemplated at the institutional level and for individual cases of MRSA pneumonia. The use of vancomycin therapy in patients with MRSA pneumonia caused by isolates with MICs between 1 and 2 mg/mL should be undertaken with caution, and alternative therapies should be considered.


Effectiveness of high-dose barium enema filling for colonic diverticular bleeding.
Therapeutic barium enema was first reported in 1970. The long-term recurrence rate of colonic diverticular bleeding after therapeutic barium enema was compared with that of endoscopic haemostasis. This study included 57 consecutive patients admitted between 2003 and 2008 with colonic diverticular bleeding in whom conservative treatment failed to stop bleeding within 3 h of hospital admission. Lower gastrointestinal endoscopy was performed immediately after admission. In 75% of patients, bleeding was from the right colon, and any identifiable source of bleeding was treated by endoscopic haemostasis. Cases with an undetectable source received high-dose barium impaction therapy. Treatment was as follows: Group A (n = 37) solely by endoscopic haemostasis; Group B (n = 11) solely by therapeutic barium enema group, and Group C (n = 9) by endoscopic haemostasis and therapeutic barium enema. At a follow up of seven (median; range: 1-56) months, recurrent bleeding rates were 18/37 (48.6%), 6/11 (54.5%) and 2/9 (22.2%) (P = 0.3930). High-dose barium enema is as effective as endoscopic haemostasis for the prevention of recurrent diverticular bleeding.


Impact of a district-wide health center strengthening intervention on healthcare utilization in rural Rwanda: Use of interrupted time series analysis.
Evaluations of health systems strengthening (HSS) interventions using observational data are rarely used for causal inference due to limited data availability. Routinely collected national data allow use of quasi-experimental designs such as interrupted time series (ITS). Rwanda has invested in a robust electronic health management information system (HMIS) that captures monthly healthcare utilization data. We used ITS to evaluate impact of an HSS intervention to improve primary health care facility readiness on health service utilization in two rural districts of Rwanda. We used controlled ITS analysis to compare changes in healthcare utilization at health centers (HC) that received the intervention (n = 13) to propensity score matched non-intervention health centers in Rwanda (n = 86) from January 2008 to December 2012. HC support included infrastructure renovation, salary support, medical equipment, referral network strengthening, and clinical training. Baseline quarterly mean outpatient visit rates and population density were used to model propensity scores. The intervention began in May 2010 and was implemented over a twelve-month period. We used monthly healthcare utilization data from the national Rwandan HMIS to study changes in the (1) number of facility deliveries per 10,000 women, (2) number of referrals for high risk pregnancy per 100,000 women, and (3) the number of outpatient visits performed per 1,000 catchment population. PHIT HC experienced significantly higher monthly delivery rates post-HSS during the April-June season than comparison (3.19/10,000, 95% CI: [0.27, 6.10]). In 2010, this represented a 13% relative increase, and in 2011, this represented a 23% relative increase. The post-HSS change in monthly rate of high-risk pregnancies referred increased slightly in intervention compared to control HC (0.03/10,000, 95% CI: [-0.007, 0.06]). There was a small immediate post-HSS increase in outpatient visit rates in intervention compared to control HC (6.64/1,000, 95% CI: [-13.52, 26.81]). We failed to find strong evidence of post-HSS increases in outpatient visit rates or referral rates at health centers, which could be explained by small sample size and high baseline nation-wide health service coverage. However, our findings demonstrate that high quality routinely collected health facility data combined with ITS can be used for rigorous policy evaluation in resource-limited settings.


Initiation of antiretroviral therapy at higher nadir CD4+ T-cell counts is associated with reduced arterial stiffness in HIV-infected individuals.
HIV infection is associated with increased rates of cardiovascular disease. We sought to evaluate whether initiation of HIV therapy at higher nadir CD4(+) T-cell counts might reduce cardiovascular risk, as measured by arterial stiffness. We conducted a cross-sectional study of 80 HIV-infected men who were antiretroviral-treated with undetectable plasma HIV RNA levels. Participants underwent noninvasive assessment of arterial stiffness by pulse wave analysis (augmentation index normalized for heart rate of 75 bpm) and carotid-femoral pulse wave velocity, both sensitive measures of cardiovascular risk. A generalized linear model was used to determine the relationship between cardiovascular and HIV-related predictors, and arterial stiffness. In unadjusted analyses, predictors of arterial stiffness included age, blood pressure, antihypertensive medication use, and nadir CD4(+) T-cell count below 350 cells/microl (all P < 0.05). After adjusting for both cardiovascular risk factors (age, blood pressure, antihypertensive medication use, diabetes, hypercholesterolemia, and smoking) and HIV-related covariates, nadir CD4(+) T-cell count below 350 cells/microl was independently associated with a 0.41 m/s increase in pulse wave velocity (95% confidence interval 0.03-0.79, P = 0.03) and a 7.3% increase in augmentation index (augmentation index normalized for heart rate of 75 bpm; 95% confidence interval 2.6-11.9, P = 0.003). Neither duration of antiretroviral therapy nor exposure to protease inhibitors was associated with arterial stiffness. Among treated HIV-infected individuals, arterial stiffness is independently associated with both traditional cardiovascular risk factors as well as a low nadir CD4(+) T-cell count. Our data suggest that cardiovascular risk among HIV-infected individuals could be reduced through early initiation of antiretroviral therapy, before CD4 T-cell counts are depressed, a concept that should be tested prospectively in future studies.


The effects of whole body vibration therapy on bone mineral density and leg muscle strength in older adults: a systematic review and meta-analysis.
A systematic review and meta-analysis of randomized controlled trials was undertaken to determine whether whole body vibration improves bone mineral density and leg muscle strength in older adults. Sources included MEDLINE, CINAHL, EMBASE, PEDro, PubMed, Science Citation Index and the reference list of each eligible article. Article search and selection was performed independently by two researchers. The methodological quality of each selected article was rated by the PEDro scale. Thirteen randomized trials (18 articles) totalling 896 subjects fulfilled the selection criteria. Four were considered to have good or excellent methodological quality and the rest were rated as fair. Meta-analyses revealed that whole body vibration has no significant effect on hip or lumbar spine bone mineral density in older women when compared with no intervention or active exercise (P > 0.05). Whole body vibration, however, had a significant treatment effect on knee extension dynamic strength (standardized mean difference = 0.63, P = 0.006), leg extension isometric strength (standardized mean difference = 0.57, P = 0.003), and functional measures of leg muscle strength such as jumping height (standardized mean difference = 0.51, P = 0.010) and performance in sit-to-stand (standardized mean difference = 0.72, P < 0.001) among older adults compared with no intervention. Whole body vibration is beneficial for enhancing leg muscle strength among older adults. However, the review suggests that whole body vibration has no overall treatment effect on bone mineral density in older women. No randomized trial has examined the effects of whole body vibration on bone mineral density in older men.


Hyporeflective pagetoid cells: a new clue for amelanotic melanoma diagnosis by reflectance confocal microscopy.
Amelanotic melanoma represents a diagnostic challenge both clinically and dermoscopically. Few studies based on case series have explored the possibility of using reflectance confocal microscopy (RCM) to diagnose amelanotic melanoma. To validate a new confocal feature, named hyporeflective pagetoid cells (HPCs), for the diagnosis of amelanotic melanoma. A group of 20 amelanotic melanomas and a control population of nonpigmented melanocytic naevi (10), hypo/nonpigmented nonmelanocytic lesions (20) and pigmented melanomas (20), imaged by RCM, were retrospectively evaluated. The presence of HPCs and other diagnosis-specific confocal features was assessed and correlated with histopathology. HPCs were present, and usually abundant, in the majority of amelanotic melanomas (85%). As expected, they were also observed in Spitz naevi. On histopathology, they were correlated with pagetoid infiltration of hypomelanotic melanocytes in all melanocytic lesions. Few nonmelanocytic lesions (three squamous cell carcinomas, two seborrhoeic keratoses and one basal cell carcinoma) showed the presence of HPCs. In these cases, they corresponded to enlarged or dyskeratotic keratinocytes by histopathology. The identification of HPCs in the epidermis is a new parameter that is frequently found in amelanotic melanoma. Possible confounders are represented by atypical keratinocytes that can be present in nonmelanocytic lesions. However, the whole architecture and the presence of additional diagnostic criteria should be considered in order to obtain a correct diagnosis.


A CK2-dependent mechanism for activation of the JAK-STAT signaling pathway.
JAK-STAT signaling is involved in the regulation of cell survival, proliferation, and differentiation. JAK tyrosine kinases can be transiently activated by cytokines or growth factors in normal cells, whereas they become constitutively activated as a result of mutations that affect their function in tumors. Specifically, the JAK2V617F mutation is present in the majority of patients with myeloproliferative disorders (MPDs) and is implicated in the pathogenesis of these diseases. In the present study, we report that the kinase CK2 is a novel interaction partner of JAKs and is essential for JAK-STAT activation. We demonstrate that cytokine-induced activation of JAKs and STATs and the expression of suppressor of cytokine signaling 3 (SOCS-3), a downstream target, are inhibited by CK2 small interfering RNAs or pharmacologic inhibitors. Endogenous CK2 is associated with JAK2 and JAK1 and phosphorylates JAK2 in vitro. To extend these findings, we demonstrate that CK2 interacts with JAK2V617F and that CK2 inhibitors suppress JAK2V617F autophosphorylation and downstream signaling in HEL92.1.7 cells (HEL) and primary cells from polycythemia vera (PV) patients. Furthermore, CK2 inhibitors potently induce apoptosis of HEL cells and PV cells. Our data provide evidence for novel cross-talk between CK2 and JAK-STAT signaling, with implications for therapeutic intervention in JAK2V617F-positive MPDs.


Post-transcriptional suppression of cytosolic ascorbate peroxidase expression during pathogen-induced programmed cell death in tobacco.
As a means to eliminate pathogen-infected cells and prevent diseases, programmed cell death (PCD) appears to be a defense strategy employed by most multicellular organisms. Recent studies have indicated that reactive oxygen species, such as O2.- and H2O2, play a central role in the activation and propagation of pathogen-induced PCD in plants. However, plants contain several mechanisms that detoxify O2.- and H2O2 and may inhibit PCD. We found that during viral-induced PCD in tobacco, the expression of cytosolic ascorbate peroxidase (cAPX), a key H2O2 detoxifying enzyme, is post-transcriptionally suppressed. Thus, although the steady state level of transcripts encoding cAPX was induced during PCD, as expected under conditions of elevated H2O2, the level of the cAPX protein declined. In vivo protein labeling, followed by immunoprecipitation, indicated that the synthesis of the cAPX protein was inhibited. Although transcripts encoding cAPX were found to associate with polysomes during PCD, no cAPX protein was detected after in vitro polysome run-off assays. Our findings suggest that viral-induced PCD in tobacco is accompanied by the suppression of cAPX expression, possibly at the level of translation elongation. This suppression is likely to contribute to a reduction in the capability of cells to scavenge H2O2, which in turn enables the accumulation of H2O2 and the acceleration of PCD.


Transient inflammatory-like state and microbial dysbiosis are pivotal in establishment of mucosal homeostasis during colonisation of germ-free mice.
The gut microbiota is increasingly recognised as a key-player in defining the health status of the gastrointestinal tract. Recently, we demonstrated that colonisation of healthy germfree mice with a conventional microbiota (conventionalisation) elicits temporal and region specific host-microbe communication responses that lead to the establishment of a microbiota-accommodating homeostatic state within 30 days. Here, the microbiota composition profiles, mucosal transcriptomes and plasma-analytes in germ-free and conventionalised C57/BL 6 J mice were assessed to decipher the features of the distinctive and pivotal events occurring four days after initiation of the conventionalisation process. The dominance of the microbial genera Helicobacter, Sphingomonas and Mucispirillum in the gut microbiota coincided with the transient mounting of proinflammatory responses in the mucosa and the transiently elevated levels of specific (inflammatory) cytokines and amines in plasma. The overrepresented microbes have previously been associated with the potential to cause disease under certain conditions, illustrating that conventionalisation proceeds through a transient state that resembles situations associated with dysbiosis. However, no overt mucosal inflammation was observed, suggesting a pivotal role of the overrepresented bacterial groups in priming and maturation of the immune system during the process of conventionalisation. These findings imply that the transiently elevated relative overgrowth of particular microbial genera functions as pivotal adjuvants to elicit the corresponding proinflammatory cascades, which precede the full maturation of the different arms of the immune system following these events and is required to achieve a microbiota-accommodating homeostasis in healthy animals.


Phlebotomus (Paraphlebotomus) riouxi: a synonym of Phlebotomus chabaudi without any proven vectorial role in Tunisia and Algeria.
Phlebotomus (Paraphlebotomus) riouxi Depaquit, Léger & Killick-Kendrick (Diptera: Psychodidae) was described as a typological species based on a few morphological characters distinguishing it from Phlebotomus (Paraphlebotomus) chabaudi Croset, Abonnenc & Rioux. The naming of P. riouxi coincided with its incrimination as a rural vector of Leishmania tropica Wright (junior synonym: Leishmania killicki Rioux, Lanotte & Pratlong) in Tataouine governorate, an arid region of southern Tunisia. The current report finds insufficient evidence to incriminate either phlebotomine sandfly as a vector of L. tropica in North Africa. Phlebotomus riouxi was found not to have the characteristics of a phylogenetic or biological species, and therefore it is synonymized with P. chabaudi. Both taxa were recorded together for the first time in Tunisia, in Tataouine, where three of 12 males showed intermediate morphology and both sexes of each taxon were not characterized by specific lineages of the nuclear gene elongation factor-1α or the mitochondrial gene cytochrome b, for which a long 3' terminal fragment is recommended for phlebotomine phylogenetics. This case study indicates that the eco-epidemiology of leishmaniasis should focus more on identifying key components of vectorial transmission that are susceptible to interventions for disease control, rather than on defining sibling species of vectors.


Recombinant human erythropoietin for chronic renal failure anaemia in pre-dialysis patients.
Treatment with recombinant human erythropoietin (rHu EPO) in dialysis patients has been shown to be highly effective in terms of correcting anaemia and improving quality of life. There is debate concerning the benefits of rHu EPO use in pre-dialysis patients which may accelerate the deterioration of renal function. However the opposing view is that if rHu EPO is as effective in pre-dialysis patient's, improving the patients sense of well-being may result in the onset of dialysis being delayed. To assess the effects of rHu EPO use in pre-dialysis patients with renal anaemia. The initial search included 13 electronic databases (1980 to May 2001) an internet search (August 1997), handsearching of Kidney International (1983 to May 1997), contact with known investigators and biomedical companies, and reference list of relevant articles. For this update we searched the Cochrane Renal Group's specialised register (June 2004) and The Cochrane Library (Issue 3, 2004). Randomised controlled trials (RCTs) or quasi-RCTs comparing the use of rHu EPO with no treatment or placebo in pre-dialysis patients. Only published data were used. Quality assessment was performed by two assessors independently. Data were abstracted by a single author onto a standard form, a sample of which was checked by another author. Results were expressed as relative risk (RR) or weighted mean difference (WMD) with 95% confidence intervals (CI). Fifteen trials (461 participants) were included. There was a marked improvement in haemoglobin (WMD 1.82 g/dL, 95% CI 1.35 to 2.28) and haematocrit (WMD 9.85%, 95% CI 8.35 to 11.34) with treatment and a decrease in the number of patients requiring blood transfusions (RR 0.32, 95% CI 0.12 to 0.83). The data from studies reporting quality of life or exercise capacity demonstrated an improvement in the treatment group. Most of the measures of progression of renal disease showed no statistically significant difference. No significant increase in adverse events was identified. Treatment with rHu EPO in pre-dialysis patients corrects anaemia, avoids the requirement for blood transfusions and also improves quality of life and exercise capacity. We were unable to assess the effects of rHu EPO on progression of renal disease, delay in the onset of dialysis or adverse events. Based on the current evidence, decisions on the putative benefits in terms of quality of life are worth the extra costs of pre-dialysis rHu EPO need careful evaluation.


[Vulvovaginal candidiasis in girls (guidelines for a practitioner)].
There are many publications on the problems of the vaginal candidiasis treatment. Still, the actuality is in the frequency of the relapses and registration of the pediatric cases. Unfortunately, the majority of the pediatrists prescribe antibiotics but either forget to prescribe the simultaneous use of antifungal drugs, or prescribe nystatin, an antimycotic, that is known to be active only in the intestine lumen. As a result, candidiasis of the stomatopharynx or vagina is developed. Of no less importance is the fact of marketing many generics in Russia, which often prove to be false after their detailed investigation. The paper presents specific characteristics pertaining to the origin and development of vulvovaginal candidiasis in girls and indicates drugs with proved efficacy in normalization of the vagina microbiocenosis in girls.


Vascularized radial forearm free tissue transfer for lining in nasal reconstruction.
Total and near-total nasal reconstruction requires the surgeon to replace external nasal cover, skeletal support, and internal nasal lining. The successful result must re-create the form and function of the original nose. In large defects, traditional sources of internal lining may be unavailable. The study describes the recreation of nasal lining in three patients with extensive nasal defects with vascularized radial forearm tissue. Retrospective review of three patients who underwent nasal reconstruction with radial forearm for internal lining, costal cartilage grafts for skeletal support, and paramedian forehead flap for cover. The charts of three patients who underwent total nasal reconstruction with radial forearm tissue transfer for lining were retrospectively reviewed. The technique was evaluated. The authors present a method for internal lining reconstruction in extensive nasal defects. They discuss the advantages and disadvantages of this method. Three patients underwent successful total nasal reconstruction with radial forearm tissue transfer for lining, costal cartilage for skeletal support, and paramedian forehead flap. None of the patients had adequate septal mucosa or nasal subunit skin to support mucosal rotation grafts or epithelial turn-in flaps. All patients have completed reconstruction and have satisfactory nasal form and function. Loss of the lining flap or graft loss did not occur. Vascularized radial forearm tissue supplies ample quantities of skin to recreate nasal lining. The tissue provides excellent support of graft material, and it prevents contracture of the covering flap. Because of its bulk and donor site morbidity, free forearm tissue transfer should not be considered for reconstruction of smaller defects when another lining flap will suffice.


Natural perspective projections for head-mounted displays.
The display units integrated in today's head-mounted displays (HMDs) provide only a limited field of view (FOV) to the virtual world. In order to present an undistorted view to the virtual environment (VE), the perspective projection used to render the VE has to be adjusted to the limitations caused by the HMD characteristics. In particular, the geometric field of view (GFOV), which defines the virtual aperture angle used for rendering of the 3D scene, is set up according to the display field of view (DFOV). A discrepancy between these two fields of view distorts the geometry of the VE in a way that either minifies or magnifies the imagery displayed to the user. It has been shown that this distortion has the potential to affect a user's perception of the virtual space, sense of presence, and performance on visual search tasks. In this paper, we analyze the user's perception of a VE displayed in a HMD, which is rendered with different GFOVs. We introduce a psychophysical calibration method to determine the HMD's actual field of view, which may vary from the nominal values specified by the manufacturer. Furthermore, we conducted two experiments to identify perspective projections for HMDs, which are identified as natural by subjects--even if these perspectives deviate from the perspectives that are inherently defined by the DFOV. In the first experiment, subjects had to adjust the GFOV for a rendered virtual laboratory such that their perception of the virtual replica matched the perception of the real laboratory, which they saw before the virtual one. In the second experiment, we displayed the same virtual laboratory, but restricted the viewing condition in the real world to simulate the limited viewing condition in a HMD environment. We found that subjects evaluate a GFOV as natural when it is larger than the actual DFOV of the HMD--in some cases up to 50 percent--even when subjects viewed the real space with a limited field of view.


Early executive functioning in a global context: Developmental continuity and family protective factors.
This study extends the methodological and theoretical understanding of executive functions (EFs) in preschoolers from low- and middle-income countries (LMIC). First, the authors describe a rigorous process of adapting and evaluating six EF tasks to produce a culturally and developmentally appropriate measure of emerging EFs in a large sample of at-risk children in rural Pakistan. Next, the authors identify critical developmental and family factors that relate to preschoolers' EFs over the first 4 years of life. Direct assessment of children's general cognitive skills at age two showed developmental continuity with EFs at age four, and these early cognitive skills mediated the effect of an antecedent parenting intervention on EFs as well as associations of targeted individual and family factors with EFs. Furthermore, directly assessed maternal cognitive capacities and observed maternal scaffolding uniquely predicted EFs in preschoolers. This study is also the first to demonstrate a significant overlap between direct assessments of IQ and EFs in young children from LMIC. Children's general intelligence mediated the associations of EFs with antecedent physical growth and cognitive skills as well as concurrent family factors (maternal verbal intelligence, maternal scaffolding, and home stimulation). After controlling for shared variance between preschoolers' general intelligence and EFs, three factors emerged as unique predictors of EFs: exposure to an early parenting intervention, physical growth status at age two, and number of older siblings. The findings have important implications for the design of interventions that aim to improve EFs in young children in LMIC. A video abstract of this article can be viewed at https://vimeo.com/316329544/5abde94cd7.


Adverse events from diagnostic and therapeutic joint injections: a literature review.
This review article classifies the various adverse reactions arising from intra-articular injections by severity, diagnostic category, and whether they are due to corticosteroid, local anesthetic or viscosupplementation injections. Life-threatening and serious adverse events from intra-articular injections are rare and range from local complications to systemic afflictions. Measures to reduce the likelihood of an adverse event occurring are outlined and patients with significant features in their clinical histories, predisposing them to adverse events, are highlighted.


Exposures of healthy and asthmatic volunteers to concentrated ambient ultrafine particles in Los Angeles.
Adult volunteers (17 healthy, 14 asthmatic) were exposed in a controlled environmental chamber to concentrated ultrafine particles (UFP) collected in a Los Angeles suburb with substantial motor vehicle pollution. Exposures lasted 2 h with intermittent exercise. Inhaled particle counts (mean 145,000/cm(3), range 39,000-312,000) were typically 7-8 times higher than ambient levels. Mass concentrations (mean 100 microg/m(3), range 13-277) were not highly correlated with counts. Volunteers were evaluated for lung function, symptoms, exhaled nitric oxide (eNO), Holter electrocardiography, and inflammatory markers in peripheral blood and induced sputum. Relative to control (filtered air) studies, UFP exposures were associated with a 0.5% mean fall in arterial O(2) saturation estimated by pulse oximetry (p < .01), a 2% mean fall in forced expired volume in 1 sec (FEV(1)) the morning after exposure (p < .05), and a transient slight decrease in low-frequency (sympathetic) power in Holter recordings during quiet rest (p < .05). Healthy and asthmatic subjects were not significantly different across most endpoints. Thus, this initial experimental study of human volunteers exposed to concentrated Los Angeles area ambient UFP showed some acute deleterious cardiopulmonary responses, which, although generally small and equivocal as in previous studies of larger sized concentrated ambient particles, might help to explain reported adverse health effects associated with urban particulate pollution.


On the hippocampus and learned conditional responding: effects of aspiration versus ibotenate lesions.
To study the possible involvement of the hippocampus in learned conditional responding, rats with aspiration lesions of the hippocampus and others that had the hippocampus removed with ibotenic acid were trained on concurrent Pavlovian conditional and nonconditional discriminations. In agreement with the results reported by Ross et al. (1984), animals that had the hippocampus removed with aspiration were unable to learn the conditional discrimination, but learned the simple nonconditional discrimination without difficulty. In contrast, rats that had the hippocampus removed with ibotenic acid did not differ from controls in learning either discrimination. Furthermore, transfer test results were consistent with the hypothesis that ibotenate-lesioned rats performed conditional operations to solve the conditional discrimination problem. Histological analysis indicated that the ibotenate lesions resulted in the removal of the hippocampus and dentate gyrus with minimal involvement of other structures. In aspiration hippocampal animals there was less overall damage to the hippocampus, but there was also extensive damage to the axons passing in alveus and fimbria, together with bilateral loss of cells in the subicular complex, the cingulate gyrus, and the cortex. Since rats with ibotenate lesions had more complete removal of the hippocampus, yet learned both discriminations, the impaired conditional responding found in aspiration hippocampals must be due to extrahippocampal damage.


Veterans Finding Community and a "Home" Within an Emergency Housing Environment.
In April 2020, the Department of Veterans Affairs responded to the COVID-19 pandemic and escalating unsheltered homelessness in Los Angeles by sanctioning a tent turned tiny shelter encampment at the West Los Angeles Veterans Affairs medical center. Initially, staff offered linkages to on-campus VA healthcare. However, as many Veterans living in the encampment struggled to avail themselves of these services, our "encampment medicine" team was launched to provide on-site care coordination and healthcare at the tiny shelters. This case study showcases the team's engagement with a Veteran experiencing homelessness struggling with opioid use disorder and depicts how this co-located, comprehensive care team allowed for trusting care relationships formed with, and empowerment of the Veterans living in the encampment. The piece highlights a healthcare model that engages with persons experiencing homelessness on their own terms while building trust and solidarity, focuses on the sense of community that formed in the tiny shelter encampment, and gives recommendations for how homeless services might adapt to use the strengths of this unique community.


Malignant giant cell tumor of the vulva.
Giant cell malignant fibrous histiocytoma or giant cell tumor of the soft parts (GCTSP) is a rare soft tissue tumor. GCTSP has an unpredictable behavior; the majority of the reported cases showed benign histology and those that showed malignant morphologic features were extremely rare. To the best of our knowledge, GCTSP has never been reported to involve the vulva in the English literature. We report the first case of malignant GCTSP of the vulva. Histologic features and the immunoprofile of the tumor and differential diagnosis are discussed in detail. Although extremely rare, consideration of the potential occurrence of GCTSP in the vulva is recommended to avoid a potential diagnostic pitfall.


High-resolution mapping of copy number aberrations and identification of target genes in hepatocellular carcinoma.
Hepatocarcinogenesis involves complex combinations of molecular events, such as genetic aberrations, epigenetic changes, and alterations in gene expression. To elucidate the mechanism of hepatocarcinogenesis, it is necessary to reconstruct these molecular events at each level. This article presents a review of copy number analyses of hepatocellular carcinoma (HCC) using traditional comparative genomic hybridization (CGH), arraybased CGH (aCGH), and single nucleotide polymorphism (SNP) arrays. A number of studies have applied CGH technology for copy number analysis of HCC and have indicated the significance of correlations of frequent genomic aberrations with various clinicopathological parameters, prediction of recurrence and prognosis, and treatment selection, followed by comprehensive genomic analysis using aCGH with much higher resolution. Furthermore, we present our data regarding genomic aberrations of HCC obtained using the Genome Imbalance Map (GIM) algorithm, which simultaneously detects DNA copy number alterations and loss of heterozygosity using SNP arrays, and the Expression Imbalance Map (EIM) algorithm, which detects mRNA expression imbalance correlated with chromosomal regions. Using these two algorithms, we integrated the expression profiles, locus information, and genomic aberrations in a systematic manner, which is effective for detecting structural genomic abnormalities, such as chromosomal gains and losses, and showed that gene expression profiles are subject to chromosomal bias.


Phase-field-crystal calculation of crystal-melt surface tension in binary alloys.
A phase field crystal (PFC) density functional for binary mixtures is coarse grained and a formalism for calculating the simultaneous concentration, temperature, and density dependence of the surface energy anisotropy of a solid-liquid interface is developed. The methodology systematically relates bulk free energy coefficients arising from coarse graining to thermodynamic data, while gradient energy coefficients are related to molecular properties. Our coarse-grained formalism is applied to the determination of surface energy anisotropy in two-dimensional Zn-Al films, a situation relevant for quantitative phase field simulations of dendritic solidification in zinc coatings.


Maternal Immune Activation Causes Social Behavior Deficits and Hypomyelination in Male Rat Offspring with an Autism-Like Microbiota Profile.
Maternal immune activation (MIA) increases the risk of autism spectrum disorder (ASD) in offspring. Microbial dysbiosis is associated with ASD symptoms. However, the alterations in the brain-gut-microbiota axis in lipopolysaccharide (LPS)-induced MIA offspring remain unclear. Here, we examined the social behavior, anxiety-like and repetitive behavior, microbiota profile, and myelination levels in LPS-induced MIA rat offspring. Compared with control offspring, MIA male rat offspring spent less time in an active social interaction with stranger rats, displayed more anxiety-like and repetitive behavior, and had more hypomyelination in the prefrontal cortex and thalamic nucleus. A fecal microbiota analysis revealed that MIA offspring had a higher abundance of Alistipes, Fusobacterium, and Ruminococcus and a lower abundance of Coprococcus, Erysipelotrichaies, and Actinobacteria than control offspring, which is consistent with that of humans with ASD. The least absolute shrinkage and selection operator (LASSO) method was applied to determine the relative importance of the microbiota, which indicated that the abundance of Alistipes and Actinobacteria was the most relevant for the profile of defective social behavior, whereas Fusobacterium and Coprococcus was associated with anxiety-like and repetitive behavior. In summary, LPS-induced MIA offspring showed an abnormal brain-gut-microbiota axis with social behavior deficits, anxiety-like and repetitive behavior, hypomyelination, and an ASD-like microbiota profile.


Prevalence and assemblage of Giardia duodenalis in a case-control study of children under 5 years from Jimma, Southwest Ethiopia.
Giardia duodenalis is a common pathogenic intestinal protozoan parasite with high prevalence in developing countries, especially among children. The distribution of giardia assemblages among humans and their clinical relevance remains controversial. This study aimed to determine the prevalence and assemblage of Giardia among children under 5 years of age in Jimma, Southwest Ethiopia. Employing a case-control design, 606 children presenting with diarrhea at Jimma university medical center and Serbo Health Center were enrolled from December 2016 to July 2018 along with 617 matched controls without diarrhea. Giardia was detected and typed using real-time PCR. Univariate and multivariate regression analysis was performed. The total prevalence of Giardia was 41% (501/1223) and did not differ significantly between cases and controls (40% vs 42%). Prevalence increased by age, with the highest prevalence seen in children aged ≥ 25 months. Children without diarrhea with a history of diarrhea during the last month were more likely to be Giardia positive compared to children with no history diarrhea (OR 1.8 and 95%CI; 1.1-2.9). Regardless of current diarrhea symptoms, assemblage B predominated with 89%, followed by assemblage A (8%) and mixed infection assemblage A and B (3%). We report a high prevalence of Giardia by PCR detection in Jimma, Ethiopia, with assemblage B being predominant. There was a similar distribution of Giardia assemblages between children with and without diarrhea. Increasing age was a risk factor for Giardia infection. Community-based prevention and control strategies need to be employed to decrease the risk of giardia infection.


Black tea supplementation improves antioxidant status in rats subjected to oxidative stress.
The protective effect of black tea extract (BTE) against HgCl2-induced oxidative damage in Wistar rats was investigated. Rats were injected with HgCl2 (5 mg/kg body weight in 0.9% NaCl) to induce oxidative stress. The aqueous BTE (2.5%) was prepared from CTC (curl, tear, crush) grade tea. BTE was fed to control and HgCl2-treated rats by gavage at a dose of 1 ml/(100 g body weight d). Biomarkers of oxidative stress, such as the erythrocyte plasma membrane redox system (PMRS) activity, lipid peroxidation, and advanced oxidation protein products (AOPP), increased by 166, 31, and 373%, respectively, in response to HgCl2 treatment, while intracellular glutathione and plasma antioxidant potential, i.e. ferric reducing ability (FRAP) decreased by 75 and 22%, respectively. BTE protected the rats against HgCl2-induced oxidative damage and raised the antioxidant potential in control rats. Due to its strong antioxidant effect in vivo, black tea intake may provide a significant health-promoting effect to humans.


Ramsay Hunt syndrome in renal transplantation recipient: a case report.
Ramsay Hunt syndrome develops upon reactivation of a latent virus within the geniculate ganglion. The patient presents with acute facial paralysis, severe ear pain, and a vesicular eruption of the external auditory canal and concha. Varicella zoster virus seropositivity occurs among approximately 90% of members of society. In these persons, virus reactivation may occur especially with advancing age and immunosuppression. We present a case of Ramsay Hunt syndrome that developed in a 35-year-old male patient, who had undergone a renal transplantation 8 months prior and had received maintenance immunosuppression.


[Common anemias in neonatology].
We describe the four most common groups of neonatal anemia and their treatments, with particular emphasis on erythropoietin therapy. The hemolytic anemias include the ABO incompatibility (much more frequent, nowadays, than the Rh incompatibility, which has nearly disappeared following the use of anti-D immunoglobulin in postpartum Rh-negative mothers), hereditary spherocytosis and G-6-PD deficiency. Among hypoplastic anemias, that caused by Parvovirus B19 predominates, by far, over Diamond-Blackfan anemia, alpha-thalassemia and the rare sideroblastic anemias. "Hemorrhagic" anemias occur during twin-to-twin transfusions, or during feto-maternal transfusions. Finally, the multifactorial anemia of prematurity develops principally as a result of the rapid expansion of the blood volume in this group of patients. Erythropoietin therapy, often at doses much higher than those used in the adult, should be seriously considered in most cases of non-hypoplastic neonatal anemias, to minimise maximally the use of transfusions.


Eating out intensity, ultra-processed foods and BMI among Albanian youth.
Ultra-processed foods (UPF) and eating out of home (OH) are changing nutrition, particularly among youth in constrained settings. We aimed to assess the role of eating OH intensity on the associations of UPF and unprocessed or minimally processed foods (UMPF) with BMI among Albanian youth. Cross-sectional. Albania, a south-eastern European country. 281 youth, predominantly females. UPF and UMPF were defined based on NOVA, while eating OH intensity based on energy percentage from OH foods. Multivariable models tested associations of UPF and UMPF with BMI stratified by eating OH intensity, controlled for relevant covariates including diet quality, portion size and costs. The respondents age ranged between 18 and 23 years with a female predominance (87·5 %). Mean energy from UPF and UMPF was 846 (sd: 573·0) and 802·9 (422·5) kcals, respectively. Among substantial at home eaters UPF intake was not associated (β = −0·07, 95 % CI (−0·13, 0·267)) with BMI; however, UMPF negatively associated with BMI (β = −0·24, 95 % CI (−0·43, −0·06)). Among those defined as substantial OH eaters, UPF (β = 0·24, 95 % CI (0·08, 0·40)) and UMPF (β = 0·18, 95 % CI (0·04, 0·33)) were positively associated with BMI. Our findings provide evidence for the hypothesis that eating OH plays an important role in the association of UPF and UMPF with BMI in youth. While causality cannot be established due to cross-sectional design, to the best of our knowledge, we provide the first assessment of UPF and UMPF intake in a south-eastern European setting, while highlighting the need for establishing and integrating youth nutrition into national nutritional surveillance systems for key dietary risk factors in Albania.


Tritium ( 3 H) Retention In Mice: Administered As HTO, DTO or as 3 H-Labeled Amino-Acids.
The objective of this study was to compare the biokinetics of injected H-labeled light (HTO) and heavy (DTO) water in CBA/CaJ mice and to compare the organ distribution and/or body content of H administered by chronic ingestion for 1 mo to C57Bl/6J mice, as either H-labeled water or H-labeled amino acids (glycine, alanine and proline). HTO and DTO were administered to CBA/CaJ mice by single intraperitoneal injection and body retention was determined for up to 384 h post-injection. Tritium-labeled water or H-labeled amino acids were given to C57Bl/6J mice ad libitum for 30 d in drinking water. Body content and organ distribution of H during the period of administration and subsequent to administration was determined by liquid scintillation counting. No differences were found between the biokinetics of HTO and DTO, indicating that data generated using HTO can be used to help assess the consequences of H releases from heavy water reactors. The results for H-water showed that the concentration of radionuclide in the mice reached a peak after about 10 d and dropped rapidly after the cessation of H administration. The maximum concentration reached was only 50% of that in the water consumed, indicating that mice receive a significant fraction of their water from respiration. Contrary to the findings of others, the pattern of H retention following the administration of a cocktail of the labeled amino acids was very little different from that found for the water. This is consistent with the suggestion that most of the ingested amino acids were rapidly metabolized, releasing water and carbon dioxide.


Clinical screening for HIV in a health centre setting in urban Kenya: an entry point for voluntary counselling, HIV testing and early diagnosis of HIV infection?
A study was conducted among patients attending a public health centre in Nairobi, Kenya in order to (a) verify the prevalence of HIV, (b) identify clinical risk factors associated with HIV and (c) determine clinical markers for clinical screening of HIV infection at the health centre level. Of 304 individuals involved in the study,107(35%) were HIV positive. A clinical screening algorithm based on four clinical markers, namely oral thrush, past or present TB, past or present herpes zoster and prurigo would pick out 61 (57%) of the 107 HIV-positive individuals. In a resource-poor setting, introducing a clinical screening algorithm for HIV at the health centre level could provide an opportunity for targeting voluntary counselling and HIV testing, and early access to a range of prevention and care interventions.


Low emotion-oriented coping and informal help-seeking behaviour as major predictive factors for improvement in major depression at 5-year follow-up in the adult community.
Given the broad range of biopsychosocial difficulties resulting from major depressive disorder (MDD), reliable evidence for predictors of improved mental health is essential, particularly from unbiased prospective community samples. Consequently, a broad spectrum of potential clinical and non-clinical predictors of improved mental health, defined as an absence of current major depressive episode (MDE) at follow-up, were examined over a 5-year period in an adult community sample. The longitudinal population-based PsyCoLaus study from the city of Lausanne, Switzerland, was used. Subjects having a lifetime MDD with a current MDE at baseline assessment were selected, resulting in a subsample of 210 subjects. Logistic regressions were applied to the data. Coping styles were the most important predictive factors in the present study. More specifically, low emotion-oriented coping and informal help-seeking behaviour at baseline were associated with the absence of an MDD diagnosis at follow-up. Surprisingly, neither formal help-seeking behaviour, nor psychopharmacological treatment, nor childhood adversities, nor depression subtypes turned out to be relevant predictors in the current study. The paramount role of coping styles as predictors of improvement in depression found in the present study might be a valuable target for resource-oriented therapeutic models. On the one hand, the positive impact of low emotion-oriented coping highlights the utility of clinical interventions interrupting excessive mental ruminations during MDE. On the other hand, the importance of informal social networks raises questions regarding how to enlarge the personal network of affected subjects and on how to best support informal caregivers.


Diffuse optical spectroscopic imaging correlates with final pathological response in breast cancer neoadjuvant chemotherapy.
Diffuse optical spectroscopic imaging (DOSI) non-invasively and quantitatively measures tissue haemoglobin, water and lipid. Pilot studies in small groups of patients demonstrate that DOSI may be useful for longitudinal monitoring and predicting breast cancer neoadjuvant chemotherapy pathological response. This study evaluates the performance of a bedside DOSI platform in 34 breast cancer patients followed for several months. DOSI optical endpoints obtained at multiple timepoints are compared with final pathological response. Thirty-six stage II/III breast cancers (34 patients) were measured in vivo with DOSI prior to, in the middle of and after the completion of pre-surgical neoadjuvant chemotherapy. Cancer therapies ranged from standard anthracyclines to targeted therapies. Changes in DOSI-measured parameters at each timepoint were compared against final surgical pathology. Absolute changes in the tumour-to-normal (T/N) ratio of tissue deoxyhaemoglobin concentration (ctHHb) and relative changes in the T/N ratio of a tissue optical index (TOI) were most sensitive and correlate to pathological response. Changes in ctHHb and TOI were significantly different between tumours that achieved pathological complete response (pCR) versus non-pCR. By therapy midpoint, mean TOI-T/N changes were 47±8 versus 20±5 per cent for pCR versus non-pCR subjects, respectively (Z=0.011). Changes in ctHHb and TOI scaled significantly with the degree of pathological response (non-, partial and complete). DOSI measurements of TOI separated pCR from non-pCR by therapy midpoint regardless of drug or dosing strategy. This approach is well suited to monitoring breast tumour response and may provide feedback for optimizing therapeutic outcomes and minimizing side-effects.


Responses of embryonic germ cells of the radiation-sensitive Medaka mutant to gamma-irradiation.
The radiation-sensitive mutant "ric1" has a defect in the repair mechanism of DNA double strand breaks induced by gamma-rays in early embryogenesis. In this study, the new radiation-sensitive Medaka (Oryzias latipes) strain, ric1olvas-GFP was established to monitor the development of germ cells in vivo. The development of germ cells was normal in ric1olvas-GFP, but embryonic germ cells at Stage 7 (32-cell stage) and Stage 33 (extensive proliferating stage of PGCs) showed higher radiosensitivity. There was no sex difference in germ cell radiosensitivity at Stage 7, but female embryos showed higher radiosensitivity than male at Stage 33. In embryos obtained by crossing ric1 female with olvas-GFP male, germ cells showed similar radiosensitivity to ric1olvas-GFP and increased sensitivity compared to embryos obtained from crossing wild-type female with olvas-GFP male at Stage 7. These results suggest that germ cells have the ric1 dependent DNA repair system during embryogenesis and the maternal ric1gene factor may play a critical role in radiosensitivity at an early developmental stage.


Taxonomic changes and non-native species: An overview of constraints and new challenges for macroinvertebrate-based indices calculation in river ecosystems.
Freshwater ecosystems face many threats in the form of reduced water quantity, poor water quality and the loss of biodiversity. As a result, aquatic biomonitoring tools are required to enable the evaluation of these critical changes. Currently, macroinvertebrate-based indices are globally the most widely used biomonitoring tools in fluvial ecosystems. However, very little is known about the potential effects of changes in taxonomic understanding (updating of classification and nomenclature) or the presence of new non-native species for biotic indices calculation. This is especially relevant given that errors, incorrect classification or exclusion of new/updated nomenclature may affect ecological status evaluations and have direct consequences for the management and conservation of freshwater systems. In this discussion paper the main constraints, challenges and implications of these issues are outlined and case studies from a range of European countries are discussed. However, similar challenges affect rivers and managers globally and will potentially be amplified further in the future. Bioassessment science needs to be open to improvements, and current tools and protocols need to be flexible so that they can be updated and revised rapidly to allow new scientific developments to be integrated. This discussion highlights specific examples and new ideas that may contribute to the future development of aquatic biomonitoring using macroinvertebrates and other faunal and floral groups in riverine ecosystems.


Outcome measures in clinical studies of ankle osteoarthritis: a systematic review.
To explore and describe the outcome measures reported in primary research of ankle osteoarthritis (OA) and to propose aligned health-related domains. Six databases were searched, and studies were screened by two independent reviewers. Studies of participants with ankle OA who were> 18 years of age and reported outcome measure data were included. Non-English, animal, cadaveric, reviews, and studies with< 5 participants were excluded. Outcome measures were examined for content and mapped to health-related domains. 1386 studies were identified, of which 547 met selection criteria - reporting 250 outcome measures. Most commonly reported measures were the American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale (n = 257 studies), plain radiographs to measure ankle alignment (n = 211), numerical rating scale for pain severity (n = 177) and goniometry to measure ankle range of motion (n = 148). Outcome measures were organised into 19 domains. The most common domains were pain severity (315 (58%) studies), ankle alignment (254 (46%)), ankle motion (181 (33%)), disability (169 (31%)) and health-related quality of life (128 (23%)). These domains fell into the Outcome Measures in Rheumatology (OMERACT) core areas of life impact and pathophysiological manifestations. Many outcome measures are used in ankle OA research, most of which assess joint alignment, pain, and motion. Based on the outcome measures identified, we proposed 19 possible health-related domains, predominantly in the OMERACT core areas of life impact and pathophysiological manifestations of ankle OA. Clinicians and researchers can use this review in guiding selection of outcome measures.


Integrons in Xanthomonas: a source of species genome diversity.
Integrons are best known for assembling antibiotic resistance genes in clinical bacteria. They capture genes by using integrase-mediated site-specific recombination of mobile gene cassettes. Integrons also occur in the chromosomes of many bacteria, notably beta- and gamma-Proteobacteria. In a survey of Xanthomonas, integrons were found in all 32 strains representing 12 pathovars of two species. Their chromosomal location was downstream from the acid dehydratase gene, ilvD, suggesting that an integron was present at this site in the ancestral xanthomonad. There was considerable sequence and structural diversity among the extant integrons. The majority of integrase genes were predicted to be inactivated by frameshifts, stop codons, or large deletions, suggesting that the associated gene cassettes can no longer be mobilized. In support, groups of strains with the same deletions or stop codons/frameshifts in their integrase gene usually contained identical arrays of gene cassettes. In general, strains within individual pathovars had identical cassettes, and these exhibited no similarity to cassettes detected in other pathovars. The variety and characteristics of contemporary gene cassettes suggests that the ancestral integron had access to a diverse pool of these mobile elements, and that their genes originated outside the Xanthomonas genome. Subsequent inactivation of the integrase gene in particular lineages has largely fixed the gene cassette arrays in particular pathovars during their differentiation and specialization into ecological niches. The acquisition of diverse gene cassettes by different lineages within Xanthomonas has contributed to the species-genome diversity of the genus. The role of gene cassettes in survival on plant surfaces is currently unknown.


Stichoposide C Exerts Anticancer Effects on Ovarian Cancer by Inducing Autophagy via Inhibiting AKT/mTOR Pathway.
Stichoposide C (STC) is a triterpene glycoside isolated from Thelenota ananas, which is previously demonstrated to wide spectrum of anticancer effects against various tumor cells. However, the antitumor effects and underlying molecular mechanisms in ovarian cancer (OC) cells are not fully understood. Here, we examined if and through which mechanisms STC exerts anticancer effects on OC. CCK-8 and colony formation assays were used to detect cell viability and proliferation. Flow cytometry was used to detect apoptosis and cell cycle arrest. Protein expression and phosphorylation were measured by Western blotting analysis. Confocal fluorescence microscopy was used to observe the autophagy flux. Autophagosome formation was observed via transmission electron microscopy. Antitumor effect of STC was investigated in patient-derived organoids (PDOs) and A2780 subcutaneous xenograft tumors. STC was found that not only exerted antiproliferation activity and apoptosis but also induced autophagy. Mechanistically, STC induced autophagy via inhibited the AKT/mTOR signaling pathway in ovarian cancer cells. In addition, STC and an autophagy inhibitor 3-methyladenine (3-MA) combination treatment showed significant synergetic effects on inhibiting proliferation and promoting apoptosis in vitro. Consistent with cell experiments, STC also inhibited the growth of two OC PDOs. Finally, STC markedly reduced the growth of A2780 subcutaneous xenograft tumors without organ toxicity and activated autophagy in vivo. Stichoposide C exerts in vitro and in vivo anticancer effects on ovarian cancer by inducing autophagy via inhibiting AKT/mTOR pathway. The findings warrant further prove for STC as a potential therapeutic agent for ovarian cancer.


Muscarinic receptors promote pacemaker fate at the expense of secondary conduction system tissue in zebrafish.
Deterioration or inborn malformations of the cardiac conduction system (CCS) interfere with proper impulse propagation in the heart and may lead to sudden cardiac death or heart failure. Patients afflicted with arrhythmia depend on antiarrhythmic medication or invasive therapy, such as pacemaker implantation. An ideal way to treat these patients would be CCS tissue restoration. This, however, requires precise knowledge regarding the molecular mechanisms underlying CCS development. Here, we aimed to identify regulators of CCS development. We performed a compound screen in zebrafish embryos and identified tolterodine, a muscarinic receptor antagonist, as a modifier of CCS development. Tolterodine provoked a lower heart rate, pericardiac edema, and arrhythmia. Blockade of muscarinic M3, but not M2, receptors induced transcriptional changes leading to amplification of sinoatrial cells and loss of atrioventricular identity. Transcriptome data from an engineered human heart muscle model provided additional evidence for the contribution of muscarinic M3 receptors during cardiac progenitor specification and differentiation. Taken together, we found that muscarinic M3 receptors control the CCS already before the heart becomes innervated. Our data indicate that muscarinic receptors maintain a delicate balance between the developing sinoatrial node and the atrioventricular canal, which is probably required to prevent the development of arrhythmia.


The effect of FloSeal on mucosal healing after endoscopic sinus surgery: a comparison with thrombin-soaked gelatin foam.
The optimal form of nasal packing after endoscopic sinus surgery (ESS) still has not been established Although wide variations exist among sinus surgeons, the goals are adequate hemostasis, rapid healing, and patient comfort. Preliminary studies indicated that FloSeal (FS), a novel absorbable hemostatic paste used as a nasal pack, was associated with minimal postoperative discomfort and effective hemostasis. This study was designed to evaluate the effects of this agent on mucosal healing in ESS. Twenty consecutive patients underwent bilateral ESS. For each patient, one ethmoid cavity was randomized to receive FS and the other received thrombin-soaked gelatin foam. The extent of granulation tissue and adhesion formation was evaluated at 6-8 weeks after surgery. No significant differences were observed between the FS and the thrombin-soaked gelatin foam groups with respect to the preoperative Lund-Mackay score, extent of surgery performed, or need for additional nasal packing. However, the FS group showed clear trends toward increased granulation tissue (p = 0.007) and adhesion (p = 0.006) formation. Absorbable hemostatic agents are associated with a high degree of patient comfort and provide hemostasis comparable with traditional techniques. Different materials may induce differential patterns of mucosal healing, potentially affecting the ultimate result of ESS.


The course of asthma activity: a population study.
Unlike most chronic diseases, which tend to progress over time, asthma is known to persist, possibly resolve, and/or present with any combination of remissions and relapses. As a result, its course has been difficult to characterize and its prognosis difficult to predict. To quantify the proportion of individuals with asthma who have active disease and, of those, the proportion who experience significant gaps in their asthma activity; and to determine factors associated with asthma activity. Universal population health administrative databases were used to identify all individuals with asthma living in Ontario, Canada, in 1993 and follow them for 15 years. Active asthma was indicated by 1 or more physician claims for asthma. Of 613,394 individuals with asthma in 1993, 504,851 (82.3%) had active disease in subsequent years. Of those who had complete follow-up, 74.6% experienced a gap of 2 or more years in their asthma activity. Previous asthma claims, older and younger age, and a codiagnosis of chronic obstructive pulmonary disease correlated with greater asthma activity. Over 15 years, most individuals with asthma in Ontario, Canada, had active disease that was interspersed by periods of inactivity when they did not require medical attention and were likely in remission. These analyses offer insight into the natural course of asthma activity that may help improve the ability to predict an individual's course of disease.


Effects of Caffeine Supplementation on Performance in Ball Games.
Although a large body of evidence exists documenting the ergogenic properties of caffeine, most studies have focused on endurance performance. However, findings from endurance sports cannot be generalized to performance in ball games where, apart from having a high level of endurance, successful athletic performances require a combination of physiological, technical and cognitive capabilities. The purpose of this review was to critically evaluate studies that have examined the effect of a single dose of caffeine in isolation on one or more of the following performance measures: total distance, sprint performance, agility, vertical jump performance and accuracy in ball games. Searches of three major databases resulted in 19 studies (invasion games: 13; net-barrier games: 6) that evaluated the acute effects of caffeine on human participants, provided the caffeine dose administered, and included a ball games specific task or simulated match. Improvements in sprint performance were observed in 8 of 10 studies (80%), and vertical jump in 7 of 8 studies (88%). Equivocal results were reported for distance covered, agility and accuracy. Minor side effects were reported in 4 of 19 studies reviewed. Pre-exercise caffeine ingestion between 3.0 and 6.0 mg/kg of body mass appears to be a safe ergogenic aid for athletes in ball games. However, the efficacy of caffeine varies depending on various factors, including, but not limited to, the nature of the game, physical status and caffeine habituation. More research is warranted to clarify the effects of caffeine on performance measures unique to ball games, such as agility and accuracy. It is essential that athletes, coaches and practitioners evaluate the risk-benefit ratio of caffeine ingestion strategies on an individual case-by-case basis.


Extracellular matrix: a new player in memory maintenance and psychiatric disorders.
How the brain performs higher cognitive functions such as learning and memory is traditionally studied by investigating how neurons work. However, over the past two decades, evidence has accumulated which suggests that components of the extracellular matrix contribute to the storing of information through learning processes. Thus, matrix regulation – either changes in the protein composition of the perineural network surrounding neurons or cleavage of this network by specific metalloproteases – could be relevant to the many psychiatric disorders that are shaped by previous experiences, i.e. by learning and plasticity. This includes disorders which are a direct consequence of past experiences and ones where previous experiences constitute a risk factor. Psychotherapy is one of the first-line treatments for most psychiatric conditions, and involves learning and plasticity. Here, we review selected publications pertaining to experience dependence in psychiatric conditions and summarise evidence of roles for the extracellular matrix in learning and memory. We then suggest how control of the extracellular matrix could be leveraged for innovative treatments and, more generally, discuss possible aetiological effects of extracellular matrix alterations in psychiatric disorders.


[Primary orthostatic tremor: report of 4 cases].
We report on four cases of primary orthostatic tremor. The purpose of this study is the rarity of this type of tremor and the differential diagnosis with other tremors. The electrophysiological study showed a 15-20 Hz tremor frequency in our cases. There are clinical, electrophysiological and therapeutic differences of primary orthostatic tremor in report to other tremors of legs, according to the literature and characteristics of our cases.


A comparative test of adaptive hypotheses for sexual size dimorphism in lizards.
It is commonly argued that sexual size dimorphism (SSD) in lizards has evolved in response to two primary, nonexclusive processes: (1) sexual selection for large male size, which confers an advantage in intrasexual mate competition (intrasexual selection hypothesis), and (2) natural selection for large female size, which confers a fecundity advantage (fecundity advantage hypothesis). However, outside of several well-studied lizard genera, the empirical support for these hypotheses has not been examined with appropriate phylogenetic control. We conducted a comparative phylogenetic analysis to test these hypotheses using literature data from 497 lizard populations representing 302 species and 18 families. As predicted by the intrasexual selection hypothesis, male aggression and territoriality are correlated with SSD, but evolutionary shifts in these categorical variables each explain less than 2% of the inferred evolutionary change in SSD. We found stronger correlations between SSD and continuous estimates of intrasexual selection such as male to female home range ratio and female home range size. These results are consistent with the criticism that categorical variables may obscure much of the actual variation in intrasexual selection intensity needed to explain patterns in SSD. In accordance with the fecundity advantage hypothesis, SSD is correlated with clutch size, reproductive frequency, and reproductive mode (but not fecundity slope, reduced major axis estimator of fecundity slope, length of reproductive season, or latitude). However, evolutionary shifts in clutch size explain less than 8% of the associated change in SSD, which also varies significantly in the absence of evolutionary shifts in reproductive frequency and mode. A multiple regression model retained territoriality and clutch size as significant predictors of SSD, but only 16% of the variation in SSD is explained using these variables. Intrasexual selection for large male size and fecundity selection for large female size have undoubtedly helped to shape patterns of SSD across lizards, but the comparative data at present provide only weak support for these hypotheses as general explanations for SSD in this group. Future work would benefit from the consideration of alternatives to these traditional evolutionary hypotheses, and the elucidation of proximate mechanisms influencing growth and SSD within populations.


Intercellular adhesion molecule-1 K469E and angiotensinogen T207M polymorphisms in coronary slow flow.
To investigate intercellular adhesion molecule-1 (ICAM1) and angiotensinogen (AGT) gene polymorphisms, as related to atherosclerosis and endothelial dysfunction, in coronary slow flow (CSF). The participants in this study were 48 patients with CSF and 67 patients with normal coronary flow as controls. The K469E polymorphism of ICAM1 (rs5498) and the T207M polymorphism of AGT (rs4762) were determined using the polymerase chain reaction amplification method. Baseline demographic parameters were similar in both groups. The mean thrombolysis in myocardial infarction frame count was significantly higher in patients with CSF (23.8 ± 5.1) compared to the controls (13.3 ± 2.6, p < 0.001). A significant association was found between the ICAM1 K allele and CSF (OR: 1.96, 95% CI: 1.15-3.35, p = 0.013). There was no difference in the frequency of AGT T207M genotypes in the patients with CSF and the control subjects. This study showed that K469E polymorphisms of ICAM1 that play a role in atherosclerotic pathogenesis are related to CSF.


The treatment of urinary tract infections in women with diabetes mellitus.
Forty-five women with diabetes mellitus and urinary tract infections have been followed an average of 34 mo on treatment protocols based on localization of infection as determined by the presence or absence of antibody-coated bacteria (ACB). Treatment was usually, but not exclusively, trimethoprim-sulfamethoxazole. Two weeks of oral therapy was equally efficacious to 6 wk of treatment in asymptomatic women with antibody-coated bacteria (ACB)-positive infection in eradicating bacteriuria. Recurrences in all groups were predominantly reinfections with differing serotypes or species of microorganisms. The sustained remission rate (fractional extraction) after initial treatment was similar to other reported groups, but possibly less efficacious with recurrences. Suppressive therapy with trimethoprim-sulfamethoxazole for repeated recurrences effectively prevented infection but provided no posttreatment benefit. A high prevalence of underlying structural genitourinary tract abnormalities, usually detectable on pelvic examination, and which were not direct consequences of diabetes mellitus, were possible contributing factors to recurrent infection in this patient group. Progressive elevation in serum creatinine in seven patients with initial ACB-positive infections appeared to relate more closely to diabetic nephropathy rather than chronic pyelonephritis. ACB-positivity correlated well with elevated serum antibody titers and the presence of underlying anatomic abnormalities, but ACB categorization did not lead to improved therapeutic strategy or outcome and hence was of limited clinical usefulness.


Optical coherence tomography imaging for analysis of follicular development in ovarian tissue.
We describe the application of optical coherence tomography (OCT) for noninvasive analysis of follicular development in mouse ovaries. Ovaries contain many follicles and oocytes. Quantification of follicles at various developmental stages is an indication of the ability of an ovary to provide oocytes capable of fertilization. Three-dimensional structural OCT images identified each developmental stage, from a primary follicle (50 μm in diameter) to an antral follicle (350 μm in diameter), in the ovary of a 25.5-day-old mouse. We discovered time-varying OCT signals at the oocytes that differentiated them from surrounding tissues. These signals were clearly enhanced by interframe intensity-based Doppler OCT techniques. The OCT technology was effective in analyzing the development of follicles and oocytes in ovaries.


EEG coherence in Alzheimer's dementia.
In Alzheimer's dementia (AD) axonal disruption and cholinergic deficit lead to impaired cortical connectivity and to a decrease in EEG alpha coherence. The aim of the present study was to assess the usefulness of coherence parameters of the EEG for the diagnostics of AD. Quantitative EEG analyses were performed in 31 AD patients and 17 cognitively unimpaired depressive controls, both groups without psychopharmacological treatment. Differences between groups were examined and the diagnostic significance of EEG parameters was assessed by means of stepwise logistic regression analyses. In the AD patients global theta power was increased, left temporal alpha coherence and interhemispheric theta coherence were decreased. Left temporal alpha coherence and global theta power allowed an identification of AD patients with a sensitivity of 87% and a specificity of 77%. Quantitative analyses, especially the determination of left temporal alpha coherence, may enhance the usefulness of the EEG in the diagnostics of AD.


Impact of dyslipidaemia on arterial structure and function in urban indigenous Australians.
Premature cardiovascular disease (CDV) is highly prevalent in urban Indigenous Australians. We studied arterial structure and function in 144 volunteers aged 15-66 years to assess the role of dyslipidaemia and other traditional vascular risk factors on cardiovascular risk in young and older urban Indigenous Australians. We assessed carotid intima-media thickness (CIMT) by high-resolution B-mode ultrasound imaging of the common carotid artery and peripheral wave reflection using applanation tonometry to obtain the aortic augmentation index (AI) in Indigenous Australian participants of the Darwin Region Urban Indigenous Diabetes (DRUID) study. Participants aged 15-24 years demonstrated fewer cardiovascular risk factors than the older group (25-66 years) and predictors of CIMT and AI differed between younger and older groups. CIMT was higher in the older group (0.67mm vs. 0.61mm, p=0.004) and in those with diabetes (0.81mm vs. 0.67mm, p<0.001). AI was higher in the older group (24% vs. 0%, p<0.001), but was not affected by diabetes status. On multivariate regression analysis, low HDL-cholesterol was the only independent predictor of CIMT in the younger group; triglycerides, heart rate (inverse) and height (inverse) were independent predictors of AI in the same group. Dyslipidaemia (low HDL-cholesterol or elevated triglycerides) is independently associated with non-invasive measures of cardiovascular disease in a relatively healthy and young subgroup of this high-risk population. We propose that triglycerides and low HDL-cholesterol may represent the most useful commonly measured clinical indicators of cardiovascular risk in young, urban Indigenous Australians.


Epigenomic footprints across 111 reference epigenomes reveal tissue-specific epigenetic regulation of lincRNAs.
Tissue-specific expression of lincRNAs suggests developmental and cell-type-specific functions, yet tissue specificity was established for only a small fraction of lincRNAs. Here, by analysing 111 reference epigenomes from the NIH Roadmap Epigenomics project, we determine tissue-specific epigenetic regulation for 3,753 (69% examined) lincRNAs, with 54% active in one of the 14 cell/tissue clusters and an additional 15% in two or three clusters. A larger fraction of lincRNA TSSs is marked in a tissue-specific manner by H3K4me1 than by H3K4me3. The tissue-specific lincRNAs are strongly linked to tissue-specific pathways and undergo distinct chromatin state transitions during cellular differentiation. Polycomb-regulated lincRNAs reside in the bivalent state in embryonic stem cells and many of them undergo H3K27me3-mediated silencing at early stages of differentiation. The exquisitely tissue-specific epigenetic regulation of lincRNAs and the assignment of a majority of them to specific tissue types will inform future studies of this newly discovered class of genes.


Structures of human pannexin 1 reveal ion pathways and mechanism of gating.
Pannexin 1 (PANX1) is an ATP-permeable channel with critical roles in a variety of physiological functions such as blood pressure regulation1, apoptotic cell clearance2 and human oocyte development3. Here we present several structures of human PANX1 in a heptameric assembly at resolutions of up to 2.8 angström, including an apo state, a caspase-7-cleaved state and a carbenoxolone-bound state. We reveal a gating mechanism that involves two ion-conducting pathways. Under normal cellular conditions, the intracellular entry of the wide main pore is physically plugged by the C-terminal tail. Small anions are conducted through narrow tunnels in the intracellular domain. These tunnels connect to the main pore and are gated by a long linker between the N-terminal helix and the first transmembrane helix. During apoptosis, the C-terminal tail is cleaved by caspase, allowing the release of ATP through the main pore. We identified a carbenoxolone-binding site embraced by W74 in the extracellular entrance and a role for carbenoxolone as a channel blocker. We identified a gap-junction-like structure using a glycosylation-deficient mutant, N255A. Our studies provide a solid foundation for understanding the molecular mechanisms underlying the channel gating and inhibition of PANX1 and related large-pore channels.


Photoacoustic imaging of the dynamics of a dye-labeled IgG4 monoclonal antibody in subcutaneous tissue reveals a transient decrease in murine blood oxygenation under anesthesia.
Over 100 monoclonal antibodies have been approved by the U.S. Food and Drug Administration (FDA) for clinical use; however, a paucity of knowledge exists regarding the injection site behavior of these formulated therapeutics, particularly the effect of antibody, formulation, and tissue at the injection site. A deeper understanding of antibody behavior at the injection site, especially on blood oxygenation through imaging, will help design improved versions of the therapeutics for a wide range of diseases. The aim of this research is to understand the dynamics of monoclonal antibodies at the injection site as well as how the antibody itself affects the functional characteristics of the injection site [e.g., blood oxygen saturation (sO2)]. We employed triple-wavelength equipped functional photoacoustic imaging to study the dynamics of dye-labeled and unlabeled monoclonal antibodies at the site of injection in a mouse ear. We injected a near-infrared dye-labeled (and unlabeled) human IgG4 isotype control antibody into the subcutaneous space in mouse ears to analyze the injection site dynamics and quantify molecular movement, as well as its effect on local hemodynamics. We performed pharmacokinetic studies of the antibody in different regions of the mouse body to show that dye labeling does not alter the pharmacokinetic characteristics of the antibody and that mouse ear is a viable model for these initial studies. We explored the movement of the antibody in the interstitial space to show that the bolus area grows by ∼300% over 24 h. We discovered that injection of the antibody transiently reduces the local sO2 levels in mice after prolonged anesthesia without affecting the total hemoglobin content and oxygen extraction fraction. This finding on local oxygen saturation opens a new avenue of study on the functional effects of monoclonal antibody injections. We also show the suitability of the mouse ear model to study antibody dynamics through high-resolution imaging techniques. We quantified the movement of antibodies at the injection site caused by the interstitial fluid, which could be helpful for designing antibodies with tailored absorption speeds in the future.


A biologically constrained model of the whole basal ganglia addressing the paradoxes of connections and selection.
The basal ganglia nuclei form a complex network of nuclei often assumed to perform selection, yet their individual roles and how they influence each other is still largely unclear. In particular, the ties between the external and internal parts of the globus pallidus are paradoxical, as anatomical data suggest a potent inhibitory projection between them while electrophysiological recordings indicate that they have similar activities. Here we introduce a theoretical study that reconciles both views on the intra-pallidal projection, by providing a plausible characterization of the relationship between the external and internal globus pallidus. Specifically, we developed a mean-field model of the whole basal ganglia, whose parameterization is optimized to respect best a collection of numerous anatomical and electrophysiological data. We first obtained models respecting all our constraints, hence anatomical and electrophysiological data on the intrapallidal projection are globally consistent. This model furthermore predicts that both aforementioned views about the intra-pallidal projection may be reconciled when this projection is weakly inhibitory, thus making it possible to support similar neural activity in both nuclei and for the entire basal ganglia to select between actions. Second, we predicts that afferent projections are substantially unbalanced towards the external segment, as it receives the strongest excitation from STN and the weakest inhibition from the striatum. Finally, our study strongly suggests that the intrapallidal connection pattern is not focused but diffuse, as this latter pattern is more efficient for the overall selection performed in the basal ganglia.


Sorafenib improves alkylating therapy by blocking induced inflammation, invasion and angiogenesis in breast cancer cells.
Molecular targeted compounds are emerging as a strategy to improve classical chemotherapy. Herein, we describe that using low dose of the multikinase inhibitor sorafenib improves cyclophosphamide antitumor activity by inhibiting angiogenesis, metastasis and promoting tumor healing in MDA-MB231 xenografts and the 4T1-12B syngeneic breast cancer metastasis model. Mechanistic studies in MDA-MB231 cells revealed that alkylation upregulates inflammatory genes/proteins such as COX-2, IL8, CXCL2 and MMP1 in a MEK1/2-ERK1/2-dependent manner. These proteins enrich the secretome of cancer cells, stimulating cell invasion and angiogenesis via autocrine and paracrine mechanisms. Sorafenib inhibits MEK1/2-ERK1/2 pathway thereby decreasing inflammatory genes and mitigating cell invasion and angiogenesis at basal and alkylation-induced conditions whereas NRF2 and ER stress pathways involved in alkylation survival are not affected. In non-invasive/non-angiogenic breast cancer cells (SKBR3 and MCF7), alkylation did not elicit inflammatory responses with the only sorafenib effect being ERK1/2-independent ROS-dependent cytotoxicity when using higher drug concentrations. In summary, our data show that alkylating agents may elicit inflammatory responses that seems to contribute to malignant progression in specific breast cancer cells. Identifying and targeting drivers of this phenotype may offer opportunities to optimize combined drug regimens between classical chemotherapeutics and targeted agents.


Abortion Rights and the Child Welfare System: How Dobbs Exacerbates Existing Racial Inequities and Further Traumatizes Black Families.
This article explores how abortion bans in states with large Black populations will exacerbate existing racial inequities in those states' child welfare systems.


The Role of MMP8 in Cancer: A Systematic Review.
Matrix metalloproteinases (MMPs) have traditionally been considered as tumor promoting enzymes as they degrade extracellular matrix components, thus increasing the invasion of cancer cells. It has become evident, however, that MMPs can also cleave and alter the function of various non-matrix bioactive molecules, leading to both tumor promoting and suppressive effects. We applied systematic review guidelines to study MMP8 in cancer including the use of MMP8 as a prognostic factor or as a target/anti-target in cancer treatment, and its molecular mechanisms. A total of 171 articles met the inclusion criteria. The collective evidence reveals that in breast, skin and oral tongue cancer, MMP8 inhibits cancer cell invasion and proliferation, and protects patients from metastasis via cleavage of non-structural substrates. Conversely, in liver and gastric cancers, high levels of MMP8 worsen the prognosis. Expression and genetic alterations of MMP8 can be used as a prognostic factor by examination of the tumor and serum/plasma. We conclude, that MMP8 has differing effects on cancers depending on their tissue of origin. The use of MMP8 as a prognostic factor alone, or with other factors, seems to have potential. The molecular mechanisms of MMP8 in cancer further emphasize its role as an important regulator of bioactive molecules.


Urinary tract infections in children.
A five-year review of pediatric patients with urinary tract infections shows that absolute colony counts are not satisfactory as the sole criterion for urinary tract infection. Prior to culture results, patients can be treated empirically if the urine is nitrite-positive or if there is more than an occasional organism per high power field on unspun urine. In this series, no diagnostic or therapeutic benefit resulted from localizing studies. Patients with enuresis and infection should undergo radiologic evaluation for an anatomic abnormality.


Cost modeling of preoperative axillary ultrasound and fine-needle aspiration to guide surgery for invasive breast cancer.
Preoperative axillary lymph node ultrasound (US) and fine-needle aspiration (FNA) biopsy can identify a proportion of node-positive patients and avoid sentinel lymph node (SLN) surgery and direct surgical treatment. We compared the costs with preoperative US/FNA to without US/FNA (standard of care) for invasive breast cancer. Using decision-analytic software we constructed a model to assess the costs associated with the two preoperative strategies. Diagnostic test sensitivities and specificities were obtained from literature review. Costs were derived from Medicare payment rates and actual resource utilization. Base-case results were fully probabilistic to capture parameter uncertainty in economic results. Base-case results estimate total mean costs per patient of $10,947 ("$" indicates US dollars throughout) with the US/FNA strategy and $10,983 with standard of care, an incremental cost savings of $36, on average, per patient [95% confidence interval (CI) of cost difference: -$248 to $179]. Most (63%) of the simulations resulted in cost saving with axillary US/FNA. One-way sensitivity analyses suggest that results are sensitive to assumed diagnostic and surgical costs and selected diagnostic test parameters. US/FNA approach was similar in costs or cost saving relative to the standard of care for all tumor stages. The additional cost of performing axillary US with possible FNA in every patient is balanced, on average, by the savings from avoiding SLN in cases where metastasis can be documented preoperatively. Routine use of preoperative axillary US with FNA to guide surgical planning can decrease the overall cost of patient care for invasive breast cancer.


Improving shape depiction under arbitrary rendering.
Based on the observation that shading conveys shape information through intensity gradients, we present a new technique called Radiance Scaling that modifies the classical shading equations to offer versatile shape depiction functionalities. It works by scaling reflected light intensities depending on both surface curvature and material characteristics. As a result, diffuse shading or highlight variations become correlated with surface feature variations, enhancing concavities and convexities. The first advantage of such an approach is that it produces satisfying results with any kind of material for direct and global illumination: we demonstrate results obtained with Phong and Ashikmin-Shirley BRDFs, Cartoon shading, sub-Lambertian materials, perfectly reflective or refractive objects. Another advantage is that there is no restriction to the choice of lighting environment: it works with a single light, area lights, and interreflections. Third, it may be adapted to enhance surface shape through the use of precomputed radiance data such as Ambient Occlusion, Prefiltered Environment Maps or Lit Spheres. Finally, our approach works in real time on modern graphics hardware making it suitable for any interactive 3D visualization.


Combining wide-field super-resolution microscopy and electron tomography: rendering nanoscopic correlative arrays on subcellular architecture.
In this chapter, the authors outline in full detail, an uncomplicated approach that enables the combination of wide-field fluorescence super-resolution microscopy with electron tomography, thereby providing an approach that affords the best possible confidence in the structures investigated. The methodical steps to obtain these high-throughput correlative nanoscopic arrays will be visually explored and outlined in detail. The authors will demonstrate the feasibility of the method on cultured Caco-2 colorectal cancer cells that are labeled for filamentous actin. The presented images, morphometric data, and generated models illustrate the strengths of our correlative approach for future advanced structural-biology-oriented questions. Correlative nanoscopy applications can be readily found in which there is a need to reveal biomolecular information at unprecedented resolution on subcellular behavior in various biological and pathobiological processes.


In vivo measurement of water self diffusion in the human brain by magnetic resonance imaging.
A new pulse sequence for in vivo diffusion measurements by magnetic resonance imaging (MRI) is introduced. The pulse sequence was tested on phantoms to evaluate the accuracy, reproducibility and inplane variations. The sensitivity of the sequence was tested by measuring the self diffusion coefficient of water with different temperatures. This phantom study showed that the water self diffusion could be measured accurately and that the inplane deviation was less than +/- 10 per cent. Seven healthy volunteers were studied with a 10 mm thick slice through the lateral ventricles, clear differences between grey and white matter as well as regional differences within the white matter were seen. In two patients with infarction, alternations in water self diffusion were seen in the region of the infarct. Likewise, pronounced changes in brain water self diffusion were observed in a patient with benign intracranial hypertension. The results indicate that brain water self diffusion can be measured in vivo with reasonable accuracy. The clinical examples suggest that diffusion measurements may be clinically useful adding further information about in vivo MR tissue characterization.


The Airways' Mechanical Stress in Lung Disease: Implications for COPD Pathophysiology and Treatment Evaluation.
The airway epithelium stretches and relaxes during the normal respiratory cycle, and hyperventilation exaggerates this effect, resulting in changes in lung physiology. In fact, stretching of the airways influences lung function and the secretion of airway mediators, which in turn may cause a potentially injurious inflammatory response. This aim of the present narrative review was to illustrate the current evidence on the importance of mechanical stress in the pathophysiology of lung diseases with a particular focus on chronic obstructive pulmonary disease (COPD) and to discuss how this may influence pharmacological treatment strategies. Overall, treatment selection should be tailored to counterpart the effects of mechanical stress, which influences inflammation both in asthma and COPD. The most suitable treatment approach between a long-acting β2-agonists/long-acting antimuscarinic-agonist (LABA/LAMA) alone or with the addition of inhaled corticosteroids should be determined based on the underlying mechanism of inflammation. Noteworthy, the anti-inflammatory effects of the glycopyrronium/indacaterol combination on hyperinflation and mucociliary clearance may decrease the rate of COPD exacerbations, and it may synergistically improve bronchodilation with a double action on both the cyclic adenosine monophosphate (cAMP) and the acetylcholine pathways.


Optimal stopover model: A state-dependent habitat selection model for staging passerines.
During their seasonal migration, birds stage in areas comprising stopover sites of varying quality. Given that migrating birds have a limited information about their environment, they may land at a low-quality stopover site in which their fuel deposition rate (FDR) is low. Birds landing at such sites should decide either to extend their stopover duration or to quickly depart in search for a better site. These decisions, however, strongly depend on their body condition upon landing. To understand the decision-making process of passerines within a stopover area, comprising stopover sites of varying quality, prior to the crossing of a large ecological barrier, we constructed a state-dependent habitat selection model. The model assumes that even if migrating birds have an expectation of encountered area quality, they cannot control for their initial landing site. Once landing, movement between low- and high-quality stopover sites will occur only if the body condition of these birds is high to the extent that they can entail the energetic cost of movement. Birds in the model aim to maximize their fuel load at the end of the stopover period, to suffice for successfully crossing a large ecological barrier. The model is based on empirical data on autumn migrating Blackcaps Sylvia atricapilla, collected at two important stopover sites in the Negev desert of Israel. Migrating passerines staging at these two sites differ in their FDR and body condition. The model shows that the optimal behaviour when arriving at a low-quality stopover site is to abandon it quickly. However, as lean individuals cannot entail the costs of searching for an alternative site, they have no other choice but to stay there even if their chances to successfully cross the Sahara Desert ahead are low. Our model can be applied to other ecological systems. Proper use of this model may allow good assessment of stopover site quality, as indicated by the bird's FDR, regardless of specific site characteristics. Hence, it can help applying targeted management decisions regarding the maintenance of stopover sites or establishment of new ones.


Enhanced radiometric detection of Mycobacterium paratuberculosis by using filter-concentrated bovine fecal specimens.
A commercial radiometric medium, BACTEC 12B, was modified by addition of mycobactin, egg yolk suspension, and antibiotics (vancomycin, amphotericin B, and nalidixic acid). Decontaminated bovine fecal specimens were filter concentrated by using 3-microns-pore-size, 13-mm-diameter polycarbonate filters, and the entire filter was placed into the radiometric broth. Comparison of the radiometric technique with conventional methods on 603 cattle from 9 Mycobacterium paratuberculosis-infected herds found that of 75 positive specimens, the radiometric technique detected 92% while conventional methods detected 60% (P less than 0.0005). Only 3.9% of radiometric cultures were contaminated. To measure the effect of filter concentration of specimens on the detection rate, 5 cattle with minimal and 5 with moderate ileum histopathology were sampled weekly for 3 weeks. M. paratuberculosis was detected in 33.3% of nonfiltered specimens and 76.7% of filtered specimens (P less than 0.005). Detection rates were directly correlated with the severity of disease, and the advantage of specimen concentration was greatest on fecal specimens from cattle with low-grade infections. Detection times were also correlated with infection severity: 13.4 +/- 5.9 days with smear-positive specimens, 27.9 +/- 8.7 days with feces from cows with typical subclinical infections, and 38.7 +/- 3.8 days with fecal specimens from cows with low-grade infections. Use of a cocktail of vancomycin, amphotericin B, and nalidixic acid for selective suppression of nonmycobacterial contaminants was better than the commercial product PANTA (Becton Dickinson Microbiologic Systems, Towson, Md.) only when specimens contained very low numbers of M. paratuberculosis. Radiometric culture of filter-concentrated specimens generally doubled the number of positive fecal specimens detected over conventional methods, making it a useful tool for diagnosis and control of bovine paratuberculosis.