Early prevention of diabetes microvascular complications in people with hyperglycaemia in Europe. ePREDICE randomized trial. Study protocol, recruitment and selected baseline data.
To assess the effects of early management of hyperglycaemia with antidiabetic drugs plus lifestyle intervention compared with lifestyle alone, on microvascular function in adults with pre-diabetes. Trial design: International, multicenter, randomised, partially double-blind, placebo-controlled, clinical trial. Males and females aged 45-74 years with IFG, IGT or IFG+IGT, recruited from primary care centres in Australia, Austria, Bulgaria, Greece, Kuwait, Poland, Serbia, Spain and Turkey. Participants were randomized to placebo; metformin 1.700 mg/day; linagliptin 5 mg/day or fixed-dose combination of linagliptin/metformin. All patients were enrolled in a lifestyle intervention program (diet and physical activity). Drug intervention will last 2 years. Primary Outcome: composite end-point of diabetic retinopathy estimated by the Early Treatment Diabetic Retinopathy Study Score, urinary albumin to creatinine ratio, and skin conductance in feet estimated by the sudomotor index. Secondary outcomes in a subsample include insulin sensitivity, beta-cell function, biomarkers of inflammation and fatty liver disease, quality of life, cognitive function, depressive symptoms and endothelial function. One thousand three hundred ninety one individuals with hyperglycaemia were assessed for eligibility, 424 excluded after screening, 967 allocated to placebo, metformin, linagliptin or to fixed-dose combination of metformin + linagliptin. A total of 809 people (91.1%) accepted and initiated the assigned treatment. Study sample after randomization was well balanced among the four groups. No statistical differences for the main risk factors analysed were observed between those accepting or rejecting treatment initiation. At baseline prevalence of diabetic retinopathy was 4.2%, severe neuropathy 5.3% and nephropathy 5.7%. ePREDICE is the first -randomized clinical trial with the aim to assess effects of different interventions (lifestyle and pharmacological) on microvascular function in people with pre-diabetes. The trial will provide novel data on lifestyle modification combined with glucose lowering drugs for the prevention of early microvascular complications and diabetes. - ClinicalTrials.Gov Identifier: NCT03222765 - EUDRACT Registry Number: 2013-000418-39.


Prevalence of Frailty in Nursing Home Residents According to Various Diagnostic Tools.
Although the theoretical foundations of frailty are well established in the literature, it remains an evolving concept lacking any unique definition or diagnostic criteria for use in clinical practice and epidemiological research. No consensus exists about the accurate prevalence rates of frailty. The various operational definitions of frailty can at least partly explain such discrepancies. To compare the prevalence of frailty, measured with different diagnostic tools, among elderly nursing home residents. This is an analysis of baseline data collected among the SENIOR (Sample of Nursing home Elderly Individuals: an Observational Research) cohort. Nursing homes. A total of 662 volunteer subjects from 28 nursing homes were included in this analysis. Among them, the mean age was 83.2 ± 8.99 years and 484 (72.5%) of them were women. The percentages of frail and non-frail subjects were calculated according to 10 different definitions. Prevalence of frailty varies from 1.70% (Frailty Index) to 76.3% (Groningen Frailty Indicator) depending on the tool used. The prevalence of frailty is highly dependent on the diagnostic tool used. It would be necessary to reach a consensus on which diagnostic tools to use if one wishes to have comparable data obtained in epidemiological studies.


[An experimental study of auto-allergy evoked by staphylococcus under conditions of primary and secondary immunological response].
Experiments were conducted on rabbits and albino mice; it was shown that the capacity of the animal organism to reject the skin autotransplant formed 7 to 10 days after the primary immunization and persisted for a period of 45 days. Repeated vaccination of mice 24 hours before the operation aided the take of the skin autotransplants, and 7 days before--promoted their rejection. Intravenous revaccination of the operated animals also intensified the rejection reactions; the process of the transplant rejection was accompanied by a marked fall in the level of staphylococcus- and autoantibodies. In the unoperated animals intravenous revaccination with staphylovaccine caused production of antibodies by the secondary type. Deposits of fixed gamma-globulin were found on the 6th-8th day after the transplantation in the autotransplant and its bed in mice primarily immunized with staphylovaccine. Marked circulatory disturbances, necrobiotic processes, mononuclear infiltration of the derma with neutrophils were revealed pathomorphologically in the rejecting skin transplant.


Intramedullary epidermoid cysts.
Intramedullary inclusion cysts are extremely rare within the rostral spinal cord. In this case report the authors outline the clinical features and surgical treatment of one dermoid cyst and one epidermoid cyst of the cervicothoracic junction. The authors also include a relevant literature discussion regarding the treatment and the embryological origin of these lesions.


Plasmonic structured illumination microscopy.
We propose a super resolution imaging technique called plasmonic structured illumination microscopy (PSIM), which combines the structured illumination microscopy technique with the tunable surface plasmon interference. Because of the high-resolution enabled by using surface plasmon interference as an illumination source, PSIM possesses higher image resolving power compared with conventional structured illumination microscopy. To demonstrate the technique, we present two specific types of plasmonic structure designs for PSIM. The final images from the simulations show 3-fold and 4-fold resolution improvement compared with conventional epi-fluorescence microscopy.


Immunohistochemical expression of pi class glutathione S-transferase in the basal cell layer of benign prostate tissue following chronic treatment with finasteride.
Glutathione S-transferases (GST) may prevent carcinogenesis through inactivation of reactive electrophiles by conjugation to reduced glutathione. Treatment directed at the induction or preservation of GST-pi expression in normal epithelium could have a profound impact on the prevention of prostate neoplasia. Finasteride, a 5-alpha-reductase inhibitor, is used as a chemopreventive agent because it blocks the conversion of testosterone to its byproduct which promotes prostate tumour growth. To investigate GST-pi expression immunohistochemically in benign prostate tissue from untreated patients and from patients chronically treated with finasteride. Immunostaining with anti-GST-pi antibody was performed on 10 (cysto-) prostatectomy, eight simple prostatectomy, and three transurethral prostatectomy specimens. The first set of 10 prostates was from untreated patients operated on for bladder cancer. The other cases were from patients with benign prostatic hyperplasia and chronically treated with finasteride. None of the specimens in either group showed prostatic cancer, prostatic intraepithelial neoplasia, urothelial carcinoma, or chronic prostatitis. Specimens were evaluated for the presence, intensity, and distribution of immunostaining. Diffuse cytoplasmic immunostaining was observed in the basal cell layer of the untreated specimens. Some variability in the expression of GST-pi was seen within each zone and also between the prostate zones. Only a minority of the secretory cells was stained weakly, mainly in the subnuclear region of the cells facing an uninterrupted basal cell layer. Staining was more homogeneously diffuse in the cytoplasm of the luminal cells facing the basement membrane directly. In the benign epithelium of the finasteride treated specimens the circumferential staining of the basal cells appeared to be more continuous than in the untreated cases, the gaps in the stained basal cell layer being fewer, shorter, or even absent in some ducts and acini. There was no variability in the intensity of staining of the basal cell layer, all the cells being intensely stained in a uniform way. The intensity of staining of the secretory cells was not influenced by finasteride treatment. Following chronic treatment with finasteride the immunohistochemical expression of pi class glutathione S-transferase in the benign prostate ducts and acini is upregulated in relation to an expanded basal cell layer. This could indicate that finasteride acts as a GST-pi inducer.


Effect of vitamin E supplementation on platelet thromboxane A2 production in type I diabetic patients. Double-blind crossover trial.
Vitamin E deficiency is associated with increased platelet aggregation, which can be normalized through vitamin E supplementation. In diabetes, increased platelet thromboxane A2 (TXA2) production is correlated with decreased platelet vitamin E content. We therefore investigated the effect of 400 mg DL-alpha-tocopherol acetate daily for 4 wk on ADP- and collagen-induced platelet aggregation and platelet TXA2 production in 22 type I (insulin-dependent) diabetic patients without macroangiopathy and with no or only minimal microangiopathy by a double-blind placebo-controlled crossover study. Platelet aggregation was induced in platelet-rich plasma by two or three different concentrations of ADP and collagen. TXA2 was measured by the stable spontaneous breakdown product thromboxane B2 by a specific radioimmunoassay. Whereas metabolic control remained unchanged during the study period, platelet TXA2 production was significantly (P less than .05 and P less than .01) reduced at each ADP concentration and at two of three collagen concentrations. Because increased TXA2 production of diabetic platelets is thought to play an important pathogenetic role in diabetic angiopathy, we conclude that vitamin E treatment could be beneficial with respect to platelet-vessel-wall interaction and thus might be promising for the prevention of diabetic angiopathy.


Intralesional Sclerotherapy - A Novel Approach for The Treatment of Intraoral Haemangiomas.
In infancy and childhood haemangiomas are the most common neoplasms in head and neck region with an occurrence of about 60%. Approximately 40%-50% of all haemangiomas resolve incompletely, leaving permanent changes in the skin, such as telangiectases, epidermal atrophy, hypopigmentation or redundant skin with fibro-fatty residue but a few stubborn, problematic haemangiomas may result in serious disfigurement and dysfunction, and even become life-threatening. Most haemangiomas are managed by conservative methods that include corticosteroids (either systemic or local injection), sclerotherapy, interferon-alpha, laser therapy, embolization, cryotherapy, and radiation. Due to risk of haemorrhaging, surgical removal for small vascular lesions is not considered and it is more invasive than sclerotherapy. This case report presents the efficacy of intralesional sclerotherapy for the management of haemangiomas on dorsum and lateral border of tongue.


Incidence and Impact of Dysglycemia in Patients with Sepsis Under Moderate Glycemic Control.
Glycemic control strategies for sepsis have changed significantly over the last decade, but their impact on dysglycemia and its associated outcomes has been poorly understood. In addition, there is controversy regarding the detrimental effects of hyperglycemia in sepsis. To evaluate the incidence and risks of dysglycemia under current strategy, we conducted a preplanned subanalysis of the sepsis cohort in a prospective, multicenter FORECAST study. A total of 1,140 patients with severe sepsis, including 259 patients with pre-existing diabetes, were included. Median blood glucose levels were approximately 140 mg/dL at 0 and 72 h indicating that blood glucose was moderately controlled. The rate of initial and late hyperglycemia was 27.3% and 21.7%, respectively. The rate of early hypoglycemic episodes during the initial 24 h was 13.2%. Glycemic control was accompanied by a higher percentage of initial and late hyperglycemia but not with early hypoglycemic episodes, suggesting that glycemic control was targeted at excess hyperglycemia. In nondiabetic patients, late hyperglycemia (hazard ratio, 95% confidence interval; P value: 1.816, 1.116-2.955, 0.016) and early hypoglycemic episodes (1.936, 1.180-3.175, 0.009) were positively associated with in-hospital mortality. Further subgroup analysis suggested that late hyperglycemia and early hypoglycemic episodes independently, and probably synergistically, affect the outcomes. In diabetic patients, however, these correlations were not observed. In conclusion, a significantly high incidence of dysglycemia was observed in our sepsis cohort under moderate glycemic control. Late hyperglycemia in addition to early hypoglycemia was associated with poor outcomes at least in nondiabetic patients. More sophisticated approaches are necessary to reduce the incidence of these serious complications.


Cognitive coupling during reading.
We hypothesize that cognitively engaged readers dynamically adjust their reading times with respect to text complexity (i.e., reading times should increase for difficult sections and decrease for easier ones) and failure to do so should impair comprehension. This hypothesis is consistent with theories of text comprehension but has surprisingly been untested. We tested this hypothesis by analyzing 4 datasets in which participants (N = 484) read expository texts using a self-paced reading paradigm. Participants self-reported mind wandering in response to pseudorandom thought-probes during reading and completed comprehension assessments after reading. We computed two measures of cognitive coupling by regressing each participant's paragraph-level reading times on two measures of text complexity: Flesch-Kincaid Grade Level and Word Concreteness scores. The two coupling measures yielded convergent findings: coupling was a negative predictor of mind wandering and a positive predictor of both text- and inference-level comprehension. Goodness-of-fit, measured with Akaike information criterion, also improved after adding coupling to the reading-time only models. Furthermore, cognitive coupling mediated the relationship between mind wandering and comprehension, supporting the hypothesis that mind wandering engenders a decoupling of attention from external stimuli. (PsycINFO Database Record


Effector caspase Dcp-1 and IAP protein Bruce regulate starvation-induced autophagy during Drosophila melanogaster oogenesis.
A complex relationship exists between autophagy and apoptosis, but the regulatory mechanisms underlying their interactions are largely unknown. We conducted a systematic study of Drosophila melanogaster cell death-related genes to determine their requirement in the regulation of starvation-induced autophagy. We discovered that six cell death genes--death caspase-1 (Dcp-1), hid, Bruce, Buffy, debcl, and p53-as well as Ras-Raf-mitogen activated protein kinase signaling pathway components had a role in autophagy regulation in D. melanogaster cultured cells. During D. melanogaster oogenesis, we found that autophagy is induced at two nutrient status checkpoints: germarium and mid-oogenesis. At these two stages, the effector caspase Dcp-1 and the inhibitor of apoptosis protein Bruce function to regulate both autophagy and starvation-induced cell death. Mutations in Atg1 and Atg7 resulted in reduced DNA fragmentation in degenerating midstage egg chambers but did not appear to affect nuclear condensation, which indicates that autophagy contributes in part to cell death in the ovary. Our study provides new insights into the molecular mechanisms that coordinately regulate autophagic and apoptotic events in vivo.


Microdissection-based allelotyping discriminates de novo tumor from intrahepatic spread in hepatocellular carcinoma.
A total of 103 cases of hepatocellular carcinoma (HCC) arising in native livers discovered at the time of transplantation underwent allelic loss analysis. HCC mutational allelotyping targeted 10 genomic loci (1p, 3p, 5q, 7q, 8q, 9p, 10q, 17p, 17q, 18q) using 18 polymorphic microsatellite markers situated in proximity to known tumor suppressor genes associated with human carcinogenesis. Gene analysis was performed on microdissected tissue samples removed from 4-microm thick histologic sections at specific topographic sites selected on the basis of representative cellular characteristics. Microdissection targets included largest tumor nodule at 2 locations as well as up to 3 additional tumor nodules in each case. HCC genotyping characteristics including mutational profile and cumulative fractional allelic loss (FAL) were correlated with clinical and pathologic features. Individual nodules of HCC showed 2 patterns of mutational change: (1) essentially concordant mutational profiles consistent with intrahepatic spread of tumor, or (2) discordant mutational profiles consistent with independent primary cancer formation. In 15 of 56 cases (27%) in which the HCC was in a multinodular, bilobar form (T4), sufficient discordance in the allelic loss profile enabled a more accurate T-stage classification with better prediction of recurrence-free survival. In conclusion, microdissection genotyping of HCC is an effective and objective means to (1) distinguish between de novo HCC tumor formation versus intrahepatic spread of cancer and to (2) improve on current methods for prediction of tumor aggressiveness and recurrence-free survival after liver transplantation.


Actin cross-linking domain of Aeromonas hydrophila repeat in toxin A (RtxA) induces host cell rounding and apoptosis.
The repeat in toxin (Rtx) of an environmental isolate ATCC 7966 of Aeromonas hydrophila consists of six genes (rtxACHBDE) organized in an operon similar to the gene organization found for the Rtx of the Vibrio species. The first gene in this operon (rtxA) encodes an exotoxin in vibrios, while other genes code for proteins needed for proper activation of RtxA and in secretion of this toxin from Vibrio cholerae. However, the RtxA of ATCC 7966, as well as from the clinical isolate SSU of A. hydrophila, was exclusively expressed and produced during co-infection of this pathogen with the host, e.g., HeLa cells, indicating that rtxA gene expression required host cell contact. Within the RtxA, an actin cross-linking domain (ACD) exists and to investigate the functionality of this domain, several truncated versions of ACD were generated to discern its minimal biological active region. Such genetically modified genes encoding ACD, which were truncated on either the NH(2) or the COOH terminal, as well as on both ends, were expressed from a bidirectional promoter of the pBI-enhanced green fluorescent protein (EGFP) vector in a HeLa-Tet-Off cell system. We demonstrated that only the full-length ACD of RtxA from A. hydrophila catalyzed the covalent cross-linking of the host cellular actin, whereas the ACD truncated on the NH(2), COOH or both ends did not exhibit such actin cross-linking characteristics. Further, we showed that the full-length ACD of A. hydrophila RtxA disrupted the actin cytoskeleton of HeLa cells, resulting in their rounding phenotype. Finally, our data provided evidence that the full-length ACD of RtxA induced host cell apoptosis. Our study is the first to report that A. hydrophila possesses a functional RtxA having an ACD that contributes to the host cell apoptosis, and hence could represent a potential virulence factor of this emerging human pathogen.


Social modification of alcohol consumption in inbred mice.
The strain-specific "preference" for, or "aversion" to, an alcohol solution in a choice situation on the part of C57BL and DBA mice is believed to be under genetic control. But social rearing conditions are now shown to alter the voluntary consumption of alcohol, so that DBA weanling mice housed for 7 weeks with adult C57BL mice increase--and C57BL weanling mice housed with DBA adults decrease--their alcohol intake. Although substantial and highly significant changes in alcohol self-selection occur, strain-specific phenotypes are not reversed.


Levels of Cognitive Control: A Functional Magnetic Resonance Imaging-Based Test of an RDoC Domain Across Bipolar Disorder and Schizophrenia.
In recent years, the boundaries of psychopathology as defined by diagnostic categories have been criticized as inadequately 'carving nature at its joints' with respect to the neurobiology of major mental disorders. In 2010 the NIMH launched the Research Domain Criteria (RDoC) framework for understanding mental illnesses as brain circuit disorders that extend beyond DSM-defined diagnoses. In the present study we focus on cognitive dysfunction, a core feature of schizophrenia (SZ) and bipolar disorder (BPD), and use functional magnetic resonance imaging (fMRI) during a cognitive control (CC) task in recent onset patients to test the hypothesis that at a behavioral and underlying neural circuitry level these deficits exist on a continuum (as opposed to showing categorical differences) across the two disorders. In total, 53 healthy controls, 24 recent (<1 y) onset patients with BPD Type I with psychotic features, and 70 recent onset patients with SZ performed the AX-Continuous Performance Task while undergoing event-related fMRI at 1.5 T. In addition to behavior task-associated response was examined in frontoparietal regions-of-interest. In an a priori contrast-based analysis, significant deficits across patient groups (vs controls) were observed on CC-associated performance as well as frontoparietal response. These analyses further revealed a continuum of deficits in which BPD showed intermediate levels of CC relative to controls and SZ. Poor CC was associated with poverty and disorganization symptoms across patient groups. These results support the hypothesis that CC dysfunction in BPD and SZ reflects a continuum of deficits that cuts across traditional, DSM-based classification. Implications for the neurobiology of these diseases are discussed.


Episodic evolution of coadapted sets of amino acid sites in mitochondrial proteins.
The rate of evolution differs between protein sites and changes with time. However, the link between these two phenomena remains poorly understood. Here, we design a phylogenetic approach for distinguishing pairs of amino acid sites that evolve concordantly, i.e., such that substitutions at one site trigger subsequent substitutions at the other; and also pairs of sites that evolve discordantly, so that substitutions at one site impede subsequent substitutions at the other. We distinguish groups of amino acid sites that undergo coordinated evolution and evolve discordantly from other such groups. In mitochondrion-encoded proteins of metazoans and fungi, we show that concordantly evolving sites are clustered in protein structures. By analysing the phylogenetic patterns of substitutions at concordantly and discordantly evolving site pairs, we find that concordant evolution has two distinct causes: epistatic interactions between amino acid substitutions and episodes of selection independently affecting substitutions at different sites. The rate of substitutions at concordantly evolving groups of protein sites changes in the course of evolution, indicating episodes of selection limited to some of the lineages. The phylogenetic positions of these changes are consistent between proteins, suggesting common selective forces underlying them.


A festschrift for Roland L. Weinsier: nutrition scientist, educator, and clinician.
Roland L. Weinsier, M.D., Dr.P.H., devoted himself to the fields of nutrition and obesity for more than 35 years. He contributed outstanding work related to the treatment of obesity through dietary and lifestyle change; metabolic/energetic influences on obesity, weight loss, and weight regain; body composition changes accompanying weight loss and regain; the health benefits and risks of weight loss; nutrition education for physicians; and nutrition support of sick patients. He served on the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) National Task Force on Prevention and Treatment of Obesity, as Chair of the University of Alabama at Birmingham's Department of Nutrition Sciences, and as Founder and Director of its NIDDK-funded Clinical Nutrition Research Center. He was a long-time and active member of NAASO, serving in the roles of Councilor, Publications Committee Chair, Continuing Medical Education Course Director, Public Relations Committee Chair, and Membership Committee Co-Chair, to name just a few. He was well respected as a staunch defender of NAASO's scientific integrity in these roles. Sadly, Roland Weinsier died on November 27, 2002. He will be missed and remembered by many as a revered and beloved teacher, mentor, healer, and scholar.


SRRF: Universal live-cell super-resolution microscopy.
Super-resolution microscopy techniques break the diffraction limit of conventional optical microscopy to achieve resolutions approaching tens of nanometres. The major advantage of such techniques is that they provide resolutions close to those obtainable with electron microscopy while maintaining the benefits of light microscopy such as a wide palette of high specificity molecular labels, straightforward sample preparation and live-cell compatibility. Despite this, the application of super-resolution microscopy to dynamic, living samples has thus far been limited and often requires specialised, complex hardware. Here we demonstrate how a novel analytical approach, Super-Resolution Radial Fluctuations (SRRF), is able to make live-cell super-resolution microscopy accessible to a wider range of researchers. We show its applicability to live samples expressing GFP using commercial confocal as well as laser- and LED-based widefield microscopes, with the latter achieving long-term timelapse imaging with minimal photobleaching.


Co-expression of cytokeratins and neurofilament proteins in a permanent cell line: cultured rat PC12 cells combine neuronal and epithelial features.
The cytoskeleton of the rat cultured cell line PC12, which is widely used in cell biology as a model system for neuron-like differentiation, displays an unusual combination of intermediate-sized filaments (IFs). As determined by electron microscopy, immunolocalization, and biochemical analyses, these cells contain, in addition to neurofilaments, an extended meshwork of bundles of cytokeratin IFs comprising cytokeratins A and D, equivalent to human cytokeratin polypeptides Nos. 8 and 18, irrespective of whether they are grown in the presence or absence of nerve growth factor. The two IF systems differ in their fibrillar arrays, the neurofilaments being concentrated in perinuclear aggregates similar to those found in certain neuroendocrine tumors of epithelial origin. We conclude that PC12 cells permanently co-express IFs of both the epithelial and the neuronal type and thus present an IF combination different from those of adrenal medulla cells and pheochromocytomas, i.e., the putative cells of origin of the line PC12. The IF cytoskeleton of PC12 cells resembles that of various neuroendocrine tumors derived from epithelial cells. The results show that the development of a number of typical neuronal differentiation features is compatible with the existence of an epithelial type IF cytoskeleton, i.e., cytokeratins. The implications of these findings concerning the validity of the PC12 cell line as a model for neuronal differentiation and possible explanations of the origin of cells with this type of IF co-expression are discussed.


Acute methanol poisonings reported to the Drug and Poison Information Center in Izmir, Turkey.
The demographics, sources and outcomes of methanol poisoning have not been described in Turkey. Our study identified the profile of acute methanol exposures reported to Drug and Poison Information Center (DPIC) in Izmir, Turkey, from 1993 to 2002. Data analysis included patient demographics, sources of methanol, reason for the exposure, clinical effects and outcomes of methanol poisoning. The DPIC recorded 30,485 calls concerning poisoning; 996 (3.3%) alcohol poisonings were recorded and 113 (11.3%) of them were methanol poisonings. There were 91 (80.5%) males and 22 (19.5%) females with a mean age of 34.7+/-1.3 y (range 19-65) and 4.8+/-0.9 y (range 1-18) in adults and children, respectively. The sources of methanol were eu de cologne (72.6%), spirits (10.6%) and antifreeze (2.7%). Accidental poisoning occurred in all children between 0 and 12 y old, abuse (55.7%) and intentional poisoning (27.3%) were predominant in adults. Clinical signs in all cases were central nervous system symptoms (45.1%), metabolic acidosis (23.0%), visual symptoms (21.2%) and gastrointestinal symptoms (10.6%). Sixteen patients (14.1%) died, 63 (55.8%) had complete recovery and 1 (0.9%) had irreversible visual problems. Most patients with methanol poisoning may die or present serious morbidity without appropriate treatment in a health care facility. Methanol for producing cheap "eu de colognes" in Turkey is the principal reason for severe poisoning and deaths. Public education about colognes and legislative control of cologne production are important in preventing methanol poisoning.


13C-NMR studies of acetate and methanol metabolism by methylotrophic Pseudomonas strains.
The metabolism of [2-13C]acetate by Pseudomonas M27(Icl-) and Pseudomonas MA(Icl+) was studied in vivo using 13C-NMR spectroscopy. The flux of 13C-label into bicarbonate, glutamate and citrate was observed in both organisms. In addition 13C-labelled alpha, alpha-trehalose was synthesized as a major metabolite by Pseudomonas M27 but not by Pseudomonas MA. The presence of this disaccharide in cell extracts of Pseudomonas AM1(Icl-) grown with [13C]methanol was also observed. The data from analysis of the trehalose multiplet signal observed in the spectra of Pseudomonas M27 cell extracts were consistent with the absence of the glyoxylate cycle in this methylotroph.


The Chaotic Behavior of the Spread of Infection during the COVID-19 Pandemic in Japan.
In December 2019, China reported a new virus identified as SARS-CoV-2, causing COVID-19, which soon spread to other countries and led to a global pandemic. Although many countries imposed strict actions to control the spread of the virus, the COVID-19 pandemic resulted in unprecedented economic and social consequences in 2020 and early 2021. To understand the dynamics of the spread of the virus, we evaluated its chaotic behavior in Japan. A 0-1 test was applied to the time-series data of daily COVID-19 cases from January 26, 2020 to August 5, 2021 (3 days before the end of the Tokyo Olympic Games). Additionally, the influence of hosting the Olympic Games in Tokyo was assessed in data including the post-Olympic period until October 8, 2021. Even with these extended time period data, although the time-series data for the daily infections across Japan were not found to be chaotic, more than 76.6% and 55.3% of the prefectures in Japan showed chaotic behavior in the pre- and post-Olympic Games periods, respectively. Notably, Tokyo and Kanagawa, the two most populous cities in Japan, did not show chaotic behavior in their time-series data of daily COVID-19 confirmed cases. Overall, the prefectures with the largest population centers showed non-chaotic behavior, whereas the prefectures with smaller populations showed chaotic behavior. This phenomenon was observed in both of the analyzed time periods (pre- and post-Olympic Games); therefore, more attention should be paid to prefectures with smaller populations, in which controlling and preventing the current pandemic is more difficult.


The reliability of parafoveal cone density measurements.
Adaptive optics scanning light ophthalmoscopy (AOSLO) enables direct visualisation of the cone mosaic, with metrics such as cone density and cell spacing used to assess the integrity or health of the mosaic. Here we examined the interobserver and inter-instrument reliability of cone density measurements. For the interobserver reliability study, 30 subjects with no vision-limiting pathology were imaged. Three image sequences were acquired at a single parafoveal location and aligned to ensure that the three images were from the same retinal location. Ten observers used a semiautomated algorithm to identify the cones in each image, and this was repeated three times for each image. To assess inter-instrument reliability, 20 subjects were imaged at eight parafoveal locations on one AOSLO, followed by the same set of locations on the second AOSLO. A single observer manually aligned the pairs of images and used the semiautomated algorithm to identify the cones in each image. Based on a factorial study design model and a variance components model, the interobserver study's largest contribution to variability was the subject (95.72%) while the observer's contribution was only 1.03%. For the inter-instrument study, an average cone density intraclass correlation coefficient (ICC) of between 0.931 and 0.975 was calculated. With the AOSLOs used here, reliable cone density measurements can be obtained between observers and between instruments. Additional work is needed to determine how these results vary with differences in image quality.


The interaction of the ribotoxin α-sarcin with complex model lipid vesicles.
Fungal ribotoxins are extracellular RNases that inactivate ribosomes by cleaving a single phosphodiester bond at the universally conserved sarcin-ricin loop of the large rRNA. However, to reach the ribosomes, they need to cross the plasma membrane. It is there where these toxins show their cellular specificity, being especially active against tumoral or virus-infected cells. Previous studies have shown that fungal ribotoxins interact with negatively charged membranes, typically containing phosphatidylserine or phosphatidylglycerol. This ability is rooted on their long, non-structured, positively charged loops, and its N-terminal β-hairpin. However, its effect on complex lipid mixtures, including sphingophospholipids or cholesterol, remains poorly studied. Here, wild-type α-sarcin was used to evaluate its interaction with a variety of membranes not assayed before, which resemble much more closely mammalian cell membranes. The results confirm that α-sarcin is particularly sensitive to charge density on the vesicle surface. Its ability to induce vesicle aggregation is strongly influenced by both the lipid headgroup and the degree of saturation of the fatty acid chains. Acyl chain length is indeed particularly important for lipid mixing. Finally, cholesterol plays an important role in diluting the concentration of available negative charges and modulates the ability of α-sarcin to cross the membrane.


Some graphical considerations in time series analysis.
The pictorial information in a stationary time series as depicted by crossings of levels and crossings of random levels and related quantities is studied. It is shown that such graphical features are directly connected with the covariance function and hence with the spectral density. Many of these features can be actually applied in estimation and in the study of extremes. In the Gaussian case, the finite dimensional distributions are completely determined by the axis crossings and by the crossings of a random curve (to be defined) if the process is essentially bounded. Certain graphical patterns are suggested for a fast recognition of low-order ARMA models.


Cardiovascular effects of haemorrhagic shock in spleen intact and in splenectomized dogs.
Cardiac performance was evaluated during haemorrhagic shock in 27 dogs with spleens intact, 24 splenectomized, and 23 splenectomized transfused dogs that were given a volume of packed red blood cells simulating splenic contraction. Contractile changes were evaluated by calculating dP/dt at 20 mmHg developed pressure (dP/dt DP20), and by relating stroke work to left ventricular end-diastolic volume measured by biplane cinefluorography. Although heart rate increased comparably during early shock, cardiac output, stroke volume, maximal dP/dt, dP/dt DP20, and arterial blood pressure decreased more in splenectomized and splenectomized transfused dogs than in those with spleens intact. During shock dP/dt DP20 was more depressed in the splenectomized and splenectomized transfused dogs than in those with spleens intact. In addition, an increase in left ventricular end-diastolic volume was accompanied by an increase in left ventricular stroke work in dogs with spleens intact. In contrast, stroke work remained depressed in both splenectomized groups despite increased left ventricular volume. Progressive acidosis and decreased left ventricular blood flow were similar in all dogs during haemorrhage. The greater reduction in left ventricular performance during haemorrhagic shock in the splenectomized and splenectomized transfused dogs was not related to excess lactate, changes in plasma volume, or red blood cell mass. Decreased left ventricular performance, despite improved ventricular filling, indicates greater cardiac dysfunction during haemorrhagic shock. This study suggests that, in dogs, the spleen maintains left ventricular performance during haemorrhage by mechanisms other than autotransfusion.


The relative cost of outpatient telemedicine services.
This study compares the costs of offering outpatient care to primarily orthopedic and dermatology patients via live, interactive telemedicine to the estimated costs of direct face-to-face care for the same patients. A simple, yet detailed methodology was used to evaluate the cost of adding telemedicine to a health care delivery system, using a "hub-and-spoke" model located in Minnesota. The costs and cost savings of telemedicine were evaluated from the perspectives of patients, providers, insurers, employers, and society as a whole. Sensitivity analysis was used to investigate the impact of various factors on the model. The variable cost of a telemedicine referral was $144, versus an estimated face-to-face referral cost of $183. Reductions in patient travel costs and in lost employee productivity were the principal benefits of the system. The break-even point, where total costs equal total cost savings, equalled 1,449 consultations annually. Sensitivity analyses indicated that the breakeven point varies from a low of 152 telemedicine consultations for a "best case" scenario to no possible breakeven point for a "worst case" scenario. At the system's current level of 300 consultations per year, the telemedicine system is estimated to add $45,000 to society's costs of providing medical care for these patients. The additional cost is primarily due to personnel expenses and an increase in the volume of specialty care. Patients see specialists more often due to improved access to care and lower transportation costs. Providers bear the cost while patients and employers enjoy substantial savings.


Mechanical strain opens connexin 43 hemichannels in osteocytes: a novel mechanism for the release of prostaglandin.
Mechanosensing bone osteocytes express large amounts of connexin (Cx)43, the component of gap junctions; yet, gap junctions are only active at the small tips of their dendritic processes, suggesting another function for Cx43. Both primary osteocytes and the osteocyte-like MLO-Y4 cells respond to fluid flow shear stress by releasing intracellular prostaglandin E2 (PGE2). Cells plated at lower densities release more PGE2 than cells plated at higher densities. This response was significantly reduced by antisense to Cx43 and by the gap junction and hemichannel inhibitors 18 beta-glycyrrhetinic acid and carbenoxolone, even in cells without physical contact, suggesting the involvement of Cx43-hemichannels. Inhibitors of other channels, such as the purinergic receptor P2X7 and the prostaglandin transporter PGT, had no effect on PGE2 release. Cell surface biotinylation analysis showed that surface expression of Cx43 was increased by shear stress. Together, these results suggest fluid flow shear stress induces the translocation of Cx43 to the membrane surface and that unapposed hemichannels formed by Cx43 serve as a novel portal for the release of PGE2 in response to mechanical strain.


Barriers to medical care for homeless families compared with housed poor families.
To evaluate health access and health services utilization of homeless families we selected a systematic sample of 194 homeless families from 10 shelters in Los Angeles and 196 housed poor families from the same geographic regions of Los Angeles selected from welfare offices. Both samples relied primarily on Medicaid for their health insurance (61% and 96%). However, more homeless families than housed poor families were currently uninsured (26% vs 2%), had lost health insurance over the past year (50% vs 21%), and had spent a greater percentage of the past year uncovered by health insurance (22% vs 6%). Homeless families were much less likely to report a regular provider for preventive care (81% vs 94%) or for sick care (72% vs 95%). Moreover, of those reporting a regular provider, homeless families were more likely than housed poor families to use emergency departments or clinics rather than private offices for both preventive care (35% vs 15%) and sick care (37% vs 26%). Barriers to health care more frequently prevented homeless families from obtaining care (38% vs 28%). These findings suggest that homeless families have greater problems of access to health care than other poor families, related to lack of insurance, lack of a regular primary care provider, and other barriers. Programs to address these barriers for homeless families are presented.


Dorsal root ganglion stimulation of injured sensory neurons in rats rapidly eliminates their spontaneous activity and relieves spontaneous pain.
Dorsal root ganglion field stimulation (GFS) relieves evoked and spontaneous neuropathic pain by use-dependent blockade of impulse trains through the sensory neuron T-junction, which becomes complete within less than 1 minute for C-type units, also with partial blockade of Aδ units. We used this tool in the spinal nerve ligation (SNL) rat model to selectively block sensory neuron spontaneous activity (SA) of axotomized neurons at the fifth lumbar (L5) level vs blockade of units at the L4 level that remain uninjured but exposed to inflammation. In vivo dorsal root single-unit recordings after SNL showed increased SA in L5 units but not L4 units. Ganglion field stimulation blocked this SA. Ganglion field stimulation delivered at the L5 dorsal root ganglion blocked mechanical hyperalgesia behavior, mechanical allodynia, and ongoing spontaneous pain indicated by conditioned place preference, whereas GFS at L4 blocked evoked pain behavior but not spontaneous pain. In vivo single-unit recordings of spinal cord dorsal horn (DH) wide-dynamic-range neurons showed elevated SA after SNL, which was reduced by GFS at the L5 level but not by GFS at the L4 level. In addition, L5 GFS, but not L4 GFS, increased mechanical threshold of DH units during cutaneous mechanical stimulation, while L5 GFS exceeded L4 GFS in reducing evoked firing rates. Our results indicate that SA in injured neurons supports increased firing of DH wide-dynamic-range neurons, contributing to hyperalgesia, allodynia, and ongoing pain. Ganglion field stimulation analgesic effects after nerve injury are at least partly attributable to blocking propagation of this SA.


Balanced Chromosomal Rearrangements Associated with Hypoprolificacy in Australian Boars (Sus scrofa domesticus).
Balanced chromosomal rearrangements, mainly reciprocal translocations, are considered to be the causative agent of several clinical conditions in farmed pigs, resulting in hypoprolificacy and economic losses. Literature suggests that reciprocal translocations are heritable and can occur de novo. The prevalence rate of these balanced structural rearrangements of chromosomes differs from country to country and varies between 0.5% and 3.3%. The Australian pig population is descendent of a small founder population and has since been a closed genetic group since the 1980s. Hence, any incident of reciprocal translocation along with the pedigree of boars that contribute sperm for artificial insemination has the potential to have an economic consequence. To date, there has been no published account for screening of reciprocal translocation associated with hypoprolificacy in the Australian pig population. In this study, we performed standard and molecular cytogenetic analyses to identify evidence of chromosome rearrangements and their association with hypoprolificacy in a representative 94 boar samples from a commercial nucleus herd. We identified three novel rearrangements between chromosomes 5 and 14, between chromosomes 9 and 10, and between chromosomes 10 and 12. In addition, we also detected a reciprocal translocation between chromosomes 3 and 16 that has previously been detected in pig herds in France. The prevalence rate was 6.38% within the samples used in this study. All four rearrangements were found to have an association with hypoprolificacy. Further study and routine monitoring will be necessary to identify any further rearrangements that will allow breeders to prevent the propagation of reciprocal translocations from generation to generation within the Australian pig population.


Pancreatic Tumor Microenvironment Factor Promotes Cancer Stemness via SPP1-CD44 Axis.
Tumor-microenvironment factors and cancer stem cells (CSCs) play a critical role in the aggressiveness of pancreatic cancer (PC). However, the degree to which tumor-microenvironment factors promote stemness remains unexplored. Here, we examined whether cancer-associated fibroblasts (CAFs) promote CSC features in PC. PC cells were treated long-term (30, 60, and 90 days) with conditioned media (CM)-derived from normal human fibroblasts (NFs) and CAFs. The stemness features of tumorsphere formation and stemness populations, along with CSCs markers, were analyzed using 2-dimensional and 3-dimensional sodium alginate bead-based co-culture models. Immunohistochemistry and immunofluorescence staining were performed for CSCs and fibroblast markers in autochthonous KrasG12D/+; Trp53R172H/+; Pdx1-Cre mice and human pancreatic tumors. Polymerase chain reaction array and gene knockdown were performed to identify the mechanism of stemness enrichment. Long-term treatment of PC cells with CAF-CM enriched stemness, as indicated by significantly higher CD44+, ALDH+, and AF+ populations in PC cells. Increased tumorsphere formation and elevated CSC, self-renewal, and drug-resistance markers in CAF-CM-treated PC cells were observed. In addition, CAFs co-cultured with PC cells in the 3-dimensional model showed a substantial increase in stemness features. CD44 and α-smooth muscle actin were positively correlated and their expressions progressively increased from the early to late stages of KrasG12D/+; Trp53R172H/+; Pdx1-Cre mouse and human pancreatic tumors. Osteopontin/secreted phosphoprotein 1 was identified as the top differentially overexpressed gene in CAF-CM-treated PC cells and knockdown of osteopontin/secreted phosphoprotein 1 significantly reduced stemness characteristics in CAF-CM-treated PC cells. Our data uncovered novel insight into the interplay between CAF and enrichment of stemness population through the osteopontin/secreted phosphoprotein 1-CD44 axis in PC.


An antibody-based molecular switch for continuous small-molecule biosensing.
We present a generalizable approach for designing biosensors that can continuously detect small-molecule biomarkers in real time and without sample preparation. This is achieved by converting existing antibodies into target-responsive "antibody-switches" that enable continuous optical biosensing. To engineer these switches, antibodies are linked to a molecular competitor through a DNA scaffold, such that competitive target binding induces scaffold switching and fluorescent signaling of changing target concentrations. As a demonstration, we designed antibody-switches that achieve rapid, sample preparation-free sensing of digoxigenin and cortisol in undiluted plasma. We showed that, by substituting the molecular competitor, we can further modulate the sensitivity of our cortisol switch to achieve detection at concentrations spanning 3.3 nanomolar to 3.3 millimolar. Last, we integrated this switch with a fiber optic sensor to achieve continuous sensing of cortisol in a buffer and blood with <5-min time resolution. We believe that this modular sensor design can enable continuous biosensor development for many biomarkers.


[Some problems of the study and representation of Siberian flora biodiversity in connection with its conservation].
The present knowledge of flora of Siberia is quite insufficient, which is a considerable obstacle to the detection of its biodiversity for conserving the gene pool. Planning conservation measures should be focused not only on species, but also on intraspecific taxa and their phylogenetic uniqueness. In the absence of genetic data, available morphological and geographical methods should be used, so that, when it is impossible to establish the actual origin and relationship of taxa, the existing morphological diverstity is at least represented, as far as it is known to be based on genetic diversity. Phenetic maps can be of much use in the study of intraspecific morphological diversity. The estimation of geographic variability and morphological diversity, as well as the evaluation of territories, can be based on such maps. To represent adequately the biodiversity existing within poorly studied, presumably hybrid plant groups, until actual origin and relationship are known, they should probably be forcedly and provisionally considered as a special type of hybrid complexes, representing the unclear present day taxonomic situation. Such complexes could include populations and individuals with morphological characters of two or more different species, until the systematic position of such populations and individuals is further explored. Until the actual taxonomic status and relationship of the components are established, they could be regarded as subspecies permitted by the Code, or as certain recorded morphological deviations from the type, without assigning any taxonomic status to them--depending on the available data on variability and distribution. In the future, the resulting provisional information on morphological diversity would help to concentrate the efforts of biologists, in possession of the newest methods, on the most important objects, and serve as the scientific base for effective measures aimed at the conservation and management of the vast gene pool of the Siberian flora.


[The right to health? Medical theoretical discussion of the Europe-China cultural comparison].
This paper suggests that a "right to health" is not a result of recent developments in health care politics. Rather, a "right to health" lies at the very conceptual foundation of a new type of medicine that emerged in ancient Greece and China in the second half of the first millennium BCE. Concomitant with the acceptance of laws as an essential precondition for social stability in the polis democracy and in the ever growing political entities at the end of the Zhou era, a notion of laws of nature emerged that was soon extended to an interpretation of the healthy and diseased states of the human organism. In view of the Chinese situation available sources indicate, however, that in the same way as not all intellectuals believed in the complex imperial structure as the best possible social organisation, only a fraction of Chinese medical theoreticians supported a medicine based on the notions of systematic correspondence. Hence the conceptualization of health care in China over the past two millennia was marked by a dichotomy that can be seen, albeit less clearly, in the history of European medicine as well. One style of thought saw a limited number of diseased states of a human organism as the cause of an unlimited number of individual pathological conditions. Disease was considered a deviation from norms well-defined by the yinyang and Five Agents theories. Persons abiding by the laws of yinyang and Five Agents were promised a right to health. The alternative style of thought focussed on individual ailment, and stimulated its followers to accumulate ever more substances, combined in ever more recipes, to be prepared for innumerable possibilities of illness. This approach failed to acknowledge the value of norms and laws of nature, and was based on a notion of an inevitability of illness. The present paper discusses the ideological background and historical data of these approaches, as well as the different therapeutic strategies, i.e., acupuncture and pharmaceutical prescriptions, that were associated with them.


Antagonist of interferon-inducible protein 10/CXCL10 ameliorates the progression of autoimmune sialadenitis in MRL/lpr mice.
Mononuclear cell infiltration of the salivary glands is a major feature of Sjögren's syndrome (SS) and its animal model. Local generation of chemokines and the presence of chemokine receptors on the infiltrating cells may be involved in this process. We undertook the present study to investigate the expression of chemokines during the development of autoimmune sialadenitis in MRL/lpr mice and the therapeutic effect of chemokine antagonists on sialadenitis. NH2-terminal-truncated interferon-inducible protein 10 (IP-10)/CXCL10 analogs were transfected into a nonmetastatic fibroblastoid cell line, MRL/N-1, and injected subcutaneously into MRL/lpr mice, and the effects on sialadenitis were monitored. IP-10 analogs truncated by 5 or more amino acid residues from the N-terminal failed to induce chemotaxis and calcium influx by CXCR3-expressing cells. Of these, the most potent antagonist (AT) (IP-10-AT) was a molecule with methionine added after removal of the 5 N-terminal amino acid residues. Significantly increased expression of the Th1-associated chemokines IP-10, monokine induced by interferon-gamma/CXCL9, and interferon-inducible T cell chemoattractant/CXCL11 was induced in the ductal epithelium by interferon-gamma produced in the salivary glands, whereas expression of the Th2-associated chemokines thymus and activation-regulated chemokine (TARC)/CCL17 and monocyte-derived chemokine/CCL22 was almost undetectable during sialadenitis. Inoculation of IP-10-AT into MRL/lpr mice during the early stage of sialadenitis significantly reduced periductal mononuclear cell infiltration and parenchymal destruction compared with these features in control and TARC-AT-bearing mice. This was due to a significant reduction in infiltration of CXCR3+ T cells, predominantly Th1 cells, resulting in decreased interferon-gamma production. We prepared a novel potent IP-10 antagonist and demonstrated its ability to ameliorate the progression of autoimmune sialadenitis. This agent may provide a new therapeutic approach to SS.


Inhibition of Glut1 by WZB117 sensitizes radioresistant breast cancer cells to irradiation.
Breast cancer is the most common type of cancer with high incidence in women. Currently, identifying new therapies that selectively inhibit tumor growth without damaging normal tissue are a major challenge of cancer research. One of the features of cancer cells is that they do not consume more oxygen even under normal oxygen circumstances but prefer to aerobic glycolysis through the enhanced catabolism of glucose and glutamine. In this study, we investigate the mechanisms of the radioresistance in breast cancer cells. Human breast cancer cells MDA-MB-231 and MCF-7 were treated with radiation alone, Glut1 inhibitor alone or the combination of both to evaluate cell glucose metabolism and apoptosis. By the establishment of radioresistant cell line, we investigate the mechanisms of the combined treatments of radiation with Glut1 inhibitor in the radioresistant cells. The glucose metabolism and the expression of Glut1 are significantly stimulated by radiotherapy. We report the radioresistant breast cancer cells exhibit upregulated Glut1 expression and glucose metabolism. In addition, we observed overexpression of Glut1 renders breast cancer cells resistant to radiation and knocking down of Glut1 sensitizes breast cancer cells to radiation. We treated breast cancer cells with radiation and WZB117 which inhibits Glut1 expression and glucose metabolism and found the combination of WZB117 and radiation exhibits synergistically inhibitory effects on breast cancer cells. Finally, we demonstrate the inhibition of Glut1 re-sensitizes the radioresistant cancer cells to radiation. This study reveals the roles of Glut1 in the radiosensitivity of human breast cancer. It will provide new mechanisms and strategies for the sensitization of cancer cells to radiotherapy through regulation of glucose metabolism.


Severe Maternal Morbidity and Risk of Mortality Beyond the Postpartum Period.
To examine long-term risks of mortality after a pregnancy complicated by severe maternal morbidity. We analyzed a longitudinal cohort of 1,229,306 women who delivered in the province of Quebec, Canada from 1989 through 2016. Severe maternal morbidity included conditions such as cerebrovascular accidents, acute renal failure, severe preeclampsia, and other life-threatening complications. The outcome was in-hospital mortality after the last pregnancy, categorized as postpartum (42 days or fewer after delivery) and long-term (43 days to 29 years after delivery). We estimated hazard ratios (HRs) ofr mortality with 95% CI for severe maternal morbidity compared with no severe morbidity, using Cox regression models adjusted for maternal characteristics. Severe maternal morbidity occurred in 2.9% of women. The mortality rate associated with severe maternal morbidity was 0.86 per 1,000 person-years compared with 0.41 per 1,000 person-years for no morbidity. Compared with no morbidity, severe maternal morbidity was associated with two times the rate of death any time after delivery (95% CI 1.81-2.20). Severe cardiac complications (HR 7.00, 85% CI 4.94-9.91), acute renal failure (HR 4.35, 95% CI 2.66-7.10), and cerebrovascular accidents (HR 4.03, 95% CI 2.17-7.48) were the leading morbidities associated with mortality after 42 days. Women who experience severe maternal morbidity have an accelerated risk of mortality beyond the postpartum period compared with women who do not experience severe morbidity. More intensive clinical follow-up may be merited for women with serious pregnancy complications.


Making sense of GWAS: using epigenomics and genome engineering to understand the functional relevance of SNPs in non-coding regions of the human genome.
Considerable progress towards an understanding of complex diseases has been made in recent years due to the development of high-throughput genotyping technologies. Using microarrays that contain millions of single-nucleotide polymorphisms (SNPs), Genome Wide Association Studies (GWASs) have identified SNPs that are associated with many complex diseases or traits. For example, as of February 2015, 2111 association studies have identified 15,396 SNPs for various diseases and traits, with the number of identified SNP-disease/trait associations increasing rapidly in recent years. However, it has been difficult for researchers to understand disease risk from GWAS results. This is because most GWAS-identified SNPs are located in non-coding regions of the genome. It is important to consider that the GWAS-identified SNPs serve only as representatives for all SNPs in the same haplotype block, and it is equally likely that other SNPs in high linkage disequilibrium (LD) with the array-identified SNPs are causal for the disease. Because it was hoped that disease-associated coding variants would be identified if the true casual SNPs were known, investigators have expanded their analyses using LD calculation and fine-mapping. However, such analyses also identified risk-associated SNPs located in non-coding regions. Thus, the GWAS field has been left with the conundrum as to how a single-nucleotide change in a non-coding region could confer increased risk for a specific disease. One possible answer to this puzzle is that the variant SNPs cause changes in gene expression levels rather than causing changes in protein function. This review provides a description of (1) advances in genomic and epigenomic approaches that incorporate functional annotation of regulatory elements to prioritize the disease risk-associated SNPs that are located in non-coding regions of the genome for follow-up studies, (2) various computational tools that aid in identifying gene expression changes caused by the non-coding disease-associated SNPs, and (3) experimental approaches to identify target genes of, and study the biological phenotypes conferred by, non-coding disease-associated SNPs.


Non-linear effects of transcranial direct current stimulation as a function of individual baseline performance: Evidence from biparietal tDCS influence on lateralized attention bias.
Transcranial direct current stimulation (tDCS) is a well-established technique for non-invasive brain stimulation (NIBS). However, the technique suffers from a high variability in outcome, some of which is likely explained by the state of the brain at tDCS-delivery but for which explanatory, mechanistic models are lacking. Here, we tested the effects of bi-parietal tDCS on perceptual line bisection as a function of tDCS current strength (1 mA vs 2 mA) and individual baseline discrimination sensitivity (a measure associated with intrinsic uncertainty/signal-to-noise balance). Our main findings were threefold. We replicated a previous finding (Giglia et al., 2011) of a rightward shift in subjective midpoint after Left anode/Right cathode tDCS over parietal cortex (sham-controlled). We found this effect to be weak over our entire sample (n = 38), but to be substantial in a subset of participants when they were split according to tDCS-intensity and baseline performance. This was due to a complex, nonlinear interaction between these two factors. Our data lend further support to the notion of state-dependency in NIBS which suggests outcome to depend on the endogenous balance between task-informative 'signal' and task-uninformative 'noise' at baseline. The results highlight the strong influence of individual differences and variations in experimental parameters on tDCS outcome, and the importance of fostering knowledge on the factors influencing tDCS outcome across cognitive domains.


Quantitative Determination of the Glucosinolates Sinigrin and Progoitrin by Specific Antibody ELISA Assays in Brussels Sprouts.
Glucosinolates from Brussels sprout samples were extracted using an effective concentration of 2% phosphoric acid followed by a neutralization step and heat treatment for removal of inactivated protein. The (potentially) bitter glucosinolates sinigrin and progoitrin were found to be stable during this new extraction protocol. Antisera, as raised against hemisuccinate-linked glucosinolate conjugates, were very specific in sandwich ELISA assays for their corresponding substrates. The ELISA assays showed maximally 7.4% cross-reactivity to other aliphatic glucosinolates and were log-linear from the nM to µM range. In comparison to the standard HPLC method, the sinigrin and progoitrin ELISA respectively slightly and considerably overestimate the actual content of these glucosinolates. The progoitrin content of samples as determined either with the ELISA assay or by HPLC, however, is highly correlated (r(2) = 0.92, n = 12, p < 0.01), suggesting that the former assay is also applicable for the screening of the progoitrin content in Brussels sprout samples.


Tn4201, a beta-lactamase transposon in Staphylococcus aureus.
We report the preliminary characterization of a 6.7-kilobase transposon, Tn4201, encoding resistance to penicillin associated with the conjugative plasmid pCRG1600 in Staphylococcus aureus. Tn4201 is capable of inverting in orientation (frequently observed in derivatives of pCRG1600) and is expressed equally well in either orientation. The element is also capable of movement to alternative plasmid and chromosomal sites. Tn4201 exhibits rec-independent transposition in an apparent site-specific manner and may play an important role in the resistance of staphylococci to beta-lactam compounds.


Role of individual ionic current systems in the SA node hypothesized by a model study.
This paper discusses the development of a cardiac sinoatrial (SA) node pacemaker model. The model successfully reconstructs the experimental action potentials at various concentrations of external Ca2+ and K+. Increasing the amplitude of L-type Ca2+ current (I(CaL)) prolongs the duration of the action potential and thereby slightly decreases the spontaneous rate. On the other hand, a negative voltage shift of I(CaL) gating by a few mV markedly increases the spontaneous rate. When the amplitude of sustained inward current (I(st)) is increased, the spontaneous rate is increased irrespective of the I(CaL) amplitude. Increasing [Ca2+](o) shortens the action potential and increases the spontaneous rate. When the spontaneous activity is stopped by decreasing I(CaL) amplitude, the resting potential is nearly constant (-35 mV) over 1-15 mM [K+](o) as observed in the experiment. This is because the conductance of the inward background non-selective cation current balances with the outward [K+](o)-dependent K+ conductance. The unique role of individual voltage- and time-dependent ion channels is clearly demonstrated and distinguished from that of the background current by calculating an instantaneous zero current potential ("lead potential") during the course of the spontaneous activity.


Trans-regulation of myogenin promoter/enhancer activity by c-ski during skeletal-muscle differentiation: the C-terminus of the c-Ski protein is essential for transcriptional regulatory activity in myotubes.
c-ski gene product is a nuclear protein with myogenesis-promoting and transforming activities. We have analysed the effects of c-ski transfection on the promoter/enhancer activity of the upstream region of the myogenin gene during in vitro myogenesis using CAT reporter assay. When co-transfected with c-ski into myogenic C2C12 cells, promoter/enhancer activity was efficiently suppressed in proliferating cells, but the myogenesis-induced increase in activity was potentiated approximately ten times more (150-fold in the ski-transfected cells) than the ordinary increase (12-fold in the mock) 48 h after induction of differentiation. In non-myogenic 10T1/2 cells, c-ski transfection caused persistent suppression of promoter/enhancer activity in both proliferating and growth-arrested (i.e. myogenesis-inducing) conditions. Thus the ski-dependent potentiation of myogenin gene transcriptional activity appears to be specific for myogenesis. The C-terminal region (amino acids 595-663) of the c-Ski protein was essential for the potentiating activity in myotubes. Other members of the ski-gene family, snoN and snoA, were ineffective in transactivation, possibly because of the defect in the corresponding C-terminal region. c-Ski protein underwent a mobility shift on SDS/PAGE after in vitro myogenesis which may explain the conversion of the activity from suppressive in myoblasts to potentiating in myotubes. Deletion analysis of the upstream region of the myogenin gene revealed that a responsive element to c-ski in myotubes is located at a distinct site upstream of the basal promoter/enhancer region.


[Clinical diagnosis and prognosis of the course of congenital heart defects with pulmonary stenosis].
An analysis of 433 observations is presented (164 cases of isolated pulmonary stenosis, 132 cases of its combination with atrial septal defect, and 137--with ventricular septal defect), the patients being 1 year 1 month to 36 years old, and the form of their heart disease being verified during surgery on a "dry" heart. The mentioned diseases were classified into 3 groups according to the tactical importance of the pulmonary stenosis. Haemodynamic studies in patients with pulmonary stenosis and an intact ventricular septum have demonstrated that with age right-ventricular hypertension progresses the faster the greater the pulmonary artery valve is stenosed. A combination of a valvular stenosis with a large ventricular communication is accompanied by a levelling of the pressure in both ventricles, its absolute figures being somewhat higher in patients over 16 years of age.


Activation of β- and α2-adrenergic receptors stimulate tubulin polymerization and promote the association of Gβγ with microtubules in cultured NIH3T3 cells.
Microtubules (MTs) constitute a crucial part of the cytoskeleton and are essential for cell division and differentiation, cell motility, intracellular transport, and cell morphology. Precise regulation of MT assembly and dynamics is essential for the performance of these functions. Although much progress has been made in identifying and characterizing the cellular factors that regulate MT assembly and dynamics, signaling events in this process is not well understood. Gβγ, an important component of the G protein-coupled receptor (GPCR) signaling pathway, has been shown to promote MT assembly in vitro and in cultured NIH3T3 and PC12 cells. Using the MT depolymerizing agent nocodazole, it has been demonstrated that the association of Gβγ with polymerized tubulin is critical for MT assembly. More recently, Gβγ has been shown to play a key role in NGF-induced neuronal differentiation of PC12 cells through its interaction with tubulin/MTs and modulation of MT assembly. Although NGF is known to exert its effect through tyrosine kinase receptor TrkA, the result suggests a possible involvement of GPCRs in this process. The present study was undertaken to determine whether agonist activation of GPCR utilizes Gβγ to promote MT assembly. We used isoproterenol and UK 14,304, agonists for two different GPCRs (β- and α2-adrenergic receptors, respectively) known to activate Gs and Gi respectively, with an opposing effect on production of cAMP. The results demonstrate that the agonist activation of β- and α2-adrenergic receptors promotes the association of Gβγ with MTs and stimulates MT assembly in NIH3T3 cells. Interestingly, the effects of these two agonists were more prominent when the cellular level of MT assembly was low (30% or less). In contrast to MT assembly, actin polymerization was not affected by isoproterenol or UK 14, 304 indicating that the effects of these agonists are limited to MTs. Thus, it appears that, upon cellular demand, GPCRs may utilize Gβγ to promote MT assembly. Stimulation of MT assembly appears to be a novel function of G protein-mediated signaling.


Monitoring lipase/esterase activity by stopped flow in a sequential injection analysis system using p-nitrophenyl butyrate.
Lipases and esterases are biocatalysts used at the laboratory and industrial level. To obtain the maximum yield in a bioprocess, it is important to measure key variables, such as enzymatic activity. The conventional method for monitoring hydrolytic activity is to take out a sample from the bioreactor to be analyzed off-line at the laboratory. The disadvantage of this approach is the long time required to recover the information from the process, hindering the possibility to develop control systems. New strategies to monitor lipase/esterase activity are necessary. In this context and in the first approach, we proposed a lab-made sequential injection analysis system to analyze off-line samples from shake flasks. Lipase/esterase activity was determined using p-nitrophenyl butyrate as the substrate. The sequential injection analysis allowed us to measure the hydrolytic activity from a sample without dilution in a linear range from 0.05-1.60 U/mL, with the capability to reach sample dilutions up to 1000 times, a sampling frequency of five samples/h, with a kinetic reaction of 5 min and a relative standard deviation of 8.75%. The results are promising to monitor lipase/esterase activity in real time, in which optimization and control strategies can be designed.


Inferior Wall Myocardial Infarction in Severe COVID-19 Infection: A Case Report.
BACKGROUND The novel coronavirus disease (COVID-19) has been declared a pandemic. With the ever-increasing number of COVID-19 patients, it is imperative to explore the factors related to the disease to aid patient management until a definitive vaccine is ready, as the disease is not limited to the respiratory system alone. COVID-19 has been associated with various cardiovascular complications including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism. The infection is severe in patients with pre-existing cardiovascular disease, and a systemic inflammatory response due to a cytokine storm in severe COVID-19 cases can lead to acute myocardial infarction. CASE REPORT We present the case of a 56-year-old man with cardiovascular risk factors including coronary artery disease, hypertension, ischemic cardiomyopathy, and hyperlipidemia, who had COVID-19-induced pneumonia complicated with acute respiratory distress syndrome. He subsequently developed myocardial infarction during his hospitalization at our facility. He had a significant contact history for COVID-19. He was managed with emergent cardiac revascularization after COVID-19 was confirmed by real-time reverse transcription-polymerase chain reaction testing from a nasopharyngeal swab as per hospital policy for admitted patients. Apart from dual antiplatelet therapy, tocilizumab therapy was initiated due to the high interleukin-6 levels. His hospitalization was complicated by hemodialysis and failed extubation and intubation, resulting in a tracheostomy. Upon improvement, he was discharged to a long-term facility with a plan for outpatient follow-up. CONCLUSIONS In high-risk patients with COVID-19-induced pneumonia and cardiovascular risk factors, a severe systemic inflammatory response can lead to atherosclerotic plaque rupture, which can manifest as acute coronary syndrome.


Differences in clinicopathologic variables between Borrelia C6 antigen seroreactive and Borrelia C6 seronegative glomerulopathy in dogs.
Rapidly progressive glomerulonephritis has been described in dogs that seroreact to Borrelia burgdorferi, but no studies have compared clinicopathologic differences in Lyme-seroreactive dogs with protein-losing nephropathy (PLN) versus dogs with Borrelia-seronegative PLN. Dogs with Borrelia C6 antigen-seroreactive PLN have distinct clinicopathologic findings when compared to dogs with Borrelia seronegative PLN. Forty dogs with PLN and Borrelia C6 antigen seroreactivity and 78 C6-seronegative temporally matched dogs with PLN. Retrospective prevalence case-control study. Clinical information was retrieved from records of dogs examined at the University of California, Davis, Veterinary Medical Teaching Hospital. Histopathologic findings in renal tissue procured by biopsy or necropsy of dogs with PLN were reviewed. Retrievers and retriever mixes were overrepresented in seroreactive dogs (P < .001). Seroreactive dogs were more likely to have thrombocytopenia (P < .001), azotemia (P = .002), hyperphosphatemia (P < .001), anemia (P < .001), and neutrophilia (P = .003). Hematuria, glucosuria, and pyuria despite negative urine culture were more likely in seroreactive dogs (all P ≤ .002). Histopathologic findings were consistent with immune-complex glomerulonephritis in 16 of 16 case dogs and 7 of 23 control dogs (P = 006). Prevalence of polyarthritis was not different between groups (P = .17). C6 seroreactivity in dogs with PLN is associated with a clinicopathologically distinct syndrome when compared with other types of PLN. Early recognition of this syndrome has the potential to improve outcomes through specific aggressive and early treatment.


Refined magic-angle coil spinning resonator for nanoliter NMR spectroscopy: enhanced spectral resolution.
The magic-angle coil spinning (MACS) resonator allows a simple approach for nanoliter nuclear magnetic resonance (NMR) detections with enhanced sensitivity and high-resolution under sample magic-angle spinning (MAS). Currently, the spectral resolution acquired with MACS is not efficient for detailed characterization of semisolids like biopsies, where subhertz resolution is necessary. Here, we describe the two sources of line broadening from MACS, sample temperature gradient and anisotropic magnetic susceptibility, and present a refined high-resolution magic-angle coil spinning (HR-MACS) resonator that improves the spectral resolution. We demonstrate with the high quality HR-MACS NMR spectra of micronematodes and tissue biopsy, and illustrate its potential for NMR-based metabolomics of nanoliter tissue samples.


A meta-analysis of the effects of exercise training on left ventricular remodeling following myocardial infarction: start early and go longer for greatest exercise benefits on remodeling.
The effects of variations in exercise training on left ventricular (LV) remodeling in patients shortly after myocardial infarction (MI) are important but poorly understood. Systematic review incorporating meta-analysis using meta-regression. Studies were identified via systematic searches of: OVID MEDLINE (1950 to 2009), Cochrane Central Register of Controlled Trials (1991 to 2009), AMED (1985 to 2009), EMBASE (1988 to 2009), PUBMED (1966 to 2009), SPORT DISCUS (1975 to 2009), SCOPUS (1950 to 2009) and WEB OF SCIENCE (1950 to 2009) using the medical subject headings: myocardial infarction, post myocardial infarction, post infarction, heart attack, ventricular remodeling, ventricular volumes, ejection fraction, left ventricular function, exercise, exercise therapy, kinesiotherapy, exercise training. Reference lists of all identified studies were also manually searched for further relevant studies. Studies selected were randomized controlled trials of exercise training interventions reporting ejection fraction (EF) and/or ventricular volumes in patients following recent MI (≤ 3 months) post-MI patients involving control groups. Studies were excluded if they were not randomized, did not have a 'usual-care' control (involving no exercise), evaluated a non-exercise intervention, or did not involve human subjects. Non-English studies were also excluded. After screening of 1029 trials, trials were identified that reported EF (12 trials, n = 647), End Systolic Volumes (ESV) (9 trials, n = 475) and End Diastolic Volumes (EDV) (10 trials, n = 512). Meta-regression identified that changes in EF effect size difference decreased as the time between MI and initiation of the exercise program lengthened, and increased as the duration of the program increased (Q = 25.48, df = 2, p < 0.01, R2 = 0.76). Greater reductions in ESV and EDV (as indicated by effect size decreases) occurred with earlier initiation of exercise training and with longer training durations (ESV: Q = 23.89, df = 2, p < 0.05, R2 = 0.79; EDV: Q = 27.42, df = 2, p < 0.01, R2 = 0.83). Differences remained following sensitivity analysis. Each week that exercise was delayed required an additional month of training to achieve the same level of benefit on LV remodeling. Exercise training has beneficial effects on LV remodeling in clinically stable post-MI patients with greatest benefits occurring when training starts earlier following MI (from one week) and lasts longer than 3 months.


Strategy for Nasal Reconstruction in Atypical Facial Clefts.
It is difficult to put forward a strategy for the treatment of nasal clefts due to the rarity and diversity of anatomical aberrations of these cases contrary to the common nasal affection in cleft lip and palate patients, which differ in severity rather than differing in the morbid anatomy. This simple strategy for correction of these nasal clefts will hopefully help surgeons to achieve better results. In the mean time I intended to describe the morbid anatomy of these cases by choosing examples of each morbid anatomy.


[Density of distribution of nerve cells in the nuclei of the cat's trigeminal complex].
The results of calculation of nerve cells density in each of the four nuclei composing the nuclear complex of the trigeminal nerve are presented. The quantitative data were processed by non-parametrical statistical method. It was established that the whole rostral half of the trigeminal complex of the nuclei had greater density of cell distribution, than the caudal one. Especially pronounced was the difference in the density of disposition of cells between the nuclei occupying the extreme-caudal and rostral position in the general complex of nuclei. Comparison of the obtained facts with the literature data and the author's previous investigations has shown that the revealed distinctions are in agreement with pecularities of the structural functional organizations of the trigeminal complex, according to which the structure is changed from the caudal to rostral end to be more isolated from the reticular formation, and the function is changed to conduct more delicate differentiated stimuli.


Ultrasound-Enhanced Chemiluminescence for Bioimaging.
Tissue imaging has emerged as an important aspect of theragnosis. It is essential not only to evaluate the degree of the disease and thus provide appropriate treatments, but also to monitor the delivery of administered drugs and the subsequent recovery of target tissues. Several techniques including magnetic resonance imaging (MRI), computational tomography (CT), acoustic tomography (AT), biofluorescence (BF) and chemiluminescence (CL), have been developed to reconstruct three-dimensional images of tissues. While imaging has been achieved with adequate spatial resolution for shallow depths, challenges still remain for imaging deep tissues. Energy loss is usually observed when using a magnetic field or traditional ultrasound (US), which leads to a need for more powerful energy input. This may subsequently result in tissue damage. CT requires exposure to radiation and a high dose of contrast agent to be administered for imaging. The BF technique, meanwhile, is affected by strong scattering of light and autofluorescence of tissues. The CL is a more selective and sensitive method as stable luminophores are produced from physiochemical reactions, e.g. with reactive oxygen species. Development of near infrared-emitting luminophores also bring potential for application of CL in deep tissues and whole animal studies. However, traditional CL imaging requires an enhancer to increase the intensity of low-level light emissions, while reducing the scattering of emitted light through turbid tissue environment. There has been interest in the use of focused ultrasound (FUS), which can allow acoustic waves to propagate within tissues and modulate chemiluminescence signals. While light scattering is decreased, the spatial resolution is increased with the assistance of US. In this review, chemiluminescence detection in deep tissues with assistance of FUS will be highlighted to discuss its potential in deep tissue imaging.


Intravascular hemolysis and renal insufficiency after bone marrow transplantation.
Renal disease has not been considered a major late complication of bone marrow transplantation. Of 31 evaluable pediatric patients undergoing allogeneic or autologous bone marrow transplantation for neuroblastoma or acute lymphoblastic leukemia, 14 developed a hemolytic anemia, microscopic hematuria, and renal insufficiency at a median of 5 months (range, 3 to 7 months) posttransplant. Renal biopsies were performed in two patients at the onset of kidney disease and showed mesangiolysis with intraglomerular capillary aneurysm formation, mesangial proliferation, and focal thickening and splitting of the glomerular basement membranes. The clinical presentation, time to onset of renal disease, and biopsy material are consistent with a diagnosis of radiation nephritis, a previously uncommon finding in this patient group. The high incidence of this syndrome in the current report may have been due to the combination of intensive chemotherapy and total-body irradiation in the conditioning regimens.


Regulation of JNK signaling by GSTp.
Studies of low basal Jun N-terminal kinase (JNK) activity in non-stressed cells led us to identify a JNK inhibitor that was purified and identified as glutathione S-transferase Pi (GSTp) and was characterized as a JNK-associated protein. UV irradiation or H2O2 treatment caused GSTp oligomerization and dissociation of the GSTp-JNK complex, indicating that it is the monomeric form of GSTp that elicits JNK inhibition. Addition of purified GSTp to the Jun-JNK complex caused a dose-dependent inhibition of JNK activity. Conversely, immunodepleting GSTp from protein extracts attenuated JNK inhibition. Furthermore, JNK activity was increased in the presence of specific GSTp inhibitors and a GSTp-derived peptide. Forced expression of GSTp decreased MKK4 and JNK phosphorylation which coincided with decreased JNK activity, increased c-Jun ubiquitination and decreased c-Jun-mediated transcription. Co-transfection of MEKK1 and GSTp restored MKK4 phosphorylation but did not affect GSTp inhibition of JNK activity, suggesting that the effect of GSTp on JNK is independent of the MEKK1-MKK4 module. Mouse embryo fibroblasts from GSTp-null mice exhibited a high basal level of JNK activity that could be reduced by forced expression of GSTp cDNA. In demonstrating the relationships between GSTp expression and its association with JNK, our findings provide new insight into the regulation of stress kinases.


Tbx1 is expressed at multiple sites of epithelial-mesenchymal interaction during early development of the facial complex.
TBX1 encodes a T-box-containing transcription factor, which is thought to be a key player in the aetiology of the DiGeorge and Velocardiofacial syndromes (DGS/VCFS). In addition to defects affecting structures derived from the pharyngeal pouches, these patients exhibit varying degrees of facial dysmorphology and cleft palate. We have analysed the expression of murine Tbx1 during early facial development and found transcripts at sites of known epithelial-mesenchymal interaction. In particular, Tbx1 was expressed in epithelium of the early facial processes, including the fronto-nasal, medial and lateral nasal and palatine. Transcripts were also localised to the epithelium of developing tooth germs and hair follicles at several stages during their early development. Together, these expression domains suggest a role for Tbx1 in mediating epithelial-mesenchymal signalling in regions of the developing face, a finding which is consistent with the spectrum of facial deformity encountered amongst subjects affected by DGS/VCFS.


Chimaeric and constitutive DNA fingerprints in the common marmoset (Callithrix jacchus).
Marmosets normally produce dizygotic twins sharing placental blood vessels and exchanging bone marrow cells. Each individual is therefore likely to be a blood chimaera. To date, marmosets had only been DNA fingerprinted using blood samples and probes 33.6 and 33.15, resulting in highly similar fingerprints among litter mates and little variation between other individuals, thereby limiting this method's use for individual identification and parentage testing. In this study, novel probes were applied to detect greater polymorphism and to produce individual-specific DNA fingerprints. As expected, blood DNA profiles of twins and triplets were virtually identical, confirming chimaerism in this tissue and identifying litter mates. Furthermore, these profiles were sufficiently variable to distinguish between sibs from different litters and between all other individuals. To produce individual-specific DNA fingerprints, the use of DNA extracted from tissues poor in leukocytes was essential. The findings demonstrate that, despite extensive blood chimaerism, marmoset colonies can be effectively DNA fingerprinted for indicidual identification, zygosity testing, and relationship studies.


The recognition of facial affect in autistic and schizophrenic subjects and their first-degree relatives.
Autism and schizophrenia are considered to be substantially influenced by genetic factors. The endophenotype of both disorders probably also includes deficits in affect perception. The objective of this study was to examine the capacity to detect facially expressed emotion in autistic and schizophrenic subjects, their parents and siblings. Thirty-five subjects with autism and 102 of their relatives, 21 schizophrenic subjects and 46 relatives from simplex (one child affected) and multiplex (more than one child affected) families, as well as an unaffected control sample consisting of 22 probands completed a 50-item computer-based test to assess the ability to recognize basic emotions. The autistic subjects showed a poorer performance on the facial recognition test than did the schizophrenic and the unaffected individuals. In addition, there was a tendency for subjects from multiplex families with autistic loading to score lower on the test than individuals from simplex families with autistic loading. Schizophrenic subjects and their relatives as well as siblings and parents of autistic subjects did not differ from the sample of unaffected subjects in their ability to judge facial affect. Findings corroborate the assumption that emotion detection deficits are part of the endophenotype of autism. In families with autistic children, the extent of facial recognition deficits probably indexes an elevation in familial burden. It seems unlikely that problems in emotion perception form a consistent part of the endophenotype of schizophrenia or the broader phenotype in relatives of patients with psychosis or autism.


Saturation in milk and meat fats.
Meat and milk products from ruminants (cows, goats, sheep, and beef animals) contribute 35 to 40 percent of the fat in the average American diet. Such fat is highly saturated, containing less than about 4 percent polyunsaturated fatty acids. The unsaturated plant lipids (fats) ordinarily consumed by the ruminant are hydrogenated (saturated) in the rumen. Transport and incorporation of this hydrogenated fat into meat and milk follows. Rumen hydrogenation does not take place until the fat is broken down to free fatty acids, thus establishing the fact that lipolysis is an essential feature of the process. Circumvention of this lipolysis may lead to more-unsaturated meat and milk fat.


Risk factors for the acquisition of imipenem-resistant Acinetobacter baumannii in a burn unit: An appraisal of the effect of colonization pressure.
Imipenem-resistant Acinetobacter baumannii (IRAB) is a major threat for critically ill patients, including those admitted to burn units. Recent studies have suggested that colonization pressure (the proportion of patients or patient-days harbouring the pathogen of interest) is an important driver of the risk for acquisition of multidrug-resistant organisms. With that in mind, we conducted a cohort study, enrolling 208 patients admitted to a burn unit from November 2008 through December 2009. The outcome of interest was the acquisition of IRAB. In addition to the usual risk factors, we assessed the impact of colonization pressure. The number of wound excisions (odds ratio (OR) 12.06, 95% confidence interval (CI) 2.82-51.64) and the number of antimicrobials used (OR 22.82, 95% CI 5.15-101.19) were significant risk factors for the outcome of interest. On the other hand, colonization pressure (measured for whole time of exposure or up to the last 14, 7, or 3 days) was not associated with the risk for IRAB acquisition.


Correlation between Clinical Outcomes and Baseline CT and CT Angiographic Findings in the SWIFT PRIME Trial.
Patient selection for endovascular therapy remains a great challenge in clinic practice. We sought to determine the effect of baseline CT and angiography on outcomes in the Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke (SWIFT PRIME) trial and to identify patients who would benefit from endovascular stroke therapy. The primary end point was a 90-day modified Rankin Scale score of 0-2. Subgroup and classification and regression tree analysis was performed on baseline ASPECTS, site of occlusion, clot length, collateral status, and onset-to-treatment time. Smaller baseline infarct (n = 145) (ASPECTS 8-10) was associated with better outcomes in patients treated with thrombectomy versus IV tPA alone (66% versus 41%; rate ratio, 1.62) compared with patients with larger baseline infarcts (n = 44) (ASPECTS 6-7) (42% versus 21%; rate ratio, 1.98). The benefit of thrombectomy over IV tPA alone did not differ significantly by ASPECTS. Stratification by occlusion location also showed benefit with thrombectomy across all groups. Improved outcomes after thrombectomy occurred in patients with clot lengths of ≥8 mm (71% versus 43%; rate ratio, 1.67). Outcomes stratified by collateral status had a benefit with thrombectomy across all groups: none-fair collaterals (33% versus 0%), good collaterals (58% versus 44%), and excellent collaterals (82% versus 28%). Using a 3-level classification and regression tree analysis, we observed optimal outcomes in patients with favorable baseline ASPECTS, complete/near-complete recanalization (TICI 2b/3), and early treatment (mean mRS, 1.35 versus 3.73), while univariate and multivariate logistic regression showed significantly better results in patients with higher ASPECTS. While benefit was seen with endovascular therapy across multiple subgroups, the greatest response was observed in patients with a small baseline core infarct, excellent collaterals, and early treatment.


Effects of exogenous amines on mammalian cells, with particular reference to membrane flow.
We have reviewed the evidence that amines accumulate in intracellular vesicles of low pH, such as lysosomes and endosomes. There is consequent elevation of intravesicular pH, and inhibition of receptor-ligand dissociation often results from this pH change. We have argued that the capacity for fusion of such vesicles is also reduced by the high pH. We suggest that the variety of effects of amines on membrane flow and macromolecular transport we describe are at least partly due to such reduced fusion (Figs. 1 and 2). We propose that an internal low pH may facilitate heterologous vesicle-vesicle and vesicle-plasma membrane fusion. There is some evidence that clathrin can accelerate phospholipid vesicle fusion in vitro at low pH (Blumenthal et al., 1983) but no direct evidence on the role of intravesicular pH. This idea is consistent not only with the preceding discussion, but also with the fact that the intracellular membrane-bound compartments least involved in fusion events (e.g. mitochondria) are of neutral or alkaline internal pH. Membrane fusion is certainly required for the formation of vesicles at the periphery of the Golgi apparatus, and possibly earlier in the transport and processing of biosynthetic products in the Golgi (Bergeron et al., 1982). Thus the accumulation of amines in the Golgi may be responsible for several effects on the flow of macromolecules along their translocation pathways. The status of the plasma membrane in this view is complex. It might be argued that the pH dictating the fusion step in endocytosis is that of the extracellular fluid, in which case the inhibitory effects of amines on this process are not explained. However, the rapidity of acidification of the newly formed endocytic vesicles allows the possibility that plasma membrane invaginations might temporarily sequester areas which are of lower pH than that of the bulk extracellular fluid even before fusion, since the proton pumping enzyme(s) are probably present on the plasma membrane. Were this the case, then an acid pH could again be a factor determining membrane fusion at the plasma membrane. The inhibition of endocytosis by weak bases thus may again reflect elevation of pH in a sequestered compartment. From the data on the dependence of response on the concentration of amines, we anticipate that most responses involving membrane flow will be biphasic, with inhibitory effects at low amine concentration, giving way to stimulatory ones at higher concentrations. We suggest that the reported dichotomy between different amines in intracellular membrane fusion systems (D'Arcy Hart, 1982) may result from this concentration dependence.(ABSTRACT TRUNCATED AT 400 WORDS)


Competitive Exclusion: The exclusion principle is recast in the context of a generalized scheme for interspecific interactions.
Two species, A and B, interact when their niches alpha and beta intersect in space and time. The composite element AB may be either more, less, or equally effective in regulation. It is suggested that the first condition exists when the overlap between alpha and beta is small; this leads, on a large scale, to complex biocenotic phenomena in which components of a tremendously diversified biota may coexist. The coupling AB is likely, on the other hand, to be antagonistic to optimization of regulation by the whole community; in this case, it is postulated, one of the components (the less effective regulator acting alone) is purged. This is competitive exclusion, and it develops when alpha and beta intersect greatly. Between these extremes of cooperation and competition lies an area of niche intersection in which AB is not much better or worse than A or B alone. This case gives rise to passive coexistence of A and B. These are the extremes; even a cursory consideration of the permutational possibilities for niche intersection gives an immediate concept of the overwhelming variety of possible interspecific interactions and a glimpse of the dangers inherent in overemphasizing a single aspect. It is therefore advocated that the principle of competitive exclusion be regarded as only a small segment of a broad class of interspecific phenomena (9).