Gamma-IFN-inducible-lysosomal thiol reductase modulates acidic proteases and HLA class II antigen processing in melanoma.
HLA class II-restricted antigen (Ag) processing and presentation are important for the activation of CD4+ T cells, which are the central orchestrating cells of immune responses. The majority of melanoma cells either expresses, or can be induced to express, HLA class II proteins. Thus, they are prime targets for immune mediated elimination by class II-restricted CD4+ T cells. We have previously shown that human melanoma cells lack an important enzyme, gamma interferon-inducible lysosomal thiol-reductase (GILT), capable of perturbing immune recognition of these tumors. Here, we show that GILT expression in human melanoma cells enhances Ag processing and presentation via HLA class II molecules. We also show that GILT expression influences the generation of active forms of cysteinyl proteases, cathepsins B, L and S, as well as an aspartyl protease cathepsin D in melanoma cells. Mechanistic studies revealed that GILT does not regulate acidic cathepsins at the transcriptional level; rather it colocalizes with the cathepsins and influences HLA class II Ag processing. GILT expression in melanoma cells also elevated HLA-DM molecules, which favor epitope loading onto class II in the endolysosomal compartments, enhancing CD4+ T cell recognition. These data suggest that GILT-expressing melanoma cells could prove to be very promising for direct antigen presentation and CD4+ T cell recognition, and may have direct implications for the design of cancer vaccines.


[The variation of Caspase3 activity in tanshinone induced NB4 cells apoptosis].
To study the variation and role of Caspase3 activity in the process of Tanshinone (Tan II A) induced NB4 cells apoptosis. NB4 cell apoptosis induced by Tan II A was demonstrated by cell morphology, DNA content analysis and DNA fragmentation assay. Caspase3 activity was determined by spectrofluorometry, and its inhibitory assay was performed using N-acetyl-Asp-Glu-Val-Asp-aldehyde(AC-DEVD-CHO). Tan II A could induce NB4 cell apoptosis accompanied with increase of caspase3 activity. The induction of NB4 cell apoptosis by use of Tan II A could be partially inhibited by AC-DEVD-CHO. The induction of NB4 cell apoptosis by Tan II A could be fulfilled by activating Caspase3.


Cardiac catheter assessment of congenital heart disease prior to total cavopulmonary connection.
This paper summarises the rationale behind cardiac catheter assessment prior to surgical completion of the Fontan circulation in hearts with univentricular pathology.


Genetic study of red cell esterase D polymorphism by ultrathin layer isoelectric focusing. Distribution in the Veneto population (Italy).
Human red cell Esterase D (EsD) was analyzed by isoelectric focusing (IEF) on ultrathin-layer polyacrylamide gel with a pH range of 5.0-6.0. Hemolysates were treated with Dithiothreitol to avoid loss of activity and change of the isozyme patterns by in vitro storage effects. In our sample of 951 unrelated persons from Veneto, seven different phenotypes were observed. The following allele frequencies were calculated: EsD1 = 0.8476, EsD2 = 0.1336, EsD5 = 0.0178, and EsDV = 0.0010.


The projection of the lateral geniculate nucleus to area 17 of the rat cerebral cortex. IV. Terminations upon spiny dendrites.
The forms of the spiny dendrites in layer IV receiving degenerating thalamocortical axon terminals have been examined in serial thin sections. Reconstructions of segments of these dendrites show that the axon terminals synapse with both the dendritic spines and the dendritic shafts. No main shafts of apical dendrites of pyramidal neurons were found to synapse with the thalamic afferents, which are received mainly by spiny dendrites 1-2 micron in diameter, at least some of which appear to be the oblique branches of apical dendrites. The forms of these postsynaptic dendrites are so variable that is concluded they arise from more than one morphological type of neuron. The conclusion based on this and previous articles in the series is that most neuronal elements in layer IV which form asymmetric synaptic junctions are potential recipients of the thalamocortical afferents.


Identification a unique disulfidptosis classification regarding prognosis and immune landscapes in thyroid carcinoma and providing therapeutic strategies.
Thyroid carcinoma (THCA) is a common type of cancer worldwide, and its incidence has been increasing in recent years. Disulfidptosis, a recently defined form of metabolic-related regulated cell death (RCD), has been shown to play a sophisticated role in antitumor immunity. However, its mechanisms and functions are still poorly understood and the association between disulfidptosis and the prognosis of patients with papillary thyroid carcinoma remains to be elucidated. This study aims to investigate the connection between disulfidptosis and the prognosis of thyroid cancer, while also developing a prognostic index based on disulfidptosis genes. We utilized 24 genes associated with disulfidptosis to create the classification and model. To gather data, we sourced gene expression profiles, somatic mutation information, copy number variation data, and corresponding clinical data from the TCGA database for patients with thyroid cancer. Additionally, we obtained single-cell transcriptome data GSE184362 from the Gene Expression Omnibus (GEO) database for further analysis. In this study, we utilized 24 genes associated with disulfidptosis to identify two distinct groups with different biological processes using non-negative matrix factorization (NMF). Our findings showed that Cluster 1 is associated with chemokines, interleukins, interferons, checkpoint genes, and other important components of the immune microenvironment. Moreover, cluster 1 patients with high IPS scores may be more sensitive to immunotherapy. We also provide drug therapeutic strategies for each cluster patients based on the IC50 of each drug. The Enet model was chosen as the optimal model with the highest C-index and showed that patients with high risk had a worse prognosis and weak cell-to-cell interactions in THCA. Finally, we established a nomogram model based on multivariable cox and logistic regression analyses to predict the overall survival of THCA patients. This research provides new insight into the impact of disulfidptosis on THCA. Through a thorough examination of disulfidptosis, a new classification system has been developed that can effectively predict the clinical prognosis and drug sensitivity of THCA patients.


Adrenal vein sampling: substantial need for technical improvement at regional referral centres.
Adrenal vein sampling (AVS) is the gold standard for localization of aldosterone producing adenoma. The anatomy of the right adrenal vein makes this procedure technically demanding and it may yield no clinical information if the adrenal veins are not adequately cannulated. Having frequently observed the technical failure of AVS, we undertook a review of 220 procedures in British Columbia, Canada. Subjects were retrospectively identified through the laboratory information system. The following were collected: demographics, screening aldosterone concentration and renin activity/mass, results of dynamic function tests, AVS aldosterone and cortisol results. Standard calculations were performed on AVS data and site-specific success rates were compared. The effect of adrenocorticotropin hormone (ACTH) stimulation on the selectivity index (SI) and lateralization index (LI) were explored. The overall technical success-rate of AVS procedures was only 44% in procedures where no ACTH-stimulation was used (n=200) but this rose significantly (p<0.01) to 82% for those employing ACTH (n=139). ACTH-stimulation significantly increased the median SI (left: 5.8 vs 36.7, p<0.01; right: 7.0 vs 51.2, p<0.01), and salvaged 36 procedures from yielding no information, 21 of which demonstrated lateralization of aldosterone production. In 64 cases showing lateralization both pre and post-stimulation, ACTH significantly decreased the median LI from 5.4 to 2.2, p<0.01, creating substantial risk for spurious loss of lateralization. The technical success of AVS is lower than reported elsewhere. Provided that effects on the LI are considered, the use of ACTH-stimulation during AVS assists in the identification of unilateral forms of PA.


[Ejaculation disorders in multiple sclerosis: Prospective study of 44 patients].
To analyze in a descriptive way the ejaculation disorders during MS and to study the correlations between dysejaculations, other sexual, urinary and anorectal disorders. Prospective, monocentric, non-interventional study. Ejaculation disorders were assessed by Premature Ejaculation Profile (PEP) scores, intravaginal latency, and the Male Sexual Health Questionnaire - Ejaculation (MSHQ-Ej). The sexual disorders were evaluated by the International Index of Erectile Function (IIEF15) and the Sclerosis Intimacy and Sexuality Questionnaire-19 (MSISQ). Forty-four men of mean age 46.8 (±10.3) years, with an average EDSS of 5.0 (±1.5) were included. According to the MSHQ-Ej score, ejaculation disorders were present in 28 out of 44 patients included (64%); 26/44 (59%) had an orgasm disorder, 23/44 (52%) a delay in ejaculation, 26/44 (59%) a decrease in ejaculation flow, 24/44 (55%) decreased ejaculated volume, 18/44 (41%) decreased ejaculation frequency, 15/44 (33%) ejaculatory pain and 11 34 (25%) showed systematic non ejaculation. The PEP score showed premature ejaculation in 14 patients (32%). The intra-vaginal latency time was less than 1minute in 6 patients (13.6%). There was a statistically significant correlation between ejaculation disorders and erectile dysfunction (P<0.05, correlation coefficient at 0.53) but no statistically significant correlation between ejaculation disorders and urinary or ano-rectal disorders. Dysejaculation was present in 64% of MS. These disorders were mainly characterized by a decrease in the volume of the ejaculation, the strength of ejaculation and the delay in ejaculation. 4.


Importance of well-being to hypertensive patients.
Well-being may be adversely affected in hypertensive patients by the disease process and its complications, other concomitant diseases, especially depression and anxiety, and the treatment prescribed. The adverse consequences of both pharmacologic and nonpharmacologic treatment are discussed, with emphasis on the psychologic consequences of such treatment. The wider impact of side effects on the daily lives of patients is discussed--the quality-of-life approach. Areas considered include work performance and leisure activities. The problem of interpreting any changes in quality-of-life measures is considered.


Use of anorectal manometry for evaluation of postoperative results of patients with anorectal malformation: a study from Kuwait.
The objective of this study is to use anorectal manometry for functional assessment of early postoperative results after corrective surgery for anorectal malformations (ARMs) in children and compare manometric observations with age-matched controls. Parents were counseled and management strategies were planned according to the manometric assessments. From August 2005 to September 2009, 32 patients who underwent surgery for ARM were assessed postoperatively with anorectal manometry using a water-perfused anorectal motility catheter to record anal canal length or high-pressure zone, resting pressure of anal canal (RP), and rectoanal inhibitory reflex (RAIR). These patients were divided in 2 groups (infants, <1 year; children, >1 year) according to the age at the time of performance of anorectal manometry that was done at 6 months or later following stoma closure or anoplasty. Out of these 32 patients, high anomaly was present in 13, whereas 19 had low type of defect. Manometric anal canal length of the children with high and low ARM was 2.10 ± .44 and 2.25 ± .53 cm, respectively, which was significantly shorter than that of their age-matched controls(P < .05). In patients with high ARM, RP in infants (17 ± 7.7 mm of Hg) and children (21 ± 9.4 mm of Hg) was lower than that of controls (RP in infants = 42.43 ± 8.19 mm of Hg, RP in children = 43.43 ± 8.79 mm of Hg, P < .001). In patients with low ARM, RP in infants (34 ± 8.6 mm of Hg, P = .002) and children (26 ± 9.9 mm of Hg, P = .001) was lower than that in controls. Presence of RAIR was demonstrated in 5 (38.4%) of 13 patients with high ARM and in 11 (57.9%) of 19 cases with low ARM. Parental counseling was done after this early evaluation, and management strategies like bowel management program and biofeedback training were planned according to the results of the tests. Our anorectal manometric results suggest that patients with ARM had short anal canal with lower RP and impaired RAIR, which could affect the ultimate functional outcome in these patients. Thus, postoperative anorectal manometric evaluation of the patients with ARM can give more realistic information about future continence and might help in planning future treatment strategies like bowel management program or biofeedback training.


Choroid plexus arteriovenous malformation (AVM) in a newborn. Case report.
We report here on an unusual case of AVM with intraventricular hemorrhage in a full-term newborn infant. Clinical and radiological findings are discussed in the light of the recent literature.


Modeled and Measured Underwater Sound Isopleths and Implications for Marine Mammal Mitigation in Alaska.
Before operating air guns in Alaska, industry is usually required to model underwater sound isopleths, some of which have implications for the mitigation and monitoring of potential marine mammal impacts. Field measurements are often required to confirm or revise model predictions. We compared modeled and measured air gun sound isopleths from 2006 to 2012 and found poor agreement. Natural variability in the marine environment, application of precautionary correction factors, and data interpretation in the generation of circular isopleths all contributed to the observed poor agreement. A broader understanding of the realities of modeled and measured underwater sound isopleths will contribute to improved mitigation practices.


Basil polysaccharides: A review on extraction, bioactivities and pharmacological applications.
Traditional Chinese Medicine has been widely used in China and is regarded as the most commonly used treatment. As a natural plant used in traditional Chinese Medicine, Basil has various functions associated with a number of its components. There are many compositions in basil including polysaccharides, naphtha, steroids, flavone, coumarins, vitamins, and so on. Among these, polysaccharides play a significant role in based therapeutics. The article summarizes that basil polysaccharides have a lot of biological activities and pharmacological applications, such as their antitumor activity, antioxidant activity, anti-aging activity, immunity enhancement effect, hypolipidemic and anti-atherosclerotic effects, antibacterial effect, treatment of diabetes mellitus, and so on. This review summarized the extraction method, purification method, compositions, pharmacological applications, molecular weight, biological activities, and prospects of basil polysaccharides, providing a basis for further study of basil and basil polysaccharides.


Iceland-genetic counseling services.
This brief report aims to give an overview of the history and current status of clinical genetics services in Iceland and specific genetic counseling considerations for Iceland's population. Presently, there are two part time medical geneticists and one full time genetic counselor with an MSc education from Cardiff, within the Department of Genetic and Molecular Medicine, based in Iceland's only tertiary healthcare facility, Landspitali, the National University Hospital. An oncologist (20 %) also contributes to the cancer genetic counseling service. In addition, a pediatric medical geneticist has a 25 % appointment at the Children's Hospital. No other health care organization offers genetic counseling, and there are no private genetic counseling services.


Orthostatic hypotension (OH) and mortality in relation to age, blood pressure and frailty.
Systolic hypertension and OH, as with many other deficits, accumulate with age. This deficit accumulation results in frailty: enhanced vulnerability to adverse outcomes. This study evaluated OH in relation to age, frailty, systolic hypertension, and mortality. In the population-based Canadian Study of Health and Aging second clinical examination, complete data were available on 1347 people, mean age=83.3 (SD=6.4)years. A frailty index (FI) was calculated from a 52-item Comprehensive Geriatric Assessment (CGA), yielding an FI-CGA from 0 (no deficits) to 1.0 (52 deficits). The mean change in blood pressure from lying to standing was 7.3±15.6 mmHg (range +94 to -60). In total, 239 people (17.7%) had OH (change >20 mmHg systolic or >10 mmHg diastolic). Mean systolic blood pressure was higher (155.8±23.3 mmHg) in people with OH than in those without (141.4±23 mmHg), as was the FI-CGA (0.18 vs. 0.16). OH increased with frailty and systolic hypertension, but not age. Unadjusted, OH was associated with an increased risk of death (relative risk=1.21, 95% confidence interval 1.19-1.23). Adjusted for frailty, this result was not significant. OH may be a marker of the system dysregulation seen in frailty, but as a state variable is a less powerful marker of vulnerability than is the FI-CGA.


Deregulated GSK3beta activity in colorectal cancer: its association with tumor cell survival and proliferation.
Glycogen synthase kinase 3beta (GSK3beta) reportedly has opposing roles, repressing Wnt/beta-catenin signaling on the one hand but maintaining cell survival and proliferation through the NF-kappaB pathway on the other. The present investigation was undertaken to clarify the roles of GSK3beta in human cancer. In colon cancer cell lines and colorectal cancer patients, levels of GSK3beta expression and amounts of its active form were higher in tumor cells than in their normal counterparts; these findings were independent of nuclear accumulation of beta-catenin oncoprotein in the tumor cells. Inhibition of GSK3beta activity by phosphorylation was defective in colorectal cancers but preserved in non-neoplastic cells and tissues. Strikingly, inhibition of GSK3beta activity by chemical inhibitors and its expression by RNA interference targeting GSK3beta induced apoptosis and attenuated proliferation of colon cancer cells in vitro. Our findings demonstrate an unrecognized role of GSK3beta in tumor cell survival and proliferation other than its predicted role as a tumor suppressor, and warrant proposing this kinase as a potential therapeutic target in colorectal cancer.


Evidence for multivalent structure of T-cell antigen receptor complex.
The T-cell antigen receptor (alpha beta or gamma delta TCR) is known to associate with four polypeptides (CD3 gamma, delta, epsilon and zeta) to form the TCR-CD3 complex. Although the six chains are well characterized, the molecular mass of the TCR-CD3 complex and stoichiometry of the components are currently uncertain. We analysed the TCR of a T-T hybridoma which expresses two distinct heterodimers. When the hybridoma was incubated with a mAb (MR9.2) specific for the V alpha 10V beta 5.1 heterodimer, both of the heterodimers were lost from the cell surface, as measured with mAb MR9.2 and MR9.7 (V alpha 1V beta 1-specific). The ability to co-modulate V alpha 1V beta 1 and V alpha 10V beta 5.1 suggested that TCR complexes could contain two alpha beta-heterodimers. Density gradient sedimentation analysis provided further evidence for higher order TCR. The sedimentation patterns of the TCR were compared to that of the B-cell antigen receptor and the well-characterized VSV membrane G-protein as well as to soluble marker proteins. Maximal cell surface murine and human TCR sedimentation coefficients were substantially greater than the 9-10S predicted for a 210 kDa monovalent alpha beta gamma delta epsilon 2 zeta 2 structure. The TCR sedimented in mild non-ionic detergents as large 18 +/- 3S complexes co-migrating with a 443 kDa marker protein. In contrast, the IgM B-cell antigen receptor had a maximal sedimentation coefficient of 10 +/- 3S, consistent with a predicted size of approximately 300 kDa. Taken together, the results suggested that T-cell antigen receptors can contain more than one alpha beta-heterodimer which could be incorporated into a minimal divalent 10-chain TCR-CD3 complex (e.g. alpha beta gamma epsilon epsilon delta zeta zeta alpha beta).


Does Noise From Shipping and Boat Traffic Affect Predator Vigilance in the European Common Hermit Crab?
The effect of noise on predator vigilance in Pagurus bernhardus was explored in this study. Latency of the first response, emergence time, and response type were measured from hermit crabs during continuous and variable vessel noise and two controls. The mean (±SE) response latency was longer for the noise treatments (continuous, 18.19 ± 2.78 s; variable, 11.39 ± 1.48 s) than for the controls (ambient, 7.21 ± 0.82 s; silent, 6.66 ± 0.95 s). Response type and emergence time were not significantly affected but were more variable during the noise treatments than during the controls. Noisy conditions may increase predation risk, suggesting potential fitness consequences for invertebrates.


Pathophysiology of tics and Tourette syndrome.
Tics are involuntary movements that can affect one or more muscles producing simple or complex movements. Blink reflex and startle reflex studies disclose an increased excitability of brainstem interneurons. Analysis of voluntary movement shows that when advance visual information is reduced, patients with tics and Tourette syndrome become progressively slower in completing motor sequences. Sensorimotor integration is abnormally processed. Studies of the contingent negative variation demonstrate abnormalities of movement preparation and the investigation of premotor potentials shows that in some patients tics are not preceded by a normal premotor potential. Magnetic stimulation studies demonstrate an increased excitability of cortical motor cortex. Functional MRI, PET and SPECT studies show abnormal activation of cortical and subcortical areas. Dysfunction of basal ganglia-thalamo-cortical projections affects sensorimotor, language and limbic cortical circuits, and may explain why patients with Tourette syndrome have difficulty in inhibiting unwanted behaviors and impulses.


[Implantable hemodynamic monitoring devices].
Heart failure is one of the most frequent diagnoses in hospital admissions in Germany. In the majority of these admissions acute decompensation of an already existing chronic heart failure is responsible. New mostly wireless and remote strategies for monitoring, titration, adaptation and optimization are the focus for improvement of the treatment of heart failure patients and the poor prognosis. The implantation of hemodynamic monitoring devices follows the hypothesis that significant changes in hemodynamic parameters occur before the occurrence of acute decompensation requiring readmission. Three different hemodynamic monitoring devices have so far been investigated in clinical trials employing right ventricular pressure, left atrial pressure and pulmonary artery pressure monitoring. Only one of these systems, the CardioMENS™ HF monitoring system, demonstrated a significant reduction of hospitalization due to heart failure over 6 months in the CHAMPION trial. The systematic adaptation of medication in the CHAMPION trial significantly differed from the usual care of the control arm over 6 months. This direct day to day management of diuretics is currently under intensive investigation; however, further studies demonstrating a positive effect on mortality are needed before translation of this approach into guidelines. Without this evidence a further implementation of pressure monitoring into currently used devices and justification of the substantial technical and personnel demands are not warranted.


A higher energy-adjusted Dietary Inflammatory Index is positively associated with total and visceral body fat in young male adults.
The energy-adjusted Dietary Inflammatory Index (E-DII™) has been associated with a high body mass index and markers of chronic diseases. Also, pro-inflammatory diets with a high E-DII have been positively associated with metabolic disturbances such as glucose intolerance and type II diabetes mellitus. However, it is unclear whether E-DII scores are positively associated with body fat percentage and visceral fat per se. This cross-sectional study aimed to evaluate whether the E-DII is associated with body fat content and metabolic health indicators in lean and obese young men. The present study was conducted on 59 participants, without comorbidities, not using tobacco, medication and nutritional supplements. Dietary data were obtained by 3-day food records to calculate E-DII scores based on 28 food parameters. Body composition was assessed by dual X-ray absorptiometry (DXA). Blood samples were taken to measure fasting glucose, insulin, triacylglycerols, total cholesterol, and low- and high-density lipoprotein cholesterol. An oral glucose tolerance test also was performed. Associations were determined by mixed-effects linear regression. E-DII scores ranged from -3.48 to +3.10. Energy intake was similar across E-DII tertiles. After adjusting for covariates, the highest E-DII tertile was associated with increased body fat, visceral adipose tissue and waist circumference. There was no association between E-DII scores and glycaemic parameters. In young participants, a dietary pattern with a higher E-DII (i.e., pro-inflammatory) score was associated with high body fat and markers of central adiposity assessed by DXA, regardless of body mass.


Immunohistochemical localization of aldehyde and xanthine oxidase in rat tissues using polyclonal antibodies.
Tissues from male Wistar rats, fixed with 4% paraformaldehyde and embedded in paraffin, were studied with immunoperoxidase techniques using polyclonal antibodies raised against aldehyde oxidase or xanthine oxidase purified from rat liver. Immunohistochemical studies demonstrated that aldehyde oxidase-bearing cells were strongly stained in renal tubules, esophageal, gastric, intestinal and bronchial epithelium as well as liver cytoplasm. Weak but positive immunoreactivity was observed on the pulmonary alveolar epithelial cells, gastric glands and intestinal goblet cells. In contrast, it was demonstrated that cells with xanthine oxidase were strongly stained in renal tubules, esophageal, gastric, and small and large intestinal and bronchial epithelia etc. Positive immunostaining was also found in adrenal gland, skeletal muscle, spleen and cerebral hippocampus. Immunoreactivity againt aldehyde oxidase was not found in adrenal gland, spleen, mesentery or aorta, while immunoreactivity against xanthine oxidase was not found in mesentery or aorta. Although the significance of this ubiquitous and similar localization of aldehyde and xanthine oxidase seems unclear at present, these results may provide a clue as to the full understanding of the pathophysiological role of these oxidases in tissues.


Effects of Simultaneous Exposure to a Western Diet and Wheel-Running Training on Brain Energy Metabolism in Female Rats.
In the pathogenesis of central nervous system disorders (e.g., neurodegenerative), an important role is attributed to an unhealthy lifestyle affecting brain energy metabolism. Physical activity in the prevention and treatment of lifestyle-related diseases is getting increasing attention. We performed a series of assessments in adult female Long Evans rats subjected to 6 weeks of Western diet feeding and wheel-running training. A control group of lean rats was fed with a standard diet. In all experimental groups, we measured physiological parameters (animal weights, body composition, serum metabolic parameters). We assessed the impact of simultaneous exposure to a Western diet and wheel-running on the cerebrocortical protein expression (global proteomic profiling), and in the second part of the experiment, we measured the cortical levels of protein related to brain metabolism (Western blot). Western diet led to an obese phenotype and induced changes in the serum metabolic parameters. Wheel-running did not reduce animal weights or fat mass but significantly decreased serum glucose level. The global proteome analysis revealed that the altered proteins were functionally annotated as they were involved mostly in metabolic pathways. Western blot analysis showed the downregulation of the mitochondrial protein-Acyl-CoA dehydrogenase family member 9, hexokinase 1 (HK1)-enzyme involved in principal glucose metabolism pathways and monocarboxylate transporter 2 (MCT2). Wheel-running reversed this decline in the cortical levels of HK1 and MCT2. The cerebrocortical proteome is affected by a combination of physical activity and Western diet in female rats. An analysis of the cortical proteins involved in brain energy metabolism provides a valuable basis for the deeper investigation of changes in the brain structure and function induced by simultaneous exposure to a Western diet and physical activity.


Spatially separate docking sites on ERK2 regulate distinct signaling events in vivo.
Inhibitors of the oncogenic Ras-MAPK pathway have been intensely pursued as therapeutics. Targeting this pathway, however, presents challenges due to the essential role of MAPK in homeostatic functions. The phosphorylation and activation of MAPK substrates is regulated by protein-protein interactions with MAPK docking sites. Active ERK1/2 (extracellular signal-regulated kinase 1/2)-MAPKs localize to effectors containing DEF (docking site for ERK, (F)/(Y) -X-(F)/(Y) -P)- or D-domain (docking domain) motifs. We have examined the in vivo activity of ERK2 mutants with impaired ability to signal via either docking site. Mutations in the DEF-domain binding pocket prevent activation of DEF-domain-containing effectors but not RSK (90 kDa ribosomal S6 kinase), which contains a D domain. Conversely, mutation of the ERK2 CD domain, which interacts with D domains, prevents RSK activation but not DEF-domain signaling. Uncoupling docking interactions does not compromise ERK2 phosphotransferase activity. ERK2 DEF mutants undergo regulated nuclear translocation but are defective for Elk-1/TCF transactivation and target gene induction. Thus, downstream branches of ERK2 signaling can be selectively inhibited without blocking total pathway activity. Significantly, several protooncogenes contain DEF domains and are regulated by ERK1/2. Therefore, disrupting ERK-DEF domain interactions could be an alternative to inhibiting oncogenic Ras-MAPK signaling.


Inhibition of prostanoid synthesis protects against neuronal damage induced by focal ischemia in rat brain.
Changes in prostanoids concentration and effects of the non-specific COX inhibitor indomethacin on prostanoids levels and extension of tissue damage were studied following focal ischemia induction in the fronto-parietal region of rat brain. Ischemia was induced in animals bearing a transcerebral microdialysis probe by injection of Rose Bengal, a photosensitive dye, followed by light activation. Prostanoid levels were determined in the dialysate using immunoenzymatic techniques. PGD2 levels rose significantly up to 237+/-22 pg/ml compared to a basal level measured before ischemia induction which was below the detection limit. TXB2 changes were smaller and had a different time course. Treatment with indomethacin abolished the ischemia-induced PGD2 release and reduced the extent of injury to the area by 43+/-3.7%. These results suggest that prostanoid release may play an important role in neurodegenerative processes and that cyclooxygenase inhibitors may contribute to protect against cerebral tissue damage.


Synthesis of choline and ethanolamine phospholipids with thiophosphoester bonds as substrates for phospholipase C.
Spectrophotometric assays of esterases are sensitive, rapid, and quite specific when thioester substrates are used. Glycerophospholipids with thiophosphoester bonds may be useful as substrates for phospholipase C (EC 188.8.131.52). These have been made from mercaptoglycerol and mercaptoethanol. The thiols were oxidized to disulfides, acylated, and reduced with dithiothreitol. Phosphocholine derivatives were made by the classical methods for oxyphosphoesters. The phosphatidyl choline analogue was converted to the phosphatidyl ethanolamine analogue by transphosphatidylation with cabbage phospholipase D and ethanolamine. Structures were proved with enzymic hydrolysis, infrared spectra, TLC behavior, and elemental analyses. The synthesized compounds were rac-1-S-phosphocholine-2,3-O-didecanoyl-1-mercapto-2,3-propanediol, 1-S-phosphoethanolamine-2,3-O-didecanoyl-1-mercapto-2,3-propanediol, and 1-S-phosphocholine-2-O-hexadecanoyl-1-mercapto-2-ethanol.


Identifying Subgroups of Major Depressive Disorder Using Brain Structural Covariance Networks and Mapping of Associated Clinical and Cognitive Variables.
Identifying data-driven subtypes of major depressive disorder (MDD) holds promise for parsing the heterogeneity of MDD in a neurobiologically informed way. However, limited studies have used brain structural covariance networks (SCNs) for subtyping MDD. This study included 145 unmedicated patients with MDD and 206 demographically matched healthy control subjects, who underwent a structural magnetic resonance imaging scan and a comprehensive neurocognitive battery. Patterns of structural covariance were identified using source-based morphometry across both patients with MDD and healthy control subjects. K-means clustering algorithms were applied on dysregulated structural networks in MDD to identify potential MDD subtypes. Finally, clinical and neurocognitive measures were compared between identified subgroups to elucidate the profile of these MDD subtypes. Source-based morphometry across all individuals identified 28 whole-brain SCNs that encompassed the prefrontal, anterior cingulate, and orbitofrontal cortices; basal ganglia; and cerebellar, visual, and motor regions. Compared with healthy control subjects, individuals with MDD showed lower structural network integrity in three networks including default mode, ventromedial prefrontal cortical, and salience networks. Clustering analysis revealed two MDD subtypes based on the patterns of structural network abnormalities in these three networks. Further profiling revealed that patients in subtype 1 had younger age of onset and more symptom severity as well as greater deficits in cognitive performance than patients in subtype 2. Overall, we identified two MDD subtypes based on SCNs that differed in their clinical and cognitive profile. Our results represent a proof-of-concept framework for leveraging these large-scale SCNs to parse heterogeneity in MDD.


Paeonol repurposing for cancer therapy: From mechanism to clinical translation.
Paeonol (PAE) is a natural phenolic monomer isolated from the root bark of Paeonia suffruticosa that has been widely used in the clinical treatment of some inflammatory-related diseases and cardiovascular diseases. Much preclinical evidence has demonstrated that PAE not only exhibits a broad spectrum of anticancer effects by inhibiting cell proliferation, invasion and migration and inducing cell apoptosis and cycle arrest through multiple molecular pathways, but also shows excellent performance in improving cancer drug sensitivity, reversing chemoresistance and reducing the toxic side effects of anticancer drugs. However, studies indicate that PAE has the characteristics of poor stability, low bioavailability and short half-life, which makes the effective dose of PAE in many cancers usually high and greatly limits its clinical translation. Fortunately, nanomaterials and derivatives are being developed to ameliorate PAE's shortcomings. This review aims to systematically cover the anticancer advances of PAE in pharmacology, pharmacokinetics, nano delivery systems and derivatives, to provide researchers with the latest and comprehensive information, and to point out the limitations of current studies and areas that need to be strengthened in future studies. We believe this work will be beneficial for further exploration and repurposing of this natural compound as a new clinical anticancer drug.


Hardness, an indicator of the mechanical competence of cancellous bone.
Hardness and calcium content in compact bone are strongly related. Variation in Young's modulus is produced mainly by variations in mineralisation. Therefore, there should be a relationship between hardness and Young's modulus. We demonstrate this. The calcium content of cancellous bone and adjacent compact bone in several species shows little difference, the cancellous bone having approximately 10% less calcium. The hardness of cancellous bone in Bos is approximately 12% less than that of adjacent compact bone, and the calcium is approximately 2% less. These lines of evidence make it unlikely that the Young modulus of cancellous bone material is much different from that of compact bone. Similar evidence suggests that the yield stress of cancellous bone is similar to that of adjacent compact bone.


Italian prescribing patterns in obsessive-compulsive disorder.
The aim of the present study was to investigate psychopharmacological prescribing patterns in a large sample (n = 1815) of patients suffering from obsessive-compulsive disorder (OCD) recruited in 4 Italian centers specialized in OCD, in comparison to available national and international guidelines. The centers were asked to complete a specific data sheet questionnaire on patients' therapeutic status. Statistical analyses were carried out by SPSS. The results showed that almost all patients referred to the centers of Milan, Pisa and Rome received psychotropic medications, whereas only 59.9% (313) did so in Turin. Selective serotonin reuptake inhibitors were the most used drugs ranging between 49.0% and 71.5%. Clomipramine was prescribed more often in Rome and Pisa than in Milan and Turin. The same was true for other tricyclic antidepressants. Second-generation antipsychotics were more often prescribed in Pisa and in Milan. Mood stabilizers were almost exclusively used in Pisa. Taken together, the overall findings would suggest that, although the main Italian centers specialized in OCD follow available guidelines, a certain degree of variability does exist. This may depend on the different educational background, availability of other specific therapeutic strategies, as well as varying levels of severity and comorbidity of the patients.


Neurotrophic factors promote the maturation of developing sensory neurons before they become dependent on these factors for survival.
We have studied the early development of chicken embryo sensory neurons in culture before they become dependent on neurotrophic factors for survival. During this period, they undergo a distinct change in morphology:initially they have small, spindle-shaped, phase-dark cell bodies, which become spherical and phase bright and extend long neurites. Although this maturational change occurs in isolated cells grown in chemically defined medium, it is accelerated by brain-derived neurotrophic factor (BDNF) or neurotrophin-3 and is retarded by antisense oligonucleotides that inhibit expression of the common, low affinity neurotrophic factor receptor (gp75NGFR) and by antisense BDNF oligonucleotides. We conclude that neurotrophic factors play a role in the earliest stages of sensory neuron development and suggest that they operate by an autocrine mechanism at this time.


Quantifying compliance and acceptance through public and private social conformity.
Social conformity is a class of social influence whereby exposure to the attitudes and beliefs of a group causes an individual to alter their own attitudes and beliefs towards those of the group. Compliance and acceptance are varieties of social influence distinguished on the basis of the attitude change brought about. Compliance involves public, but not private conformity, while acceptance occurs when group norms are internalised and conformity is demonstrated both in public and in private. Most contemporary paradigms measuring conformity conflate compliance and acceptance, while the few studies to have addressed this issue have done so using between-subjects designs, decreasing their sensitivity. Here we present a novel task which measures compliance and acceptance on a within-subjects basis. Data from a small sample reveal that compliance and acceptance can co-occur, that compliance is increased with an increasing majority, and demonstrate the usefulness of the task for future studies of conformity.


[Influence of the enteral feeding of levorotatory arginine on severely burned patients during shock stage].
To investigate the effects and the mechanism of action of postburn dietary supplementation of levorotatory arginine (L-Arg) on burn shock resuscitation in severely burned patients. This study was designed to be a prospective, randomized, single blinded and controlled one. Twenty burn patients with total burn surface area (TBSA) more than 30% were enrolled and randomized into two groups; 1) Group A (n = 10): enteral feeding of 50 g/L glucose normal saline (GNS) 500 ml per day containing L-Arg (400 mg/kg.day) at equal pace with fluid infusion for shock resuscitation for 4 days. 2) Group C (n = 10): enteral feeding with only 50 g/L GNS 500 ml per day for 4 days. All of the twenty patients received equal amount of enteral feeding via an intra-gastric tube with the aid of an enteral feeding pump, started within 24 postburn hours (PBH). Venous blood was harvested from all the patients in both groups on 1, 2, 3 and 4 postburn day (PBD) for the determination of serum content of nitric oxide (NO), malondialdehyde (MDA) and the activity of serum superoxide dismutase (SOD). And the arterial content of lactate (BL) was also determined concomitantly. The results indicated that the serum SOD activity in group A was increased after burns, peaked on 4 PBD (68 +/- 23 U/ml), and it was obviously higher than that in group C (31 +/- 9 U/ml, P < 0.01). The serum contents of MDA and NO were decreased in both groups after burns. On 2 PBD, the serum NO level in group A decreased to the lowest level (50 +/- 14 micromol/L), which was obviously lower compared with group C (78 +/- 22 micromol/L, P < 0.01). On 4 PBD, serum MDA levels in group A (3.4 +/- 0.8 micromol/L) and group C (3.5 +/- 1.3 micromol/L) were decreased to the lowest level. The BL content in group A was obviously lower than that in group C on 2 and 3 PBD (P < 0.05 or 0.01). Enteral supplementation of L-arginine can decrease excessive NO production to a relatively normal level, and it might be beneficial to resuscitation of burn shock. It might also exert a protective effect against ischemia/reperfusion injury to burn patients.


The plurennial life cycles of the European Tettigoniidae (Insecta: Orthoptera) : 3. The effect of drought and the variable duration of the initial diapause.
The effect of drought on embryonic development and on hatching was studied in 13 European Tettigoniidae species. Drought can affect development in three different ways: (1) Embryonic development proceeds slower than if the eggs are in contact with water; (2) it stops (for final diapause) in an earlier embryonic stage; (3) it affects maintenance and termination of the initial embryonic diapause.In many Tettigoniidae species, the initial diapause is prolonged, and may last several years. Without draught stress, between 1 and 7 cold treatments in the laboratory, and with eggs of the Tettigonia-species between 1 and 6 winters in the field were necessary to enable all eggs to complete initial diapause. In Central European species, the number of eggs maintaining initial diapause significantly increased when the eggs had no contact with water at the time when they should recover from diapause. In contrast, termination of initial diapause in Tettigonia caudata from Greece, when the environment became favorable for growth again, was highest in that group of eggs that had lost most water in a preceding period of drought. The importance of the prolonged initial diapause for the survival of unpredictable adverse conditions is discussed.


Cataract extraction in spontaneous low-flow indirect dural bilateral carotid cavernous fistula.
Cataract extraction in a carotid cavernous fistula can cause multiple intraoperative complications during surgery. This was a case of bilateral, indirect, carotid, cavernous fistula, type D. The patient developed cataract and visual deterioration in both eyes. We present the difficulties we encountered during extracapsular cataract surgery on one of the eyes. Cataract extraction was done successfully. A self-sealing scleral incision was made. An intraocular lens was implanted. Cataract extraction can be done in carotid cavernous fistulas; however, the surgeon should be extremely cautious during the surgery.


Renal Functional and Perioperative Outcomes of Selective Versus Complete Renal Arterial Clamping During Robot-Assisted Partial Nephrectomy: Early Single-Center Experience With 39 Cases.
The objective of this study was to investigate clinical outcomes in patients undergoing selective versus conventional complete renal arterial clamping during robot-assisted partial nephrectomy (RAPN). This study included 19 patients with renal tumors who received RAPN incorporating selective arterial clamping (group 1). The renal functional as well as perioperative outcomes in group 1 were compared with those in 20 patients with renal tumors undergoing RAPN with total clamping of the renal artery (group 2) during the same period. In group 1, tumor resection under selective arterial clamping could be completed in all patients without intraoperative conversion to conventional RAPN with total clamping. There were no significant differences in the tumor size, RENAL nephrometry score, or preoperative estimated glomerular filtration rate (eGFR) between groups 1 and 2. Furthermore, no significant differences were noted in the estimated blood loss, operative time, or warm ischemia time between the 2 groups. Although there was no significant difference in the rate of decrease in eGFR 4 weeks after RAPN between the 2 groups, the rate of decrease in eGFR 1 week after RAPN in group 1 was significantly lower than that in group 2. The choice of selective or total clamping was also identified as an independent predictor of a postoperative decrease in eGFR by > 10% at 1 week, but not 4 weeks, after RAPN. A precise segmental clamping technique is feasible and safe for performing RAPN, resulting in an improved postoperative renal function, particularly early after surgery.


A comparative study of the two alternative larval forms of Hymenolepis nana, the dwarf tapeworm, with special reference to the process of excystment.
Studies of the cysticercoids of Hymenolepis nana from insects and from mouse villi revealed important differences in cyst structure and function. The insect form resists low pH unless treated with bile salts which render the cyst permeable and reduce infectivity to mice. Bile salts are not essential for scolex activation. Activation is inhibited by pH 2.5 and under and by 1% succinic acid up to pH 4.0. The importance of scolex immobility and energy conservation in relation to cyst impermeability is discussed. The villus cysticercoid has no special insulating layer. It is vulnerable to low pH and cannot infect mice orally. Bile salts are without effect and excystment occurs unaided by external agents. The structural differences between the two forms revealed by the electron microscope may be attributed to changes in the relative rates of development of the various tissues.


Transient ST-segment elevation in subarachnoid hemorrhage.
Electrocardiographic manifestation mimicking the hyperacute phase of myocardial infarction and the electrical alternans of the elevated ST-segment in association with subarachnoid hemorrhage were reported in two patients with no evidence of heart disease. In both cases the ST-segment changes were transient and there were no persistent changes suggestive of underlying myocardial damage or ischemia. These findings suggested that the electrocardiographic changes were probably secondary to subarachnoid hemorrhage and not an expression of primary myocardial disease. The electrocardiographic abnormalities could be explained by altered autonomic activity to coronary arteries or directly to the myocardium.


Altered gut microbiota and its association with inflammation in patients with chronic thromboembolic pulmonary hypertension: a single-center observational study in Japan.
The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is considered to be associated with chronic inflammation; however, the underlying mechanism remains unclear. Recently, altered gut microbiota were found in patients with pulmonary arterial hypertension (PAH) and in experimental PAH models. The aim of this study was to characterize the gut microbiota in patients with CTEPH and assess the relationship between gut dysbiosis and inflammation in CTEPH. In this observational study, fecal samples were collected from 11 patients with CTEPH and 22 healthy participants. The abundance of gut microbiota in these fecal samples was assessed using 16S ribosomal ribonucleic acid (rRNA) gene sequencing. Inflammatory cytokine and endotoxin levels were also assessed in patients with CTEPH and control participants. The levels of serum tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, and macrophage inflammatory protein (MIP)-1α were elevated in patients with CTEPH. Plasma endotoxin levels were significantly increased in patients with CTEPH (P < 0.001), and were positively correlated with TNF-α, IL-6, IL-8, and MIP-1α levels. The 16S rRNA gene sequencing and the principal coordinate analysis revealed the distinction in the gut microbiota between patients with CTEPH (P < 0.01) and control participants as well as the decreased bacterial alpha-diversity in patients with CTEPH. A random forest analysis for predicting the distinction in gut microbiota revealed an accuracy of 80.3%. The composition of the gut microbiota in patients with CTEPH was distinct from that of healthy participants, which may be associated with the elevated inflammatory cytokines and endotoxins in CTEPH.


Development of 4H-pyridopyrimidines: a class of selective bacterial protein synthesis inhibitors.
We have identified a series of compounds that inhibit protein synthesis in bacteria. Initial IC50's in aminoacylation/translation (A/T) assays ranged from 3 to14 μM. This series of compounds are variations on a 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol scaffold (e.g., 4H-pyridopyrimidine). Greater than 80 analogs were prepared to investigate the structure-activity relationship (SAR). Structural modifications included changes in the central ring and substituent modifications in its periphery focusing on the 2- and 6-positions. An A/T system was used to determine IC50 values for activity of the analogs in biochemical assays. Minimum inhibitory concentrations (MIC) were determined for each analog against cultures of Enterococcus faecalis, Moraxella catarrhalis, Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli tolC mutants and E. coli modified with PMBN. Modifications to the 2-(pyridin-2-yl) ring resulted in complete inactivation of the compounds. However, certain modifications at the 6-position resulted in increased antimicrobial potency. The optimized compounds inhibited the growth of E. faecalis, M. catarrhalis, H. influenzae, S. pneumoniae, S. aureus, E. coli tolC, mutants and E. coli modified with PMBN with MIC values of 4, ≤ 0.12, 1, 2, 4, 1, 1 μg/ml, respectively. IC50 values in biochemical assay were reduced to mid-nanomolar range. 4H-pyridopyrimidine analogs demonstrate broad-spectrum inhibition of bacterial growth and modification of the compounds establishes SAR.


Dapsone for treatment of erythema nodosum.
Erythema Nodosum (EN) is the most common form of septal panniculitis, with over 100 reported infectious, malignant, inflammatory, idiopathic, and autoimmune causes.


Do endorphin residues of beta lipotropin in hormone reinforce reproductive functions?
The beta-endorphin residue of pituitary beta-lipotropin hormone, which regulates utilization and storage of body fat, is several times more potent than morphine in raising pain tolerance. It also produces habituation and dependency behavior. Recently it was found to be present in amniotic fluid and to be a releaser of prolactin. It now appears that the placenta is a rich source of endorphins. These findings may open a new chapter in understanding molecular determinants of behavior patterns responsible for natural selection and survival of vertebrate species. Clinical application of basic information and new concepts relating endorphins to maternal behavior patterns and neonatal physiology is the purpose of this communication. A brief review of the literature, some data from [3H]opiate-binding assays, observation of maternal performance, and reports of maternity patients' feelings and motivations suggesting that these hormone molecules mediate formation of affectional attitude, appetitive systems, and maternal behavior will be presented.


Cysteinyl leukotriene-dependent interleukin-5 production leading to eosinophilia during late asthmatic response in guinea-pigs.
Allergic airway eosinophilia is suppressed by cysteinyl leukotriene (CysLT) receptor (CysLT1 receptor) antagonists in several species including humans and guinea-pigs, suggesting that CysLTs are directly or indirectly involved in induction of the response. We examined the effect of CysLT antagonists (pranlukast and MCI-826) on antigen inhalation-induced eosinophilia in peripheral blood and lung, and on IL-5 activity in serum during late increase of airway resistance (late asthmatic response, LAR) in sensitized guinea-pigs. Guinea-pigs inhaled ovalbumin (OVA) + Al(OH)3 and OVA mists alternately for sensitization and challenge, respectively, once every 2 weeks. At the fifth challenge, the effects of CysLT antagonists and an anti-IL-5 antibody (TRFK-5) on the occurrence of LAR, and blood and lung eosinophilia, which appeared at 5 h after challenge, were examined. The time-course of IL-5 activity in the serum after the challenge was evaluated by measuring in vitro 'eosinophil survival prolongation activity'. The influence of CysLT antagonists on IL-5 activity was assessed. CysLT antagonists and TRFK-5 completely abolished blood and lung eosinophilia. LAR was suppressed by both MCI-826 and TRFK-5 by 40-50%. Sera obtained from sensitized, challenged animals 3 h and 4 h after challenge induced an obvious prolongation of eosinophil survival. The activity of the sera was completely neutralized by prior exposure to TRFK-5, suggesting that it reflected IL-5 activity. Increased IL-5 activity in the serum was inhibited by both pranlukast and MCI-826 by over 90%. CysLTs produced after antigen provocation sequentially induced IL-5 production from some immune component cells via CysLT1 receptor activation. Thus, it is likely that CysLTs indirectly cause antigen-induced eosinophilia through IL-5 production.


Translocation t(1;11)(q21;q23), a new subgroup within M4 acute nonlymphocytic leukemia.
A case of acute myelomonocytic leukemia (M4) with a t(1;11)(q21;q23) as the sole chromosome anomaly is presented. The results, taken with those of previously published cases, point to the possibility of a subgroup within M4.


Functional analysis of elective nephron-sparing surgery vs radical nephrectomy for renal tumors larger than 4 cm.
To preserve renal function, nephron sparing surgery (NSS) for renal tumors should be performed. Little is known about perioperative morbidity and long-term functional outcome of patients after elective NSS compared with radical nephrectomy (RN) in renal tumors >4 cm. Eight-hundred twenty-nine patients were treated with either RN (n = 641) or NSS (n = 188) for renal tumors >4 cm. After pairing the cohort for age, grading, TNM, size, gender, and preoperative renal function and excluding patients with imperative indication and metastases, 247 patients remained for functional analysis. Serum creatinine (SCr) values were used to estimate glomerular filtration rate (eGFR) via Modification of Diet in Renal Disease. Chronic kidney disease (CKD) was defined as eGFR <60 mL/min/1.73 m(2) and regression analyses were used to identify clinical risk factors for CKD and perioperative complications stratified by the Clavien-Dindo score. The Charlson comorbidity index was similar between patients undergoing NSS (n = 101) and RN (n = 146) (P = .583). The complication rates did not differ significantly between both groups (P = .091). Age (OR 0.94, P = .009), ASA score 3+4 (OR 3.55, P = .004), RN (OR 10.75, P < .001), and preoperative eGFR (OR 1.06, P < .001) were independent risk factors for developing CKD postoperatively, whereas tumor size had no impact (OR 1.01, P = .245). Overall survival was comparable between the groups (P = .896). Although overall survival was similar, patients undergoing RN for renal tumors >4 cm had a significantly higher risk of developing CKD than patients treated with NSS. Complication rate did not differ significantly between both groups, even for tumors >7 cm. Our findings support elective NSS for tumors >4 cm, whenever NSS is technically feasible for maintaining renal function.


Complete small intestinal obstruction due to band formation in low-grade appendiceal mucinous neoplasm: A rare case report and literature review.
Intestinal obstruction due to external compression is a rare condition, and those caused by appendiceal neoplasms like low-grade appendiceal mucinous neoplasms are extremely rare. A 67-year-old post-menopausal female, with no history of prior abdominal surgery, presented to the emergency room with constipation for 2 days, and peri-umbilical pain and non-projectile bilious vomiting for 19 h. There was mild abdominal distension and diffuse tenderness. After ultrasonography and Computed Tomography (CT) of the abdomen and pelvis, a provisional diagnosis of complete small bowel obstruction secondary to perforated mucinous neoplasm of the appendix was made. An emergency exploratory laparotomy was performed followed by ileo-cecal resection and ileocolic anastomosis. Intraoperative findings revealed bands extending from the appendix to the ileum forming a closed loop with gangrenous spots in the distal ileum and ascitic fluid with mucin. Later, histopathological examination findings were consistent with low-grade appendiceal mucinous neoplasm (LAMN). We reviewed three cases of intestinal obstruction, caused by compression from a LAMN, including the presented case. Preoperative diagnosis of the cause of small intestinal obstruction on CT is sometimes challenging. Hence, in patients with intestinal obstruction with a transition point in the right lower quadrant of the abdomen on CT, a high index of suspicion for an appendiceal etiology is required. LAMN with an associated band should be considered as one of the differential diagnoses in the patient presenting with symptoms of complete small intestinal obstruction without prior abdominal surgery.


Liver-specific lysosomal acid phosphatase deficiency (Apl) on mouse chromosome 17.
Apl, a gene involved in the processing of lysosomal acid phosphatase in mouse liver, has been mapped on Chromosome 17. The gene order and map distances in per cent recombination of the loci studied are T (20.6 +/- 3.4) Pgk-2 (7.4 +/- 2.2) Apl. Thus, Apl is at least 7 cM distal to H-2 on this chromosome. In addition, strain-specific allelic variants for Apl have been demonstrated on cellulose acetate gels, a quick and inexpensive method of electrophoresis.


Analysis of patient flow into dialysis: role of education in choice of dialysis modality.
Despite advances in predialysis care, morbidity and mortality remain high. To analyze end-stage renal disease (ESRD) patient demographics and clinical data on education on dialysis treatment options, type of chronic renal replacement therapy (RRT), and effects of planned versus non-planned dialysis start. 621 patients, from 24 Spanish hospitals, who started RRT in 2002. Peritoneal or vascular access at dialysis initiation was considered "planned." 304 (49%) patients were non-planned and half of them had prior nephrology follow-up. Of the patients with >3 months nephrology follow-up (76% of all), only half were educated on dialysis modalities. Dialysis education was associated with planned start in 73.4% versus 26% in non-educated patients (p < 0.05), shorter follow-up (55 vs 65 months, p = 0.033), more medical visits in the prior year (6.5 vs 4.4, *p < 0.001), more patients starting peritoneal dialysis (31% vs 8.3%*), and more specific follow-up by ESRD unit versus general nephrology care (63% vs 26%*). Non-planned start was associated with older age (63 vs 60.6 years, p = 0.06), fewer medical visits (4.6 vs 6.4*), less education about modality options, and greater use of hemodialysis (92% vs 75%*). Planned patients had better biochemical parameters at start of dialysis. Despite nephrology follow-up, half the patients did not have a planned dialysis start. Planned start was associated with better clinical status. More patients chose peritoneal dialysis when educated about dialysis modality options. ESRD-specific units were more likely to provide patient education.


Correction to: Comparative effects of sertraline, haloperidol or olanzapine treatments on ketamine-induced changes in mouse behaviours.
In the original publication of the article, occurrences of "{F(Becker and Grecksch 2004; Onaolapo et al. 2016b)" should have been "{F(5, 54)" throughout the article.


Application of deep learning for image-based Chinese market food nutrients estimation.
With commercialization of deep learning (DL) models, daily precision dietary record based on images from smartphones becomes possible. This study took advantage of DL techniques on visual recognition tasks and proposed a suite of big-data-driven DL models regressing from food images to their nutrient estimation. We established and publicized the first food image database from the Chinese market, named ChinaMartFood-109. It contained 10,921 images with 23 nutrient contents, covering 18 main food groups. Inception V3 was optimized using other state-of-the-art deep convolutional neural networks, achieving up to 78 % and 94 % for top-1 and top-5 accuracy, respectively. Besides, this research compared three nutrient estimation algorithms and achieved the best regression coefficient (R2) by normalization + AM compared with arithmetic mean and harmonic mean, validating applicability in practice as well as theory. These encouraging results provide further evidence supporting artificial intelligence in the field of food analysis.


Accurate determination of small one-bond heteronuclear residual dipolar couplings by F1 coupled HSQC modified with a G-BIRD(r) module.
We report a G-BIRD(r) modified coupled HSQC experiment for the accurate determination of one-bond heteronuclear residual dipolar couplings. The G-BIRD(r) module has been employed to refocus the long-range coupling evolution of the heteronucleus during the t1 frequency labeling period. As a result, the crosspeaks obtained are split by only the direct one-bond coupling that can be extracted by measuring simple frequency differences between singlet maxima. Additionally the decoupling of long-range multiple bond splittings leads to considerable sensitivity enhancement. The modification also has been applied in a TROSY sequence resulting in a significant sensitivity and resolution improvement.


Apoptosis and myocardial infarction.
Myocardial infarction was produced in rats and the contribution of apoptotic and necrotic myocyte cell death was measured quantitatively. Myocyte cell death by apoptosis involved 2.8 million cells at 2 hours after coronary artery occlusion and necrosis only 90,000 cells. Myocyte apoptosis continued to represent the major form of cell death, affecting 6.6 million cells at 4.5 hours, whereas myocyte necrosis peaked at 1 day, including 1.1 million cells. Apoptotic myocyte cell death was also present in the surviving portion of the wall adjacent to and remote from the infarcted myocardium where it peaked at 1-2 days. At this interval, 700/10(6) and 110/10(6) myocyte nuclei were undergoing apoptosis in the non-infarcted tissue bordering on and away from the ischemic area, respectively. Myocyte necrosis was absent in the viable myocardium after infarction. Since mechanical forces produced by pathologic loads may activate apoptosis, papillary muscles were exposed to high levels of resting tension in vitro and the magnitude of cell death in these samples was determined. Overstretching resulted in a 21-fold increase in apoptotic myocyte cell death which was coupled with the formation of reactive oxygen species, side-to-side slippage of myocytes, and depressed tension generation of the myocardium. In conclusion, apoptotic myocyte cell death plays a major role in ventricular remodeling after infarction, but whether physical forces, oxidant stress, architectural rearrangement of myocytes, and impaired force development of the myocardium in vivo are causaly related requires further investigation.


Design of Ionic-Liquid-Based Hybrid Polymer Materials with a Magnetoactive and Electroactive Multifunctional Response.
Multifunctional materials with sensor and actuator capabilities play an increasing role in modern technology. In this scope, hybrid materials with magnetic sensing and an electromechanical actuator response based on magnetic ionic liquids (MILs) and the polymer poly(vinylidene fluoride) (PVDF) have been developed. MILs comprising different cation alkyl chain lengths [Cnmim]+ and sharing the same anion [FeCl4]- were incorporated at 20 wt % into the PVDF matrix and the morphological, physical, chemical, and functional properties of the materials were evaluated. An increasing IL alkyl chain length leads to the formation of a porous structure, together with an increase in the electroactive PVDF β-phase content of the polymer and a decrease in the crystallinity degree and thermal stability. The magnetic susceptibility of the [Cnmim][FeCl4]/PVDF films reveals a paramagnetic behavior. The multifunctional response is characterized by a magnetoionic response that decreases with increasing IL alkyl chain length, the highest magnetoionic coefficient (1.06 ± 0.015 V cm-1 Oe-1) being observed for [C2mim][FeCl4]/PVDF. The electromechanical actuator response is characterized by a highest displacement of 1.1 mm for the [C4mim][FeCl4]/PVDF film by applying a voltage of 4 V at a frequency of 100 mHz. Further, their solution processing makes these multiresponsive materials compatible with additive manufacturing technologies.


A comparative study of the prevalence, outcome, and prediction of bacteremia in children.
We undertook a prospective, concurrent comparison of the prevalence, predictability, and outcome of bacteremia in children from 3 to 24 months of age with temperatures greater than or equal to 39.5 degrees C in three diverse clinical settings: primarily black lower-class children at an inner-city hospital (n = 532), primarily white middle-class children at a suburban hospital (n = 160), and primarily white middle-class children in offices of pediatricians in private practice (n = 94). The prevalence of bacteremia for the entire study sample (3.1% to 7.4%) and outpatients only (1.9% to 5.9%) was not statistically different among the three groups. There were no statistically significant differences among the three groups in identifying children with bacteremia (P greater than 0.05). There was no racial, geographic, or socioeconomic predilection for bacteremia in infants. At the first visit, antibiotics were prescribed (most commonly for otitis media) for 23 of the 25 bacteremic patients who were not initially hospitalized. One patient with otitis media developed meningitis. The others had uncomplicated courses and were well by 96 hours (most by 48 hours). In office settings, private practitioners were no better in predicting bacteremia in familiar patients than they were with first-time patients. Information from blood culture did not appear to alter patient management. We conclude, therefore, that routine blood cultures are unnecessary for all highly febrile infants given antibiotics.


A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors.
MK-5108 is a potent/highly selective Aurora A kinase inhibitor. A randomized Phase I study of MK-5108, administered p.o. BID Q12h on days 1-2 in 14-21 day cycles either alone (MT; Panel1/n = 18; 200 to 1800 mg) or in combination (CT; Panel2/n = 17; 100 to 225 mg) with IV docetaxel 60 mg/m(2), determined the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (Panel1, only) and tumor response in patients with advanced solid tumors. This study was terminated early due to toxicities in Panel2 at MK-5108 doses below the anticipated PK exposure target. 35 patients enrolled (33 evaluable for tumor response). No dose-limiting toxicities (DLTs) were observed in Panel1; three patients had 3 DLTs in Panel2 (G3 and G4 febrile neutropenia at 200 and 450 mg/day, respectively; G3 infection at 450 mg/day). In Panel1, AUC0-12hr and Cmax increased less than dose proportionally following the first MT dose but increased roughly dose proportionally across 200 to 3600 mg/day after 4th dose. The t1/2 ranged from 6.6 to 13.5 h across both panels. No clear effects on immunohistochemistry markers were observed; however, significant dose-related increases in gene expression were seen pre-/post-treatment. Best responses were 9/17 stable disease (SD) (Panel1) as well as 1/16 PR and 7/16 SD (Panel2) (450 mg/day). MK-5108 MT was well tolerated at doses up to 3600 mg/day with plasma levels exceeding the minimum daily exposure target (83 μM*hr). The MTD for MK-5108 + docetaxel (CT) was established at 300 mg/day, below the exposure target. Use of pharmacodynamic gene expression assays to determine target engagement was validated.


Herbivory on Diplacus aurantiacus shrubs in sun and shade.
This study tested the hypothesis that carbon allocation to the production of leaf antiherbivore chemicals reflects the intensity of herbivory and interacts with resource allocation to photosynthesis. The amount of herbivory by Euphydryas chalcedona butterfly larvae was measured on Diplacus aurantiacus shrubs growing in different daily solar irradiance regimes. The amount of herbivory sustained by plants was directly related to the degree of solar irradiance the shrubs received and to characteristics which vary with light intensity, e.g. leaf specific weight, but not to leaf resin or nitrogen content. Carbon allocation to the defense of leaf area was marginally related to the light regime, but was not directly related to photosynthetic income.


Perceptions of how well graduates are prepared for the role of pre-registration house officer: a comparison of outcomes from a traditional and an integrated PBL curriculum.
Most medical schools in the UK have been engaged in major curriculum reform based on their premises of what might improve undergraduate medical education. In 1994 the course at the medical school of the University of Manchester changed to an integrated course using problem-based learning throughout and with increased emphasis on community-based medical education. This study explores whether the new curriculum has produced any differences in perceptions of how well graduates are prepared for the role of pre-registration house officer. A postal questionnaire was used to survey 1998 Manchester graduates (traditional course) and 1999 Manchester graduates (new course), three months into their first pre-registration house officer placement. A similar questionnaire was sent to the educational supervisors who were supervising the graduates. The questionnaire was designed to measure perceptions of levels of preparedness for the role of pre-registration house officer, using a list of broad areas of competence and specific skills listed in the General Medical Council's 'The New Doctor'. Graduates rated the new course significantly more effective for 12 of the 19 broad competences and eight of the 13 specific skills that were listed. The 'new' graduates rated their understanding of disease processes lower than the 'traditional' graduates, but there was no difference in the ratings given by the educational supervisors for this. Overall the educational supervisors rated the new course as better preparing graduates in five of the competences. Overall, the evaluation shows that a major change in curriculum approach has changed the profile of the perceived preparedness of graduates for entering professional practice.


Selectivity of pirenzepine in the central nervous system. II. Differential effects of pirenzepine and scopolamine on performance of a representational memory task.
The behavioral effects of the two muscarinic antagonists scopolamine and pirenzepine were examined using a representational memory task for rats in a T-maze. Rats were pretrained to a criterion of 100% correct responses for daily sessions of 10 paired-run trials. The training procedures eliminated all neophobic or wary responses, and response times were invariably short (less than 3 s). Following the initial training sessions, guide cannulae were surgically implanted bilaterally over the hippocampus of each animal. Following recovery from surgery, animals were injected with saline (0.5 microliter to each hippocampus), scopolamine hydrobromide (0.5 microliter of a 60 mg/ml solution (30 micrograms) to each side), or pirenzepine (0.5 microliter of a 69.1 mg/ml solution (34.6 micrograms) to each side) according to a fixed schedule. Saline injections aimed between the blades of the dorsal dentate gyrus failed to produce any change in the performance of the memory task. Initial doses of scopolamine, applied to the same area, produced a decrease in the percentage of correct responses as did the initial dose of pirenzepine. In contrast to pirenzepine, scopolamine also produced increases in response times even to the point of defaulted trials (response times greater than 90 s) in some animals following drug injections. Saline injections failed to produce significant impairments on the days following scopolamine injections, although animals receiving pirenzepine injections were still impaired on the two days immediately following the initial pirenzepine injection. Subsequent doses of pirenzepine were ineffective in producing an impairment of performance while scopolamine injections were less effective than the initial dose.(ABSTRACT TRUNCATED AT 250 WORDS)


Fraser-cryptophthalmos syndrome with colonic atresia.
Fraser cryptophthalmos syndrome is a severe genetic disorder comprising of cryptophthalmos, syndactyly and genitourinary abnormalities. Gastrointestinal malformations are also increasingly being described. We describe a neonate with this syndrome having colonic atresia leading to cecal rupture and pneumoperitoneum.


Improved molecular detection of Burkholderia cepacia genomovar III and Burkholderia multivorans directly from sputum of patients with cystic fibrosis.
Optimum detection of the Burkholderia cepacia complex (BCC) from sputum of patients with cystic fibrosis (CF) is essential in preventing patient-to-patient transmission of this organism. The aim of this study was to develop an improved PCR assay with reference to sensitivity for the direct detection of BCC organisms from CF sputum employing the recA locus. The sensitivity results of three recA PCR assays were compared using various combinations of previously published primers. These included (i) a single-round approach using the primer set BCR1/BCR2, yielding a 1036-bp product, (ii) a single-round approach using the primer set BCR1/Mr, yielding a 465-bp product, and (iii) a semi-nested PCR (SN-PCR) approach using the primer set BCR1/BCR2 followed by BCR1/Mr. The sensitivity of these assays were determined by spiking B. cepacia-free sputum with known numbers of four strains of BCC, namely, genomovar II [B. multivorans] (C1576), genomovar IIIa (C5424, C6433) and genomovar IIIb (C1394). Following optimization, the chosen assay was performed on 14 patients. Employment of the single-round assay with BCR1/BCR2 was the least sensitive with a detection threshold of 10(7) cfu/g sputum for GIIIa and GIIIb, and 10(8) cfu/g sputum for GII. Sensitivity was improved by targeting the smaller amplification region of the recA locus (465 bp) employing the BCR1/Mr primer pair, in combination with a single-round approach, whereby the detection threshold was improved by 1 log for each genomovar. Employment of the semi-nested assay demonstrated optimum sensitivity, whereby the detection threshold increased to 10(1) and 10(2) cfu/g sputum for genomovar IIIa/IIIb and genomovar II, respectively. Subsequent genomovar characterisation can be performed by sequencing of the PCR amplicon without the need for culture which may be beneficial in patients in the initial stages of colonisation or who are transiently colonised and who may be culture-negative for BCC.


Farnesyltransferase inhibitors and anti-Ras therapy.
The oncoprotein encoded by mutant ras genes is initially synthesized as a cytoplasmic precursor which requires posttranslational processing to attain biological activity; farnesylation of the cysteine residue present in the CaaX motif located at the carboxy-terminus of all Ras proteins is the critical modification. Once farnesylated and further modified, the mature Ras protein is inserted into the cell's plasma membrane where it participates in the signal transduction pathways that control cell growth and differentiation. The farnesylation reaction that modifies Ras and other cellular proteins having an appropriate CaaX motif is catalyzed by a housekeeping enzyme termed farnesyl-protein transferase (FPTase). Inhibitors of this enzyme have been prepared by several laboratories in an effort to identify compounds that would block Ras-induced cell transformation and thereby function as Ras-specific anticancer agents. A variety of natural products and synthetic organic compounds were found to block farnesylation of Ras proteins in vitro. Some of these compounds exhibit antiproliferative activity in cell culture, block the morphological alterations associated with Ras-transformation, and can block the growth of Ras-transformed cell lines in tumor colony-forming assays. By contrast, these compounds do not affect the growth or morphology of cells transformed by the Raf or Mos oncoproteins, which do not require farnesylation to achieve biological activity. The efficacy and lack of toxicity observed with FPTase inhibitors in an animal tumor model suggest that specific FPTase inhibitors may be useful for the treatment of some types of cancer.


Arrhythmogenesis--a European perspective.
Arrhythmogenesis as an effect of antiarrhythmic therapy is a relatively recent concern. Satisfactory definitions are lacking, but 2 categories, clinical and technical, can be recognized. Although arrhythmogenesis is an international problem and multifactorial, its expression depends on variables that differ according to geographic location. In Europe, use of antiarrhythmic therapy is more conservative than it is in the U.S. In the U.S., many antiarrhythmic drugs commonly used in Europe are either recently released, are on limited release or are available only in investigational protocols. Mexiletine, class IC agents and sotalol are agents in routine use in Europe. All have arrhythmogenic potential, although this appears lowest with mexiletine.


The role of carotid intimal thickness testing and risk prediction in the development of coronary atherosclerosis.
Carotid ultrasonography is a safe and available noninvasive diagnostic tool that provides information about the carotid arteries' characteristics and may be used for early detection of coronary artery disease as well as cardiovascular and stroke event risk stratifications. We performed a systematic search of articles discussing carotid ultrasonography in the English literature recorded in PubMed from 2010 to September 2012. Generally, the studies showed that internal carotid artery intima-media thickness is a more powerful variable than common carotid artery intima-media thickness. Moreover, the presence of carotid plaque and plaque volumes are more reliable and accurate estimators of coronary artery disease and risk of a stroke or cardiovascular event than intima-media thickness.


The effects of dietary approaches to stop hypertension diet on weight loss, anti-Müllerian hormone and metabolic profiles in women with polycystic ovary syndrome: A randomized clinical trial.
This study was designed to evaluate the effects of the dietary approaches to stop hypertension (DASH diet) on weight loss, anti-Müllerian hormone (AMH) and metabolic profiles in women with polycystic ovary syndrome (PCOS). A randomized controlled clinical trial was conducted among 60 overweight or obese patients with PCOS. Patients were randomly assigned to receive either low-calorie DASH (N=30) or control diet (N=30) for 12 weeks. The DASH and control diets were consisted of 52%-55% carbohydrates, 16%-18% proteins and 30% total fats; however, the DASH diet was designed to be rich in fruits, vegetables, whole grains, low-fat dairy products, cholesterol and refined grains. Both diets were equicaloric. Adherence to the DASH diet, compared to the control diet, resulted in a significant decrease in BMI (-1.6±0.5 vs -1.2±0.7 kg/m2 , P=.02). Significant decreases in AMH (-1.1±3.1 vs +0.3±0.7 ng/mL, P=.01), insulin (-25.2±51.0 vs -1.2±28.8 pmol/L, P=.02), homoeostasis model of assessment-estimated insulin resistance (-0.9±2.0 vs -0.1±1.0, P=.02), free androgen index (FAI; -0.03±0.09 vs +0.06±0.21, P=.02) and malondialdehyde (MDA) levels (-0.5±0.4 vs +0.2±0.3 μmol/L, P<.001), and significant increases in quantitative insulin sensitivity check index (+0.01±0.03 vs -0.004±0.01, P=.02), sex hormone-binding globulin (SHBG; +3.7±8.5 vs -1.5±7.2 nmol/L, P=.01) and nitric oxide (NO; +9.0±4.9 vs +0.6±2.3 μmol/L, P<.001) were also seen in the DASH group compared with the control group. Adherence to the DASH diet for 12 weeks among PCOS women had beneficial effects on BMI, AMH, insulin metabolism, SHBG, FAI, NO and MDA levels.


Effect of continuous intra-incisional bupivacaine on postoperative pain in non-traumatic spinal fixation surgeries: a randomized controlled trial.
Continuous injection of local anesthetics by using surgical wound catheters for postoperative pain relief has gained acceptance in recent years. However, whether this method can be alternatively used instead of systemic opioids in different surgical procedures has not yet been elucidated. The aim was to investigate the effect of continuous injection of bupivacaine through a catheter inside the surgical wound on reducing the postoperative pain of lumbar spine fusion surgeries. In this clinical trial, 31 patients undergoing non-traumatic lumbar spine stabilization surgery were randomly assigned to receive (n = 15) or do not receive (n = 16) bupivacaine through a catheter inside the surgical wound, postoperatively. Pain intensity (NRS), dose of required morphine, and drug-related complications within 24 hours of intervention were assessed and compared by the Mann-Whitney and independent t-test. Mean pain intensity was significantly lower in the case group over the first postoperative hour in the recovery room (p < 0.001), which continued for the first 2 hours after entering the ward. The mean morphine intake was lower in the bupivacaine group during the first postoperative 24 hours (16 ± 0.88 vs. 7.33 ± 0.93 mg, p < 0.001). The two groups were not significantly different regarding drug-related complications. Continuous intra-incisional infusion of bupivacaine helped better pain reduction during the early postoperative hours while sparing morphine consumption in the first postoperative day.


An improved, sensitive, non-radioactive in situ hybridization method for the detection of cytokine mRNAs.
We established an improved non-radioactive in situ hybridization (ISH) method to detect mRNA of cytokines in cell preparations and tissues. Via this method we could demonstrate various cytokines in stimulated peripheral blood mononuclear cells (PBMC), lymphoid cell lines and human lymphoid tissues. The probes for the in situ hybridization were made by labelling cytokine-specific PCR products with digoxigenin (Dig) in a repeated PCR. This resulted in an intrinsic labelling of the probe with several Dig-UTP molecules. Incorporation of Dig-11-dUTPs was shown on ethidium bromide-stained agarose gels by a higher molecular weight of the PCR products with incorporated Dig-dUTPs when compared to control PCR products without digoxigenin. Cytospin-centrifuged cells of PHA-stimulated PBMC or lymphoid cell lines and frozen sections of various human lymphoid tissues were hybridized with the Dig-labelled cytokine probes and the hybridized probes were detected immuno-histochemically. In this way, we detected and localized cytokine mRNAs (IL-2, IL-4, IL-6, IL-8, IL-10) in PBMC, in the human T-cell line Jurkat, in the follicular lymphoma cell line DoHH2, and in human lymph nodes and tonsils. The in situ hybridization had a high sensitivity as the results correlated closely with the detection of cytokine mRNA by reverse transcriptase-PCR (RT-PCR) data from the same samples. We showed that Jurkat and DoHH2 cells produce several cytokines constitutively and that, after activation with the phorbol ester PMA, expression of several cytokine mRNAS was enhanced.


Testosterone regulates the haemoglobin concentration in male puberty.
In a longitudinal study of male puberty 20 boys were examined every three months for at least two years. Haemoglobin concentration was determined and related to changes in serum testosterone concentrations. The data show a steep increase in serum testosterone during puberty (p less than 0.001) followed with a five months delay, by a significant increase in haemoglobin concentration (p less than 0.001). It is concluded that the steep increase in serum testosterone during puberty produces an acute stimulation of erythropoietin leading to an increase in erythrocyte production and thereby to a detectable increase in haemoglobin concentration a few months thereafter. The present study supports the idea that the selection of the relevant reference range for haemoglobin in boys should depend on the state of physical developments as expressed by serum testosterone.


Problems of bovine leucosis control and prophylaxis in industrial breeding conditions.
Industrial cattle-breeding in Bulgaria is characterized by large cattle-breeding complexes holding 500, 1,000 or 2,000 dairy cows; farms specialized in rearing calves for breeding purposes, and calves fattening units holding 2,000, 5,000 or 10,000 animals. A specific technology has been introduced for management purposes. This high concentration and specialization creates specific organisational problems for antiepizootic control measures. Bovine leucosis has been brought from abroad by imported breedings animals. A complex system for leucosis prophylaxis and control is obligatorily implemented. It is supervized and financed by the state. Particular care is taken of ensuring protective measures for import breeding animals. The infected farms are put under strict quarantine. The animals which show a positive reaction during complex diagnostic tests are slaughtered and the meat is used after heat-processing. The milk is heat-processed too and sent for further utilization. Calves born in infected farms are not fit for breeding purposes but for fattening only.


The infrared and Raman spectra of trans- and cis-tetrachloro-tetramethylbicyclopropylidene.
The title compounds trans- and cis-2,2,2',2'-tetrachloro-3,3,3',3'-tetramethyl-bicyclopopylidene were synthesized, and their infrared and Raman spectra were recorded. Non-coincidence between the IR and Raman bands of the trans compound suggested C(2h) symmetry and a planar ring system. In the cis compound most of the IR and Raman bands coincided and a C(2v) symmetry seems likely. The exocyclic CC double bond gave rise to a medium/weak Raman band at 1,847 cm(-1) in the trans compound. In the cis derivative IR and Raman bands both at 1,825 cm(-1) were observed. From similarities with related molecules, the ring breathing, the antisymmetric ring stretch, the CCl(2) out-of-phase and in-phase stretch and the out-of-plane ring bending modes have been tentatively assigned for the trans and cis compounds.


Six-minute walking test and long term prognosis in patients with asymptomatic aortic valve stenosis.
Management of asymptomatic patients with aortic valve stenosis is challenging due to the elusive relationship between symptomatic status and hemodynamic parameters in addition to the occurrence of cardiovascular death. The 6-minute walking test (6MWT) reflects overall hemodynamic function and could contribute to risk assessment in such patients. One hundred sixteen asymptomatic patients (peak velocity>2.5m/s and left ventricular ejection fraction >50% assessed by echocardiographic screening; 85 males; aged 72±8years) underwent clinical workup, transthoracic echocardiography and a 6MWT. The mean distance covered by patients able to perform the 6MWT (n=107) was 422±90m. Patients were grouped in tertiles according to distance covered in the 6MWT: Short, intermediate and long distance patients. During a median follow-up of 5.5years (IQR 4.5-6.3), 29 (25%) patients died, 10 (9%) from cardiovascular causes. Multivariate analysis revealed that short distance patients (≤390m) were at higher risk of all-cause mortality (HR: 2.44; 95% CI: 1.05-5.67; p=0.04) and cardiovascular mortality (HR: 6.12; 95% CI: 1.18-31.83; p=0.03). For every 100m covered, the risk of all-cause mortality decreased by 35% (HR: 0.65; 95% CI: 0.43-0.99; p=0.04). Long distance patients (>465m) did not experience cardiovascular deaths during follow-up. In asymptomatic patients with aortic valve stenosis, the 6MWT is an independent predictor of all-cause and cardiovascular mortality. It is of incremental value to the echocardiographic evaluation, suggesting that the 6MWT might be useful to guide clinical follow-up intervals and treatment strategy.


Parametric optimization of the production of cellulose nanocrystals (CNCs) from South African corncobs via an empirical modelling approach.
In this study, cellulose nanocrystals (CNCs) were obtained from South African corncobs using an acid hydrolysis process. The delignification of corncobs was carried out by using alkali and bleaching pretreatment. Furthermore, the Box-Behnken Design (BBD) was used as a design of experiment (DOE) for statistical experimentations that will result in logical data to develop a model that explains the effect of variables on the response (CNCs yield). The effects (main and interactive) of the treatment variables (time, temperature, and acid concentration) were investigated via the response methodology approach and the obtained model was used in optimizing the CNCs yield. Surface morphology, surface chemistry, and the crystallinity of the synthesized CNC were checked using scanning electron microscopy (SEM), a Fourier Transform Infra-red spectroscopy (FTIR), and an X-ray diffraction (XRD) analysis, respectively. The SEM image of the raw corncobs revealed a smooth and compact surface morphology. Results also revealed that CNCs have higher crystallinity (79.11%) than South African waste corncobs (57.67%). An optimum yield of 80.53% CNCs was obtained at a temperature of 30.18 °C, 30.13 min reaction time, and 46 wt% sulfuric acid concentration. These optimized conditions have been validated to confirm the precision. Hence, the synthesized CNCs may be suitable as filler in membranes for different applications.


Computational estimation of tricarboxylic acid cycle fluxes using noisy NMR data from cardiac biopsies.
The aerobic energy metabolism of cardiac muscle cells is of major importance for the contractile function of the heart. Because energy metabolism is very heterogeneously distributed in heart tissue, especially during coronary disease, a method to quantify metabolic fluxes in small tissue samples is desirable. Taking tissue biopsies after infusion of substrates labeled with stable carbon isotopes makes this possible in animal experiments. However, the appreciable noise level in NMR spectra of extracted tissue samples makes computational estimation of metabolic fluxes challenging and a good method to define confidence regions was not yet available. Here we present a computational analysis method for nuclear magnetic resonance (NMR) measurements of tricarboxylic acid (TCA) cycle metabolites. The method was validated using measurements on extracts of single tissue biopsies taken from porcine heart in vivo. Isotopic enrichment of glutamate was measured by NMR spectroscopy in tissue samples taken at a single time point after the timed infusion of 13C labeled substrates for the TCA cycle. The NMR intensities for glutamate were analyzed with a computational model describing carbon transitions in the TCA cycle and carbon exchange with amino acids. The model dynamics depended on five flux parameters, which were optimized to fit the NMR measurements. To determine confidence regions for the estimated fluxes, we used the Metropolis-Hastings algorithm for Markov chain Monte Carlo (MCMC) sampling to generate extensive ensembles of feasible flux combinations that describe the data within measurement precision limits. To validate our method, we compared myocardial oxygen consumption calculated from the TCA cycle flux with in vivo blood gas measurements for 38 hearts under several experimental conditions, e.g. during coronary artery narrowing. Despite the appreciable NMR noise level, the oxygen consumption in the tissue samples, estimated from the NMR spectra, correlates with blood-gas oxygen uptake measurements for the whole heart. The MCMC method provides confidence regions for the estimated metabolic fluxes in single cardiac biopsies, taking the quantified measurement noise level and the nonlinear dependencies between parameters fully into account.


An analysis of antidepressant prescribing trends in England 2015-2019.
Background Growing concerns about the impact of coronavirus disease 2019 (COVID-19) will likely lead to increased mental health diagnoses and treatment. To provide a pre-COVID-19 baseline, we have examined antidepressant prescribing trends for 5 years preceding COVID-19. Methods A retrospective analysis of anonymised data on medicines prescribed by GPs in England from the Open-Prescribing Database (January 2015 to December 2019) identified the 10 most prescribed antidepressant and, for comparison, cardiovascular medicines. Results Prescription items for the 10 most prescribed antidepressants rose 25% from 58 million (2015) to 72 million (2019). Citalopram was the most prescribed antidepressant; prescriptions for sertraline rose fastest at 2 million items year on year. Over the same period, costs for antidepressant prescribing fell 27.8%. Across all Clinical Commissioning Groups (CCGs) in England, antidepressant prescribing levels, adjusted for population were positively correlated with the index of multiple deprivation (IMD) score. In comparison, prescribing for the top 10 most prescribed cardiovascular medicines increased by 2.75% from 207 million (2015) to 213 million (2019) items. Limitations Anonymised data in the Open-Prescribing Database means no patient diagnoses or treatment plans are linked to this data. Conclusion Antidepressant prescribing, particularly sertraline, is increasing. Prescribing is higher in more deprived regions, but costs are falling to < 2% of all items prescribed. Absolute numbers of prescriptions for cardiovascular medicines are higher, likely reflecting the greater prevalence of cardiovascular disease, and are rising more slowly. This study will enable future work to look at the impact of COVID-19 on prescribing for mental health.


Prion assemblies: structural heterogeneity, mechanisms of formation, and role in species barrier.
Prions are proteinaceous pathogens responsible for a wide range of neurodegenerative diseases in animal and human. Prions are formed from misfolded, ß-sheet rich, and aggregated conformers (PrPSc) of the host-encoded prion protein (PrPC). Prion replication stems from the capacity of PrPSc to self-replicate by templating PrPC conversion and polymerization. The question then arises about the molecular mechanisms of prion replication, host invasion, and capacity to contaminate other species. Studying these mechanisms has gained in recent years further complexity with evidence that PrPSc is a pleiomorphic protein. There is indeed compelling evidence for PrPSc structural heterogeneity at different scales: (i) within prion susceptible host populations with the existence of different strains with specific biological features due to different PrPSc conformers, (ii) within a single infected host with the co-propagation of different strains, and (iii) within a single strain with evidence for co-propagation of PrPSc assemblies differing in their secondary to quaternary structure. This review summarizes current knowledge of prion assembly heterogeneity, potential mechanisms of formation during the replication process, and importance when crossing the species barrier.