Postbiotics and paraprobiotics: A review of current evidence and emerging trends.
In recent years, new probiotic-related concepts such as postbiotics and paraprobiotics have been coined to indicate that non-viable microorganisms or bacterial-free extracts may provide benefits to the host by offering additional bioactivities to probiotics, including but not limited to anti-inflammatory, immunomodulatory, anti-proliferative and antioxidant activities. Despite in vitro and in vivo studies that support the promising use of postbiotics and paraprobiotics as health promoters, the mechanism of action and the signaling pathway involved have not yet been fully elucidated. Therefore, the aim of this chapter is to provide an overview of novel probiotic-related concepts and the scientific evidence that supports their bioactivities as well as the possible mechanisms underlying their health-promoting effects. Additionally, current trends in food, feed, and pharmaceutical applications are discussed.


Synthesis of Sulfur-Containing Exo-Bicyclic Dienes and Their Diels-Alder Reactions To Access Thiacycle-Fused Polycyclic Systems.
The stereocontrolled synthesis of unprecedented sulfur-containing exo-bicyclic 1,3-dienes is reported through a palladium-catalyzed reductive cyclization of sulfur-linked 2-bromoenynes. The fused bicyclic structure provides a better stability to the thiacyclic diene compared to the simple 3,4-dimethylenetetrahydrothiophene. Their reactivity toward several dienophiles has been investigated, and various original thiacycle-fused polycyclic systems have been obtained with high or total diastereoselectivity. Moreover, they are the first exo-bicyclic dienes used in Diels-Alder reactions. The relative configurations of four cycloadducts have been unambiguously assigned by X-ray crystallographic analysis. Mechanistic details of the cycloadditions have been examined by computational means.


Identification and precursor frequency analysis of a common T cell epitope motif in mitochondrial autoantigens in primary biliary cirrhosis.
The immunodominant antimitochondrial antibody response in patients with primary biliary cirrhosis (PBC) is directed against the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Based on our earlier observations regarding peripheral blood mononuclear cell (PBMC) T cell epitopes, we reasoned that a comparative analysis of the precursor frequencies of PDC-E2 163-176-specific T cells isolated from PBMC, regional hepatic lymph nodes, and from the liver of PBC patients would provide insight regarding the role of T cells in PBC. Results showed a disease-specific 100-150-fold increase in the precursor frequency of PDC-E2 163-176-specific T cells in the hilar lymph nodes and liver when compared with PBMC from PBC patients. Interestingly, autoreactive T cells and autoantibodies from PBC patients both recognize the same dominant epitope. In addition, we demonstrated cross-reactivity of PDC-E2 peptide 163-176-specific T cell clones with PDC-E2 peptide 36-49 and OGDC-E2 peptide 100-113 thereby identifying a common T cell epitope "motif" ExETDK. The peptide 163-176-specific T cell clones also reacted with purified native PDC-E2, suggesting that this epitope is not a cryptic determinant. These data provide evidence for a major role for PDC-E2 peptide 163-176 and/or peptides bearing a similar motif in the pathogenesis of PBC.


The role of recombinant human M-CSF, IL-3, GM-CSF and calcitriol in clonal development of osteoclast precursors in primate bone marrow.
Evidence suggests that among the myeloid colony-stimulating factors (CSFs), macrophage-CSF (M-CSF) is important in normal development of osteoclasts. To understand the role of M-CSF and other myeloid CSFs on clonal growth of osteoclast progenitors, isolated monkey bone marrow cells expressing the CD34 antigen were grown in soft agar or methylcellulose cultures in the presence of recombinant human M-CSF, granulocyte-macrophage CSF (GM-CSF), interleukin-3 (IL-3), calcitriol and various combinations of these factors. Day-10 to day-20 colonies were stained for tartrate-resistant acid phosphatase (TRAP) in order to identify putative osteoclast progenitors. Colonies were scored as follows: if greater than 80% of the cells in a colony contained TRAP it was scored as TRAP-positive; between 20% and 80%, TRAP-mix; and less than 20%, TRAP-negative. Further identification of osteoclast progenitors was made by simultaneous autoradiographic detection of calcitonin receptors on TRAP-stained colonies grown in methylcellulose. Among the 3 CSFs tested alone, GM-CSF stimulated the greatest number of TRAP-positive colonies; however, M-CSF and IL-3 in combination stimulated an even greater number of TRAP-positive colonies at all time points. Such additive effect was not observed between GM-CSF and IL-3. When calcitriol was added, the following increases in day-20 TRAP-positive colonies occurred: with M-CSF, 189%; with IL-3, 109%; with the combination of M-CSF and IL-3, 52%; and with GM-CSF there was no change. In the presence of calcitriol, 75% of IL-3 plus M-CSF-induced TRAP-containing colonies demonstrated calcitonin receptors over their TRAP-positive cells, whereas with M-CSF, GM-CSF or IL-3 each alone, 0 to 25% of TRAP-containing colonies had calcitonin receptor over TRAP-positive cells. These results suggest that IL-3, M-CSF and calcitriol stimulate a subpopulation of hemopoietic progenitors, likely osteoclast progenitors, that can give rise to TRAP-positive cells simultaneously expressing calcitonin receptors.


Follicular neoplasms of the thyroid in men older than 50 years of age. A DNA flow cytometric study.
The clinical behavior of follicular neoplasms of the thyroid in elderly men can be difficult to predict on histologic grounds alone. To assess the usefulness of DNA flow cytometry in predicting the metastatic potential of these tumors, the authors studied 44 primary and metastatic follicular neoplasms of the thyroid by DNA flow cytometry of paraffin-embedded tissue. The neoplasms were obtained from 44 men ranging in age from 50 to 79 years (mean, 60). There were 29 follicular adenomas, 11 primary follicular carcinomas (neoplasms with capsular and/or vascular invasion), and 4 metastatic follicular carcinomas. Follow-up information was available on 40 of the 44 patients. The mean follow-up was 114 months. Twenty-five of the 29 follicular adenomas had a diploid DNA content, 2 (7%) were tetraploid, and the DNA histograms on 2 were not interpretable. All patients with follicular adenomas had no evidence of disease (NED) at last follow-up. Eight of the 11 primary follicular carcinomas were diploid. Six of these patients had NED, one died with carcinoma at 82 months, and no follow-up was available on one. Three (27%) of the primary follicular carcinomas were aneuploid or tetraploid. Two of these patients had NED, and the third died with carcinoma 84 months after diagnosis. Two of the four metastatic follicular carcinomas were diploid and two (50%) were aneuploid or tetraploid. One of the two patients with diploid metastatic follicular carcinomas died with carcinoma, as did one of the two patients with aneuploid metastatic follicular carcinomas. These results suggest the following: (1) follicular carcinomas are more likely to be aneuploid or tetraploid than are follicular adenomas; (2) follicular neoplasms without capsular or vascular invasion may include a small number of aneuploid or tetraploid tumors; and (3) DNA ploidy does not add to the prognostic value of histologic studies alone.


Characterization of isolates and clones of Leishmania by analysis of kinetoplast DNA.
The genetic characterization of pathogenic isolates of Leishmania was attempted by analysis of the molecular properties of kinetoplast DNA (kDNA) minicircles. Unit minicircle size is not conserved during speciation of Leishmania since the minicircles of strains and clones of L t major are smaller (700 bp) than those found in certain strains of L mexicana ssp (820 bp), L donovani (850 bp) or L t tropica (900 bp). Schizodeme analysis of minicircles reveals a high degree of sequence divergence in kDNA of Leishmania with the degree of microheterogeneity varying between species. This sequence divergence allows the discrimination of species, strains, and clones of Leishmania into schizodemes . Southern blot hybridization experiments reveal that at high stringency overall minicircle sequence homology is conserved among clones and strains of one species (L t major) but not between different species. This property of minicircle DNA permits the use of kDNA probes as a species-specific diagnostic test for the identification of unknown Leishmania isolates. The properties of kDNA from an L t tropica strain LRC- L32 (a " recidiva " organism) are so diverged from those of L t major strains as to support the classification [22, 23] of L t tropica and L t major as separate species of Leishmania rather than subspecies of L tropica.


Differentiation of bovine coronavirus (bcov) genotypes by a restriction enzyme assay.
This article reports the use of the GsuI restriction enzyme to differentiate genotypes of Bovine Coronavirus (BCoV), based on an 18-nucleotide deletion of S1-coding region found in one of the two genotypes. It was concluded that this assay can be used as a rapid tool for BCoV genotypes differentiation.


Enhanced intestinal insulinotropic effect in streptozotocin-diabetic rats.
To study the intestinal insulinotropic effects in the diabetic state, an investigation was made into the release of insulin from isolated rat pancreas perfused with portal venous effluent (PVE) obtained from the isolated perfused intestine of streptozotocin-induced diabetic rats. Rat intestine was perfused with Krebs-Ringer bicarbonate medium for 1 h, and the PVE was collected from both untreated and glucose-treated intestines of control and diabetic rats. The PVE, after adjusting its glucose concentration to the desired level, was used as the perfusing medium for the pancreas of a different rat. Glucose concentration in the perfusion medium was maintained at 5.5 mM for 20 min and at 16.7 mM for the next 30 min. Insulin output from pancreas perfused with PVE from untreated intestine of diabetic rats (252 +/- 45 ng/30 min, mean +/- SD) was similar to that of controls (269 +/- 72 ng/30 min). Pancreatic insulin output with PVE from glucose-treated intestine of diabetic rats (579 +/- 100 ng/30 min) was significantly greater compared with either that using PVE from untreated intestine of diabetic rats (P less than 0.01) or that from glucose-treated intestine of control rats (368 +/- 57 ng/30 min) (P less than 0.02). These results indicate that the insulinotropic effect is markedly enhanced in streptozotocin-induced diabetic rats.


Tumor Endothelial Marker 8 Promotes Proliferation and Metastasis via the Wnt/β-Catenin Signaling Pathway in Lung Adenocarcinoma.
Tumor endothelial marker 8 (TEM8), also known as ANTXR1, was highly expressed in cancers, and was identified as a biomarker for early diagnosis and prognosis in some cancers. However, the clinical role and molecular mechanisms of TEM8 in lung adenocarcinoma (LUAD) are still unclear. The present study aimed to explore its clinical value and the molecular mechanisms of TEM8 underlying the progression of LUAD. Our study found the elevation of TEM8 in LUAD cell lines and tissues. What's more, we observed that the TEM8 expression level was associated with tumor size, primary tumor, and AJCC stage, and LUAD patients with high TEM8 expression usually have a poor prognosis. Then, we conducted a series of experiments by the strategy of loss-of-function and gain-of-function, and our results suggested that the knockdown of TEM8 suppressed proliferation, migration, and invasion and induced apoptosis in LUAD whereas overexpression of TEM8 had the opposite effect. Molecular mechanistic investigation showed that TEM8 exerted its promoting effects mainly through activating the Wnt/β-catenin signaling pathway. In short, our findings suggested that TEM8 played a crucial role in the progression of LUAD by activating the Wnt/β-catenin signaling pathway and could serve as a potential therapeutic target for LUAD.


Selection of β-Blocker in Patients With Cirrhosis and Acute Myocardial Infarction: A 13-Year Nationwide Population-Based Study in Asia.
Background It is not clear whether β1-selective or nonselective β-blockers should be used in patients with cirrhosis and acute myocardial infarction. Methods and Results Medical records were retrieved from Taiwan NHIRD (National Health Insurance Research Database) during 2001-2013. Patients were excluded for age <20, previous acute myocardial infarction, contraindication to β-blockers, chronic obstructive pulmonary disease, asthma, or atrioventricular conduction disease. Patients who died during index admission, had a follow-up <6 months, had a medication ratio of either β1-selective or nonselective β-blocker <80%, or who switched between β-blockers were also excluded. Patients on β1-selective blockers and nonselective β-blockers were propensity score matched and compared for outcome. Primary outcomes were 1- and 2-year cardiovascular events, liver adverse outcomes, and all-cause mortality. A total of 203 595 patients with acute myocardial infarction were enrolled, of whom 6355 had cirrhosis. After screening for exclusion criteria, 1769 patients (655 patients on β-blockers and 1114 patients not on β-blockers) were eligible for analysis. Among patients on β-blockers, propensity score matching was performed, and 218 patients on β1-selective blockers and 218 patients on nonselective β-blockers were studied. During a 2-year follow-up, patients on β1-selective blockers had significantly fewer major cardiac and cerebrovascular events (hazard ratio=0.62; 95% confidence interval=0.42-0.91; P=0.014), a trend toward lower all-cause mortality (hazard ratio=0.66; 95% confidence interval=0.38-1.14; P=0.135), and nonworsening liver outcome (hazard ratio=0.66; 95% confidence interval=0.38-1.14; P=0.354). Conclusions In patients with cirrhosis and acute myocardial infarction, selecting a β-blocker is a clinical dilemma. Our study showed that the use of β1-selective blockers is associated with lower risks of major cardiac and cerebrovascular events.


A prevalence study of autism in tuberous sclerosis.
An estimate of the prevalence of autism in tuberous sclerosis (TSC) was made by interviewing the parents of 21 children between ages 3 and 11 ascertained during a previous population study of the condition in the West of Scotland. Five of the children (24%) were rated autistic and a further four (19%), all of whom were girls, had socially impaired behavior categorized as pervasive developmental disorder, without fulfilling all the DSM-III-R criteria for autism. One further boy had disruptive attention-seeking behavior that had excluded him from his normal school. The estimated prevalence from this study of autism in TSC is 1 in 4 children in general, and 1 in 2 of those with mental retardation. Tuberous sclerosis could be a significant cause of autism and pervasive developmental disorders, particularly in girls.


Functionalisation of PLLA nanofiber scaffolds using a possible cooperative effect between collagen type I and BMP-2: impact on colonization and bone formation in vivo.
The reconstruction of large bone defects after injury or tumor resection often requires the use of bone substitution. Artificial scaffolds based on synthetic biomaterials can overcome disadvantages of autologous bone grafts, like limited availability and donor side morbidity. Among them, scaffolds based on nanofibers offer great advantages. They mimic the extracellular matrix, can be used as a carrier for growth factors and allow the differentiation of human mesenchymal stem cells. Differentiation is triggered by a series of signaling processes, including integrin and bone morphogenetic protein (BMP), which act in a cooperative manner. The aim of this study was to analyze whether these processes can be remodeled in artificial poly-(l)-lactide acid (PLLA) based nanofiber scaffolds in vivo. Electrospun matrices composed of PLLA-collagen type I or BMP-2 incorporated PLLA-collagen type I were implanted in calvarial critical size defects in rats. Cranial CT-scans were taken 4, 8 and 12 weeks after implantation. Specimens obtained after euthanasia were processed for histology and immunostainings on osteocalcin, BMP-2 and Smad5. After implantation the scaffolds were inhomogeneously colonized and cells were only present in wrinkle- or channel-like structures. Ossification was detected only in focal areas of the scaffold. This was independent of whether BMP-2 was incorporated in the scaffold. However, cells that migrated into the scaffold showed an increased ratio of osteocalcin and Smad5 positive cells compared to empty defects. Furthermore, in case of BMP-2 incorporated PLLA-collagen type I scaffolds, 4 weeks after implantation approximately 40 % of the cells stained positive for BMP-2 indicating an autocrine process of the ingrown cells. These findings indicate that a cooperative effect between BMP-2 and collagen type I can be transferred to PLLA nanofibers and furthermore, that this effect is active in vivo. However, this had no effect on bone formation. The reason for this seems to be an unbalanced colonization of the scaffolds with cells, due to insufficient pore size.


The Diagnostic Value of Language Screening in Primary Progressive Aphasia: Validation and Application of the Sydney Language Battery.
The three variants of primary progressive aphasia (PPA) differ in clinical presentation, underlying brain pathology, and clinical course, which stresses the need for early differentiation. However, brief cognitive tests that validly distinguish between all PPA variants are lacking. The Sydney Language Battery (SYDBAT) is a promising screening instrument that can be used as a first step in a comprehensive neuropsychological assessment to distinguish PPA subtypes, but evidence on its validity and reliability is to date limited. In the current study, the validation and diagnostic value of the SYDBAT are described for discriminating PPA subtypes as well as distinguishing PPA from mild cognitive impairment (MCI) or Alzheimer's dementia (AD). Forty-five patients with PPA (13 with semantic PPA, 20 with logopenic PPA, and 12 with nonfluent/agrammatic PPA), 25 MCI patients, 13 AD patients, and 50 cognitively unimpaired controls were included in this study. Both patients and controls completed the SYDBAT-NL (Dutch version). Performance on and predictive ability of the four subtests (i.e., Naming, Word Comprehension, Repetition, and Semantic Association) were assessed. In addition, construct validity and internal consistency were examined. Different SYDBAT performance patterns were found across PPA and non-PPA patient groups. While a discriminant function analysis based on SYDBAT subtest scores could predict PPA subtype with 78% accuracy, it was more difficult to disentangle PPA from non-PPA patients based on SYDBAT scores alone. For assisting in clinical interpretation, simple rules were set up and translated into a diagnostic decision tree for subtyping PPA, which was capable of diagnosing a large proportion of the cases. Satisfying validity and reliability measures were found. The SYDBAT is an easy-to-use and promising screen for assessing single-word language processes, which may contribute to the differential diagnostic process of PPA and the assessment of language impairment in MCI and AD. It can be easily implemented for initial screening of patients in a memory clinic.


Occult Blood in Feces Is Associated with Increased Risk of Psoriasis.
The fecal immunochemistry test (FIT) has been proposed as a surrogate marker of intestinal inflammation. Psoriasis is a chronic inflammatory skin disease that is linked to underlying systemic inflammatory conditions, including inflammatory bowel disease. We investigated the association between occult blood in feces and the risk of psoriasis using data from the National Health Insurance System. This study was conducted involving 1,395,147 individuals who underwent health examinations from January 2009 to December 2012 and were followed up until the end of 2017. The incidence of psoriasis (per 1,000 person-years) was 3.76 versus 4.14 (FIT-negative versus FIT-positive group) during a median follow-up of 6.68 years. In the multivariable-adjusted model, the hazard ratios for psoriasis were 1.03 for one positive FIT result, 1.12 for two positive FIT results, and 1.34 for three positive FIT results compared with negative FIT results. The risk of psoriasis was significantly increased in patients with positive FIT results compared to the FIT-negative population.


Effects of sulpiride and chlorpromazine on regional cerebral glucose metabolism in schizophrenic patients as determined by positron emission tomography.
Positron emission tomography (PET) was used to determine regional brain glucose metabolism in schizophrenic patients (n = 17) before and during neuroleptic treatment. The patients had not been treated with neuroleptics for at least 3 weeks before the first study. All suffered from acute psychotic symptoms and were hospitalized to obtain neuroleptic treatment. After determination of regional brain metabolism without neuroleptic treatment, 11 patients were treated with sulpiride (800 mg/day) and 6 patients were treated with chlorpromazine (400 mg/day) over 5-6 weeks before the second PET investigation. The control group consisted of seven healthy male volunteers, also investigated twice 5 weeks apart. The PET investigation was made with the subject in a resting state. The tracer was uniformly labelled 11C-glucose. The metabolism was determined bilaterally in 15 brain regions cortical, as well as central regions. Metabolic rates differed among the groups. The sulpiride group had lower metabolic rates than the controls and the schizophrenic patients later treated with chlorpromazine. The sulpiride group, in which absolute metabolic rates were determined, were clinically more autistic and chronic than the chlorpromazine group. It was proposed that these facts could explain the lower metabolic rates in the sulpiride group. A significant change in metabolism in relation to drug treatment was only found in one brain region. The selective D2-receptor antagonist sulpiride increased the metabolic rate in the right lentiform nucleus in comparison with the patients treated with chlorpromazine and the controls. Likewise, relative metabolic rates were increased only in the right lentiform nucleus. Negative correlations between intensity of clinical symptoms and metabolism indicated that emotional tone and drive were related to brain metabolism. No correlations were found between drug concentrations and metabolism or clinical symptoms.


A method for the quantification of synchrony and oscillatory properties of neuronal activity.
Interactions between neurones can be analysed by simultaneously recording from several cells and computing correlation functions between the respective activities. Recent studies have revealed that neuronal responses are often synchronous and exhibit an oscillatory temporal structure. These two properties are commonly assessed together from correlation functions. In order to evaluate these variables independently a method was devised for the quantification of a generalized Gabor function that was fitted to the correlograms. The performance of the method was tested on a large data set from cat area 17 and its stability was examined with respect to its dependence on the number of free parameters. The results demonstrate that the proposed fitting algorithm is robust in that it is rather independent of starting conditions and converges to optimal fits even with different settings of free variables. The fitted correlation function allow for an automatic and independent classification of synchrony on the one hand and oscillatory firing patterns on the other.


An atlas of a rare neuronal surface antigen in the rat central nervous system.
The mature nervous system contains functional synaptic networks composed of neuronal sets and subsets whose identity and maintenance may rely on external surface molecules specific for these neuronal subdivisions. Such molecules may reside permanently on specific neurons, serving to identify those neurons within a complex population. From a collection of monoclonal antibodies made to the Torpedo cholinergic synaptosome preparation, we have identified several antibodies that bind the surface of some, but not all, neurons of the mature rat brain (Kushner and Stephenson, 1983; Kushner, 1984). In the present study we catalog which neurons of the entire rat brain and spinal cord are immunopositive for one of these antibodies, Tor 23. The atlas we have compiled can be used (1) on a practical level to guide affinity purifications and neuronal cell sorting, and (2) more esoterically to address whether surface antigenic sets of neurons share or define a common functional property. In the forebrain, Tor 23-positive neurons predominate as a rare cell type of the inner cortical laminae. In the midbrain, few cells stain. In the hindbrain, labeled neurons are dispersed among several nuclei. The exceptions to these observations, areas that almost exclusively contain Tor 23-immunopositive neurons, are the spinal cord ventral horn, the deep cerebellar nuclei, some cerebellar-related nuclei, selected auditory nuclei, the supraoptic and paraventricular nuclei of the hypothalamus, and the CA2 pyramidal neurons of the hippocampus. The neurons that bind Tor 23 are related biochemically by virtue of that shared epitope alone. Whether they are related in a functional manner is a separate issue. Tor 23 demarks many motor-related structures, specifically, the ventral horn motor lamina, the orofacial motor nuclei 5 and 7, the ambiguus nucleus, the deep cerebellar nuclei, the pontine reticulotegmental nucleus, the lateral reticular nucleus, the gigantocellular reticular nucleus, the red nucleus, and neurons within the motor and somatosensory cortices. The overlap of Tor 23 with motor structures suggests that Tor 23 is a motor system marker.


Cardiovascular Disease Risk Factors in Ghana during the Rural-to-Urban Transition: A Cross-Sectional Study.
Populations in sub-Saharan Africa are shifting from rural to increasingly urban. Although the burden of cardiovascular disease is expected to increase with this changing landscape, few large studies have assessed a wide range of risk factors in urban and rural populations, particularly in West Africa. We conducted a cross-sectional, population-based survey of 3317 participants from Ghana (≥18 years old), of whom 2265 (57% female) were from a mid-sized city (Sunyani, population ~250,000) and 1052 (55% female) were from surrounding villages (populations <5000). We measured canonical cardiovascular disease risk factors (BMI, blood pressure, fasting glucose, lipids) and fibrinolytic markers (PAI-1 and t-PA), and assessed how their distributions and related clinical outcomes (including obesity, hypertension and diabetes) varied with urban residence and sex. Urban residence was strongly associated with obesity (OR: 7.8, 95% CI: 5.3-11.3), diabetes (OR 3.6, 95% CI: 2.3-5.7), and hypertension (OR 3.2, 95% CI: 2.6-4.0). Among the quantitative measures, most affected were total cholesterol (+0.81 standard deviations, 95% CI 0.73-0.88), LDL cholesterol (+0.89, 95% CI: 0.79-0.99), and t-PA (+0.56, 95% CI: 0.48-0.63). Triglycerides and HDL cholesterol profiles were similarly poor in both urban and rural environments, but significantly worse among rural participants after BMI-adjustment. For most of the risk factors, the strength of the association with urban residence did not vary with sex. Obesity was a major exception, with urban women at particularly high risk (26% age-standardized prevalence) compared to urban men (7%). Overall, urban residents had substantially worse cardiovascular risk profiles, with some risk factors at levels typically seen in the developed world.


Do cold weather temperatures affect the efficacy of skin decontamination?
Skin decontamination in cold weather temperatures might be challenging due to the aggravating circumstances. However, no information is available on the efficacy of commonly used procedures in winter conditions. Therefore, the efficacy of the reactive skin decontamination lotion (RSDL) and soapy water decontamination following skin exposure to the nerve agent VX was evaluated at three ambient air temperatures (-5°C, -15°C and room temperature). Experiments were performed in vitro using human dermatomed skin. The ability of RSDL to degrade VX at the three different air temperatures was separately evaluated. The ambient air temperature in experiments without decontamination did not influence the penetration rate of VX through skin. RSDL decontamination was highly efficient in removing VX from skin when performed in all three ambient temperatures, despite the slower agent degradation rate of VX at the lower temperatures. Decontamination with soapy water at RT resulted in an increased skin penetration of VX compared with the control without decontamination; however, in colder temperatures the VX skin penetration was similar to the corresponding control without decontamination. At RT, dry removal prior to washing with soapy water did not improve decontamination of VX compared with washing solely with soapy water. This study demonstrated high efficacy of RSDL decontamination following skin exposure to VX also at cold temperatures. The previously reported 'wash-in' effect of soapy water on VX skin penetration was reduced at cold temperatures. Altogether, this study found a scientific basis to establish guidelines for skin decontamination of chemical casualties at cold weather temperatures.


Divergent functions of two ancient Hydra Brachyury paralogues suggest specific roles for their C-terminal domains in tissue fate induction.
Homologues of the T-box gene Brachyury play important roles in mesoderm differentiation and other aspects of early development in all bilaterians. In the diploblast Hydra, the Brachyury homologue HyBra1 acts early in the formation of the hypostome, the location of the organiser in adult Hydra. We now report the isolation and characterisation of a second Brachyury gene, HyBra2. Sequence analysis suggests that HyBra1 and HyBra2 are paralogues, resulting from an ancient lineage-specific gene duplication. We show that both paralogues acquired novel functions, both at the level of their cis-regulation as well as through significant divergence of the coding sequence. Both genes are expressed in the hypostome, but HyBra1 is predominantly endodermal, whereas HyBra2 transcripts are found primarily in the ectoderm. During bud formation, both genes are activated before any sign of evagination, suggesting an early role in head formation. During regeneration, HyBra1 is an immediate-early response gene and is insensitive to protein synthesis inhibition, whereas the onset of expression of HyBra2 is delayed and requires protein synthesis. The functional consequence of HyBra1/2 protein divergence on cell fate decisions was tested in Xenopus. HyBra1 induces mesoderm, like vertebrate Brachyury proteins. By contrast, HyBra2 shows a strong cement-gland and neural-inducing activity. Domain-swapping experiments show that the C-terminal domain of HyBra2 is responsible for this specific phenotype. Our data support the concept of sub- and neofunctionalisation upon gene duplication and show that divergence of cis-regulation and coding sequence in paralogues can lead to dramatic changes in structure and function.


Limb mechanics as a function of speed and gait: a study of functional strains in the radius and tibia of horse and dog.
Rosette strain gauges were attached to the midshaft of the radius and tibia of two horses and two dogs, which ran on a treadmill through their entire range of speed and gait. The relative magnitudes of the principal strains on the opposite cortices of each bone remained constant through the stance phase of the stride, and their orientation varied by a maximum of only 14 degrees through the entire speed range. The maximum strain rate increased linearly with speed, but the peak strain magnitude was also dependent upon the gait used, increasing incrementally by up to 59% at the transition from walk to trot, and dropping by 42% from a trot to a canter. Force transducers attached to the shoes of one horse indicated similar changes in ground load. The peak strains induced during vigorous activity are remarkably uniform in a wide range of animals. This suggests that the skeleton is scaled to provide constant safety margins between peak functional strains and those at which yield and ultimate failure occur.


Effect of Early Orthopedic Rehabilitation on Development of Complex Regional Pain Syndrome Type 1.
Complex regional pain syndrome (CRPS) is a syndrome usually occurs in one extremity and characterized by pain, tenderness with palpation, and symptoms of autonomic nervous system dysfunction. An essential factor in the etiology of CRPS is immobilization of the extremity as a result of a fracture. Delaying the start of physical medicine and rehabilitation program after removal of the plaster or splint may increase the rates of CRPS development in patients with fractures. This study aims to determine a direct relationship between delay time in rehabilitation and CRPS development. Patients admitted to our physical therapy and rehabilitation outpatient clinic within the last 3 years (January 2016 to January 2018) for orthopedic rehabilitation following fractures were retrospectively analyzed. CRPS development status, the delay time for the rehabilitation program was determined in 38 CRPS patients of 91 patients with fractures. Probit regression was used to reveal the relationship between delay time for rehabilitation and CRPS development. CRPS development rates were decreased by years (48.71% in 2016, 43.47% in 2017, and 31.03% in 2018). When cases in 2016 were taken as a reference, it was seen that cases in 2017 and 2018 were exposed to CRPS approximately 0.03% and 16.00% lower than the reference year, 2016. A delay of one day exposes the patient to approximately 0.35% more CRPS. As the delay time for rehabilitation in our clinic decreased, the incidence of CRPS decreased. The awareness of physicians and patients about the importance of early rehabilitation should be improved.


The impact of morbidity trajectories on identifying high-cost cases: using Taiwan's National Health Insurance as an example.
Incorporating longitudinal information into risk-adjustment models has been considered important. This study aimed to evaluate how morbidity trajectories impact risk-adjustment models in identifying high-cost cases. Claims-based risk adjusters, with or without morbidity trajectories derived from 3-year claims from Taiwan's National Insurance System, were used to predict being a prospective high-cost user. A random sample of Taiwanese National Health Insurance enrollees continuously enrolled from 2002 to 2005 (n = 147,892) was the study sample. A logistic regression model was employed. The performance measures, based on the split analysis, included statistical indicators (c-statistics, sensitivity and predictive positive value), proportions of true cases identified by models and medical utilization of predicted cases. As the comprehensiveness of risk adjustment models increased, the performance of the models generally increased. The effect of adding trajectories on the model performance decreased as the comprehensiveness of the model increased. Such impact was most apparent in statistical indicators and medical utilization of the predicted groups. In identifying high-cost cases, adding morbidity trajectories might be necessary only for less comprehensive risk adjustment models, and its contributions came from higher c-statistics and increasing medical utilization of predicted groups.


Use of patient-derived human immunodeficiency virus type 1 integrases to identify a protein residue that affects target site selection.
To identify parts of retroviral integrase that interact with cellular DNA, we tested patient-derived human immunodeficiency virus type 1 (HIV-1) integrases for alterations in the choice of nonviral target DNA sites. This strategy took advantage of the genetic diversity of HIV-1, which provided 75 integrase variants that differed by a small number of amino acids. Moreover, our hypothesis that biological pressures on the choice of nonviral sites would be minimal was validated when most of the proteins that catalyzed DNA joining exhibited altered target site preferences. Comparison of the sequences of proteins with the same preferences then guided mutagenesis of a laboratory integrase. The results showed that single amino acid substitutions at one particular residue yielded the same target site patterns as naturally occurring integrases that included these substitutions. Similar results were found with DNA joining reactions conducted with Mn(2+) or with Mg(2+) and were confirmed with a nonspecific alcoholysis assay. Other amino acid changes at this position also affected target site preferences. Thus, this novel approach has identified a residue in the central domain of HIV-1 integrase that interacts with or influences interactions with cellular DNA. The data also support a model in which integrase has distinct sites for viral and cellular DNA.


The value of children in African countries: insights from studies on infertility.
A number of studies have explored motives for parenthood in the Western industrialized world. These studies have documented that children are mostly desired for reasons relating to happiness and personal well-being. To date, limited data pertaining to parenthood motives in African countries exist. Insight into the value of children can, however, be derived from studies on infertility, as the negative repercussions of involuntary childlessness reflect the value of children to parents and the community. According to these studies children secure conjugal ties, offer social security, assist with labour, confer social status, secure rights of property and inheritance, provide continuity through re-incarnation and maintaining the family lineage, and satisfy emotional needs. Parenthood therefore appears to have more and, arguably, deeper roots in African communities when compared to industrialized countries.


The vagus nerve cross-sectional area on ultrasound in patients with type 2 diabetes.
Diabetic neuropathy, including autonomic neuropathy is a serious complication related to type 2 diabetes mellitus (T2D). The vagus nerve (VN) is the longest nerve in the autonomic nervous system, and since diabetic neuropathy manifests first in longer nerves, the VN is commonly affected in early diabetic autonomic neuropathy. The use of high-resolution ultrasound for peripheral and cranial nerve imaging has significantly increased over the past 2 decades. The aim of the study is to compare the cross-sectional area of the VN in patients with T2D to that of a control cohort without T2D. A total of 52 VN cross-sectional areas were recorded from patients with T2D. A total of 56 VN cross-sectional areas were also recorded from asymptomatic subjects without T2D. In each subject, high-resolution ultrasound imaging of the bilateral VNs was performed in the short-axis between the common carotid artery and the internal jugular vein. The VN cross-sectional areas were recorded and compared. In the patients with T2D, HbA1c and fasting blood glucose levels were obtained as well as the duration of T2D in years and correlated with the cross-sectional areas. The bilateral VN cross-sectional areas were similar in both cohorts. Additionally, no correlation was seen between the VN cross-sectional areas, demographics, or clinical data of T2D. Our study demonstrated normal VN cross-sectional areas in patients with T2D without any significant relation with the patients' demographic or clinical data.


The biosynthesis of shikimate metabolites.
This review covers the literature published during 2000 on the biosynthesis of compounds derived wholly or partly from intermediates on the shikimate pathway. Recent developments in the enzymology and genetics of the shikimate pathway arc also described. Enzymes involved in the biogenetic pathway to the aromatic amino acids are covered initially followed by sections dedicated to metabolites derived in some part from intermediates on the pathway. These include pyrrolnitrin. violacein. indole-3-acetic acid, coumarins, lignans, lignin, tannins, melanin, flavanoids, ubiquinone, TOPA quinone, PQQ, and tropanes.


Using a combination of MLPA kits to detect chromosomal imbalances in patients with multiple congenital anomalies and mental retardation is a valuable choice for developing countries.
Conventional karyotyping detects anomalies in 3-15% of patients with multiple congenital anomalies and mental retardation (MCA/MR). Whole-genome array screening (WGAS) has been consistently suggested as the first choice diagnostic test for this group of patients, but it is very costly for large-scale use in developing countries. We evaluated the use of a combination of Multiplex Ligation-dependent Probe Amplification (MLPA) kits to increase the detection rate of chromosomal abnormalities in MCA/MR patients. We screened 261 MCA/MR patients with two subtelomeric and one microdeletion kits. This would theoretically detect up to 70% of all submicroscopic abnormalities. Additionally we scored the de Vries score for 209 patients in an effort to find a suitable cut-off for MLPA screening. Our results reveal that chromosomal abnormalities were present in 87 (33.3%) patients, but only 57 (21.8%) were considered causative. Karyotyping detected 15 abnormalities (6.9%), while MLPA identified 54 (20.7%). Our combined MLPA screening raised the total detection number of pathogenic imbalances more than three times when compared to conventional karyotyping. We also show that using the de Vries score as a cut-off for this screening would only be suitable under financial restrictions. A decision analytic model was constructed with three possible strategies: karyotype, karyotype + MLPA and karyotype + WGAS. Karyotype + MLPA strategy detected anomalies in 19.8% of cases which account for 76.45% of the expected yield for karyotype + WGAS. Incremental Cost Effectiveness Ratio (ICER) of MLPA is three times lower than that of WGAS, which means that, for the same costs, we have three additional diagnoses with MLPA but only one with WGAS. We list all causative alterations found, including rare findings, such as reciprocal duplications of regions deleted in Sotos and Williams-Beuren syndromes. We also describe imbalances that were considered polymorphisms or rare variants, such as the new SNP that confounded the analysis of the 22q13.3 deletion syndrome.


Bradykinin-induced renal hemodynamic alterations: renin and prostaglandin relationships.
The present studies examined the role of the renin-angiotensin system as a modifier of the renal vasomotor response to bradykinin. Renal arterial bradykinin infusion (80 ng.kg-1.min-1) initially resulted in increased renal blood flow (RBF). The secretory rates of renin and prostaglandins increased after 60 min. With continued bradykinin administration (120 min) RBF and prostaglandin secretory rates returned toward control values, although renin secretory rate remained elevated (P less than 0.02). After prostaglandin synthetase inhibition, RBF decreased and bradykinin administration returned RBF to control values. Prostaglandin secretory rates decreased after meclofenamate (P less than 0.005). Continued bradykinin infusion resulted in a return of the renin secretory rate to control values. The administration of bradykinin after competitive inhibition of angiotensin II resulted in a sustained increase in renal blood flow. These results suggest that the initial bradykinin-induced renal hyperemia is only partially dependent on enhanced prostaglandin release, the increase in renin secretion by bradykinin infusion after prostaglandin synthetase inhibition is consistent with a bradykinin and renin interaction, and the lack of a sustained hyperemia after bradykinin is related to increased renin-angiotensin system activity.


Drug Burden Index and Cognitive and Physical Function in Aged Care Residents: A Longitudinal Study.
Anticholinergic/antimuscarinic and sedative medications (eg, benzodiazepines) have been found to be associated with poorer cognitive and physical function and mobility impairment in older age. However, previous studies were mostly conducted among community-dwelling older individuals and had often a cross-sectional design. Accordingly, our aim was to examine longitudinal associations between cumulative exposure to anticholinergic and sedative medications and cognitive and physical function among residents from aged care homes. Longitudinal study. A total of 4624 residents of Dutch aged care homes of whom data were collected between June 2005 and April 2014. Outcome measures were collected with the Long-Term Care Facilities assessment from the international Residential Assessment Instrument (interRAI-LTCF) and included the Cognitive Performance Scale, the Activities of Daily Living (ADL) Hierarchy scale, a timed 4-meter walk test, distance walked, hours of physical activity, and days being outside. Cumulative exposure to anticholinergic and sedative medications was calculated with the Drug Burden Index (DBI), a linear additive pharmacological dose-response model. Associations were examined with linear mixed models to take the potential dependence of observations into account (ie, data were collected at repeated assessment occasions of residents who were clustered in aged care homes). Analyses were adjusted for sex, age, dementia, comorbidity (neurological, psychiatric, cardiovascular, oncological, and pulmonary), fractures, depressive symptoms, and medications excluded from the DBI. We observed significant longitudinal associations between a higher DBI and poorer ADLs, fewer hours of physical activity, and fewer days being outside. We found no significant longitudinal association between a higher DBI and poorer cognitive function. Over time, cumulative exposure to anticholinergic and sedative medications is associated with poorer physical but not cognitive function in aged care residents. Careful monitoring of aged care residents with high cumulative anticholinergic and sedative medication exposure is needed.


Nanopatterned smart polymer surfaces for controlled attachment, killing, and release of bacteria.
Model surfaces with switchable functionality based on nanopatterned, thermoresponsive poly(N-isopropylacrylamide) (PNIPAAm) brushes were fabricated using interferometric lithography combined with surface-initiated polymerization. The temperature-triggered hydration and conformational changes of nanopatterned PNIPAAm brushes reversibly modulate the spatial concealment and exposure of molecules that are immobilized in the intervals between nanopatterned brushes. A biocidal quaternary ammonium salt (QAS) was used to demonstrate the utility of nanopatterned PNIPAAm brushes to control biointerfacial interactions with bacteria. QAS was integrated into polymer-free regions of the substrate between nanopatterned PNIPAAm brushes. The biocidal efficacy and release properties of these surfaces were tested against Escherichia coli K12. Above the lower critical solution temperature (LCST) of PNIPAAm, desolvated, collapsed polymer chains facilitate the attachment of bacteria and expose QAS moieties that kill attached bacteria. Upon a reduction of the temperature below the LCST, swollen PNIPAAm chains promote the release of dead bacteria. These results demonstrate that nanopatterned PNIPAAm/QAS hybrid surfaces are model systems that exhibit an ability to undergo noncovalent, dynamic, and reversible changes in structure that can be used to control the attachment, killing, and release of bacteria in response to changes in temperature.


Falling down a flight of stairs: The impact of age and intoxication on injury pattern and severity.
Falling down a flight of stairs is a common injury mechanism in major trauma patients, but little research has been undertaken into the impact of age and alcohol intoxication on the injury patterns of these patients. The aim of this study was to compare the impact of age and alcohol intoxication on injury pattern and severity in patients who fell down a flight of stairs. This was a retrospective observational study of prospectively collected trauma registry data from a major trauma centre in the United Kingdom comparing older and younger adult patients admitted to the Emergency Department following a fall down a flight of stairs between July 2012 and March 2015. Older patients were more likely to suffer injuries to all body regions and sustained more severe injuries to the spine; they were also more likely to suffer polytrauma (23.6% versus 10.6%; p < 0.001). Intoxicated patients were more likely to suffer injuries to the head and neck (42.9% versus 30.5%; p = 0.006) and were significantly younger than sober patients (53 versus 69 years; p < 0.001). Older patients who fall down a flight of stairs are significantly different from their younger counterparts, with a different injury pattern and a greater likelihood of polytrauma. In addition, alcohol intoxication also affects injury pattern in people who have fallen down a flight of stairs, increasing the risk of traumatic brain injury. Both age and intoxication should be considered when managing these patients.


Host Specificity and Spatial Distribution Preference of Three Pseudomonas Isolates.
Plant hosts recruit and maintain a distinct root-associated microbiota based on host and bacterium traits. However, past studies disregarded microbial strain-host specificity and spatial micro-heterogeneity of the root compartment. Using genetic manipulation, confocal laser scanning microscopy, real-time quantitative PCR, and genome sequencing we characterized the colonization patterns of three Pseudomonas spp. isolates native to wheat roots, on the micro-scale. Namely, isolates P. fluorescens NT0133, P. stutzeri NT124, and P. stutzeri NT128. All three isolates preferentially colonized wheat over cucumber roots that served as control for host specificity. Furthermore, not only had the isolates strong host specificity but each isolate had a distinct spatial distribution on the root, all within a few millimeters. Isolate P. stutzeri-NT0124 preferentially colonized root tips, whereas P. fluorescens-NT0133 showed a preference for zones distant from the tip. In contrast, isolate P. stutzeri-NT0128 had no preference for a specific niche on the root. While all isolates maintained genetic potential for motility and biofilm formation their phenotype varied significantly and corresponded to their niche preference. These results demonstrate the importance of spatial colonization patterns, governed by both niche and bacterial characteristics which will have great importance in future attempts to manipulate the plant microbiome by constructing synthetic microbial consortia.


A synthesis of radial growth patterns preceding tree mortality.
Tree mortality is a key factor influencing forest functions and dynamics, but our understanding of the mechanisms leading to mortality and the associated changes in tree growth rates are still limited. We compiled a new pan-continental tree-ring width database from sites where both dead and living trees were sampled (2970 dead and 4224 living trees from 190 sites, including 36 species), and compared early and recent growth rates between trees that died and those that survived a given mortality event. We observed a decrease in radial growth before death in ca. 84% of the mortality events. The extent and duration of these reductions were highly variable (1-100 years in 96% of events) due to the complex interactions among study species and the source(s) of mortality. Strong and long-lasting declines were found for gymnosperms, shade- and drought-tolerant species, and trees that died from competition. Angiosperms and trees that died due to biotic attacks (especially bark-beetles) typically showed relatively small and short-term growth reductions. Our analysis did not highlight any universal trade-off between early growth and tree longevity within a species, although this result may also reflect high variability in sampling design among sites. The intersite and interspecific variability in growth patterns before mortality provides valuable information on the nature of the mortality process, which is consistent with our understanding of the physiological mechanisms leading to mortality. Abrupt changes in growth immediately before death can be associated with generalized hydraulic failure and/or bark-beetle attack, while long-term decrease in growth may be associated with a gradual decline in hydraulic performance coupled with depletion in carbon reserves. Our results imply that growth-based mortality algorithms may be a powerful tool for predicting gymnosperm mortality induced by chronic stress, but not necessarily so for angiosperms and in case of intense drought or bark-beetle outbreaks.


Role of thyrotropin in triiodothyronine generation in hypothyroidism.
Most of the circulating T3 is generated by monodeiodination of T4 in extrathyroidal tissue with only minor contribution by the thyroid gland. Since T3 is the main active thyroid hormone and TSH is the major modulator of its synthesis and release by the thyroid gland, TSH may also play a significant role in synthesis and release of T3 by the peripheral tissues as documented in recent in vitro animal studies. However, the data regarding its influence on T4 metabolism in humans is lacking. Hypothyroidism may provide an appropriate environment for assessing the influence of TSH in synthesis and release of T3 by the extrathyroidal tissues, since circulating T3 is almost totally derived via peripheral conversion of T4, and serum TSH varies from subnormal levels in central hypothyroidism to a wide range of supernormal concentration in the primary variety. This study determined the relationship between serum TSH concentration and T3 and T4 ratio, a reliable index of conversion of T4 into T3 in peripheral tissues, in 75 subjects with hypothyroidism including both the primary and the central types. Serum T3 was significantly higher (p < 0.001) in primary hypothyroidism (1.48 +/- 0.13 mM/l) in comparison with the central type (0.71 +/- 0.09 mM/l) despite almost equally low serum T4 concentration in both groups. In primary hypothyroidism, T3:T4 ratio (0.026 +/- 0.0012) was significantly higher (p < 0.01) than normal (0.017 +/- 0.0010) along with supernormal TSH (71 +/- 6.4 mU/L) concentration prior to initiation of LT4 replacement therapy and normalized (0.015 +/- 0.0008) on achieving euthyroid state with correction of serum TSH level (3.8 +/- 0.3 mU/L).(ABSTRACT TRUNCATED AT 250 WORDS)


Circuit dissection of the role of somatostatin in itch and pain.
Stimuli that elicit itch are detected by sensory neurons that innervate the skin. This information is processed by the spinal cord; however, the way in which this occurs is still poorly understood. Here we investigated the neuronal pathways for itch neurotransmission, particularly the contribution of the neuropeptide somatostatin. We find that in the periphery, somatostatin is exclusively expressed in Nppb+ neurons, and we demonstrate that Nppb+somatostatin+ cells function as pruriceptors. Employing chemogenetics, pharmacology and cell-specific ablation methods, we demonstrate that somatostatin potentiates itch by inhibiting inhibitory dynorphin neurons, which results in disinhibition of GRPR+ neurons. Furthermore, elimination of somatostatin from primary afferents and/or from spinal interneurons demonstrates differential involvement of the peptide released from these sources in itch and pain. Our results define the neural circuit underlying somatostatin-induced itch and characterize a contrasting antinociceptive role for the peptide.


Effect of dipivalyl derivatives of catecholamines on cardiovascular function in the conscious dog.
Dipivalyl derivatives of epinephrine, norepinephrine and isoproterenol were injected intravenously into conscious dogs while cardiovascular variables were monitored. The dipivalyl compounds produced cardiovascular effects that were comparable to those produced by their respective parent catecholamines except that the responses had a delayed onset and a prolonged duration. The catecholamines were more potent than their derivatives; norepinephrine was 28 times, epinephrine 15 times and isoproterenol 1.7 times as effective as their respective dipivalyl derivatives. Alpha or beta adrenergic responses to the dipivalyl compounds were attenuated or abolished after alpha adrenergic blockade (phenoxybenzamine or phentolamine), or beta adrenergic blockade (propranolol), respectively, or combined alpha and beta blockade. Since other evidence indicates that the dipivalyl derivatives themselves are inactive, our results suggest that these compounds act as prodrugs that exert their cardiovascular effects only after they are biotransformed to catecholamines.


Animal Guts as Ideal Chemical Reactors: Maximizing Absorption Rates.
I solved equations that describe coupled hydrolysis in and absorption from a continuously stirred tank reactor (CSTR), a plug flow reactor (PFR), and a batch reactor (BR) for the rate of ingestion and/or the throughput time that maximizes the rate of absorption (=gross rate of gain from digestion). Predictions are that foods requiring a single hydrolytic step (e.g., disaccharides) yield ingestion rates that vary inversely with the concentration of food substrate ingested, whereas foods that require multiple hydrolytic and absorptive reactions proceeding in parallel (e.g., proteins) yield maximal ingestion rates at intermediate substrate concentrations. Counterintuitively, then, animals acting to maximize their absorption rates should show compensatory ingestion (more rapid feeding on food of lower concentration), except for the lower range of diet quality for complex diets and except for animals that show purely linear (passive) uptake. At their respective maxima in absorption rates, the PFR and BR yield only modestly higher rates of gain than the CSTR but do so at substantially lower rates of ingestion. All three ideal reactors show milder than linear reduction in rate of absorption when throughput or holding time in the gut is increased (e.g., by scarcity or predation hazard); higher efficiency of hydrolysis and extraction offset lower intake. Hence adding feeding costs and hazards of predation is likely to slow ingestion rates and raise absorption efficiencies substantially over the cost-free optima found here.


Design and validation of a dynamic discrete event stochastic simulation model of mastitis control in dairy herds.
A dynamic stochastic simulation model for discrete events, SIMMAST, was developed to simulate the effect of mastitis on the composition of the bulk tank milk of dairy herds. Intramammary infections caused by Streptococcus agalactiae, Streptococcus spp. other than Strep. agalactiae, Staphylococcus aureus, and coagulase-negative staphylococci were modeled as were the milk, fat, and protein test day solutions for individual cows, which accounted for the fixed effects of days in milk, age at calving, season of calving, somatic cell count (SCC), and random effects of test day, cow yield differences from herdmates, and autocorrelated errors. Probabilities for the transitions among various states of udder health (uninfected or subclinically or clinically infected) were calculated to account for exposure, heifer infection, spontaneous recovery, lactation cure, infection or cure during the dry period, month of lactation, parity, within-herd yields, and the number of quarters with clinical intramammary infection in the previous and current lactations. The stochastic simulation model was constructed using estimates from the literature and also using data from 164 herds enrolled with Quality Milk Promotion Services that each had bulk tank SCC between 500,000 and 750,000/ml. Model parameters and outputs were validated against a separate data file of 69 herds from the Northeast Dairy Herd Improvement Association, each with a bulk tank SCC that was > or = 500,000/ml. Sensitivity analysis was performed on all input parameters for control herds. Using the validated stochastic simulation model, the control herds had a stable time average bulk tank SCC between 500,000 and 750,000/ml.


Investigating the contribution of white matter hyperintensities and cortical thickness to empathy in neurodegenerative and cerebrovascular diseases.
Change in empathy is an increasingly recognised symptom of neurodegenerative diseases and contributes to caregiver burden and patient distress. Empathy impairment has been associated with brain atrophy but its relationship to white matter hyperintensities (WMH) is unknown. We aimed to investigate the relationships amongst WMH, brain atrophy, and empathy deficits in neurodegenerative and cerebrovascular diseases. Five hundred thirteen participants with Alzheimer's disease/mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), Parkinson's disease, or cerebrovascular disease (CVD) were included. Empathy was assessed using the Interpersonal Reactivity Index. WMH were measured using a semi-automatic segmentation and FreeSurfer was used to measure cortical thickness. A heterogeneous pattern of cortical thinning was found between groups, with FTD showing thinning in frontotemporal regions and CVD in left superior parietal, left insula, and left postcentral. Results from both univariate and multivariate analyses revealed that several variables were associated with empathy, particularly cortical thickness in the fronto-insulo-temporal and cingulate regions, sex (female), global cognition, and right parietal and occipital WMH. Our results suggest that cortical atrophy and WMH may be associated with empathy deficits in neurodegenerative and cerebrovascular diseases. Future work should consider investigating the longitudinal effects of WMH and atrophy on empathy deficits in neurodegenerative and cerebrovascular diseases.


An Examination of the Interpersonal Psychological Theory of Suicidal Behavior in Physicians.
Physicians are commonly reported to die by suicide more frequently than individuals in the general population. Thus far, few reasons for this elevated suicide risk have been empirically investigated. Although the interpersonal psychological theory of suicidal behavior (IPTS) has been suggested as a fruitful means of explaining physician suicidality, it has yet to be examined quantitatively. Four hundred nineteen Pennsylvania physicians were assessed on a number of demographics, as well as all components of the IPTS. Findings indicated that physician scores on IPTS components are comparable to other groups displaying increased suicidality (e.g., military populations, prior attempters). Perceived burdensomeness was a significant predictor of suicidal ideation, while thwarted belongingness predicted prior suicide attempts. Acquired capability did not distinguish between prior attempters and nonattempters. Preliminary findings indicate the IPTS may be a useful framework for understanding and predicting physician suicidality.


Demographic and traditional knowledge perspectives on the current status of Canadian polar bear subpopulations.
Subpopulation growth rates and the probability of decline at current harvest levels were determined for 13 subpopulations of polar bears (Ursus maritimus) that are within or shared with Canada based on mark-recapture estimates of population numbers and vital rates, and harvest statistics using population viability analyses (PVA). Aboriginal traditional ecological knowledge (TEK) on subpopulation trend agreed with the seven stable/increasing results and one of the declining results, but disagreed with PVA status of five other declining subpopulations. The decline in the Baffin Bay subpopulation appeared to be due to over-reporting of harvested numbers from outside Canada. The remaining four disputed subpopulations (Southern Beaufort Sea, Northern Beaufort Sea, Southern Hudson Bay, and Western Hudson Bay) were all incompletely mark-recapture (M-R) sampled, which may have biased their survival and subpopulation estimates. Three of the four incompletely sampled subpopulations were PVA identified as nonviable (i.e., declining even with zero harvest mortality). TEK disagreement was nonrandom with respect to M-R sampling protocols. Cluster analysis also grouped subpopulations with ambiguous demographic and harvest rate estimates separately from those with apparently reliable demographic estimates based on PVA probability of decline and unharvested subpopulation growth rate criteria. We suggest that the correspondence between TEK and scientific results can be used to improve the reliability of information on natural systems and thus improve resource management. Considering both TEK and scientific information, we suggest that the current status of Canadian polar bear subpopulations in 2013 was 12 stable/increasing and one declining (Kane Basin). We do not find support for the perspective that polar bears within or shared with Canada are currently in any sort of climate crisis. We suggest that monitoring the impacts of climate change (including sea ice decline) on polar bear subpopulations should be continued and enhanced and that adaptive management practices are warranted.


Relay-Like Exchange Mechanism through a Spin Radical between TbPc2 Molecules and Graphene/Ni(111) Substrates.
We investigate the electronic and magnetic properties of TbPc2 single ion magnets adsorbed on a graphene/Ni(111) substrate, by density functional theory (DFT), ab initio complete active space self-consistent field calculations, and X-ray magnetic circular dichroism (XMCD) experiments. Despite the presence of the graphene decoupling layer, a sizable antiferromagnetic coupling between Tb and Ni is observed in the XMCD experiments. The molecule-surface interaction is rationalized by the DFT analysis and is found to follow a relay-like communication pathway, where the radical spin on the organic Pc ligands mediates the interaction between Tb ion and Ni substrate spins. A model Hamiltonian which explicitly takes into account the presence of the spin radical is then developed, and the different magnetic interactions at play are assessed by first-principle calculations and by comparing the calculated magnetization curves with XMCD data. The relay-like mechanism is at the heart of the process through which the spin information contained in the Tb ion is sensed and exploited in carbon-based molecular spintronics devices.


Contractile properties and myosin isoenzymes of various kinds of Xenopus twitch muscle fibres.
Single twitch muscle fibres have been isolated from various parts of the iliofibularis muscle of Xenopus laevis. After measurements of their isotonic contractile properties, myosin extraction was performed on individual fibres and the extract analysed by various forms of gel electrophoresis. In agreement with previous results three major fibre types, types 1, 2, and 3 could be discerned. Both mechanical data and native isomyosin patterns indicated a further subdivision of types 1 and 2 into subtypes (1n, 1s and 2f, 2n, respectively). Transitional forms between 2n and type 3 were also identified. Types 1 and 2 had the same kinds of light chains (LC1f, LC2, LC3f), but different heavy chains (HC) as observed on 7% SDS gels. Types 3 lacked LC3 and had a more slowly migrating LC1 (LC1s); their HC migration velocity was indistinguishable from that of type 2 HC. A comparison was made between LC1/LC3 ratio and contractile parameters for nine type 1n fibres and six type 2n fibres. No clear correlation was observed between light chain proportions on the one hand and force per cross-sectional area or shortening velocity on the other. It is concluded that myosin heavy chain composition is the major determinant for contractile performance in Xenopus skeletal muscle fibres.


A monoclonal anti-HEBFPP antibody with specificity for lymphocyte surface molecules mediating adhesion to Peyer's patch high endothelium of the rat.
Cell surface molecules involved in lymphocyte adhesion to high endothelial cell venules (HEV) of Peyer's patches (PP) have been studied in the rat by using a mouse monoclonal anti-HEBFPP (1B.2) antibody. We previously showed that rat thoracic duct lymph contains a high endothelial cell binding factor termed HEBFPP, which in vitro blocks lymphocyte binding sites of HEVPP but not HEVLN. Monoclonal 1B.2 antibody was produced by fusing P3U1 myeloma cells with spleen cells of a mouse immunized with this material. Immunoprecipitation studies with 125I surface-labeled rat thoracic duct lymphocytes (TDL) showed that the antibody recognized an 80-kilodalton protein. This antigen was present in the majority of TDL, spleen, LN, and PP cells but was found on few (5 to 10%) thymus and bone marrow cells (indirect immunofluorescence). Treatment of TDL with 1B.2 antibody blocked their ability to bind in vitro to HEVPP; antibody treatment did not interfere with TDL adhesion to HEVLN. Analysis of 1B.2 antigen isolated from lymph and detergent lysates of TDL by antibody-affinity chromatography showed that this material had the capacity to block lymphocyte binding sites of HEVPP but not HEVLN. In contrast, material with such blocking activity was not isolated from detergent lysates of thymocyte, a population deficient in HEV-binding cells. The results indicate that the 1B.2 antigen is a component of the lymphocyte surface recognition structure mediating adhesion to HEVPP and provide further evidence that distinct adhesion molecules of rat TDL mediate interaction with high endothelium of LN and PP.


[Mutants of Escherichia coli K-12 with altered excision efficiency of transposons Tn5 and Tn9].
HFETn5, HFETn9 and LFETn9 mutants of Escherichia coli K-12 have been isolated. The frequency of Tn5 precise excision from the chromosomal lac operon is increased 3-660-fold in nine HFETn5 mutants. The majority of these mutations have no influence on the efficiency of precise excision of transposon Tn9, though hfeTn5-04 and hfeTn5-06 mutations decrease excision efficiency 2-13-fold. The Tn9 transposon is excised in HFETn9 mutant about 20-fold more efficiently than in the wild type strain. This mutation does not stimulate excision of Tn5 and Tn10. LfeTn9 mutation decreases excision frequency of Tn9 11-17-fold, but has no effect on Tn5 excision and increases that of Tn10 about 20-fold. The differences in genetic control and mechanisms of excision of the transposons with long and short inverted repeats are discussed.


LMU-Net: lightweight U-shaped network for medical image segmentation.
Deep learning technology has been employed for precise medical image segmentation in recent years. However, due to the limited available datasets and real-time processing requirement, the inherently complicated structure of deep learning models restricts their application in the field of medical image processing. In this work, we present a novel lightweight LMU-Net network with improved accuracy for medical image segmentation. The multilayer perceptron (MLP) and depth-wise separable convolutions are adopted in both encoder and decoder of the LMU-Net to reduce feature loss and the number of training parameters. In addition, a lightweight channel attention mechanism and convolution operation with a larger kernel are introduced in the proposed architecture to further improve the segmentation performance. Furthermore, we employ batch normalization (BN) and group normalization (GN) interchangeably in our module to minimize the estimation shift in the network. Finally, the proposed network is evaluated and compared to other architectures on publicly accessible ISIC and BUSI datasets by carrying out robust experiments with sufficient ablation considerations. The experimental results show that the proposed LMU-Net can achieve a better overall performance than existing techniques by adopting fewer parameters.


Self-help and guided self-help treatments for bulimia nervosa and binge eating disorder.
This article reviews the use of self-help and guided self-help treatments for bulimia nervosa (BN) and binge eating disorder (BED). Available data suggest that self-help and guided self-help treatments based on empirically-supported cognitive behavioral therapies (CBT) have efficacy for binge eating problems. Emerging findings from initial studies suggest that the magnitude of the differences in outcomes between certain guided-self-help CBT programs and therapist-led CBT may not be substantial, although further research is clearly indicated. Initial data suggest that self-help and guided self-help CBT programs may not only demonstrate "efficacy" but also "effectiveness"-i.e., utility in "real-world" primary care or community settings. Implications for clinical practice and for future research are discussed.


Development of a perceived exertion scale for dogs using selected physiologic parameters.
To develop a perceived exertion scale for dogs exercising on a treadmill and to assess intra- and inter-observer variability. Fifteen healthy client-owned dogs participated in paired exercise trials. Measurements of lactate, glucose, heart rate, temperature, respiratory rate and regional tissue oximetry were obtained before, during and after exercise. Perceived exertion scale scores were recorded during exercise and using video recordings to evaluate inter-observer variability. Correlations were evaluated using the Spearman's non-parametric method. Thirteen dogs completed both trials. Dogs walked or trotted on the treadmill with an average perceived exertion score of 2 in both trials. Holter heart rate was positively correlated with perceived exertion scale scores from all observers for both trials. In trial 1, plasma glucose decreased in association with increase in perceived exertion and, in trial 2, cutaneous oximetry decreased, respiratory rate increased and temperature increased with increases on the perceived exertion scale. Inter-observer perceived exertion scale scores were positively correlated in both trials. There was no intra-observer variability between trials. The perceived exertion scale correlated with the measured physiologic parameters in dogs exercising at mild to moderate intensity. The perceived exertion scale was consistent and repeatable but larger study numbers and further validation are needed before it can be widely applied.


Leadership roles and initiatives for diversity and inclusion in academic anesthesiology departments.
A cultural change in medicine has placed a renewed focus on the importance of a diverse and inclusive healthcare workforce. The methods employed by anesthesiology departments in pursuit of diversity and inclusion needs to be examined. This study's objective was to assess the frequency of established leadership infrastructures and initiatives that promote diversity and inclusion within academic anesthesiology departments. This was a cross-sectional survey study. The authors emailed an electronic survey to 98 academic anesthesiology departments to assess leadership roles, dissemination platforms and initiatives used to support diversity and inclusion. Academic anesthesiology department in the United States with at least 60 residents. The measure tested was the existence and quantification of leadership roles and initiatives directed at diversity and inclusion efforts at academic anesthesiology departments. The survey response rate was 49.4% (95% CI 39.3-59.6%). While 62.5% (95% CI 47.0-75.8%) of respondents reported having faculty members with a diversity and inclusion role, only 27.5% (95% CI 16.1-42.8%) reported a clearly defined leadership role such as vice-chair or committee chair. Seventy percent of respondents reported initiatives geared towards diversity using multiple platforms to showcase these initiatives. Based on these survey results, many anesthesia departments have developed initiatives to promote their departmental diversity. However, only a minority have established clearly defined leadership roles, which may be critical to enhance departmental success in promoting diversity and inclusion.


[Thromboprohylaxis in orthopedic surgery and traumatology].
Orthopaedic and trauma surgery are classified according 3 groups of venous thromboembolic risk. Elective total hip replacement (THR) or total knee replacement (TKR), hip fracture surgery or trauma patients are at high risk. Isolated lower extremity injury with fracture is at moderate risk whereas this risk is low without fracture as well as with knee arthroscopy. In THR and TKR, low molecular weight heparin (LMWH), fondaparinux or melagatran-ximelagatran are strongly recommended. The routine use of other anticoagulants, in particular vitamin K antagonist are not recommended. In patients at high risk of venous thromboembolism as for example trauma patients, optimal use of intermittent pneumatic compression is an alternative option in case of contra-indication to anticoagulant prophylaxis. Graduated compression stockings enhance the efficacy of pharmacological methods. In schedule surgery, initiation of prophylaxis with LMWH may be started postoperatively. To reduce the haemorrhagic risk of anticoagulants, timing of first postoperative dose is essential and is proper to each drug. Duration of prophylaxis depends on the surgical and the individual patients' risk. Extended prophylaxis in THR for up to 42 days with LMWH and up to 35 days with fondaparinux in hip fracture surgery is recommended. However extended prophylaxis after 14 days in TKR has not demonstrated a higher efficacy and should only be considered for patients with additional risk factors. In patients with isolated lower extremity injury or undergoing knee arthroscopy, LMWH should not be routinely used according to a low or a moderate risk and/or the duration of prophylaxis required. But LMWH has to be considered for patients with additional risk factors. Prophylaxis in other orthopedic procedures has not been assessed and will be extrapolated from the above recommendations.


Anti-inflammatory effects of low-dose oral theophylline in atopic asthma.
Theophylline, in addition to its bronchodilator effect, may attenuate inflammation in asthma. We did a double-blind placebo-controlled study of the effect of oral theophylline on the inflammatory response of the bronchial mucosa to inhalation of allergen in 19 atopic asthmatic subjects. Bronchoscopy and bronchial biopsy were done 24 hours after allergen inhalation before and after six weeks of treatment with oral slow-release theophylline, 200 mg 12 hourly. The mean serum concentration was 36.6 mumol/L, which is below the currently-accepted therapeutic range. After treatment with theophylline there was a significant reduction in the number of EG2-positive activated eosinophils (5.9 before and 2.1 after treatment, Wilcoxon signed rank p < 0.05) and total eosinophils (16.7 before and 7.6 after treatment, p < 0.05) beneath the epithelial basement membrane. We conclude that low-dose oral theophylline attenuates airway inflammatory response to allergen inhalation in atopic asthma.


Role of endogenous angiotensin II on sympathetic reflexes in conscious rabbits.
In the present study we sought to determine the contribution of endogenous brain stem angiotensin to renal sympathetic reflexes in conscious rabbits. Initial studies determined the subtype of receptor involved in the pressor response to angiotensin II (ANG II) administration into the fourth ventricle (4V). The AT1 antagonist losartan (0.001-10 micrograms 4V) had no effect on blood pressure alone but caused a dose-dependent blockade of the pressor effect of ANG II, with complete blockade produced by 10 micrograms, an effect that lasted for at least 3 h. The AT2 antagonist PD-123319 (0.1-1,000 micrograms) and vehicle had no effect on the ANG II pressor response. The effect of losartan (10 micrograms) on the baroreceptor, chemoreceptor, and trigeminal reflexes was examined in eight rabbits that had been implanted with 4V catheters and an electrode for recording renal sympathetic nerve activity (RSNA) 1 wk earlier. Baroreflex assessments were made during normoxia and two conditions of hypoxia (10% O2 and 10% O2 + 3% CO2) before and after 10 micrograms losartan or vehicle, on separate experimental days. During normoxia and hypoxia+CO2 losartan increased resting RSNA, the range, and upper plateau of the RSNA-MAP baroreflex curves. By contrast the marked increase in RSNA due to activation of trigeminal afferents was not affected by losartan. In conclusion the effect of losartan to increase RSNA activity in conscious rabbits, particularly during hypoxia and baroreceptor unloading, suggests that endogenous ANG II via AT1 receptors normally inhibits renal sympathetic baroreceptor and chemoreceptor reflexes.


Physical diability after retirement and occupational risk factors during working life: a cross sectional epidemiological study in the Paris area.
The aim was to examine the relationship between exposure to occupational risk factors during working life and physical disability after retirement. The study was a cross sectional epidemiological survey of a representative sample of retired subjects belonging to a supplementary pension fund in the Paris area. The study took place in the general community. 307 men and 320 women (63.1% of those approached) answered a questionnaire during home interviews. Their average age was 69 (SD4) years at the beginning of the survey. Whether or not subjects had been exposed to occupational risks was determined from their statements concerning the presence or absence of eight harmful environmental conditions while at work. Physical disability was defined as difficulty in carrying out seven basic activities of daily life. The results of univariate analyses showed significant relationships between exposure during working life to occupational risks including noise, heat, dust, carrying heavy loads, and awkward postures on the one hand, and the presence of a physical disability after retirement on the other. Multivariate analysis based on logistic regression models that took account of age, sex, and health impairments revealed a specific link between exposure to carrying heavy loads and physical disability after retirement. These results suggest that occupational risk factors might be important in determining such disability in retired people.


Can Crop Models Identify Critical Gaps in Genetics, Environment, and Management Interactions?
Increasing food demand under climate change constraints may challenge and strain agricultural systems. The use of crop models to assess genotypes performance across diverse target environments and management practices, i.e., the genetic × environment × management interaction (GEMI), can help understand suitability of genotype and agronomic practices, and possibly accelerate turnaround in plant breeding programs. However, the readiness of models to support these tasks can be debated. In this article, we point out modeling and data limitations and argue the need for evaluation and improvement of relevant process algorithms as well as model convergence. Under conditions suitable for plant growth, without meteorological extremes or soil limitation to root exploration, models can simulate resource capture, growth, and yield with relative ease. As stresses accumulate, the plant species- and genotype-specific attributes and their interactions with the soil and atmospheric environment generate a large range of responses, including conditions where resources become so limiting as to make yields very low. The space in between high and low yields is where most rainfed production occurs, and where the current model and user skill at representing GEMI varies. We also review studies comparing the performance of a large number of crop models and the lessons learned. The overall message is that improvement of models appears as a necessary condition for progress, and perhaps relevancy. Model ensembles help mitigate data input, model, and user-driven uncertainty for some but not all applications, sometimes at a very high cost. Successful model-based assessment of GEMI not only requires better crop models and knowledgeable users, but also a realistic representation of the environmental conditions of the landscape where crops are grown, which is not trivial given the 3D nature of water and nutrient transport. Models remain the best quantitative repository of our knowledge on crop functioning; they contain a narrative of plant, soil, and atmospheric functioning in computer language and train the mind to couple processes. But in our quest to tame GEMI, will they lead the way or just ride along history?


Valproic acid decreases the reparation capacity of irradiated MOLT-4 cells.
The aim of our work was to evaluate mechanisms leading to radiosensitization of MOLT-4 leukemia cells following valproic acid (VA) treatment. Cells were pretreated with 2 mM VA for 24 h followed by irradiation with a dose of 0.5 or 1 Gy. The effect of both noxae, alone and combined, was detected 1 and 24 hours after the irradiation. Induction of apoptosis was evaluated by a flow cytometry. The extent of DNA damage was further determined by phosphorylation of histone H2AX using confocal microscopy. Changes in protein expression were identified by SDS-PAGE/immunoblotting. Two-millimolar VA increased apoptosis induction after irradiation as well as phosphorylation of H2AX and provokes an increase in the level of p53 and its phosphorylation at Ser392 in 4 h post-irradiation. Likewise, p21 protein reached its maximal expression in 4 h after the irradiation of VA-treated cells. Twenty four hours later, only the p53 phosphorylated at Ser15 was detected. At the same time, the protein mdm2 (negative regulator of p53) was maximally activated. The 24-hour treatment of MOLT-4 leukemia cells with 2 mM VA results in radiosensitizing, increases apoptosis induction, H2AX phosphorylation, and also p53 and p21 activation.


Mean-field analysis of an inductive reasoning game: application to influenza vaccination.
Recently we have introduced an inductive reasoning game of voluntary yearly vaccination to establish whether or not a population of individuals acting in their own self-interest would be able to prevent influenza epidemics. Here, we analyze our model to describe the dynamics of the collective yearly vaccination uptake. We discuss the mean-field equations of our model and first order effects of fluctuations. We explain why our model predicts that severe epidemics are periodically expected even without the introduction of pandemic strains. We find that fluctuations in the collective yearly vaccination uptake induce severe epidemics with an expected periodicity that depends on the number of independent decision makers in the population. The mean-field dynamics also reveal that there are conditions for which the dynamics become robust to the fluctuations. However, the transition between fluctuation-sensitive and fluctuation-robust dynamics occurs for biologically implausible parameters. We also analyze our model when incentive-based vaccination programs are offered. When a family-based incentive is offered, the expected periodicity of severe epidemics is increased. This results from the fact that the number of independent decision makers is reduced, increasing the effect of the fluctuations. However, incentives based on the number of years of prepayment of vaccination may yield fluctuation-robust dynamics where severe epidemics are prevented. In this case, depending on prepayment, the transition between fluctuation-sensitive and fluctuation-robust dynamics may occur for biologically plausible parameters. Our analysis provides a practical method for identifying how many years of free vaccination should be provided in order to successfully ameliorate influenza epidemics.


The genetic background of uremic secondary hyperparathyroidism.
Many studies have shown how gene mutations and genetic polymorphisms could influence secondary uremic hyperparathyroidism (HPTH), modulating parathyroid (PT) function and hyperplasia. Parathyroid hormone (PTH) gene expression and hormone secretion is regulated mainly by serum calcium, with a post-transcriptional effect, and by vitamin D with a transcriptional effect. PT cells retain the ability to proliferate and to apoptose. Hyperphosphatemia, hypocalcemia and vitamin D deficiency all stimulate PT cell proliferation. In the early stage of chronic uremia, PT proliferation is polyclonal, as in diffuse hyperplasia, whereas nodular hyperplasia growth is monoclonal with an increasingly recognized genetic background. HPTH has been associated with a number of familial diseases, such as multiple endocrine neoplasia-type 1 (MEN1), multiple endocrine neoplasia-type2A (MEN2A), neurofibromatosis type1 (NF1) and HPTH with multiple ossifying jaw fibromas (HPT-JT Syndrome). The genes involved in these diseases have been also investigated in secondary HPTH (sHPTH). Moreover, in sporadic and secondary uremic HPTH, clonal rearrangement and/or oncogene overexpression, gene deletions and tumor suppressor gene inactivation have been reported. However, each condition shows different patterns of genetic abnormalities. Finally, PT function modulation by genetic polymorphisms of vitamin D and calcium receptors and of the PTH gene is reviewed.


Biotransformation profiling of [(14)C]ixabepilone in human plasma, urine and feces samples using accelerator mass spectrometry (AMS).
Ixabepilone (BMS-247550, Ixempra is a semi-synthetic analog of the natural product epothilone B and marketed for its use in the treatment of cancer. A conventional human ADME study using decay counting methods for (14)C detection could not be conducted due to the radiolytic instability of [(14)C]ixabepilone at a typical specific activity (generally 1-10 microCi/mg). However, [(14)C]ixabepilone was sufficiently stable at low specific activity (1-2 nCi/mg). These low levels required the use of accelerator mass spectrometry (AMS) for radioactivity detection. The metabolic fate of this compound was investigated in eight patients following single intravenous doses of [(14)C]ixabepilone (70 mg, 80 nCi; specific activity: 1.14 nCi/mg). Metabolite profiles in pooled urine, feces and plasma samples were determined by HPLC-AMS analysis. The major radioactive component in urine and plasma was [(14)C]ixabepilone. Feces had a small amount of ixabepilone. There were numerous other drug-related components in both urine and fecal extracts (each <6% of the administered dose). LC/MS analysis of plasma, urine and feces samples showed the presence of three degradants of ixabepilone and several oxidative metabolites (M+16, M+14 and M-2 metabolites). This study demonstrates the utility of AMS in investigating the metabolite and excretion profiles of [(14)C]ixabepilone following administration to humans.


The Unfolding Space Glove: A Wearable Spatio-Visual to Haptic Sensory Substitution Device for Blind People.
This paper documents the design, implementation and evaluation of the Unfolding Space Glove-an open source sensory substitution device. It transmits the relative position and distance of nearby objects as vibratory stimuli to the back of the hand and thus enables blind people to haptically explore the depth of their surrounding space, assisting with navigation tasks such as object recognition and wayfinding. The prototype requires no external hardware, is highly portable, operates in all lighting conditions, and provides continuous and immediate feedback-all while being visually unobtrusive. Both blind (n = 8) and blindfolded sighted participants (n = 6) completed structured training and obstacle courses with both the prototype and a white long cane to allow performance comparisons to be drawn between them. The subjects quickly learned how to use the glove and successfully completed all of the trials, though still being slower with it than with the cane. Qualitative interviews revealed a high level of usability and user experience. Overall, the results indicate the general processability of spatial information through sensory substitution using haptic, vibrotactile interfaces. Further research would be required to evaluate the prototype's capabilities after extensive training and to derive a fully functional navigation aid from its features.


Long-range function of secreted small nucleolar RNAs that direct 2'-O-methylation.
Small nucleolar RNAs (snoRNAs) are noncoding RNAs that guide chemical modifications of structural RNAs. Whereas snoRNAs primarily localize in the nucleolus, where their canonical function is to target nascent ribosomal RNAs for 2'-O-methylation, recent studies provide evidence that snoRNAs traffic out of the nucleus. Furthermore, RNA-Seq data indicate that extracellular vesicles released from cells contain snoRNAs. However, it is not known whether snoRNA secretion is regulated or whether secreted snoRNAs are functional. Here, we show that inflammation stimulates secretion of Rpl13a snoRNAs U32a (SNORD32a), U33 (SNORD33), U34 (SNORD34), and U35a (SNORD35a) from cultured macrophages, in mice, and in human subjects. Secreted snoRNAs co-fractionate with extracellular vesicles and are taken up by recipient cells. In a murine parabiosis model, we demonstrate that snoRNAs travel through the circulation to function in distant tissues. These findings support a previously unappreciated link between inflammation and snoRNA secretion in mice and humans and uncover a potential role for secreted snoRNAs in cell-cell communication.


Inhibition of Theiler's virus-mediated demyelination by peripheral immune tolerance induction.
Theiler's murine encephalomyelitis virus (TMEV), a member of the cardiovirus subfamily of the Picornaviridae, is a natural pathogen of mice. Thirty to 60 days following intracerebral infection with TMEV, susceptible inbred mouse strains develop a chronic, progressive, T cell-mediated inflammatory demyelinating disease of the central nervous system (CNS) characterized by spastic hind limb paralysis and a lifelong persistent CNS virus infection. We have examined the effect of peripheral virus-specific tolerance on the development of demyelinating disease. Treatment of SJL/J mice with TMEV-coupled, ethyl carbodiimide-treated splenocytes either before or after infection with live TMEV prevented the development of clinical disease, including inflammation and demyelination in the CNS. Prevention of clinical disease was paralleled by significant reductions in virus-specific immune responses, including delayed type hypersensitivity and T cell proliferative responses. Tolerance induction resulted in a significant reduction in the absolute numbers of mononuclear cells infiltrating the CNS, particularly the CD4+IL-2R+ T cell subset, 3, 5, and 8 wk postinfection. In contrast, tolerance induction had no effect on the numbers of CD8+IL-2R+ T cells infiltrating the CNS. Treatment with TMEV-coupled splenocytes failed to prevent the development of relapsing experimental autoimmune encephalomyelitis, demonstrating the specificity of in vivo tolerance induction. Prevention of demyelinating disease did not correlate with the increased TMEV-specific Ab responses observed in tolerized mice. These results indicate that induction of immune tolerance to TMEV can down-regulate a chronic immunopathogenic disease directed against virus Ag persisting in the CNS that normally results in a progressive demyelinating disease similar to multiple sclerosis.


Progress in diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare and heterogeneous but treatable immune-mediated neuropathy. Nerve conduction studies are considered essential for a definite diagnosis, but poor performance and misinterpretation of the results frequently leads to misdiagnosis. Nerve ultrasound and MRI could be helpful in diagnosis. Whereas typical CIDP is relatively easy to diagnose, atypical variants with distinct phenotypes can be a diagnostic challenge. Intravenous or subcutaneous immunoglobulin, corticosteroids, and plasma exchange are effective treatments, but maintenance treatments are often required for years, and treatment regimens require careful and regular adjustments to avoid undertreatment or overtreatment. Patients who do not improve, or insufficiently improve after treatment, might have specific characteristics related to a distinct disease mechanism caused by immunoglobulin G4 antibodies to nodal or paranodal proteins, and could require alternative treatments. Future studies should focus on curative and individualised treatment regimens to improve the patient's condition and to prevent further nerve damage.


Gender differences in the prevalence of mental distress in East and West Germany over time: a hierarchical age-period-cohort analysis, 2006-2021.
Mental distress has become a major public health concern. Temporal trends in psychological distress are complex and depend on numerous factors. In this study, we examined age-period-cohort effects for mental distress including gender and German region over a 15 years' time span. Data on mental distress from ten cross-sectional surveys of the general German population, covering the years from 2006 to 2021, was used. Hierarchical age-period-cohort analyses including gender and German region as predictors were performed to disentangle age, period, and cohort effects. The Patient Health Questionnaire-4 was used as a brief screener for mental distress. We found significant period and cohort effects, with peek values for mental distress in the years 2017 and 2020 and for the oldest birth cohort (born before 1946). Age did not affect mental distress when cohort- and period effects as well as gender and German region were considered. An interaction effect for gender and the German region was found. Women in West Germany reported significantly higher mental distress compared to women in East Germany. Compared to men, women reported the highest prevalence in both regions. Important political events as well as major crises can lead to an increase of mental distress in societies. Furthermore, an association between birth cohort and mental distress could be linked to socialization effects of that certain time, causing traumatic experiences or a specific coping style within this cohort group. Prevention and intervention strategies could benefit from acknowledging structural differences linked to period and cohort effects.