The diagnostic value of urinary pyridinium cross-links of collagen, serum total alkaline phosphatase, and urinary calcium excretion in neoplastic bone disease.
Bone metastases strongly affect skeletal metabolism by both their growth and their paracrine activities. However, so far no specific laboratory marker has been found to signal the spread of neoplastic disease to bone. We performed a cross-sectional study of 153 cancer patients and an equal number of healthy controls matched for sex and age, in which we determined serum levels of calcium and total alkaline phosphatase (TAP) as well as the fasting urinary excretion of calcium (uCa) and of the collagen cross-links pyridinoline (uPYD) and deoxypyridinoline (uDPD). The aim of the study was to analyze the diagnostic validity of the biochemical parameters measured with regard to neoplastic bone involvement. In the cancer group, 98 patients had overt bone metastases, as judged from radiographic and radioisotopic bone imaging. The remaining 55 patients were also in an advanced stage of disease, but there was no evidence of malignant bone involvement. In comparison to healthy controls, patients both with and without metastatic bone disease had significantly higher levels of TAP, uPYD, and uDPD (P < 0.0001). Only in cancer patients with bone metastases was the median serum calcium level higher than in the healthy controls (P < 0.02). uCa was the same in cancer patients and the control group. Within the collective of cancer patients, individuals with skeletal metastases had higher levels of serum calcium (P < 0.05), TAP (P < 0.01), and uPYD and uDPD (both P < 0.0001), than patients without evidence of malignant bone disease. uCa did not differ between the 2 groups of cancer patients. The cancer patients were then stratified into 4 subgroups according to the serum calcium level (< or = 2.6 mmol/L >) and the absence or evidence of bone metastases. This stratification revealed that in patients with bone metastases, uPYD and uDPD levels were similar in normocalcemic and hypercalcemic subjects, whereas in hypercalcemic patients, uCa levels significantly exceeded those in normocalcemic patients. When the efficacy of TAP, uCa, uPYD, and uDPD in discriminating between patients with and without bone metastases was evaluated by use of receiver-operating characteristic curves and stepwise multivariate regression analysis, uPYD was found to have the highest diagnostic validity. Using 50 mumol PYD/mol creatinine (i.e. the upper limit of normal range) as the cut-off level, the sensitivity of uPYD was 88.7%, whereas the specificity was only 41.8% (odds ratio, 5.598; 95% confidence interval, 2.547-12.306).(ABSTRACT TRUNCATED AT 400 WORDS)


Photobiomodulation on human annulus fibrosus cells during the intervertebral disk degeneration: extracellular matrix-modifying enzymes.
Destruction of extracellular matrix (ECM) leads to degeneration of the intervertebral disk (IVD), which is a major contributor to many spine disorders. IVD degeneration is induced by pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), which are secreted by immune cells, including macrophages and neutrophils. The cytokines modulate ECM-modifying enzymes such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in human annulus fibrosus (AF) cells. The resulting imbalance in catabolic and anabolic enzymes can cause generalized back, neck, and low back pain (LBP). Photobiomodulation (PBM) is known to regulate inflammatory responses and wound healing. The aim of this study was to mimic the degenerative IVD microenvironment, and to investigate the effect of a variety of PBM conditions (wavelength: 635, 525, and 470 nm; energy density: 16, 32, and 64 J/cm(2)) on the production of ECM-modifying-enzymes by AF cells under degenerative conditions induced by macrophage-conditioned medium (MCM), which contains pro-inflammatory cytokines such as TNF-α and IL-β secreted by macrophage during the development of intervertebral disk inflammation. We showed that the MCM-stimulated AF cells express imbalanced ratios of TIMPs (TIMP-1 and TIMP-2) and MMPs (MMP-1 and MMP-3). PBM selectively modulated the production of ECM-modifying enzymes in AF cells. These results suggest that PBM can be a therapeutic tool for degenerative IVD disorders.


Stratification of Lung Cancer Risk with Thoracic Imaging Phenotypes.
In lung cancer screening, estimation of future lung cancer risk is usually guided by demographics and smoking status. The role of constitutional profiles of human body, a.k.a. body habitus, is increasingly understood to be important, but has not been integrated into risk models. Chest low dose computed tomography (LDCT) is the standard imaging study in lung cancer screening, with the capability to discriminate differences in body composition and organ arrangement in the thorax. We hypothesize that the primary phenotypes identified using lung screening chest LDCT can form a representation of body habitus and add predictive power for lung cancer risk stratification. In this pilot study, we evaluated the feasibility of body habitus image-based phenotyping on a large lung screening LDCT dataset. A thoracic imaging manifold was estimated based on an intensity-based pairwise (dis)similarity metric for pairs of spatial normalized chest LDCT images. We applied the hierarchical clustering method on this manifold to identify the primary phenotypes. Body habitus features of each identified phenotype were evaluated and associated with future lung cancer risk using time-to-event analysis. We evaluated the method on the baseline LDCT scans of 1,200 male subjects sampled from National Lung Screening Trial. Five primary phenotypes were identified, which were associated with highly distinguishable clinical and body habitus features. Time-to-event analysis against future lung cancer incidences showed two of the five identified phenotypes were associated with elevated future lung cancer risks (HR=1.61, 95% CI = [1.08, 2.38], p=0.019; HR=1.67, 95% CI = [0.98, 2.86], p=0.057). These results indicated that it is feasible to capture the body habitus by image-base phenotyping using lung screening LDCT and the learned body habitus representation can potentially add value for future lung cancer risk stratification.


A comprehensive molecular study identified 12 complementation groups with 56 novel FANC gene variants in Indian Fanconi anemia subjects.
Fanconi anemia (FA) is a rare autosomal or X-linked genetic disorder characterized by chromosomal breakages, congenital abnormalities, bone marrow failure (BMF), and cancer. There has been a discovery of 22 FANC genes known to be involved in the FA pathway. This wide number of pathway components makes molecular diagnosis challenging for FA. We present here the most comprehensive molecular diagnosis of FA subjects from India. We observed a high frequency (4.42 ± 1.5 breaks/metaphase) of chromosomal breakages in 181 FA subjects. The major clinical abnormalities observed were skin pigmentation (70.2%), short stature (46.4%), and skeletal abnormalities (43.1%), along with a few minor clinical abnormalities. The combination of Sanger sequencing and Next Generation Sequencing could molecularly characterize 164 (90.6%) FA patients and identified 12 different complementation groups [FANCA (56.10%), FANCG (16.46%), FANCL (12.80%), FANCD2 (4.88%), FANCJ (2.44%), FANCE (1.22%), FANCF (1.22%), FANCI (1.22%), FANCN (1.22%), FANCC (1.22%), FANCD1 (0.61%) and FANCB (0.61%)]. A total of 56 novel variants were identified in our cohort, including a hotspot variant: a deletion of exon 27 in the FANCA gene and a nonsense variant at c.787 C>T in the FANCG gene. Our comprehensive molecular findings can aid in the stratification of molecular investigation in the diagnosis and management of FA patients.


Background factors in the decline of infant mortality in Sweden 1800-1930.
The aim of this paper is to present an overview of the changing Swedish society during the period 1800-1930 and to highlight factors which may have determined the decline in infant mortality during this period. A women's perspective will be used as a method to approach the problem. The following hypothesis has been formulated: a declining infant mortality was indirectly linked to and mediated through improvements in women's and mothers' living conditions in the past. Health information was successful when women and mothers possessed the necessary prerequisites for understanding and utilizing this information. Because of improved harvests food consumption per capita increased from the second decade of the 19th century. Deaths related to smallpox decreased from the beginning of the 19th century and fewer children under five and above died. A pronounced growth of the population due to declining mortality started from the second decade of the 19th century. The decline of infant mortality was, firstly, a combined effect of an increased intake of calories and a gradual decrease of work loads for women, which indirectly and directly influenced infants' health and survival. Fewer small-for-date infants were born, and mothers had more time for breast-feeding and child care. Secondary factors of importance were improved delivery care, health information on child care and hygiene, and declining fertility.


Protein tyrosine phosphatase L1 inhibits high-grade serous ovarian carcinoma progression by targeting IκBα.
High-grade serous ovarian cancer (HGSOC) represents most of the ovarian cancers and accounts for 70%-80 % of related deaths. The overall survival of HGSOC has not been remarkably improved in the past decades, due to the tumor dissemination in peritoneal cavity and invasion of adjacent organs. Therefore, identifying molecular biomarkers is invaluable in helping predicting clinical outcomes and developing targeted chemotherapies. Although there have been studies revealing the prognostic significance of protein tyrosine phosphatase L1 (PTPL1) in breast cancer and lung cancer, its involvement and functions in HGSOC remains to be elucidated. We retrospectively enrolled a cohort of HGSOC patients after surgical resection. And analyzed the mRNA and protein levels of PTPL1 in tissue samples. We found that PTPL1 presented a lower expression in HGSOC tissues than in adjacent normal ovarian tissues. Besides, the PTPL1 level was negatively correlated with tumor stage, implying its potential role as a tumor suppressor. Univariate and multivariate analyses identified that patients with higher PTPL1 showed a better overall survival compared to those with lower PTPL1 expression. In addition, cellular experiments confirmed the role of PTPL1 in suppressing tumor proliferation and invasion. Furthermore, we demonstrated that PTPL1 negatively regulated phosphorylation of tyrosine 42 on IκBα (IκBα-pY42). To our knowledge, this is the initial finding on PTPL1 targeting IκBα-pY42 site. Finally, our data indicated that PTPL1 suppressed tumor progression by dephosphorylating IκBα-pY42, which stabilized IκBα and attenuated nucleus translocation of NF-κB. Our study revealed a tumor-suppressing role of PTPL1 in HGSOC by targeting IκBα.


Quantification of Free Polyelectrolytes Present in Colloidal Suspension, Revealing a Source of Toxic Responses for Polyelectrolyte-Wrapped Gold Nanoparticles.
Polyelectrolyte (PE) wrapping of colloidal nanoparticles (NPs) is a standard method to control NP surface chemistry and charge. Because excess polyelectrolytes are usually employed in the surface modification process, it is critical to evaluate different purification strategies to obtain a clean final product and thus avoid ambiguities in the source of effects on biological systems. In this work, 4 nm diameter gold nanoparticles (AuNPs) were wrapped with 15 kDa poly(allylamine hydrochloride) (PAH), and three purification strategies were applied: (a) diafiltration or either (b) one round or (c) two rounds of centrifugation. The bacterial toxicity of each of these three PAH-AuNP samples was evaluated for the bacterium Shewanella oneidensis MR-1 and is quantitatively correlated with the amount of unbound PAH molecules in the AuNP suspensions, as judged by X-ray photoelectron spectroscopy, nuclear magnetic resonance experiments and quantification using fluorescent assay. Dialysis experiments show that, for a 15 kDa polyelectrolyte, a 50 kDa dialysis membrane is not sufficient to remove all PAH polymers. Together, these data showcase the importance of choosing a proper postsynthesis purification method for polyelectrolyte-wrapped NPs and reveal that apparent toxicity results may be due to unintended free wrapping agents such as polyelectrolytes.


Fibrocontractive Müller cell phenotypes in proliferative diabetic retinopathy.
To evaluate Müller cells as a potential source of fibrocontractive cells in proliferative diabetic retinopathy. Temporal changes in glial fibrillary acidic protein (GFAP), vimentin, glutamine synthetase, and alpha smooth muscle actin (alphaSMA) expression in cultures of freshly isolated porcine Müller cells were evaluated by indirect immunofluorescence and Western blotting. A similar evaluation was performed on freshly isolated Müller cells maintained in high- and low-glucose culture. Cryosections of six diabetic epiretinal tissues were evaluated for the same antigens. Müller cell changes in culture included loss of glutamine synthetase and GFAP, with coincident gains in alphaSMA immunoreactivity. Vimentin immunoreactivity persisted without obvious change. Similar changes were observed when the cells were maintained in high- or low-glucose culture medium. All six diabetic epiretinal membranes contained positively identified Müller cells with vimentin, GFAP, and glutamine synthetase immunoreactivities. There was a progressive loss of glutamine synthetase and GFAP content and a coincident increase in alphaSMA content as the cells assumed an elongated, fibroblastlike morphology. Continuous culture in high- versus low-glucose medium does not influence Müller cell phenotype changes. Positively identified Müller cells are present in diabetic epiretinal tissues and appear to undergo the same progression of phenotype changes observed in culture. Cells capable of generating tractional forces associated with proliferative diabetic retinopathy can arise from Müller cells.


Sex differences in the relationship between prolactin levels and impaired processing speed in early psychosis.
Hyperprolactinaemia is commonly observed in people with psychotic disorders due to D2 receptor blockade by antipsychotic drugs, although it may also exist in drug-naïve patients with first-episode psychosis. Recent studies suggest that hyperprolactinaemia may have a negative impact on cognitive function in people with early psychosis. We aimed to explore whether there are sex differences in the association between prolactin levels and cognitive performance in early psychosis patients. We studied 60 young patients with early psychosis (aged 18-35 years, 35% females) and a sex- and age-matched control group of 50 healthy subjects. Cognitive assessment was performed with the MATRICS Consensus Cognitive Battery. Prolactin, total cortisol, follicular-stimulating hormone, luteal hormone and sex steroids (testosterone in men, oestradiol and progesterone in women) were measured in plasma. Salivary cortisol was measured at different sampling times (awakening response, 10:00 and 23:00). Psychopathological status was assessed, and antipsychotic treatment was registered. Multiple linear regression analyses were used to explore the relationship between prolactin and cognitive tasks while adjusting for covariates. Prolactin levels were associated with impaired processing speed in men, and this association was independent of cortisol and testosterone. In women, prolactin levels were not associated with processing speed tasks, although we observed a negative effect of prolactin on verbal learning and spatial working memory in female healthy subjects. The male-dependent effect maintained its significance after adjusting for education status, antipsychotic treatment and negative symptoms. Our study demonstrates that the previously reported association between high prolactin levels and impaired cognitive processes in early psychosis is restricted to men.


Predicting aged pork quality using a portable Raman device.
The utility of Raman spectroscopic signatures of fresh pork loin (1 d & 15 d postmortem) in predicting fresh pork tenderness and slice shear force (SSF) was determined. Partial least square models showed that sensory tenderness and SSF are weakly correlated (R2 = 0.2). Raman spectral data were collected in 6 s using a portable Raman spectrometer (RS). A PLS regression model was developed to predict quantitatively the tenderness scores and SSF values from Raman spectral data, with very limited success. It was discovered that the prediction accuracies for day 15 post mortem samples are significantly greater than that for day 1 postmortem samples. Classification models were developed to predict tenderness at two ends of sensory quality as "poor" vs. "good". The accuracies of classification into different quality categories (1st to 4th percentile) are also greater for the day 15 postmortem samples for sensory tenderness (93.5% vs 76.3%) and SSF (92.8% vs 76.1%). RS has the potential to become a rapid on-line screening tool for the pork producers to quickly select meats with superior quality and/or cull poor quality to meet market demand/expectations.


Antibodies to peptides detect new hepatitis B antigen: serological correlation with hepatocellular carcinoma.
The expression of a previously unidentified gene product, encoded by the hepatitis B virus (HBV) genome, has been achieved with a recombinant SV40 expression vector. Antibodies against synthetic peptides representing defined regions of this protein were used to screen cells infected with recombinant virus as well as tissues naturally infected with HBV. A 24,000-dalton protein (p24) was detected in cells infected with recombinant virus and a 28,000-dalton protein (p28) was detected in tissues infected with HBV. The peptides or recombinant-derived protein were used as antigens to screen sera from individuals infected with HBV. Specific antibodies were detected predominantly in sera from patients with hepatocellular carcinoma. The presence of p28 in tissues infected with HBV and the appearance of specific antibodies in infectious sera establish the existence of an additional marker for HBV infection.


Everyday life consequences of substance use in adult patients with a substance use disorder (SUD) and co-occurring attention deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD): a patient's perspective.
Although the prevalence of substance use disorder (SUD) with co-occurring attention deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) is relatively high in adult patients, there is hardly any knowledge about these dual diagnoses. A recent study reported met- and unmet needs for several life domains regarding these patient groups. To improve treatment, it is necessary to identify the everyday life consequences of SUD and co-occurring ADHD or ASD in adult patients. Qualitative study using in-depth interviews. 11 SUD + ADHD and 12 SUD + ASD patients participated in the study. The interview transcripts were coded and analysed according to the seven steps for descriptive phenomenology by Colaizzi. Both patients with ADHD and patients with ASD can get caught in a jumble of thoughts and emotions which can often lead to agitation and impulsivity in the case of ADHD or passivity and melancholia in the case of ASD with co-occurring SUD in both cases. Initially substance use ameliorates the symptoms and related problems, but both patient groups can later experience even greater problems: difficulties with the structuring of daily life due to a lack of planning (SUD + ADHD) or due to a lack of initiative (SUD + ASD). Both groups indicate that structure helps them function better. They also recognize that substance use disorganizes their lives and that an absence of structure contributes to substance use in what becomes a vicious circle which needs to be broken for effective treatment and care. This study provides insight into the daily life consequences of SUD with a co-occurring ADHD or ASD. Substance use is reported to solve some ADHD- or ASD-related problems in the short run but have negative consequences in the long run (i.e., contribute to already impaired cognitive functioning). Insight is provided into what clinicians can do to break this vicious circle and thus help ADHD patients to refrain from action and ASD patients to take action.


Nail involvement in histiocytosis X. A 12-year retrospective study.
A retrospective study of nail involvement was made in 15 cases of histiocytosis X (HX). These included seven cases of Letterer-Siwe (LS) disease, four cases of Hand-Schüller-Christian disease, and four cases of eosinophilic granuloma seen at Ramathibodi Hospital, Bangkok, Thailand, during the years 1970 to 1981. Nail involvement was found in three patients with LS disease, two of whom showed fingernail and toenail dystrophy with onycholysis and subungual hyperkeratosis. Paronychial erythema and swelling with small pustules underneath some nails were seen in both of the latter patients. The remaining patient showed subungual purpura of all fingernails and toenails with slight thickening of some fingernails. The nail changes in one patient responded well to cytotoxic therapy but recurred when the disease progressed. Nail involvement seems to be one of the unfavorable prognostic signs in HX.


Effects of AIF on Knee Osteoarthritis Patients: Double-blind, Randomized Placebo-controlled Study.
Anti-inflammatory factor (AIF) is a water soluble extract of three herbs, Panax notoginseng (Burk.) F. H. Chen, Rehmannia glutinosa Libosch and Eleutherococcus senticosus. The present study aimed to investigate the safety and efficacy of herb extracts, AIF, on Korean knee osteoarthritis patients for six weeks. Fifty seven patients with knee osteoarthritis, ranging from 43 to 73 years of age, who fulfilled the "American College of Rheumatology" (ACR) classification of idiopathic osteoarthritis of knee and radiographic criteria were randomly selected and enrolled for the study. After initial screening and resting period, two capsules each of AIF (Each capsule contains; 400 mg) and similar identical placebo were administered twice a day to both groups. Pain intensity at second, fourth, and sixth weeks of study as well as one week after discontinuation of drugs was assessed by using 100 mm visual analogue scale (VAS). Changes in the Korean version of the Western Ontario and McMaster Universities (K-WOMAC) index score were compared at the initiation and completion of the study. VAS assessed by patients were significantly reduced (at visit 2; 54.64+/-14.72, at visit 4, 37.32+/-16.58, p< 0.001) after AIF administration. Results showed an improvement in the physical function of K-WOMAC scale which was significantly higher (p=0.013) in AIF than placebo group, and decreases of total K-WOMAC score were also significantly higher (p=0.030) in AIF groups than placebo group. No serious adverse effect was observed, and there was no difference in incidence of adverse effect between AIF and placebo groups. In this population of Korean patients with knee osteoarthritis, AIF was found to be safe, tolerable and effective for symptomatic improvement of pain and physical function.


A Patient-Centered Transitional Care Case Management Program: Taking Case Management to the Streets and Beyond.
In 2011, the Hunter Holmes McGuire Veterans Administration Medical Center (VAMC) in Richmond, VA, had a cumulative readmission rate and emergency department (ED) revisits for discharged Veterans of 1 in 5. In 2012, a transitional care program (TCP) was implemented to improve care coordination and outcomes among Veterans, with an emphasis on geriatric patients with chronic disease. This TCP was created with an interdisciplinary approach using intensive case management interventions, with a goal of reducing Veteran ED and hospital revisits by 30%. To examine the impact of the McGuire VAMC TCP on Veteran ED and hospital utilization and costs. Veterans being discharged to home following an inpatient admission, ED visit, and/or short rehab stay. The primary means of identifying patients for the program is through daily screening of the previous 24-hour admission and ED report, which the inpatient nurse practitioner performs. She completes an extensive review of each Veteran's electronic medical record to determine the number of ED visits and inpatient admissions at the VAMC and in the community. Initial criteria for consideration in the program included the following: more than two hospital admissions and/or ED visits in the past 90 days or at high risk for readmission based on a Care Assessment Need score of greater than 95. Two hundred Veterans participated in the program in fiscal year (FY) 2013, with 146 participating in FY 2014. A retrospective chart review of Veterans participating in the TCP in FYs 2013 and 2014 was conducted, with a focus on number of admissions and ED visits 90 days prior to admission to the TCP and 90 days following TCP admission. Average admission and ED costs for this VA were calculated to determine cost savings from pre- to post-90 days of admission and ED visits. Veterans who obtained TCP services in FYs 2013 and 2014 experienced a 67% decrease in hospital admissions and a 61% decrease in ED visits in the 90 days following participation in this program compared with the 90 days prior to participation. This produced an estimated net savings of $3,823,673 in medical center costs. In addition, registered nurse case managers (RN CMs) noted improved patient compliance and satisfaction with care and the licensed clinical social worker noted reduced caregiver burden. The results of this program demonstrate how using an interdisciplinary approach to develop patient-centered transition plans of care through intensive case management interventions improves resource utilization with substantial financial savings. This program represents a feasible option for other VAMCs as well as civilian hospitals seeking to provide cost-effective transitional care to patients upon discharge and prevent untimely readmissions. With an RN CM at the hub of patient care, this program successfully demonstrates the value of smooth care transitions.


105° field of view non-contact handheld swept-source optical coherence tomography.
We demonstrate a handheld swept-source optical coherence tomography (OCT) system with a 400 kHz vertical-cavity surface-emitting laser (VCSEL) light source, a non-contact approach, and an unprecedented single shot 105° field of view (FOV). We also implemented a spiral scanning pattern allowing real-time visualization with improved scanning efficiency. To the best of our knowledge, this is the widest FOV achieved in a portable non-contact OCT retinal imaging system to date. Improvements to the FOV may aid the evaluation of retinal diseases such as retinopathy of prematurity, where important vitreoretinal changes often occur in the peripheral retina.


An evidence-based approach to managing gunshot wounds in the emergency department.
Education regarding ballistic injuries in the emergency department is sparse and may rarely be encountered if not training or practicing in a trauma center or a military wartime setting. This article provides a comprehensive review on the management of ballistic injuries in the emergency department, including how to assess and manage gunshot wounds, how to recognize when further imaging or evaluation is needed, and how to recognize when transfer to another facility is required. Algorithms are proposed for the management of gunshot wounds based on body part: head, neck, chest and abdomen, and extremities/soft tissue.


Efficient absorption of visible radiation by gap plasmon resonators.
We demonstrate experimentally a periodic array of differently-sized and circularly-shaped gap plasmon resonators (GPRs) with the average absorption ~94% for unpolarized light in the entire visible wavelength range (400-750 nm). Finite-element simulations verify that the polarization insensitive broadband absorption originates from localized gap surface plasmons whose resonant excitations only weakly depend on the angle of incidence. Arrays of GPRs also exhibit enhanced local field intensities (~115) as revealed by scanning two-photon photoluminescence microscopy, that are spectrally correlated with the minima in corresponding linear reflection spectra.


Atrial-ventricular function in rheumatic mitral regurgitation using strain imaging.
Chronic mitral regurgitation (MR) historically has been shown to primarily affect left ventricular (LV) function. The impact of increased left atrial (LA) volume in MR on morbidity and mortality has been highlighted recently, yet the LA does not feature as prominently in the current guidelines as the LV. Thus, we aimed to study LA and LV function in chronic rheumatic MR using traditional volumetric parameters and strain imaging. Seventy-seven patients with isolated moderate or severe chronic rheumatic MR and 40 controls underwent echocardiographic examination. LV and LA function were assessed with conventional echocardiography and 2D strain imaging. LA stiffness index was greater in chronic rheumatic MR than controls (0.95 ± 1.89 vs 0.16 ± 0.13, P = 0.009). LA dysfunction was noted in the reservoir, conduit, and contractile phases compared with controls (P < 0.05). LA peak reservoir strain (ƐR), LA peak contractile strain, and LV peak systolic strain were decreased in chronic rheumatic MR compared with controls (P < 0.05). Eighty-six percent of patients had decreased LA ƐR and 58% had depressed LV peak systolic strain. Decreased ƐR and normal LV peak systolic strain were noted in 42%. Thirteen percent had normal ƐR and LV peak systolic strain. One patient had normal ƐR with decreased LV peak systolic strain. In chronic rheumatic MR, there is LA dysfunction in the reservoir, conduit, and contractile phases. In this study, LA dysfunction with or without LV dysfunction was the predominant finding, and thus, LA dysfunction may be an earlier marker of decompensation in chronic rheumatic MR.


Methylphenidate in 6-hydroxydopamine-treated developing rat pups. Effects on activity and maze performance.
In order to better devine the relationship between brain catecholaminergic mechanisms and the clinical syndrome of minimal brain dysfunction, we have developed an experimental model that has many of the features of the disorder seen in children. This model is effected by the preferential depletion of brain dopamine in 5-day-old rat pups following the intracisternal administration of 6-hydroxydopamine, and in the present investigation, we have examined the effects of methylphenidate hydrochloride (0.25 to 2.0 mg/kg) on activity levels and cognitive performance in normal and 6-hydroxydopamine treated animals. Methylphenidate therapy resulted in a significant increase in activity levels of normal rat pups 12 and 19 days of age; in contrast, methylphenidate administered to 6-hydroxydopamine-treated animals did not increase activity at 12 days of age and significantly reduced activity at 19 and 26 days. Methylphenidate had no effect on T-maze performance in normals, but significantly improved performance in 6-hydroxydopamine-treated animals. Our results suggest that the "paradoxical" response to methylphenidate found in 6-hydroxydopamine-treated rat pups may be the result of central denervation supersensitivity.


Object characterization with refractometric digital Fourier holography.
We demonstrate a digital holographic method in which two different substances in a blend are discerned. The method requires only one set of exposures and one reconstruction in the plane of focus. The phase is unwrapped by Flynn's discontinuity algorithm to produce an image of the variation of the optical distance of the illuminating wave. Objects with indices of refraction that are higher and lower than the mounting liquid are detected as regions in which the phase is increased and decreased, respectively. We also present a method for calculating the volume distribution of substrates in a sample. The method is experimentally demonstrated with crystals of NaCl and KCl.


BMP-7 fails to attenuate TGF-beta1-induced epithelial-to-mesenchymal transition in human proximal tubule epithelial cells.
In rodent models of chronic renal disease bone morphogenetic protein-7 (BMP-7) has been shown to halt disease progression and promote recovery. Subsequent studies utilizing immortalized rodent renal cell lines showed that BMP-7 was renoprotective by antagonizing TGF-beta1-stimulated epithelial-to-mesenchymal transition (EMT). The present study sought to determine if BMP-7 prevents TGF-beta1-induced EMT in primary (RPTEC) and immortalized (HK-2) human proximal tubule epithelial cells. EMT was determined by quantitative real-time PCR analysis of e-cadherin, vimentin, CTGF and TGF-beta1 transcript expression and immunocytochemical analysis of ZO-1 and alpha-smooth muscle actin (alpha-SMA) protein expression following TGF-beta1 treatment in RPTEC and HK-2 cells. In RPTEC and HK-2 cells, TGF-beta1 significantly reduced e-cadherin expression and significantly increased vimentin, CTGF and TGF-beta1 expression. TGF-beta1 also diminished ZO-1 immunoreactivity and increased alpha-SMA expression in confluent cell monolayers. Co-incubation of TGF-beta1 with an anti-TGF-beta1 neutralizing antibody substantially reduced the cytokine's effects, which indicated EMT in these cells was inhibitable. Co-administration of BMP-7 over a broad concentration range (0.01-100 microg/ml) with TGF-beta1 failed to attenuate EMT in RPTEC or HK-2 cells, as demonstrated by no inhibition of altered e-cadherin, vimentin, CTGF and TGF-beta1 expression and no restoration of ZO-1 immunoreactivity. Furthermore, when BMP-7 was applied to proximal tubule cells alone, it also decreased e-cadherin expression and increased vimentin, CTGF and TGF-beta1 expression. Additionally, BMP-7 failed to induce the mesenchymal-to-epithelial transition (MET) in NRK-49F rat renal fibroblasts. BMP-7 did however prevent TGF-beta1-mediated e-cadherin downregulation in TCMK-1 mouse renal tubular epithelial cells. BMP-7 activity was routinely confirmed by examining BMP-7-induced phosphorylation of SMADs 1/5/8, BMP-7 regulation of BMPR-IA, BMP-7-mediated reduction of IL-6 transcript expression and BMP-7-mediated reduction of secreted IL-6 and IL-8 proteins. In the present study, despite confirming BMP-7 regulation of receptor expression and induction of downstream signalling events, we were unable to demonstrate BMP-7 inhibition of EMT in either primary or immortalized human proximal tubule cells. Moreover, we were unable to demonstrate BMP-7-stimulated MET in rat renal fibroblasts. A protective effect was however observed at an elevated BMP-7 concentration in mouse renal tubular epithelial cells.


Modern development of imaging procedures in oncology.
From the oncologic point of view, imaging diagnostic techniques have been and will be of steadily increasing significance. This paper gives a survey of the present state of the art and of various aspects of current international trends in X-ray diagnostics, computed tomography, ultrasound and magnetic resonance. High tech developments raise the expenditures, so that the cost-benefit-relations have to be considered in future diagnostic strategies. Some aspects for further research tasks are mentioned. The aim of all improvements in imaging procedures is to increase the influence of diagnostic procedures on treatment planning and to improve the treatment results and, ultimately, the prognosis of cancer patients.


[Percutaneous transhepatic cholangiography with the Okuda or Chiba needle (author's transl)].
Introduction of the thin flexible needle (Chiba or Okuda needle) has revived percutaneous transhepatic cholangiography, even though there are more recent methods of investigating the biliary tract. Personal results in 65 patients demonstrate that the needle can be successfully introduced in all instances, as long as the biliary tracts are dilated, the success rate being 68% if they are not. The complication rate was 9.2%, but there was no death.


Periparturient changes in secretion and mammary uptake of insulin and in concentrations of insulin and insulin-like growth factors in milk of dairy cows.
Mammary uptake of insulin from blood was quantified near parturition in nine dairy cows, some of which were milked prepartum to induce prepartum lactogenesis. Milk samples were immunoassayed for concentrations of insulin, insulin-like growth factor I, and insulin-like growth factor II. Cows milked prepartum, but in which prepartum lactogenesis did not occur (denoted as unsuccessful group), had higher arterial concentrations and greater mammary uptake of insulin during several days immediately preceding parturition than did those with prepartum lactogenesis. Although mammary uptake of insulin was measurable before parturition, estimated uptake on postpartum d 4 through 6 was negligible. Colostrum and milk contained very substantial quantities of insulin, insulin-like growth factor I, and insulin-like growth factor II. Cows in which prepartum lactogenesis was induced (denoted as successful group) had lower concentrations of both forms of insulin-like growth factor in prepartum samples of milk. Cows of the successful group also had a decreasing prepartum profile of milk insulin, but the unsuccessful group had an increasing trend until parturition. Milk concentrations of insulin and both forms of insulin-like growth factor declined rapidly after parturition and completion of lactogenesis.


[The reaction of blood lymphocyte dehydrogenases after the incorporation of 131I and 137Cs radionuclides].
The data on the activities of dehydrogenases in rat blood lymphocytes 30, 90, 180 and 365 days after separate and combined effect of 131I (dose of 2.5 MBq/kg) and 137Cs (dose of 1.6 Mbq/kg) are presented. It has been shown that incorporation of 131I causes intensification of redox processes which is due to structure-functional disturbance in the thyroid gland. 137Cs markedly influenced the activity of some dehydrogenases in partial steps of post-irradiation development. The changes in the enzyme activities at the combined action of radionuclides are similar in many respects to data obtained in the case of 131I individual action.


Characterization of the CD48 gene demonstrates a positive element that is specific to Epstein-Barr virus-immortalized B-cell lines and contains an essential NF-kappa B site.
Epstein-Barr virus (EBV) infection of mature, resting B cells drives them to become lymphoblasts expressing high levels of cell surface molecules, such as CD48, characteristically expressed on normal activated B cells. Here, we report on the identification of an enhancer element in the CD48 gene which reproducibly confers strong transcriptional activity only in EBV-positive B-lymphoblastoid cell lines. The element is not activated upon infection of established EBV-negative B-cell lines, indicating that EBV fails to drive these cells to a fully lymphoblastoid phenotype. An NF-kappa B binding site is an essential component of the element but alone is not sufficient to account for the activity or the specificity of the element. We have detected a specific nuclear protein complex that binds to the element and show that NF-kappa B1 (p50) is a part of this complex. The EBV-encoded latent membrane protein 1 is capable of transactivating the isolated CD48 NF-kappa B site but not the intact element, suggesting that the latent membrane protein 1-driven activation of NF-kappa B/Rel must interact with other regulatory pathways to control expression of cellular genes as EBV drives resting B cells into the cell cycle.


Targeting DNA repair by coDbait enhances melanoma targeted radionuclide therapy.
Radiolabelled melanin ligands offer an interesting strategy for the treatment of disseminated pigmented melanoma. One of these molecules, ICF01012 labelled with iodine 131, induced a significant slowing of melanoma growth. Here, we have explored the combination of [131I]ICF01012 with coDbait, a DNA repair inhibitor, to overcome melanoma radioresistance and increase targeted radionuclide therapy (TRT) efficacy. In human SK-Mel 3 melanoma xenograft, the addition of coDbait had a synergistic effect on tumor growth and median survival. The anti-tumor effect was additive in murine syngeneic B16Bl6 model whereas coDbait combination with [131I]ICF01012 did not increase TRT side effects in secondary pigmented tissues (e.g. hair follicles, eyes). Our results confirm that DNA lesions induced by TRT were not enhanced with coDbait association but, the presence of micronuclei and cell cycle blockade in tumor shows that coDbait acts by interrupting or delaying DNA repair. In this study, we demonstrate for the first time, the usefulness of DNA repair traps in the context of targeted radionuclide therapy.


Observations on abnormal cells in the peripheral blood and spleen in Hodgkin's disease.
The occurrence of abnormal cells in the peripheral blood of patients with Hodgkin's disease has been described in the literature. In the present investigation several varieties of cells were found, two of which are believed to be typical of the disease. The significance of these cells in the peripheral blood is not yet clear, but there seems to be a correlation between the presence of these characteristic cells in the blood and involvement of the spleen by the disease as determined by microscopical examination. In 11 patients both abnormalities proved to be absent; 13 out of 14 other patients showed both the abnormal cells in the blood and Hodgkin lesions in the spleen.If circulating abnormal cells are indeed an indication of the presence of Hodgkin's disease in the spleen, involvement of this organ is likely to be due to or to give rise to haematogenous dissemination. The other possibility remains that both the occurrence of abnormal cells in the peripheral blood and splenic involvement are due to a multicentric origin of the disease. It seems most unlikely that the splenic lesions are consistent with localized disease still restricted to the lymphoid system. These findings challenge the validity of the present widely used so-called Rye classification of clinical stages in Hodgkin's disease.


The pivotal role of semantic memory in remembering the past and imagining the future.
Episodic memory refers to a complex and multifaceted process which enables the retrieval of richly detailed evocative memories from the past. In contrast, semantic memory is conceptualized as the retrieval of general conceptual knowledge divested of a specific spatiotemporal context. The neural substrates of the episodic and semantic memory systems have been dissociated in healthy individuals during functional imaging studies, and in clinical cohorts, leading to the prevailing view that episodic and semantic memory represent functionally distinct systems subtended by discrete neurobiological substrates. Importantly, however, converging evidence focusing on widespread neural networks now points to significant overlap between those regions essential for retrieval of autobiographical memories, episodic learning, and semantic processing. Here we review recent advances in episodic memory research focusing on neurodegenerative populations which has proved revelatory for our understanding of the complex interplay between episodic and semantic memory. Whereas episodic memory research has traditionally focused on retrieval of autobiographical events from the past, we also include evidence from the recent paradigm shift in which episodic memory is viewed as an adaptive and constructive process which facilitates the imagining of possible events in the future. We examine the available evidence which converges to highlight the pivotal role of semantic memory in providing schemas and meaning whether one is engaged in autobiographical retrieval for the past, or indeed, is endeavoring to construct a plausible scenario of an event in the future. It therefore seems plausible to contend that semantic processing may underlie most, if not all, forms of episodic memory, irrespective of temporal condition.


Plasma sphingolipids and depressive symptoms in coronary artery disease.
Depression is highly prevalent in individuals with coronary artery disease (CAD) and increases the risk of future cardiac events and mortality. Sphingolipids have been implicated in the pathophysiology of both CAD and depression. This study assessed the association between plasma sphingolipid concentrations and depressive symptoms in CAD subjects. Depressive symptoms were measured using the depression subscale of the self-reported Hospital Anxiety and Depression Scale (HADS). Sphingolipid concentrations were measured from fasting plasma samples using high-performance liquid chromatography-coupled electrospray ionization tandem mass spectrometry (LC/MS/MS). Linear regression models were used to assess associations between log-transformed concentrations of plasma sphingolipids and depressive symptoms. A total of 111 CAD patients (mean (SD) age = 63.6 ± 6.4, 84.7% male) were included. In linear regression analyses, higher plasma concentrations of ceramides C16:0 (β = 0.204, p = .026) and C18:0 (β = 0.209, p = .023) and sphingomyelin SM18:1 (β = 0.210, p = .024) were significantly associated with higher HADS depression subscale score after adjusting for covariates. Sphingolipids, in particular the ceramide species C16:0 and C18:0 and the sphingomyelin species SM18:1, may be implicated in the pathophysiology of depression in CAD. The association between plasma sphingolipid concentrations and depression should be further examined in CAD patients and in other populations.


DNA hypermethylation in sodium butyrate-treated WI-38 fibroblasts.
Sodium butyrate is very often used to alter gene expression in cultured cells. In this study, we examined the effects of this compound on various cellular events in WI-38 human embryonic lung fibroblasts in culture. During a 16-20-h treatment at sodium butyrate concentrations of between 5 and 20 mM, no adverse effects on cell morphology were observed. However, cell division and DNA synthesis were reversibly inhibited, the latter by 85, 80, and 70% at sodium butyrate concentrations of 5, 10, and 20 mM, respectively. Although overall protein synthetic activity was not significantly affected, RNA synthesis decreased to 76% of the control values at a sodium butyrate concentration of 5 mM. Butyrate treatment also caused hypermethylation of DNA cytosines as determined by differential digestion by MspI/HpaII restriction endonucleases and by high performance liquid chromatography analysis of the DNA. The 5-methylcytosine content of the DNA in untreated WI-38 fibroblasts was 2.94 +/- 0.46% of total cytosine residues, while in cultures treated with 5, 10, and 20 mM sodium butyrate, these values were 5.76 +/- 0.28, 5.91 +/- 0.37, and 6.8 +/- 0.44%, respectively. An interesting feature is that this hypermethylation occurred in DNA which was synthesized in the presence of sodium butyrate (newly synthesized) as well as in DNA which had been synthesized before butyrate administration (pre-existing DNA). The hypermethylated state was conserved only in the former situation, since the methylcytosines were rapidly lost in the subsequent generation in the latter case. It would therefore appear that methylcytosines are maintained after cell replication only if they are generated on newly synthesized DNA.


High sintering resistance of size-selected platinum cluster catalysts by suppressed Ostwald ripening.
Employing rationally designed model systems with precise atom-by-atom particle size control, we demonstrate by means of combining noninvasive in situ indirect nanoplasmonic sensing and ex situ scanning transmission electron microscopy that monomodal size-selected platinum cluster catalysts on different supports exhibit remarkable intrinsic sintering resistance even under reaction conditions. The observed stability is related to suppression of Ostwald ripening by elimination of its main driving force via size-selection. This study thus constitutes a general blueprint for the rational design of sintering resistant catalyst systems and for efficient experimental strategies to determine sintering mechanisms. Moreover, this is the first systematic experimental investigation of sintering processes in nanoparticle systems with an initially perfectly monomodal size distribution under ambient conditions.


Pan-cancer proteogenomics connects oncogenic drivers to functional states.
Cancer driver events refer to key genetic aberrations that drive oncogenesis; however, their exact molecular mechanisms remain insufficiently understood. Here, our multi-omics pan-cancer analysis uncovers insights into the impacts of cancer drivers by identifying their significant cis-effects and distal trans-effects quantified at the RNA, protein, and phosphoprotein levels. Salient observations include the association of point mutations and copy-number alterations with the rewiring of protein interaction networks, and notably, most cancer genes converge toward similar molecular states denoted by sequence-based kinase activity profiles. A correlation between predicted neoantigen burden and measured T cell infiltration suggests potential vulnerabilities for immunotherapies. Patterns of cancer hallmarks vary by polygenic protein abundance ranging from uniform to heterogeneous. Overall, our work demonstrates the value of comprehensive proteogenomics in understanding the functional states of oncogenic drivers and their links to cancer development, surpassing the limitations of studying individual cancer types.


Periconceptional over-the-counter nonsteroidal anti-inflammatory drug exposure and risk for spontaneous abortion.
To estimate the association between over-the-counter nonsteroidal anti-inflammatory drug (NSAID) exposure during the early first trimester and risk for spontaneous abortion (gestation before 20 weeks of gestation) in a prospective cohort. Women were enrolled in the Right from the Start study (2004-2010). Exposure data regarding over-the-counter NSAID use from the last menstrual period (LMP) through the sixth week of pregnancy were obtained from intake and first-trimester interviews. Pregnancy outcomes were self-reported and verified by medical records. Gestational age was determined from the LMP. Stage of development before loss was determined from study ultrasonography. Cox proportional hazards regression models were used to estimate the association between NSAID exposure and pregnancy outcome taking into account candidate confounders. Among 2,780 pregnancies, 367 women (13%) experienced a spontaneous abortion. NSAID exposure was reported by 1,185 (43%) women. NSAID exposure was not associated with spontaneous abortion risk in unadjusted models (hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.82-1.24) or models adjusted for maternal age (adjusted HR 1.00, 95% CI 0.81-1.23). Our findings suggest that use of nonprescription over-the-counter NSAIDs in early pregnancy does not put women at increased risk of spontaneous abortion.


Age-acquired resistance and predisposition to reinfection with Schistosoma haematobium after treatment with praziquantel in Mali.
The effect of age, previous intensity of infection, and exposure on reinfection with Schistosoma haematobium after treatment was studied in a cohort of 468 subjects six years of age and over living in an irrigation scheme area in Mali. Prevalence and intensity of S. haematobium infection were measured each year between 1989 and 1991, but the reinfection study period was restricted to the last year of the follow-up. Observations were made at the principal water contact sites where the number of Bulinus truncatus shedding furcocercous cercariae was recorded. A cumulative index of exposure taking into account time, duration and type of contact, and malacologic data was calculated for each subject. Univariate analysis showed that the reinfection risk decreased with age and increased with exposure and pretreatment intensity. These results were confirmed by fitting a logistic model that showed that this risk was seven times lower among those 15 years of age and older than among the 6-14-year-old children, while linear trends with exposure to infection and pretreatment intensity were significant. This study supports the concept of an age-acquired resistance to reinfection and is in favor of a predisposition to infection that raises the question of a genetic factor controlling susceptibility/resistance to S. haematobium infection.


Childhood asthma in four regions in Scandinavia: risk factors and avoidance effects.
The high and increasing prevalence of childhood asthma is a major public health issue. Various risk factors have been proposed in local studies with different designs. We have made a questionnaire study of the prevalence of childhood asthma, potential risk factors and their relations in four regions in Scandinavia (Umeå and Malmö in Sweden, Kuopio in eastern Finland and Oslo, Norway). One urban and one less urbanized area were selected in each region, and a study group of 15962 children aged 6-12 years was recruited. The prevalence of symptoms suggestive of asthma varied considerably between different areas (dry cough 8-19%, asthma attacks 4-8%, physician-diagnosed asthma 4-9%), as did the potential risk factors. Urban residency was generally not a risk factor. However, dry cough was common in the most traffic polluted area. Exposure to some of the risk factors. such as smoking indoors and moisture stains or moulds at home during the first 2 years of life, resulted in an increased risk. However, current exposure was associated with odds ratios less than one. Our findings were probably due to a combination of early impact and later avoidance of these risk factors. The effects of some risk factors were found to differ significantly between regions. No overall pattern between air pollution and asthma was seen, but air pollution differed less than expected between the areas.


Hypertension and the coronary circulation. With special attention to endothelial regulation.
Calcium channel antagonists are commonly used to treat chronic hypertension. Several studies of intact vascular tissues suggest that these agents may impair the production of the endothelium-derived relaxing factor and alter endothelium-dependent vascular relaxation. These studies are difficult to interpret because the calcium channel antagonist may have direct effects on vascular smooth muscle. In our study, a chemiluminescence assay was used to measure the release of nitrogen oxides from bovine aortic endothelial cells (BAEC) grown in monolayer. Under basal conditions, the release of nitrogen oxides was 0.2 nmol/100 mg protein and was increased approximately two-fold by 0.1 micrograms, bradykinin. Incubations with diltiazem, verapamil, and nifedipine for 60 min did not influence the basal and bradykinin-stimulated release of nitrogen oxides by BAEC. These data illustrate that the production of the endothelium-derived relaxing factor is not altered by the calcium channel antagonist, and are compatible with an absence of L-type calcium channels in vascular endothelial cells. Chronic hypertension produces myriad adverse effects in the coronary circulation. After coronary occlusion, infarct size, expressed as a function of myocardial mass perfused, is increased by 33%, and the wavefront of infarction from subendocardium to subepicardium is hastened. Both chronic and acute hypertension produce numerous abnormalities of coronary flow regulation. These include impairments of autoregulation, changes in vascular responsiveness, and alterations of endothelial cell function. Many of these may worsen the clinical consequences of ischemic heart disease, either by producing structural alterations of the coronary vasculature, or equally importantly, by altering coronary vascular responsiveness to either mechanical or neurohumoral stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)


Medical school admission test: advantages for students whose parents are medical doctors?
Admission candidates especially in medicine do not represent the socio-demographic proportions of the average population: children of parents with an academic background are highly overrepresented, and those with parents who are medical doctors represent quite a large and special group. At Göttingen University Medicine, a new admission procedure was established with the intention to broaden the base of applicants towards including candidates with previous medical training or lower final school grades. With a view to family background, we wished to know whether candidates differ in the test scores in our admission procedure. In February 2014 we asked all admission candidates of Göttingen University Medicine by questionnaire (nine closed, four open questions) about the academic background in their families, specifically, the medical background, school exam grades, and previous medical training as well as about how they prepared for the admission test. We also analysed data from admission scores of this group (semi-structured interview and four multiple mini-interviews). In addition to descriptive statistics, we used a Pearson correlation, means comparisons (t-test, analysis of variance), ANOVA, and a Scheffé test. In February 2014 nearly half of the applicants (44%) at Göttingen University Medicine had a medical background, most frequently, their parents were physicians. This rate is much higher than reported in the literature. Other socio-demographic baseline data did not differ from the percentages given in the literature. Of all applicants, 20% had previous medical training. The group of applicants with parents who were medical doctors did not show any advantage in either test-scoring (MMI and interview), their individual preparation for the admission test, or in receiving or accepting a place at medical school. Candidates with parents who were medical doctors had scored slightly lower in school exam grades. Our results suggest that there is a self-selection bias as well as a pre-selection for this particular group of applicants. This effect has to be observed during future admission procedures.


Alkylsilane-based stationary phases via a displaceable surface template approach: synthesis, characterization, and chromatographic performance.
A method is presented for the preparation of silica-based alkylsilane stationary phases using octanol as a displaceable surface template to control the rate of alkylsilane condensation with the silica surface, and thereby, the resulting alkylsilane surface coverage. This method improves upon conventional preparation schemes by allowing alkylsilane stationary phases of systematically varying surface coverage to be prepared from a single reaction mixture and a single precursor molecule without rigorous control of water content of the solution or of the silica. Octadecylsilane stationary phases ranging in surface coverage from approximately 3.5 to 6.0 micromol/m(2) were synthesized using one set of experimental conditions with variation of only the octadecylsilane/octanol ratio. The conformational order of the octadecylsilane alkyl chains was assessed using Raman spectroscopy and was found to increase with increasing surface coverage in a manner similar to stationary phases prepared by conventional routes. As chromatographic stationary phases in microbore columns for the reversed-phase separation of monosubstituted aromatic compounds, the performance of these materials is comparable to or better than that of commercially available octadecylsilane stationary phases under identical chromatographic conditions. Furthermore, the high-density stationary phases (>3.5 micromol/m(2)) prepared by this route exhibit geometric shape selectivity comparable to or better than that reported earlier for high-density octadecylsilane stationary phases prepared using conventional methods.


Requirement for chitin biosynthesis in epithelial tube morphogenesis.
Many organs are composed of branched networks of epithelial tubes that transport vital fluids or gases. The proper size and shape of tubes are crucial for their transport function, but the molecular processes that govern tube size and shape are not well understood. Here we show that three genes required for tracheal tube morphogenesis in Drosophila melanogaster encode proteins involved in the synthesis and accumulation of chitin, a polymer of N-acetyl-beta-D-glucosamine that serves as a scaffold in the rigid extracellular matrix of insect cuticle. In all three mutants, developing tracheal tubes bud and extend normally, but the epithelial walls of the tubes do not expand uniformly, and the resultant tubes are grossly misshapen, with constricted and distended regions all along their lengths. The genes are expressed in tracheal cells during the expansion process, and chitin accumulates in the lumen of tubes, forming an expanding cylinder that we propose coordinates the behavior of the surrounding tracheal cells and stabilizes the expanding epithelium. These findings show that chitin regulates epithelial tube morphogenesis, in addition to its classical role protecting mature epithelia.


A qualitative study on factors associated with intimate partner violence in Colombia.
Intimate partner violence (IPV) is a human rights violation and a serious global public health problem. This study investigated factors associated with IPV in female survivors in Colombia. Four focus group discussions with female survivors of IPV and 15 key informant interviews with professionals from psychological, social and legal services and community leaders were conducted in Cali and Tuluá. Participant recruitment was via purposive sampling. Transcripts were analysed manually taking a social constructivist standpoint and a content analysis approach. Factors associated with IPV were divided into four themes: cultural beliefs, jealousy, alcohol abuse, and personal history of IPV. The first theme was divided into: patriarchy, gender roles, normalisation of violence, and unawareness of rights, economic dependence, and 'men own women'. The sub-themes were all inter-related and underpinned by patriarchal values. IPV was described as a sociocultural construction formed by patriarchal values ingrained in community and societal norms and individual processes. Therefore, academia, governmental and non-governmental bodies and society are urged to together, create preventative, context specific strategies for individuals, communities and societies.


Laparoscopic surgical staging of stage I primary squamous cell carcinoma of the vagina.
Vaginal carcinoma is an uncommon malignancy and one of the few gynecologic malignancies that is still clinically staged. Clinical staging, which can be difficult in some instances, is potentially inaccurate, as it has been shown to be in early endometrial and ovarian carcinoma. In addition, clinical staging can result in over- or undertreatment of the disease. The lack of standardization of treatment further compounds the issue, particularly for patients with small-volume disease. We report three patients with grade 2 or 3 small-volume primary squamous cell carcinoma of the vagina who underwent pelvic lymph node sampling for staging purposes. Each patient had lesions small enough to be considered for brachytherapy only. An average of 12 lymph nodes were removed with an average operative time of 72 minutes. All procedures were performed on an outpatient basis, and there were no intraoperative or postoperative complications. In one patient, teletherapy was added to the brachytherapy because a microscopic focus of squamous cell carcinoma was discovered in an obturator lymph node. Our initial experience indicates that laparoscopic sampling of lymph nodes in patients with early vaginal carcinoma may be helpful in preventing undertreatment of these women. Individualization of treatment can be accomplished quickly and safely on an outpatient basis, and initiation of treatment is not delayed. We believe further evaluation of laparoscopic staging of primary vaginal carcinoma is indicated.


Rationale and patient selection for interventional therapies in Parkinson's disease.
Parkinson's disease (PD) is increasing in prevalence due to a growing elderly population. Although there is no cure, there are exercise therapies and medications for mild to moderate disease. For more advanced disease, infusion or surgical interventions including deep brain stimulation surgery, levodopa carbidopa intestinal gel, and subcutaneous apomorphine infusion are considered. As these interventions become increasingly available, it is imperative for a neurologist involved in the care of advanced PD to be aware of the indications and timing for these interventions. Areas covered: This article attempts to identify different patient profiles and matches them with suggested advanced therapies for PD. There is limited literature providing guidance to a busy neurologist to match the most appropriate advanced therapy to the right patient profile. This article attempts to fill that void. Expert commentary: When matching patient profiles to therapy, several features must be considered: age, frailty, cognitive status, phenotype (predominant tremor vs. akinetic rigid), side effect or complication profile (dyskinesia, hallucinations, dysautonomia), and patient's comfort with invasive therapy options.


Foal monocyte-derived dendritic cells become activated upon Rhodococcus equi infection.
Susceptibility of foals to Rhodococcus equi pneumonia is exclusive to the first few months of life. The objective of this study was to investigate the immediate immunologic response of foal and adult horse antigen-presenting cells (APCs) upon infection with R. equi. We measured the activation of the antigen-presenting major histocompatibility complex (MHC) class II molecule, costimulatory molecules CD40 and CD86, the cytokine interleukin-12 (IL-12), and the transcriptional factor interferon regulatory factor 1 (IRF-1) in monocyte-derived macrophages (mMOs) and dendritic cells (mDCs) of adult horses and foals of different ages (from birth to 3 months of age) infected with virulent R. equi or its avirulent, plasmid-cured derivative. Infection with virulent or avirulent R. equi induced (P <or= 0.01) the expression of IL-12p35 and IL-12p40 mRNAs in foal mMOs and mDCs at different ages. This response was likely mediated by the higher (P=0.008) expression of IRF-1 in foal mDCs at birth than in adult horse mDCs. R. equi infection promoted comparable expression of costimulatory molecules CD86 and CD40 in foal and adult horse cells. The cytokine and costimulatory response by foal mDCs was not accompanied by robust MHC class II molecule expression. These data suggest that foal APCs detect the presence of R. equi and respond with the expression of the Th1-inducing cytokine IL-12. Nevertheless, there seems to be a limitation to MHC class II molecule expression which we hypothesize may compromise the efficient priming of naïve effector cells in early life.


Tyrosine metabolism in health and disease: slow-release amino acids therapy improves tyrosine homeostasis in phenylketonuria.
Phenylalanine (Phe) hydroxylase (PAH) deficiency leads to hyperphenylalaninemia (HPA) and tyrosine (Tyr) depletion. We investigated Tyr homeostasis in patients with PAH deficiency and the effect of a slow-release amino acids therapy in phenylketonuria (PKU). We performed four complementary investigations: (1) Tyr concentrations were monitored in 114 patients (10.6 ± 11.9 years) with PKU on dietary treatment supplemented with traditional amino acid formulations (n=52, 1175 samples) or non-PKU HPA on a free diet (n=62, 430 samples); (2) Tyr metabolism in PKU was quantitatively evaluated in three patients by a simple Tyr oral loading test (100 mg/kg); (3) diurnal and (4) long-term Tyr concentrations were evaluated in 5 and 13 patients with PKU, respectively, who switched from traditional to slow-release amino acids therapy. 1) Tyr concentrations in the PKU population were subnormal and significantly lower than in non-PKU HPA (p<0.01); (2) the response to a Tyr loading test in PKU was normal, with basal Tyr concentrations reached within 12 h; (3) the diurnal metabolic profile in patients on slow-release amino acids therapy revealed higher morning fasting and nocturnal Tyr concentrations with respect to traditional therapy (p<0.01); (4) this picture was confirmed at follow-up, with normalization of morning fasting Tyr concentrations in patients on slow-release amino acids therapy (p<0.01) and unchanged Phe control (p=0.19). Slow-release amino acids therapy can improve Tyr homeostasis in PKU. If associated to optimized Phe control, such a metabolic goal may allow long-term clinical benefits in patients with PKU.


Siglec-E Negatively Regulates the Activation of TLR4 by Controlling Its Endocytosis.
TLR4 signaling is critical for providing effective immune protection, but it must be tightly controlled to avoid inflammation-induced pathology. Previously, we reported extensive and direct interactions between TLR and Siglec families of pattern recognition receptors. In this study, we examined the biological significance of this interaction during infection. We show that Siglec-E is required for Escherichia coli-induced endocytosis of TLR4. Siglec-E-deficient dendritic cells infected with E. coli fail to internalize TLR4. This leads to sustained TLR4 on the cell surface and activation of NF-κB and MAPK p38, resulting in high levels of TNF-α and IL-6 compared with wild-type dendritic cells. In contrast to the signaling events occurring at the plasma membrane, as a result of the inability to internalize TLR4, Siglec-E-deficient dendritic cells were also defective for TRIF-mediated IFN-β production in response to E. coli infection. Furthermore, we found that accumulation of ubiquitinated TLR4 and binding of E3 ubiquitin ligase Triad3A to TLR4 was increased significantly in bone marrow-derived dendritic cells from wild-type mice, but not from Siglec-E-deficient mice, after E. coli infection. This represents a newly discovered mechanism that regulates the signaling of TLR4 during E. coli infection.


Cognitive outcome as part and parcel of clinical outcome in brain tumor surgery.
Although validated tools (neuropsychological tests, patient reported outcomes, mood and psychological profile) were first introduced many years ago in clinical practice, the impact of the tumor itself on patient cognition has not been extensively studied. Furthermore, while outcome research is evolving in an attempt to adapt the use of different tools to the preoperative and postoperative phases, the standard guidelines for evaluating outcome after brain surgery, by neurological examination and complication assessment, are frequently neglected in the current literature. This article attempts to provide an appraisal of the evidence for the impact of surgical treatment on cognitive function of brain tumor patients within the context of general outcome.


[Cyclic nucleotides and membrane electrogenesis in cell differentiation in Neurospora crassa].
Significance of membrane electrogenic system and cyclic nucleotides for developmental regulation in lower eukaryotes was studied in Neurospora crassa. Despite of their morphological uniformity, hyphal cells were differentiated by their electrophysiological parameters--membrane potential and input resistance. The cells maintained regulated electric communication through septal pores. Such electric communication allowed the apical "cell" to compensate the energy requirements for membrane transport by means of the electrogenic mechanism of proximal zone. The photoinduced gene expression related to differentiation of reproductive structures has been shown to be mediated via cAMP. The changes of electric parameters observed in illuminated hyphal cells were controlled by the same photoregulation mechanism but were not involved in direct control of photoinduced gene expression.


Anxiety in early adulthood.
There is no doubt that the relatively recent changes in our society must have effects on the development of the early adult. These include changes in society's attitudes, permissiveness, changing roles, equal employment and wage opportunities, women's liberation, the 'single mother by desire', changing divorce laws, integrated university colleges of residence, to mention but a few factors. The effects of drugs, illegal and legal, alcohol, the motor vehicle, pollution and environmental change must also be remembered as possible sources of anxiety in early adulthood.


The prevalence and genetic diversity of Campylobacter spp. in domestic 'backyard' poultry in Canterbury, New Zealand.
Campylobacteriosis is the most commonly notified illness in New Zealand. Whilst the importance of commercial poultry in campylobacteriosis is well established, little is known about the possible role of chickens kept at home as a direct animal/faecal contact or consumption exposure pathway. The aim of this study was to determine the prevalence and genetic diversity of Campylobacter spp. in domestic backyard chicken flocks in the Canterbury region of New Zealand. Poultry faecal samples were collected from 35 domestic 'backyard' poultry flocks from urban and rural properties around the Canterbury Region of New Zealand. A total of 291 samples were collected and tested for the presence of thermotolerant Campylobacter spp. and positive isolates were analysed using pulsed-field gel electrophoresis (PFGE) using both SmaI and KpnI enzymes. There was a high prevalence of Campylobacter spp. with 86% of flocks testing positive. Campylobacter jejuni alone, Campylobacter coli alone and both C. jejuni and C. coli were detected in 20 (57%), 2 (6%) and 8 (23%) of the flocks respectively. SmaI/KpnI PFGE analysis identified 50 different genotypes across the 35 flocks. Genotype diversity richness was highest on the lifestyle block and farm properties with 43 different genotypes isolated, whilst urban properties displayed the least richness with 12 genotypes isolated. Rural flocks tended to have more different genotypes in a given flock than urban flocks. Comparison of the genotypes with the PulseNet Aotearoa Campylobacter database showed that 28 of the genotypes had previously been isolated from human cases of campylobacteriosis. Many of these were also indistinguishable from Campylobacter spp. previously isolated from retail chicken. Therefore, contact with backyard poultry or their faecal material is a potential additional infection pathway outside of exposure to the established pathways associated with the consumption of Campylobacter-contaminated commercial meat or foods cross-contaminated from contaminated poultry.


In vivo inhibition of cytokine responsiveness and graft-versus-host disease mortality by rapamycin leads to a clinical-pathological syndrome discrete from that observed with cyclosporin A.
Rapamycin (RAPA) has been shown to be a highly effective means of reducing the lethality of graft-versus-host disease (GVHD) in B10.BR recipients of allogeneic C57BL/6 donor cells. RAPA-treated mice had no clinical (e.g., weight loss, diarrhea, lethargy) or histologic evidence of classical acute or chronic GVHD but did develop a clinical-pathological syndrome consisting of ulcerative dermatitis, bile duct proliferation, and a nondestructive peribronchiolar pulmonary infiltration. Because RAPA was found to interfere with the deletion of self-reactive T cells, we wondered whether the RAPA-induced syndrome was related to failed negative selection or altered alloreactivity. We now show that the RAPA-induced syndrome is due to effects on mature, donor-derived alloreactive T cells. By titering the number of T cells infused we were able to vary the syndrome incidence. In contrast to the syndrome seen after cyclosporin A (CsA) administration, the RAPA syndrome did not require an intact thymus and the disease could not be adoptively transferred. The addition of CsA (which blocks T-cell cytokine production) to RAPA (which blocks T-cell cytokine response) prevented the generation of this syndrome, suggesting that the tissue manifestations seen in RAPA only treated recipients were caused by cytokine production and release. RAPA also caused this alloimmune syndrome in recipients of minor histocompatibility antigen disparate donor cells, showing that the RAPA effects were not restricted to a single donor-recipient strain combination or to instances in which the donor and recipient were fully major histocompatibility complex disparate. We conclude that RAPA is a highly effective means of preventing murine acute GVHD, and that when combined with CsA, warrants consideration for human investigations.


Automatic quantification of joint space narrowing and erosions in rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic disease that affects and potentially destroys the joints of the appendicular skeleton. The precise and reproducible quantification of the progression of joint space narrowing and the erosive bone destructions caused by RA is crucial during treatment and in imaging biomarkers in clinical trials. Current manual scoring methods exhibit high interreader variability, even after intensive training, and thus, impede the efficient monitoring of the disease. We propose a fully automatic quantitative assessment of the radiographic changes that result from RA, to increase the accuracy, reproducibility, and speed of image interpretation. Initial joint location estimates are obtained by local linear mappings based on texture features. Bone contours are delineated by active shape models comprised of statistical models of bone shape and local texture. These models are refined by snakes which increase the accuracy and allow for a fitting of pathological deviations from the training population. The method then measures joint space widths and detects erosions on the bone contour. Joint space widths are measured with a coefficient of variation of 2%-7% for repeated measurements and erosion detection exhibits an area under the receiver operating characteristic (ROC) curve of 0.89. Model landmarks serve as a reference system along the contour. These landmarks enable the definition of joint regions and more specific follow-up monitoring. The automatic quantification allows for a remote analysis, relevant for multicenter clinical trials, and reduces the workload of clinical experts since parts of the process can be managed by nonexpert personnel.


The food and nutrient intake of 5- to 12-year-old Australian children during school hours: a secondary analysis of the 2011-2012 National Nutrition and Physical Activity Survey.
School food intake of Australian children is not comprehensively described in literature, with limited temporal, nationally representative data. Greater understanding of intake at school can inform school-based nutrition promotion. This study aimed to describe the dietary intake of primary-aged children during school hours and its contribution to daily intake. This secondary analysis used nationally representative, cross-sectional data from the 2011 to 2012 National Nutrition and Physical Activity Survey. Dietary intake was assessed using validated 24-h dietary recalls on school days. Descriptive statistics were undertaken to determine energy, nutrients, food groups and food products consumed during school hours, as well as their contributions to total daily intake. Associations between school food intake and socio-demographic characteristics were explored. Australia. Seven hundred and ninety-five children aged 5-12 years. Children consumed 37 % of their daily energy and 31-43 % of select nutrient intake during school hours, with discretionary choices contributing 44 % of school energy intake. Most children consumed less than one serve of vegetables, meat and alternatives or milk and alternatives during school hours. Commonly consumed products were discretionary choices (34 %, including biscuits, processed meat), bread (17 %) and fruit (12 %). There were limited associations with socio-economic position variables, apart from child age. Children's diets were not aligned with national recommendations, with school food characterised by high intake of discretionary choices. These findings are consistent with previous Australian evidence and support transformation of the Australian school food system to better align school food consumption with recommendations.


Reduction of hyperlipidemia and proteinuria without growth retardation in nephritic rats by a methionine-supplemented, low-soy-protein diet.
Effect of a low-soy-protein-isolate (SPI) diet supplemented with methionine on hyperlipidemia, proteinuria, and hypoalbuminemia was studied in rats with nephrotoxic serum nephritis (NSN). Rats were fed experimental diets for 14 d after an injection of nephrotoxic serum. An 8.5%-SPI diet (8.5S), as compared with a basal 20%-SPI diet (20S), improved the hyperlipidemia, proteinura, and hypoalbuminemia secondary to NSN but retarded the growth of rats. The addition of 0.3% methionine to 8.5S (8.5SM) alleviated the growth retardation without loss of the above-mentioned beneficial effects. 8.5SM was found to suppress hepatic cholesterol synthesis compared with 20S. These results suggest that the methionine-supplemented low-SPI diet has a beneficial effect on hyperlipidemia, proteinuria, and hypoalbuminemia without inducing either growth retardation or severe fatty liver in nephritis. They also suggest that the hypocholesterolemic effect of 8.5SM in nephritic rats may be partly attributable to reduced hepatic cholesterol synthesis.


The effectiveness of adapted schema therapy for cluster C personality disorders in older adults - integrating positive schemas.
Schema therapy (ST) is an efficacious psychotherapy for personality disorders (PDs) in adults. The first empirical support for the effectiveness of ST in older adults with cluster C PDs was provided recently. ST partly focusses on the positive, but there is an increasing awareness of imbalance in the ST community because of the emphasis on negative schemas versus attention to positive schemas. Positive schemas may be important vehicles of therapeutic change in psychotherapy with older people, as it may help strengthen the healthy adult mode, and it might also help change a negative life review. Suggestions were made to increase the efficacy and feasibility of ST in older adults, including adjusting the case conceptualisation, modifying the experiential techniques, making use of the patient's wisdom and reactivating positive schemas. The aim of the current study is to investigate the feasibility and effectiveness of adapted individual ST for older adults. A multiple baseline design is used with positive and negative core beliefs as primary outcome measures. Ten older adults (age > 60 years) with cluster C PDs are treated with schema therapy, with weekly sessions during one year. This treatment phase is preceded by a baseline phase varying randomly from 4 to 8 weeks. After treatment, there is a 6-month follow-up phase with monthly booster sessions. Symptomatic distress, schema modes, early maladaptive schemas (EMS) and early adaptive schemas (EAS) are secondary outcome measures. PD will be diagnosed before baseline and after treatment phase. EAS are assessed with the Dutch version of the Young Positive Schema Questionnaire (YPSQ). To the best of our knowledge, this is the first empirical study in which positive schemas are integrated in ST treatment to examine the efficacy of an adapted form of ST for older adults. This is in line with wider developments supporting the integration of positive schema's into ST. It offers the possibility to improve the effectiveness of ST in older adults. The Netherlands National Trial Register NL8346, registered 1 February 2020.


Pragmatic clinic randomized trial to improve chronic kidney disease care: Design and adaptation due to COVID disruptions.
We describe a clinic-randomized trial to improve chronic kidney disease (CKD) care through a CKD-clinical decision support (CKD-CDS) intervention in primary care clinics and the challenges we encountered due to COVID-19 care disruption. Primary care clinics (N = 32) were randomized to usual care (UC) or to CKD-CDS. Between April 17, 2019 and March 14, 2020, more than 7000 patients had accrued for analysis by meeting study-eligibility criteria at an index office visit: age 18-75, laboratory criteria for stage 3 or 4 CKD (eGFR 15-59 mL/min/1.73 m2), and one or more opportunities algorithmically identified to improve CKD care such as blood pressure (BP) or glucose control, angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) use, discontinuance of a nonsteroidal anti-inflammatory drug (NSAID), or nephrology referral. At CKD-CDS clinics, CDS provided individualized treatment suggestions that were printed for patients and clinicians at the start of office encounters and were viewable within the electronic health record. By initial design, the impact of the CKD-CDS intervention on care gaps was to be assessed 12 months after the index date, but COVID-19 caused major disruptions to care delivery during the intervention period. In response to disruptions, the intervention was temporarily suspended while we expanded CDS use for telehealth encounters and programmed new criteria for displaying the CKD-CDS to intervention patients due to clinic closures and scheduling changes. We describe a NIH-funded pragmatic trial of web-based EHR-integrated CKD-CDS and modifications necessary mid-study to complete the study as intended in the face of COVID-19 pandemic challenges.


IFN-γ Attenuates Eosinophilic Inflammation but Is Not Essential for Protection against RSV-Enhanced Asthmatic Comorbidity in Adult Mice.
The susceptibility to respiratory syncytial virus (RSV) infection in early life has been associated with a deficient T-helper cell type 1 (Th1) response. Conversely, healthy adults generally do not exhibit severe illness from RSV infection. In the current study, we investigated whether Th1 cytokine IFN-γ is essential for protection against RSV and RSV-associated comorbidities in adult mice. We found that, distinct from influenza virus, prior RSV infection does not induce significant IFN-γ production and susceptibility to secondary Streptococcus pneumoniae infection in adult wild-type (WT) mice. In ovalbumin (OVA)-induced asthmatic mice, RSV super-infection increases airway neutrophil recruitment and inflammatory lung damage but has no significant effect on OVA-induced eosinophilia. Compared with WT controls, RSV infection of asthmatic Ifng-/- mice results in increased airway eosinophil accumulation. However, a comparable increase in eosinophilia was detected in house dust mite (HDM)-induced asthmatic Ifng-/- mice in the absence of RSV infection. Furthermore, neither WT nor Ifng-/- mice exhibit apparent eosinophil infiltration during RSV infection alone. Together, these findings indicate that, despite its critical role in limiting eosinophilic inflammation during asthma, IFN-γ is not essential for protection against RSV-induced exacerbation of asthmatic inflammation in adult mice.


[Hemodynamic aspects of the transvenous electrodestruction of the atrioventricular junction].
Transvenous electrodestruction of the atrioventricular junction is an effective method of surgical treatment for supraventricular arrhythmias (paroxysmal tachysystoles) refractory to medication. However, it is central hemodynamic status alone that can be an objective indicator of favorable clinical effect. Major central hemodynamic parameters were examined in 52 patients before and after the operation. Considerable late postoperative improvement of the general condition and normalization of major central hemodynamic parameters were noted in most cases.


Antisilencing role of the RNA-directed DNA methylation pathway and a histone acetyltransferase in Arabidopsis.
REPRESSOR OF SILENCING 1 (ROS1) is a DNA demethylation enzyme that was previously identified during a genetic screen for the silencing of both RD29A-LUC and 35S-NPTII transgenes on a T-DNA construct. Here we performed a genetic screen to identify additional mutants in which the 35S-NPTII transgene is silenced. We identified several alleles of ros1 and of the following components of the RNA-directed DNA methylation (RdDM) pathway: NRPD1 (the largest subunit of polymerase IV), RDR2, NRPE1 (the largest subunit of polymerase V), NRPD2, AGO4, and DMS3. Our results show that the silencing of 35S-NPTII in the RdDM pathway mutants is due to the reduced expression of ROS1 in the mutants. We also identified a putative histone acetyltransferase (ROS4) from the genetic screen. The acetyltransferase contains a PHD-finger domain that binds to unmethylated histone H3K4. The mutation in ROS4 led to reduction of H3K18 and H3K23 acetylation levels. We show that the silencing of 35S-NPTII and some transposable element genes was released by the ddm1 mutation but that this also required ROS4. Our study identifies a unique antisilencing factor, and reveals that the RdDM pathway has an antisilencing function due to its role in maintaining ROS1 expression.


Neurosteroids and GABA-A Receptor Function.
Neurosteroids represent a class of endogenous steroids that are synthesized in the brain, the adrenals, and the gonads and have potent and selective effects on the GABAA-receptor. 3α-hydroxy A-ring reduced metabolites of progesterone, deoxycorticosterone, and testosterone are positive modulators of GABA(A)-receptor in a non-genomic manner. Allopregnanolone (3α-OH-5α-pregnan-20-one), 5α-androstane-3α, 17α-diol (Adiol), and 3α5α-tetrahydrodeoxycorticosterone (3α5α-THDOC) enhance the GABA-mediated Cl(-) currents acting on a site (or sites) distinct from the GABA, benzodiazepine, barbiturate, and picrotoxin binding sites. 3α5α-P and 3α5α-THDOC potentiate synaptic GABA(A)-receptor function and activate δ-subunit containing extrasynaptic receptors that mediate tonic currents. On the contrary, 3β-OH pregnane steroids and pregnenolone sulfate (PS) are GABA(A)-receptor antagonists and induce activation-dependent inhibition of the receptor. The activities of neurosteroid are dependent on brain regions and types of neurons. In addition to the slow genomic action of the parent steroids, the non-genomic, and rapid actions of neurosteroids play a significant role in the GABA(A)-receptor function and shift in mood and memory function. This review describes molecular mechanisms underlying neurosteroid action on the GABA(A)-receptor, mood changes, and cognitive functions.


The diagnostic accuracy of clinical examination for estimating cardiac index in critically ill patients: the Simple Intensive Care Studies-I.
Clinical examination is often the first step to diagnose shock and estimate cardiac index. In the Simple Intensive Care Studies-I, we assessed the association and diagnostic performance of clinical signs for estimation of cardiac index in critically ill patients. In this prospective, single-centre cohort study, we included all acutely ill patients admitted to the ICU and expected to stay > 24 h. We conducted a protocolised clinical examination of 19 clinical signs followed by critical care ultrasonography for cardiac index measurement. Clinical signs were associated with cardiac index and a low cardiac index (< 2.2 L min-1 m2) in multivariable analyses. Diagnostic test accuracies were also assessed. We included 1075 patients, of whom 783 (73%) had a validated cardiac index measurement. In multivariable regression, respiratory rate, heart rate and rhythm, systolic and diastolic blood pressure, central-to-peripheral temperature difference, and capillary refill time were statistically independently associated with cardiac index, with an overall R2 of 0.30 (98.5% CI 0.25-0.35). A low cardiac index was observed in 280 (36%) patients. Sensitivities and positive and negative predictive values were below 90% for all signs. Specificities above 90% were observed only for 110/280 patients, who had atrial fibrillation, systolic blood pressures < 90 mmHg, altered consciousness, capillary refill times > 4.5 s, or skin mottling over the knee. Seven out of 19 clinical examination findings were independently associated with cardiac index. For estimation of cardiac index, clinical examination was found to be insufficient in multivariable analyses and in diagnostic accuracy tests. Additional measurements such as critical care ultrasonography remain necessary.


Effects of information and training provision in satisfaction of patients and carers in stroke rehabilitation.
Active information and training improves patient and carer knowledge of stroke and aspects of patient satisfaction, as well as reduces patient depression. To evaluate the effect of a post-stroke information and carer training intervention provided in the rehabilitation hospital setting on patient and carers' satisfaction. Nonrandomized, controlled trial with 241 patients consecutively admitted in a post-stroke rehabilitation unit and their carers. The first 140 underwent a standard rehabilitation program (control group) and the 131 following attended an additional class (intervention group). Satisfaction was assessed with the Satisfaction Pound Scale administered by telephone 6 months after stroke in 74 patients and 85 carers from the control group and in 76 patients and 73 carers from the intervention group. Over 80% of patients in both groups were satisfied with information, care and therapy during hospitalization. The amount of therapy and support at discharge were the issues that arouse greater dissatisfaction. Patient and carers' satisfaction with information, support and accessibility to rehabilitation team after hospital discharge improved after the intervention (p < 0.001). Systematic active information, training and community support provision for stroke patients and carers improves satisfaction with stroke rehabilitation programs and support received after hospital discharge.


Sexual function, dysfunction, and sexual distress in a prospective, population-based sample of mid-aged, Australian-born women.
Previous, population-based studies investigating the risk factors for sexual distress have not drawn on longitudinal data. Determine the prevalence of sexual distress and dysfunction, explore factors associated with/predictive of sexual distress, and describe changes in sexual function over a decade in a population-based sample of mid-aged women. Eleven-year prospective study of Australian-born women, aged 45-55 years, and menstruating at baseline. Short Personal Experiences Questionnaire (SPEQ) was completed in years 1 to 8 and 11 of follow-up. Female Sexual Distress Scale (FSDS) was completed in the 11th year of follow-up. Validated outcome measures were the SPEQ (total sex score <or=7 indicates low sexual function) and FSDS (score >or=15 indicates sexual distress). Two hundred fifty-seven women were interviewed in the 11th year of follow-up. All domains of sexual function declined significantly in the decade studied. Women using hormone therapy in year 11 had significantly greater responsivity and higher frequency of sexual activities than nonusers. Two hundred four women completed both the FSDS and SPEQ questionnaires. One hundred sixty-six (81%) women had an SPEQ score <or=7 of whom 34 (17% of the total sample) had an FSDS score >or=15, and were classified as having female sexual dysfunction. The multiple logistic regression analysis found that female sexual distress was concurrently associated with higher depression scores (odds ratio [OR] 1.31, 95% confidence interval [CI] 1.10, 1.56) and more negative feelings for partner (OR 0.49, 95% CI 0.32, 0.76) and predicted by prior negative feelings for partner (OR 0.31, 95% CI 0.14, 0.70), and a greater decline in total sex score (OR 0.77, 95% CI 0.59, 0.99). By the end of the sixth decade, women have low levels of sexual function. Hormone therapy may help these women maintain sexual function. A minority of these mostly postmenopausal women are significantly distressed about low sexual function. Sexual distress is associated with depression and relationship factors.


The post-translational modification landscape of commercial beers.
Beer is one of the most popular beverages worldwide. As a product of variable agricultural ingredients and processes, beer has high molecular complexity. We used DIA/SWATH-MS to investigate the proteomic complexity and diversity of 23 commercial Australian beers. While the overall complexity of the beer proteome was modest, with contributions from barley and yeast proteins, we uncovered a very high diversity of post-translational modifications (PTMs), especially proteolysis, glycation, and glycosylation. Proteolysis was widespread throughout barley proteins, but showed clear site-specificity. Oligohexose modifications were common on lysines in barley proteins, consistent with glycation by maltooligosaccharides released from starch during malting or mashing. O-glycosylation consistent with oligomannose was abundant on secreted yeast glycoproteins. We developed and used data analysis pipelines to efficiently extract and quantify site-specific PTMs from SWATH-MS data, and showed incorporating these features into proteomic analyses extended analytical precision. We found that the key differentiator of the beer glyco/proteome was the brewery, with beer from independent breweries having a distinct profile to beer from multinational breweries. Within a given brewery, beer styles also had distinct glyco/proteomes. Targeting our analyses to beers from a single brewery, Newstead Brewing Co., allowed us to identify beer style-specific features of the glyco/proteome. Specifically, we found that proteins in darker beers tended to have low glycation and high proteolysis. Finally, we objectively quantified features of foam formation and stability, and showed that these quality properties correlated with the concentration of abundant surface-active proteins from barley and yeast.