Native corrinoids from Clostridium cochlearium are adeninylcobamides: spectroscopic analysis and identification of pseudovitamin B(12) and factor A.
The corrinoids from the obligate anaerobe Clostridium cochlearium were extracted as a mixture of Co(beta)-cyano derivatives. From 50 g of frozen cells, approximately 2 mg (1.5 micromol) of B(12) derivatives was obtained as a crystalline sample. Analysis of the corrinoid sample of C. cochlearium by a combination of high-pressure liquid chromatography and UV-Vis absorbance spectroscopy revealed the presence of three cyano corrinoids in a ratio of about 3:1:1. The spectroscopic data acquired for the sample indicated the main components to be pseudovitamin B(12) (Co(beta)-cyano-7"-adeninylcobamide) (60%) and factor A (Co(beta)-cyano-7"-[2-methyl]adeninylcobamide) (20%). Authentic pseudovitamin B(12) was prepared by guided biosynthesis from cobinamide and adenine. Both pseudovitamin B(12) and its homologue, factor A, were subjected to complete spectroscopic analysis by UV-Vis, circular dichroism, mass spectrometry, and by one- and two-dimensional (1)H, (13)C-, and (15)N nuclear magnetic resonance (NMR) spectroscopy. The third component was indicated by the mass spectra to be an isomer of factor A and is likely (according to NMR) to be 7"-[N(6)-methyl]-adeninylcobamide, a previously unknown corrinoid. C. cochlearium thus biosynthesizes as its native "complete" B(12) cofactors the 7"-adeninylcobamides and two homologous corrinoids, in which the nucleotide base is a methylated adenine.


Prostaglandin generation by human and guinea pig lung tissue: comparison of parenchymal and airway responses.
Anaphylaxis of human lung is accompanied by the synthesis of prostaglandins (PG), including PGF2 alpha and PGE. In an analysis of the tissue source of these prostaglandins, parenchymal preparations of both human and guinea pig (GP) lungs were compared. Peripheral, relatively airway-free preparations of human lung generate PGF2 alpha and PGE in response to histamine and 2-methylhistamine, on H1 agonist, but not to dimaprit, an H2 agonist. GP parenchymal preparations respond in a similar fashion. Stimulation of these same preparations with KCl or carbachol caused no increase in the synthesis of either PG. In human airway preparations all three agonists (histamine, KCl, and carbachol) caused the selective generation of PGE. However, stimulation of GP airway preparations with the agonists caused the production of both PGE and PGF2 alpha. These data indicate that (1) human and GP peripheral lung tissues respond to H1, but not H2, stimulation with the generation of PGF2 alpha and PGE; (2) these parenchymal responses are specific and may not be attributed to muscle contraction; and (3) stimulation of muscle contraction in human airway preparations results in the selective generation of PGE while GP airways produce both PGE and PGF2 alpha.


Spontaneous retroperitoneal hemorrhage in a mediastinal tumor in a patient with polymyositis: a case report.
Spontaneous retroperitoneal hemorrhage is a lethal cause of acute abdomen that is most frequently related to drugs, coagulopathy and intra-abdominal tumors. In patients with polymyositis and dermatomyositis, acute abdomen is attributed to intestinal vasculitis causing ischemia, ulceration or perforation. Spontaneous retroperitoneal hemorrhage, however, has rarely been reported in patients with polymyositis. We report the case of a 65-year-old woman with newly diagnosed polymyositis and suspected thymoma who suffered from spontaneous retroperitoneal hemorrhage. She experienced two massive retroperitoneal hemorrhage episodes within 24 hours, which resulted in shock and required emergent angiographic embolization. There was no evidence of tumor, vasculitis or aneurysm from abdominal angiography and computed tomography.


Aluminum-induced granulomas in a tattoo.
A patient who developed localized, granulomatous reactions in a tattoo is described. With the use of scanning electron microscopy and energy dispersive x-ray microanalysis, both aluminum and titanium particles were found in the involved skin sections. Intradermal provocation testing with separate suspensions of aluminum and titanium induced a positive response only in the case of aluminum. Examination by scanning electron microscopy and energy dispersive x-ray microanalysis of the provoked response established aluminum as the only nonorganic element present in the test site tissue. This is the first report of confirmed aluminum-induced, delayed-hypersensitivity granulomas in a tattoo.


Efficacy of Lepidium sativum against carbon tetra chloride induced hepatotoxicity and determination of its bioactive compounds by GC⿿MS.
Lepidium sativum seed (LSS) (family: Cruciferae) has been used in traditional medicine for the treatment of jaundice, liver problems, spleen diseases and gastrointestinal disorders. It was also reported to possess antihypertensive, diuretic, anti-asthmatic, antioxidant, and anti-inflammatory activities. Attempt has been made to study hepatoprotective potential of LSS available in Saudi Arabian Market. The aim of the present study was to determine the hepatoprotective effect of ethanolic extracts of LSS against carbon tetrachloride (CCl4) induced acute liver injury in rats. The bioactive compounds responsible for this activity have been analyzed by GC⿿MS. To evaluate the hepatoprotective activity, six groups (n = 6) of rats were taken. First group was control, second was toxic and other groups received oral test solutions: 100 mg/kg silymarin, or LSS (100, 200, and 400 mg/kg), once daily for 7 consecutive days, followed by hepatotoxicity induction with CCl4. Blood and liver tissues were collected for biochemical, antioxidant and microscopic analyses. The bioactive constituents present in the extract were analyzed by GC⿿MS. Results showed that pretreatment with LSS and silymarin significantly reduced the level of serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and bilirubin (BIL), which was increased significantly in toxic group treated with only CCl4. Histological analysis of liver tissues in groups pretreated with LSS and silymarin showed mild necrosis and inflammation of the hepatocytes compared to the toxic group. GC⿿MS analysis of LSS showed the presence of twelve major fatty acids including alpha-linolenic acid as a major constituent. These results indicated that LSS exerts enhance hepatoprotective activity that could be attributed towards its antioxidant activity, coupled together with the presence of anti-inflammatory compounds in LSS extract.


Human pancreatic secretory protein profiles in the search for tumor markers.
Pancreatic cancer secretory protein profiles were shown to be different from normals by a microcomputer-assisted analysis of isoelectric focusing patterns. Two acidic protein band regions (pI 3.0 and 4.5) of the pancreatic carcinoma profiles were significantly increased, and eight protein bands (pI 3.7, 5.0, 5.5, 6.5, 6.9, 7.3, 8.0, greater than 10.0) were significantly decreased. Highly significant decreases occurred at pH 7.3 (chymotrypsinogen) and at pH 5.0 (procarboxypeptidase Al, DNase I) in nonactivated specimens. The ratio between the absorbance points at 2.08 and 2.63 cm from the anode in each protein pattern differentiated the pancreas cancer specimens from the control group. Profiles found for the control group gave pI values similar to those found in the literature. The potential value of these findings in the search for tumor markers warrants further investigation as to whether these specimens can be differentiated from those from chronic pancreatitis patients.


Michelin-tire baby syndrome resulting from diffuse smooth muscle hamartoma.
We cared for an infant who was born with the Michelin-tire baby syndrome characterized by dermatomegaly and hypertrichosis. Histology revealed a diffuse smooth muscle hamartoma.


Effect of exercise on body composition among women with ovarian cancer.
Obesity is associated with a higher risk of mortality in women with ovarian cancer. Exercise has improved body composition among cancer survivors, yet no randomized controlled trial has explored the effect of exercise on body composition in women with ovarian cancer. In this analysis, we examined the effect of a six-month aerobic exercise intervention on body composition among ovarian cancer survivors in the Women's Activity and Lifestyle Study in Connecticut (WALC). Women with ovarian cancer (N = 144) were randomized in a 1:1 ratio to 6 months of an aerobic exercise intervention or attention-control, and body composition was measured as a secondary outcome at baseline and 6 months via dual-energy X-ray absorptiometry (DEXA). Women with at least one DEXA scan were included in the analysis (N = 103). On average, participants were 57.1 (± 8.7) years old and 1.6 (± 0.9) years since diagnosis. Women randomized to exercise maintained weight during the trial (- 0.11 kg, P = 0.82), while women in attention-control gained weight (+ 1.40 kg, P = 0.03); however, the between-group difference did not reach statistical significance (P = 0.09). We found no statistically significant differences by study arm for changes in body fat percentage, bone mineral density, or lean body mass. Weight was maintained as a result of a 6-month aerobic exercise intervention among post-treatment ovarian cancer survivors. Future exercise and healthy eating interventions should consider additional measures (e.g., computer tomography scans, D3-creatinine) to more accurately assess changes in body composition. Moderate-intensity aerobic exercise may help ovarian cancer survivors maintain weight.


Clinical effectiveness of low-level laser therapy as an adjunct to eccentric exercise for the treatment of Achilles' tendinopathy: a randomized controlled trial.
To investigate the effectiveness of low-level laser therapy (LLLT) as an adjunct to a program of eccentric exercises for the treatment of Achilles' tendinopathy. Randomized controlled trial with evaluations at baseline and 4, 12, and 52 weeks. Primary care clinic. Participants with midportion Achilles' tendinopathy were randomly assigned to 2 groups (LLLT n=20: mean age ± SD, 45.6±9.1y; placebo n=20: mean age ± SD, 46.5±6.4y). The 12-week evaluation was completed by 36 participants (90%), and 33 participants (82.5%) completed the 52-week evaluation. Both groups of participants performed eccentric exercises over a 3-month period. In addition, they received either an active or placebo application of LLLT 3 times per week for the first 4 weeks; the dose was 3J per point. The primary outcome was the Victorian Institute of Sport Assessment-Achilles' questionnaire (VISA-A) score at 12 weeks; secondary outcome was a visual analog scale for pain. Outcomes were measured at baseline and 4, 12, and 52 weeks. Baseline characteristics exhibited no differences between groups. At the primary outcome point, there was no statistically significant difference in VISA-A scores between groups (P>.05). The difference in VISA-A scores at the 4-week point significantly favored the placebo group (F(1)=6.411, sum of squares 783.839; P=.016); all other outcome scores showed no significant difference between the groups at any time point. Observers were blinded to groupings. The clinical effectiveness of adding LLLT to eccentric exercises for the treatment of Achilles' tendinopathy has not been demonstrated using the parameters in this study.


Estrogen-like activity of chlordecone (kepone) on the hypothalamo-pituitary axis: effects on the pituitary enkephalin system.
Similarities between the activity of chlordecone and estrogen on the hypothalamo-pituitary axis (HPA) were examined by using the pituitary enkephalin system as a model. A single injection (25 to 75 mg/kg, ip) or repeated injections (2.5 to 10 mg/kg/day for 10 days, ip) of chlordecone caused a time- and dose-related decrease in pituitary [Met5]-enkephalin-like immunoreactivity (ME-LI) in adult rats. Similar to the reported effects of estrogen, chlordecone treatment decreased the levels of ME-LI in the anterior lobe but not in the neurointermediate lobe of male pituitaries. Furthermore, chlordecone failed to alter the pituitary levels of ME-LI in female rats. The level of another pituitary peptide hormone, beta-endorphin, was increased in male rats after chlordecone treatment, indicating some degree of selectivity of this effect. Similarities between chlordecone and estrogen were found with other pituitary hormones, i.e., implantation of diethylstilbestrol or of chlordecone in ovariectomized rats caused qualitatively similar changes in serum prolactin and luteinizing hormone levels. These results suggest that chlordecone qualitatively resembles estrogen in its effect on some HPA peptide systems.


Urinary cytokines following photodynamic therapy for bladder cancer. A preliminary report.
This preliminary study was undertaken to test for the presence of urinary cytokines whose detection would provide evidence in support of the theory that photodynamic therapy (PDT) produces an immunologic response in patients treated for bladder cancer. Gamma interferon, interleukin 1-beta, interleukin 2, and tumor necrosis factor-alpha were assayed for in the urine of 4 patients treated with photodynamic therapy for bladder cancer, in 7 control patients undergoing transurethral surgical procedures, and in 5 healthy control subjects. Quantifiable concentrations of all cytokines, except gamma interferon, were measured in urine samples from the PDT patients with the highest light energies, while no urinary cytokines were found in the PDT patient who received the lowest light energy nor in any of the control subjects. These findings suggest that a local immunologic response may occur following PDT for bladder cancer.


Upregulation of skeletal muscle PGC-1α through the elevation of cyclic AMP levels by Cyanidin-3-glucoside enhances exercise performance.
Regular exercise and physical training enhance physiological capacity and improve metabolic diseases. Skeletal muscles require peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) in the process of their adaptation to exercise owing to PGC-1α's ability to regulate mitochondrial biogenesis, angiogenesis, and oxidative metabolism. Cyanidin-3-glucoside (Cy3G) is a natural polyphenol and a nutraceutical factor, which has several beneficial effects on human health. Here, the effect of Cy3G on exercise performance and the underlying mechanisms involved were investigated. ICR mice were given Cy3G (1 mg/kg, orally) everyday and made to perform weight-loaded swimming exercise for 15 days. The endurance of mice orally administered with Cy3G was improved, enabling them to swim longer (time) and while the levels of exercise-induced lactate and fatigue markers (urea nitrogen, creatinine and total ketone bodies) were reduced. Additionally, the expression of lactate metabolism-related genes (lactate dehydrogenase B and monocarboxylate transporter 1) in gastrocnemius and biceps femoris muscles was increased in response to Cy3G-induced PGC-1α upregulation. In vitro, using C2C12 myotubes, Cy3G-induced elevation of intracellular cyclic AMP levels increased PGC-1α expression via the Ca2+/calmodulin-dependent protein kinase kinase pathway. This study demonstrates that Cy3G enhances exercise performance by activating lactate metabolism through skeletal muscle PGC-1α upregulation.


Restrictive dermopathy: report of two siblings.
Restrictive dermopathy (RD) is a rare and lethal autosomal recessive syndrome characterized by very tight, thin, and easily eroded skin and contracture of joints. We present two siblings in a family. Case 1, a female neonate, showed mild characteristic presentations of RD and survived for 16 days, and Case 2, a male neonate, was stillborn with typical severe features of RD. His skin biopsy showed typical histological findings, and genetic study revealed a homozygous nonsense mutation on the exon 6 of zinc metalloproteinase STE24 (ZMPSTE24). The exact pathogenic mechanism of RD remains poorly understood. The most recent studies on mutations in lamin A and/or ZMPSTE24 have shed some light on the pathophysiology of RD and may help direct the development of future therapeutic approaches.


T-Cell-Mimicking Nanoparticles for Cancer Immunotherapy.
Cancer immunotherapies, including adoptive T cell transfer and immune checkpoint blockades, have recently shown considerable success in cancer treatment. Nevertheless, transferred T cells often become exhausted because of the immunosuppressive tumor microenvironment. Immune checkpoint blockades, in contrast, can reinvigorate the exhausted T cells; however, the therapeutic efficacy is modest in 70-80% of patients. To address some of the challenges faced by the current cancer treatments, here T-cell-membrane-coated nanoparticles (TCMNPs) are developed for cancer immunotherapy. Similar to cytotoxic T cells, TCMNPs can be targeted at tumors via T-cell-membrane-originated proteins and kill cancer cells by releasing anticancer molecules and inducing Fas-ligand-mediated apoptosis. Unlike cytotoxic T cells, TCMNPs are resistant to immunosuppressive molecules (e.g., transforming growth factor-β1 (TGF-β1)) and programmed death-ligand 1 (PD-L1) of cancer cells by scavenging TGF-β1 and PD-L1. Indeed, TCMNPs exhibit higher therapeutic efficacy than an immune checkpoint blockade in melanoma treatment. Furthermore, the anti-tumoral actions of TCMNPs are also demonstrated in the treatment of lung cancer in an antigen-nonspecific manner. Taken together, TCMNPs have a potential to improve the current cancer immunotherapy.


Optimism and pessimism are antithetically associated with post-operative knee function in patients' undergoing total knee arthroplasty.
Personality traits, such as dispositional optimism and pessimism, have impact on a variety of health-related problems. Influence on outcome in total knee arthroplasty (TKA) could only be shown for other personality trait concepts, but not for dispositional optimism/pessimism. This study aims to examine the association of dispositional optimism/pessimism with pre-operative joint function and post-operative outcome in TKA. Data were acquired in a multicentre, cross-sectoral, prospective study (the PROMISE Trial). Patients were followed for 12 months post-operatively. Dispositional optimism/pessimism was measured pre-operatively via the revised Life Orientation Test (LOT-R), pre- and post-operative function was measured via the 12 Item Knee-osteoarthritis outcome Scores (KOOS-12). Log-linear regression models considering known confounders and t-test were carried out to show the association of LOT-R scores with pre- and post-operative KOOS-12 scores. 740 patients were analyzed. Optimistic LOT-R was significantly positively associated to the mean scores of KOOS-12 pre- and post-operative, while pessimistic LOT-R was significantly associated negatively (pre-operative: optimistic p = 0.001, pessimistic p = 0.001; post-operative optimistic: 3M p = 0.001, 6M p = 0.001, 12M p = 0.001; post-operative pessimistic: 3M p = 0.01, 6M p = 0.004, 12M p = 0.001). Optimism was positively associated with pre-operative joint function and, more importantly, post-operative functional outcome in TKA, while pessimism was associated with the opposite. Assessing patients' general personality traits prior to surgery to identify pessimistic patients, hence being at risk for poor outcome in TKA, should be considered to react to the patients' special needs and possible pessimistic expectations, i.e., through a cognitive-behavioral intervention, to potentially increase optimism and hereby post-operative outcome in TKA. Prognostic Level III.


Defense of termitaria by termitophilous ants.
Mounds of Amitermes laurensis are frequently faided by meat ants Iridomyrmex sanguineus. Of eight ant species which often cohabit with the termites, Camponotus sp. B and C were considerably dependent on the termintaria for their nest sites and effectively protected it from the attacks by meat ants. Many termite colonies cohabiting with those two ant species were vigorous, suggesting that this ant-termite relationship is mutualistic; thus, the ants were provided nest sites and probably even food and the termites were protected from destructive natural enemies.


Application of collagen triple helix repeat containing-1 and mitotic spindle apparatus antibody in small cell lung cancer diagnosis.
The clinical significance of serum collagen triple helix repeat protein-1 (CTHRC1) and mitotic spindle apparatus antibody (MSA) in the diagnosis of small cell lung cancer (SCLC). Of the 229 lung tumor patients selected, 62 patients were divided into SCLC, 94 patients with non-small cell lung cancer (NSCLC), and 73 patients with benign lung disease (BLD). The health controls (HC) had a span of 66 cases with normal physical condition. The serum extracted from each participator and enzyme-linked immunosorbent assay was adopted for measuring the serum CTHRC1 and MSA; in the meantime, automatic electrochemiluminescence immunoassay was used for the quantitative determination of serum NSA and CEA. And then, the differences in serum CTHRC1, MSA, NSE, and CEA were compared among involved groups. ① Compared with other groups, the concentrations of CTHRC1, MSA, and NSE showed a marked increase in the group of SCLC (all p < 0.01). Especially for SCLC patients with lymph node metastasis, CTHRC1 provided a notably higher level than those without metastasis. ② CTHRC1 and MSA established a diagnostic criterion with the specificity of 90.99% and 86.27% for SCLC, respectively. ③ In series, the specificity of CTHRC1 and NSE was the highest (99.30%), while MSA and NSE had the highest sensitivity (96.72%) in parallel. ④ Both CTHRC1 and MSA were hazardous factors interconnected with SCLC. Serum CTHRC1 and MSA had a more exciting prospect of application. When used in conjunction with NSE and CEA, they could optimize the clinical diagnosis value of SCLC.


Achieving Ultrahigh-Rate Planar and Dendrite-Free Zinc Electroplating for Aqueous Zinc Battery Anodes.
Despite being one of the most promising candidates for grid-level energy storage, practical aqueous zinc batteries are limited by dendrite formation, which leads to significantly compromised safety and cycling performance. In this study, by using single-crystal Zn-metal anodes, reversible electrodeposition of planar Zn with a high capacity of 8 mAh cm-2 can be achieved at an unprecedentedly high current density of 200 mA cm-2 . This dendrite-free electrode is well maintained even after prolonged cycling (>1200 cycles at 50 mA cm- 2 ). Such excellent electrochemical performance is due to single-crystal Zn suppressing the major sources of defect generation during electroplating and heavily favoring planar deposition morphologies. As so few defect sites form, including those that would normally be found along grain boundaries or to accommodate lattice mismatch, there is little opportunity for dendritic structures to nucleate, even under extreme plating rates. This scarcity of defects is in part due to perfect atomic-stitching between merging Zn islands, ensuring no defective shallow-angle grain boundaries are formed and thus removing a significant source of non-planar Zn nucleation. It is demonstrated that an ideal high-rate Zn anode should offer perfect lattice matching as this facilitates planar epitaxial Zn growth and minimizes the formation of any defective regions.


Health of the public: An academic challenge.
Academic medicine has contributed to the successes of the U.S. health care system, including excellence in biomedical research, extensive dissemination and use of medical technologies, lowered death rates for heart disease and stroke, and decreased rates of cigarette smoking. However, its substantial degree of public support and its central social role mandate that it become more involved in improving the health of the public. Relevant problems include poor health status and disproportionately high expenditures for medical care, inappropriate mix and distribution of medical manpower, and insufficient attention to chronic illness and disability. To help address these problems, Health of the Public, funded jointly by the Pew Charitable Trusts and the Rockefeller Foundation, has established programs in six academic health centers: Columbia; Johns Hopkins; Tufts; and the Universities of New Mexico, North Carolina, and Washington. These programs support population-based education for medical students and residents, research and training in clinical prevention, and reorientation of senior faculty members toward population-based concepts.


The syndrome of amniotic fluid embolism: a potential contribution of bradykinin.
Amniotic fluid embolism is a potentially fatal complication of pregnancy; although several hypotheses have been formulated, the pathophysiology of this condition is not well known. An exaggerated release of bradykinin, which is activated by products of the amniotic fluid that enter the maternal circulation, could explain the symptoms that are present in amniotic fluid embolism. The objective of this study was to assess whether bradykinin is involved in amniotic fluid embolism. The plasma bradykinin-generating capacity was measured serially in a patient who experienced amniotic fluid embolism. The plasma bradykinin-generating capacity was found to be very low at the time of the initial clinical manifestations, which were characterized by severe hypotension, cardiorespiratory arrest, and coagulopathy. This study suggests a potential role for bradykinin release in the pathophysiology of amniotic fluid embolism.


Acute administration of antipsychotics modulates Homer striatal gene expression differentially.
Typical and atypical antipsychotics, the mainstay of schizophrenia pharmacotherapy, have been demonstrated to affect differently neuronal gene expression in several preclinical paradigms. Here we report the differential gene expression of the glutamatergic post-synaptic density proteins Homer and PSD-95 in rat forebrain following acute haloperidol or olanzapine treatment. Moreover, considering the extensive interactions between dopaminergic and opioidergic systems we also measured striatal preproenkephalin mRNA. Male Sprague-Dawley rats were treated with haloperidol 1 mg/kg or olanzapine 0.5 mg/kg or vehicle, i.p. and sacrificed 3 h after the injection. Homer gene expression was significantly increased in caudate putamen and nucleus accumbens of rats treated with haloperidol and in the core of accumbens of rats treated with olanzapine. No changes were detected for Homer in prefrontal and parietal cortex in any of the experimental groups. PSD-95 gene expression was not modulated in our paradigm by administration of either typical or atypical antipsychotics. These results (1) suggest a differential modulation of Homer by typical and atypical antipsychotics; (2) confirm that Homer can be induced as an early gene with putative direct effect on neuronal plasticity and (3) demonstrate different response to antipsychotics by different classes of postsynaptic density proteins at glutamatergic synapses.


Estimating Waterborne Infectious Disease Burden by Exposure Route, United States, 2014.
More than 7.15 million cases of domestically acquired infectious waterborne illnesses occurred in the United States in 2014, causing 120,000 hospitalizations and 6,600 deaths. We estimated disease incidence for 17 pathogens according to recreational, drinking, and nonrecreational nondrinking (NRND) water exposure routes by using previously published estimates. In 2014, a total of 5.61 million (95% credible interval [CrI] 2.97-9.00 million) illnesses were linked to recreational water, 1.13 million (95% CrI 255,000-3.54 million) to drinking water, and 407,000 (95% CrI 72,800-1.29 million) to NRND water. Recreational water exposure was responsible for 36%, drinking water for 40%, and NRND water for 24% of hospitalizations from waterborne illnesses. Most direct costs were associated with pathogens found in biofilms. Estimating disease burden by water exposure route helps direct prevention activities. For each exposure route, water management programs are needed to control biofilm-associated pathogen growth; public health programs are needed to prevent biofilm-associated diseases.


Peg-interferon plus ribavirin with or without boceprevir or telaprevir for HCV genotype 1: a meta-analysis on the role of response predictors.
To compare the efficacy of pegylated-interferon (Peg-IFN) α-2a or α-2b and ribavirin given as dual therapy versus triple therapy (Peg-IFN and ribavirin plus boceprevir or telaprevir) in patients with HCV-1 chronic hepatitis naïve for anti-HCV therapy or relapsers to dual therapy in relation to the presence of constitutional, clinical and virological predictors of treatment response. Included in the meta-analysis were studies meeting these criteria: original data from randomized trials on the efficacy of dual versus triple therapy in therapy-naïve patients or relapsers; at least one primary outcome clearly defined: sustained virological response in patients with or without rapid virological response (RVR), with genotype 1a or 1b, low or high HCV load, IL28-B CC or non-CC genotype, mild or severe fibrosis; odds ratio estimates of relative risk (RR) and 95% confidence intervals; English language; and published up to the end of June 2013. Seven original studies met the inclusion criteria, allowing a meta-analysis on 3,652 patients. Triple therapy was more effective than dual, regardless of IL-28B genotype, HCV sub-genotype, liver fibrosis, and baseline HCV load. In 1,045 patients who achieved RVR, SVR was more frequently achieved with dual therapy (RR = 1.11; p = 0.002) than triple. The same results were achieved when only the therapy-naïve patients were considered. Triple therapy provides a significantly higher SVR rate than dual therapy, but dual therapy obtains a significantly higher SVR rate in patients with RVR. The data stress the clinical importance of a 4-week lead-in phase in direct-acting antiviral-based treatment.


Comparing physically abusive, neglectful, and non-maltreating parents during interactions with their children: a meta-analysis of observational studies.
To clarify the nature and extent of differences in the ways that physically abusive, neglectful, and non-maltreating parents communicate during interactions with their children. A meta-analysis was conducted of 33 observational studies comparing parent-child interactions in families where parents have a documented history of physical abuse or neglect vs. where parents have no history of child maltreatment. Parental behaviors were grouped into three clusters (positivity, aversiveness, and involvement) for comparison across studies. When comparing maltreating (physically abusive or neglectful) vs. non-maltreating parents, mean weighted effect sizes for the three behavioral clusters range from d=.46 to .62. Physically abusive parents are distinguished from non-maltreating parents more so than neglectful parents in terms of aversive behavior, whereas the reverse is true for involvement. Publication date, parent and child age, and task structure moderate the magnitude, though not direction, of differences. Parents with a documented history of child physical abuse or child neglect also are distinguished from non-maltreating parents by the levels of aversiveness, positivity, and involvement they display during interactions that constitute the parent-child relationship. Researchers and practitioners need to carefully consider sample size, length and setting of observation, and interaction tasks when using observational methods.


Molecular cytogenetic analysis of a familial pericentric inversion of chromosome 12.
We describe the application of multi-color fluorescence in situ hybridization (FISH) in the characterization of a familial pericentric inversion. Using chromosome 12 short- and long-arm specific DNA probes, fast and reliable discrimination between normal and inversion chromosome 12 or recombinant inversion chromosome 12 was possible. FISH thus provides a reliable means for prenatal detection of balanced or unbalanced chromosome 12 rearrangements in this family. This approach is possible for identification of similar chromosome rearrangements provided that probes for the putatively involved chromosome region are available.


[Tofisopam and melatonin attenuate the reorganization of circadian locomotor rhythm in rats under injection-induced stress conditions].
Repeated saline injections induce reorganization of the circadian locomotor rhythm in rats, which is manifested by increased amplitude, enhanced instability of the acrophase, and changed spectral characteristics. The benzodiazepine anxiolytic tofisopam (grandaxin, 10 mg/kg) and the pineal hormone melatonin (0.1 mg/kg) prevented the stress-induced changes in the circadian rhythm. The hormone exhibited a more optimal chronotropic activity than grandaxin.


Characterization of a putative promoter region of the human poly(ADP-ribose) polymerase gene: structural similarity to that of the DNA polymerase beta gene.
The 5'-flanking region of the human poly(ADP-ribose) polymerase gene was isolated and characterized. The nucleotide sequence of a part of the poly(ADP-ribose) polymerase gene completely matched that of the cDNA. The transcriptional initiation sites (cap sites) of this gene, located about 166-bp upstream from the translational initiation site, were identified by S1 mapping analysis. Neither CAAT box nor TATA box was found within 500-bp upstream from the cap sites of poly(ADP-ribose) polymerase gene. The 200-bp immediately upstream of the cap site had a high G+C content (76.5%) and contained double repeats of the sequence CCGCCC, putative Sp1 binding sites, and a palindromic structure. The 5'-flanking region of poly(ADP-ribose) polymerase gene also showed promoter activity in chloramphenicol acetyltransferase assay and structural similarity to that of DNA polymerase beta gene.


Studies with Brugia pahangi. 20. An investigation of 23 anthelmintics using different screening techniques.
23 anthelmintics were tested against Brugia pahangi microfilariae and infective larvae in vitro and in Aedes aegypti infected with B. pahagi and jirds (Meriones unguiculatus) infected with a B. pahangi/patei hybrid. There was little correlation between the results obtained in vitro and in infected insects and the results obtained in these tests gave no indication of the activity in jirds. Three of the compounds were macrofilaricidal in jirds and these were tested in cats infected with B. pahangi. One of these--5-benzamido-2(4-thiazolyl)-benzimidazole--was macrofilaricidal in cats and it is suggest that it should be tested in other filarial systems. It is concluded that the insect and in vitro tests are not good primary screens for filaricidal activity.


Monitoring glaucoma progression.
Monitoring progression is fundamental in managing patients with chronic open-angle glaucoma, which is as important as an early diagnosis of the disease. It is essential that both structural and functional damage be considered, in order to assure a complete and reliable assessment of progression. The optic disc and retinal nerve fiber layer damage can be evaluated using either low-tech (slit lamp biomicroscopy with a 78-diopter lens) or high-tech (HRT, OCT, GDx) methods; the latter providing a more objective and standardized analysis. The current gold standard in detecting functional damage is using standard automated perimetry (SAP). Different approaches can be used to assess SAP progression: (1) clinical judgment; (2) defect classification systems; (3) trend analysis; and, (4) event analysis. Several statistical programs are currently available to assist the ophthalmologist in the difficult task of assessing progression. Clinically relevant progression should only be considered when the change--be it structural and/or functional--is statistically significant, reproducible, and indicative of glaucomatous damage.


Association Between Genetic Predictors for C-Reactive Protein and Venous Thromboembolism With Severe Adverse Coronavirus Disease 2019 Outcomes.
To assess if genetic predictors for C-reactive protein and risk of venous thromboembolism are associated with severe outcomes among individuals who tested positive for severe acute respiratory syndrome coronavirus 2. Retrospective cohort study. U.K. Biobank. U.K. Biobank participants with European ancestry who were recorded to have a positive polymerase chain reaction test result for severe acute respiratory syndrome coronavirus 2 between March 16, 2020, and August 14, 2020. Not applicable. We constructed separate genetic risk scores for C-reactive protein and venous thromboembolism consisting of 56 and 37 genetic variants that have been significantly associated with venous thromboembolism and C-reactive protein, respectively. Among 1,126 individuals who were diagnosed with coronavirus disease 2019, 48% had a coronavirus disease 2019-related hospitalization, 16% received critical care support, 10% had critical respiratory support, and 21% died from coronavirus disease 2019. Genetic predisposition to high C-reactive protein concentrations was marginally associated with a lower risk of death from coronavirus disease 2019 (odds ratio, 0.85; 95% CI, 0.73-1.00; p = 0.05). No other associations were significant. Our results do not support associations between polygenic risk for elevated blood C-reactive protein concentrations or venous thromboembolism and severe coronavirus disease 2019 health outcomes. Thus, considering genetic predisposition associated with C-reactive protein concentrations or venous thromboembolism risk is not meaningful for predicting severe coronavirus disease 2019 health outcomes.


A nanostructure-initiator mass spectrometry-based enzyme activity assay.
We describe a Nanostructure-Initiator Mass Spectrometry (NIMS) enzymatic (Nimzyme) assay in which enzyme substrates are immobilized on the mass spectrometry surface by using fluorous-phase interactions. This "soft" immobilization allows efficient desorption/ionization while also enabling the use of surface-washing steps to reduce signal suppression from complex biological samples, which results from the preferential retention of the tagged products and reactants. The Nimzyme assay is sensitive to subpicogram levels of enzyme, detects both addition and cleavage reactions (sialyltransferase and galactosidase), is applicable over a wide range of pHs and temperatures, and can measure activity directly from crude cell lysates. The ability of the Nimzyme assay to analyze complex mixtures is illustrated by identifying and directly characterizing beta-1,4-galactosidase activity from a thermophilic microbial community lysate. The optimal enzyme temperature and pH were found to be 65 degrees C and 5.5, respectively, and the activity was inhibited by both phenylethyl-beta-d-thiogalactopyranoside and deoxygalactonojirimycin. Metagenomic analysis of the community suggests that the activity is from an uncultured, unsequenced gamma-proteobacterium. In general, this assay provides an efficient method for detection and characterization of enzymatic activities in complex biological mixtures prior to sequencing or cloning efforts. More generally, this approach may have important applications for screening both enzymatic and inhibitor libraries, constructing and screening glycan microarrays, and complementing fluorous-phase organic synthesis.


Accreditation of undergraduate and graduate medical education: how do the standards contribute to quality?
Accreditation organizations such as the Liaison Committee for Medical Education (LCME), the Royal College of Physicians and Surgeons of Canada (RCPSC), and the Accreditation Council for Graduate Medical Education (ACGME) are charged with the difficult task of evaluating the educational quality of medical education programs in North America. Traditionally accreditation includes a more quantitative rather than qualitative judgment of the educational facilities, resources and teaching provided by the programs. The focus is on the educational process but the contributions of these to the outcomes are not at all clear. As medical education moves toward outcome-based education related to a broad and context-based concept of competence, the accreditation paradigm should change accordingly.


Can radial bone mineral density and quantitative ultrasound measurements reduce the number of women who need axial density skeletal assessment?
The purpose of this study was to investigate the clinical usefulness of forearm bone mineral density (BMD) and speed of sound (SOS) at the phalanx and radius as pre-selection tests to identify women with low BMD at the axial skeleton. BMD was measured by dual-energy X-ray absorptiometry (DXA) in the forearm, lumbar spine and femoral neck. SOS at the radius and phalanx was measured using a multisite quantitative ultrasound (QUS) device. Measurements were performed on 524 consecutive women referred for the assessment of BMD. Women with a T-score <-1 and T-score < or =-2.5 at either spine or femoral neck were identified, and T-score cut-off values for the forearm DXA and QUS variables were determined. Cut-off values for the forearm BMD estimated to detect normal women and those with T-score <-1 at the axial skeleton identified a total of 82% of subjects with 91% certainty. Cut-off values for the forearm BMD determined to detect women with T-score >-2.5 and those with osteoporosis allowed the identification of 62% of the study population with 90% certainty. Cut-off values for the phalangeal and radial SOS estimated to detect normal women and those with T-score <-1 at the axial skeleton identified a total of 49% and 1% of subjects, respectively. Cut-off values estimated for QUS variables to detect women with T-score >-2.5 and those with osteoporosis at the axial skeleton either failed to detect subjects with sufficient certainty (phalangeal SOS) or detected a negligible percentage of patients (radial SOS). In conclusion, forearm BMD may be used as a pre-selection test to identify women with low BMD at the axial skeleton, thus enabling reduction of the number of women who need axial BMD assessment. SOS of the phalanges and radius appears to have less value in the detection of the women with low axial BMD.


GM-CSF Enhances Mobilization of Bone Marrow Mesenchymal Stem Cells via a CXCR4-Medicated Mechanism.
This study was conducted to investigate the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the mobilization of mesenchymal stem cells (MSCs) from the bone marrow (BM) into the peripheral blood (PB) in rats. GM-CSF was administered subcutaneously to rats at 50 μg/kg body weight for 5 consecutive days. The BM and PB of rats were collected at 1, 3, and 5 days during the administration for analysis. Upon GM-CSF administration, the number of mononuclear cells increased rapidly at day 1 both in the BM and PB. This number decreased gradually over time in the BM to below the initial amount by day 5, but was maintained at a high level in the PB until day 5. The colony-forming unit-fibroblasts were increased in the PB by 10.3-fold at day 5 of GM-CSF administration, but decreased in the BM. Compared to GM-CSF, granulocyte-colony stimulating factor (G-CSF) stimulated lower levels of MSC mobilization from the BM to the PB. Immunohistochemical analysis revealed that GM-CSF induced a hypoxic and proteolytic microenvironment and increased C-X-C chemokine receptor type 4 (CXCR4) expression in the BM. GM-CSF added to BM MSCs in vitro dose-dependently increased CXCR4 expression and cell migration. G-CSF and stromal cell derived factor-1 (SDF-1) showed similar results in these in vitro assays. Know-down of CXCR4 expression with siRNA significantly abolished GM-CSF- and G-CSF-induced MSC migration in vitro, indicating the involvement of the SDF-1-CXCR4 interaction in the mechanism. These results suggest that GM-CSF is a useful tool for mobilizing BM MSCs into the PB.


In utero anaphylaxis.
Late fetal demise and hypoxic-ischemic neurologic injury after previously normal in utero development remain devastating outcomes of pregnancy, for which no cause is identified in many cases. Based on a case encountered, I propose that some of these incidents may be due to in utero anaphylaxis to food antigens that cross the placenta. Potential allergens to which pregnant women are exposed can be transported across the placenta, and the fetus is capable of producing IgE, the antibody responsible for anaphylaxis in humans. Whether this IgE is antigen specific is controversial with some studies indicating the ability to generate IgE to food antigens prenatally. Indirect evidence for in utero production of specific IgE is the high percentage of food reactions that occur on the first postnatal exposure to the food. I propose that some cases of stillbirth and prenatal hypoxic-ischemic injury may be due to in utero anaphylaxis.


Variations of membrane fatty acids and epicuticular wax metabolism in response to oleocellosis in lemon fruit.
Oleocellosis is a physiological disorder causing blemishes on fruit surface. This study investigated the influence of oleocellosis on the membrane fatty acids and wax in lemon fruit rinds at the morphological, physiological, metabolic and molecular levels by using a variety with a high incidence rate of oleocellosis (green lemon). Oleocellosis-damaged rinds showed loose and flaky wax layers with more fissures on the surface, as well as higher contents of C16 and C18 fatty acids and very long chain (VLC) fatty alkanes while lower contents of VLC fatty aldehydes. The main differentially expressed genes, including FabZ, FAD2 and SAD6 involved in the accumulation of C16 and C18 fatty acids and CER1 involved in the transformation of VLC fatty aldehydes to VLC fatty alkanes, were up-regulated by oleocellosis. These results indicate that oleocellosis accelerates the accumulation of membrane free fatty acids and transformation of VLC fatty aldehydes to VLC fatty alkanes.


Bispecific antibodies mimicking factor VIII in hemophilia A: converting innovation to an essential medicine.
Preventive subcutaneous treatment of severe hemophilia A with bispecific antibodies that mimic the action of coagulation factor VIII (FVIII) is emerging as an effective alternative to replacement therapy with intravenous administration of FVIII concentrates, either derived from plasma or produced by biotechnology. Access to this innovative therapeutic approach for a growing number of patients worldwide increasingly appears to be a priority public health strategy. Inclusion of FVIII mimetic bispecific antibodies on the World Health Organization essential medicines list would contribute to health equity in lower-income countries.


Erratum to "Quadratus Lumborum Block as Sole, Homeostatic-Preserving Anesthetic for a Patient with Multiple System Atrophy Undergoing Open Inguinal Hernia Repair: A Case Report".
[This corrects the article DOI: 10.1155/2018/7161860.].


Quantitative nitrobluetetrazolium reduction by normal newborn monocytes.
The phagocytosis-induced metabolic burst of human newborn monocytes, as evaluated by their capacity to reduce NBT, was comparable to that of adult monocytes. The NBT reduction assay constitutes a simple method of ascertaining the functional capacity of human monocytes.


Modification by SQ 14225 of blood pressure and adrenal catecholamine response to hemorrhage.
SQ 14225 infusion to cats exposed to hemorrhage suppressed adrenomedullary catecholamine release. The immediate compensatory blood pressure response was unaffected, while the later compensatory response was of a higher magnitude in intact cats that in SQ 14225-treated animals. Adrenal gland blood flow was better preserved in SQ 14225-treated hemorrhaged cats than in cats exposed to hemorrhage only. These data emphasize the role of angiotensin II in adrenal catecholamine and blood pressure responses to hemorrhage.


Optimizing vancomycin dosage regimens in relation to high-flux haemodialysis.
To develop a population pharmacokinetic (PK) model for vancomycin in adults receiving high-flux haemodialysis (HFHD) in an effort to optimize vancomycin dosing in this population. A population PK model using NONMEM was developed using retrospective data collected from 48 vancomycin courses administered to patients (n = 37) receiving HFHD. Fixed-dose [1.5 g loading dose (LD), 1 g maintenance dose (MD)], literature-adapted weight-based (WBL; 20 mg/kg LD, 10 mg/kg MD) and hospital-adapted weight-based (WBH; 25-30 mg/kg LD, 20-25 mg/kg MD) dosage regimens were then simulated using the Monte Carlo method. The PTA was an AUC24/MIC ≥400 with success being a PTA ≥90%. The data were best described using a two-compartment model. It was observed that fixed-dose and WBL dosage regimens resulted in a PTA ≤90% for most days. The WBH dosing achieved a PTA ≥90% on most days, but there were supratherapeutic concentrations with repeated dosing of vancomycin. If HFHD was delayed by 48-72 h after the LD, the PTA would fall below 90%. A dose-optimized regimen was developed: 30 mg/kg LD and 10 mg/kg MD given on HFHD days. An additional dose of 500 mg or 1 g was administered 24 h after the LD if HFHD occurred 48-72 h post-LD. This dose-optimized regimen afforded a PTA ≥90% on all days of therapy and achieved clinically acceptable pre-haemodialysis concentrations. Current vancomycin dosage regimens used clinically do not achieve a PTA ≥90% for most days of therapy for people receiving HFHD. A dose-optimized regimen was developed, which could be implemented in clinical practice.


Combined silencing of K-ras and Akt2 oncogenes achieves synergistic effects in inhibiting pancreatic cancer cell growth in vitro and in vivo.
Cancer is a complex disease involving multiple oncogenes with diverse actions. Inhibiting only one oncogene is unlikely to eliminate the malignancy of cancer cells. The goal of this study was to investigate whether synergistic effects can be achieved by combined silencing of two oncogenes, K-ras and Akt2, which are key players in the Ras/MAPK and PI3K/Akt signaling pathways. The pancreatic cancer cell line, Panc-1, was selected for these studies as it has elevated expression of K-ras and Akt2. Compared with inhibiting each oncogene alone, simultaneously silencing the two oncogenes with RNA interference (RNAi) more effectively inhibited Panc-1 cell proliferation and colony formation, induced a significantly higher percentage of apoptosis and resulted in greater inhibition of c-myc expression in vitro. Furthermore, when delivered by polyethyleneimine into Panc-1 tumors in nude mice, RNAi simultaneously targeting K-ras and Akt2 inhibited tumor growth more efficiently than RNAi targeting the individual oncogenes. Therefore, RNAi simultaneously silencing the oncogenes K-ras and Akt2 may offer potential opportunities for pancreatic cancer gene therapy.


Correction to: Understanding Students' Transition to High School: Demographic Variation and the Role of Supportive Relationships.
The original version of the article was published with few errors in Tables 2 and 4. The correct version of the tables are presented along in this erratum.


Quantitative mapping of strain and displacement fields over HR-TEM and HR-STEM images of crystals with reference to a virtual lattice.
A method for the reciprocal space treatment of high-resolution transmission electron microscopy (HR-TEM) and high-resolution scanning transmission electron microscopy (HR-STEM) images has been developed. Named "Absolute strain" (AbStrain), it allows for quantification and mapping of interplanar distances and angles, displacement fields and strain tensor components with reference to a user-defined Bravais lattice and with their corrections from the image distortions specific to HR-TEM and HR-STEM imaging. We provide the corresponding mathematical formalism. AbStrain goes beyond the restriction of the existing method known as geometric phase analysis by enabling direct analysis of the area of interest without the need for reference lattice fringes of a similar crystal structure on the same field of view. In addition, for the case of a crystal composed of two or more types of atoms, each with its own sub-structure constraint, we developed a method named "Relative displacement" for extracting sub-lattice fringes associated to one type of atom and measuring atomic columns displacements associated to each sub-structure with reference to a Bravais lattice or to another sub-structure. The successful application of AbStrain and Relative displacement to HR-STEM images of functional oxide ferroelectric heterostructures is demonstrated.


A qualitative study to explore how parental expectations and rules influence beverage choices in early adolescence.
To understand parent beverage expectations for early adolescents (EAs) by eating occasion at home and in various settings. Descriptive study using focus group interviews and the constant comparative method for qualitative data analysis. Six focus groups were completed, and 2 were conducted in Spanish. Participants (n = 49) were mostly female (86%) and non-Hispanic white (49%) and Hispanic (33%). Parent expectations for EA beverage intake were based on health beliefs, EA preferences, and cost, whereas those related to portion sizes and frequency varied by beverage type. Parents managed beverage expectations at home and away from home by making healthful beverages available and accessible, or by offering or allowing only specific beverages. Results from this qualitative study involving a small sample of parents showed that expectations were influenced by practical concerns and managed primarily through availability practices. These issues could be addressed to improve EA beverage consumption.


[Appropriateness of the prescriptions of conventional versus new oral anticoagulants at discharge from a department of internal medicine].
The recently introduced oral direct anticoagulants (ODAs), presumably safer, and with comparable efficacy to the vitamin K antagonists (VKAs), may reshape the world of anticoagulation medicine. This study aimed to assess the prescription appropriateness of ODAs and VKAs at discharge from hospital. We performed a one year retrospective study between August 2012 and July 2013 in the department of internal medicine of a regional hospital (HVs Sion) using Electronic Medical Records. All patients receiving an ODA were included and matched to a patient treated with a VKA. The appropriateness of prescription at discharge was defined by an adequate indication and dosing, the absence of contraindication, a minimal risk of drug-drug interactions and no major bleeding or venous thromboembolism during the hospitalization. The bleeding risk was evaluated with the HAS-BLED score when the indication was atrial fibrillation (AF). Out of the 44patients included (22 with an ODA and 22 with a VKA), 38 received an appropriate prescription according to all criteria. Two patients had an inadequate dosing. A potential drug-drug interaction was detected in 3patients receiving a VKA and in 1patient receiving an ODA. No major contraindication was found, but a relative contraindication was discussed in 3cases. The majority of patients receiving an ODA for an AF had a minor bleeding risk. No significant difference was ascertained between the two groups regarding the appropriateness of prescription. Our results suggest that ODAs were cautiously used in our setting.


Characterization of a mutated Geobacillus stearothermophilus L-arabinose isomerase that increases the production rate of D-tagatose.
Characterization of a mutated Geobacillus stearothermophilus L-arabinose isomerase used to increase the production rate of D-tagatose. A mutated gene was obtained by an error-prone polymerase chain reaction using L-arabinose isomerase gene from G. stearothermophilus as a template and the gene was expressed in Escherichia coli. The expressed mutated L-arabinose isomerase exhibited the change of three amino acids (Met322-->Val, Ser393-->Thr, and Val408-->Ala), compared with the wild-type enzyme and was then purified to homogeneity. The mutated enzyme had a maximum galactose isomerization activity at pH 8.0, 65 degrees C, and 1.0 mM Co2+, while the wild-type enzyme had a maximum activity at pH 8.0, 60 degrees C, and 1.0-mM Mn2+. The mutated L-arabinose isomerase exhibited increases in D-galactose isomerization activity, optimum temperature, catalytic efficiency (kcat/Km) for D-galactose, and the production rate of D-tagatose from D-galactose. The mutated L-arabinose isomerase from G. stearothermophilus is valuable for the commercial production of D-tagatose. This work contributes knowledge on the characterization of a mutated L-arabinose isomerase, and allows an increased production rate for D-tagatose from D-galactose using the mutated enzyme.


Effect of mode of delivery on vertical human papillomavirus transmission - A meta-analysis.
A systematic review of the literature has been conducted (last update March 2014) for clinical studies reporting the prevalence of human papillomavirus (HPV) in the offspring of HPV-infected women in association to their mode of delivery. A meta-analysis was carried out according to the identification of concordant neonatal to maternal HPV types. Overall eight studies were included in the meta-analysis. Our pooled results, showed that caesarean section is associated with significantly lower rates of HPV transmission than vaginal birth (14.9% vs. 28.2%, risk ratio or RR: 0.515, 95% confidence interval or CI: 0.34-0.78). The number of caesarean sections needed to prevent one case of perinatal infection (number needed to treat or NNT) would be 7.5. As a conclusion it should be noted that caesarean section decreases the risk for perinatal HPV transmission by approximately 46%. Perinatal transmission still occurs in approximately 15% of the children born by caesarean section.


Unusual presence of Ornidia robusta (Diptera: Syrphidae) causing pig myiasis in Argentina.
Myiasis is caused by dipterous larvae from the Calliphoridae, Sarcophagidae, Muscidae, Cuterebridae, and Syrphidae families. In this work, Cochliomyia hominivorax, Chrysomya megacephala, and Ornidia robusta were identified causing vulva, ear, and leg myiasis in pigs in Tucuman province, northwestern Argentina. The report of the presence of C. hominivorax and C. megacephala is very important due to their role as myiasis-causing and disease vectors. The occurrence of Ornidia robusta is remarkable, since it constitutes the first record of myiasis in general and of myiasis in pigs in particular. Lastly, the presence of Sarcophaga spp. is also interesting, since some of them originate myiasis and are therefore of concern for cattle, wild animals, and human populations.


Malaria vaccines since 2000: progress, priorities, products.
Malaria vaccine development entered a new era in 2015 when the pre-erythrocytic Plasmodium falciparum candidate RTS,S was favorably reviewed by the European Medicines Agency and subsequently introduced into national pilot implementation programs, marking the first human anti-parasite vaccine to pass regulatory scrutiny. Since the first trials published in 1997, RTS,S has been evaluated in a series of clinical trials culminating in Phase 3 testing, while testing of other pre-erythrocytic candidates (that target sporozoite- or liver-stage parasites), particularly whole sporozoite vaccines, has also increased. Interest in blood-stage candidates (that limit blood-stage parasite growth) subsided after disappointing human efficacy results, although new blood-stage targets and concepts may revive activity in this area. Over the past decade, testing of transmission-blocking vaccines (that kill mosquito/sexual-stage parasites) advanced to field trials and the first generation of placental malaria vaccines (that clear placenta-sequestering parasites) entered the clinic. Novel antigen discovery, human monoclonal antibodies, structural vaccinology, and improved platforms promise to expand on RTS,S and improve existing vaccine candidates.


Genome-wide identification, phylogenetic and expression analysis of the maize HECT E3 ubiquitin ligase genes.
HECT (homologous to the E6AP carboxyl terminus) ubiquitin ligase genes (E3s) are enzymes with diverse functions influencing plant growth, development, and responses to abiotic stresses. However, there is relatively little information available regarding the maize HECT E3 gene family. In the present study, 12 maize HECT E3 genes (ZmUPL1 to ZmUPL12) were identified at the whole-genome level. The phylogenetic relationships, structures, and expression levels of the maize HECT E3 genes were then analyzed. On the basis of the constructed maximum likelihood phylogenetic tree, the HECT E3 genes were divided into six groups. The quantitative real-time polymerase chain reaction assay results revealed that all of the maize ZmUPL genes were expressed in most of the examined tissues and were responsive to three abiotic stresses. Considered together, the study results may provide a useful foundation for future investigations of maize stress-tolerance genes as well as functional analyses of the E3 enzymes in diverse agriculturally important crop species.


Why the American Academy of Pediatrics recommends initiating HPV vaccine at age 9.
The American Academy of Pediatrics (AAP) recommends starting the human papillomavirus (HPV) vaccine series between 9 and 12 years, at an age that the provider deems optimal for acceptance and completion of the vaccination series. This recommendation differs from the Advisory Committee on Immunization Practices (ACIP), which recommends HPV vaccination be initiated at age 11 or 12 years, stating the series can be started at age 9 years. This commentary discusses the reasoning behind AAP's decision to differ from ACIP, as the AAP and ACIP schedules are essentially harmonized for all other vaccines. Reasons include recognition that (1) vaccination uptake is suboptimal; (2) offering vaccination earlier offers provider's flexibility in introducing the vaccine; (3) initiating the vaccine at age 9 or 10 may be preferable for parents or adolescents who do not want to receive ≥3 concomitant vaccines at age 11 or 12; (4) earlier initiation may disentangle HPV recommendations from discussions of sexuality; (5) earlier recommendation might alleviate HPV vaccine hesitancy "fatigue;" (6) the immune response is robust at younger ages with no evidence of waning protection; and (7) there is a dearth of evidence supporting starting the recommendation at age 11 or 12 within the "adolescent immunization platform."


Symptoms of depression change with olfactory function.
Olfactory loss is associated with symptoms of depression. The present study, conducted on a large cohort of mostly dysosmic patients, aimed to investigate whether improvement in olfactory performance would correspond with a decrease in depression severity. In 171 participants (157 dysosmic), we assessed olfactory function and severity of depression before and after an average interval of 11 months, with many patients showing improvement in olfactory function. Separate analyses were conducted for (a) the whole group of patients and (b) the group of dysosmic patients using both classic and Bayesian approaches. For odor identification, Student t test demonstrated that the whole sample improved consistently, especially within the group of dysosmic patients. The dysosmic group also improved in odor threshold and overall olfactory function. Pearson correlation showed that an increase in olfactory function was associated with a decrease in depression severity, particularly in dysosmic patients. To conclude, the present results indicate that symptoms of depression change with olfactory function in general and odor identification in particular.


The evolution of corneal and refractive surgery with the femtosecond laser.
The use of femtosecond lasers has created an evolution in modern corneal and refractive surgery. With accuracy, safety, and repeatability, eye surgeons can utilize the femtosecond laser in almost all anterior refractive procedures; laser in situ keratomileusis (LASIK), small incision lenticule extraction (SMILE), penetrating keratoplasty (PKP), insertion of intracorneal ring segments, anterior and posterior lamellar keratoplasty (Deep anterior lamellar keratoplasty (DALK) and Descemet's stripping endothelial keratoplasty (DSEK)), insertion of corneal inlays and cataract surgery. As the technology matures, it will push surgical limits and open new avenues for ophthalmic intervention in areas not yet explored. As we witness the transition from femto-LASIK to femto-cataract surgery it becomes obvious that this innovation is here to stay. This article presents some of the most relevant advances of femtosecond lasers to modern corneal and refractive surgery.


Zm401, a short-open reading-frame mRNA or noncoding RNA, is essential for tapetum and microspore development and can regulate the floret formation in maize.
In flowering plants, pollen formation depends on the differentiation and interaction of two cell types in the anther: the reproductive cells, called microsporocytes, and somatic cells that form the tapetum. Previously, we cloned a pollen specific gene, zm401, from a cDNA library generated from the mature pollen of Zea mays. Expression of partial cDNA of zm401 in maize and ectopic expression of zm401 in tobacco suggested it may play a role in anther development. Here we present the expression and functional characterization of this pollen specific gene in maize. Zm401 is expressed primarily in the anthers (tapetal cells as well as microspores) in a developmentally regulated manner. That is, it is expressed from floret forming stage, increasing in concentration up to mature pollen. Knockdown of zm401 significantly affected the expression of ZmMADS2, MZm3-3, and ZmC5, critical genes for pollen development; led to aberrant development of the microspore and tapetum, and finally male-sterility. Zm401 possesses highly conserved sequences and evolutionary conserved stable RNA secondary structure in monocotyledon. These data show that zm401 could be one of the key growth regulators in anther development, and functions as a short-open reading-frame mRNA (sORF mRNA) and/or noncoding RNA (ncRNA).


Introducing handheld computing into a residency program: preliminary results from qualitative and quantitative inquiry.
Although published reports describe specific handheld computer applications in medical training, we know very little yet about how, and how well, handheld computing fits into the spectrum of information resources available for patient care and physician training. This paper reports preliminary quantitative and qualitative results from an evaluation study designed to track changes in computer usage patterns and computer-related attitudes before and after introduction of handheld computing. Pre-implementation differences between residents and faculty s usage patterns are interpreted in terms of a "work role" construct. We hypothesize that over time residents and faculty will adopt, adapt, or abandon handheld computing according to how, and how well, this technology supports their successful completion of work role-related tasks. This hypothesis will be tested in the second phase of this pre- and post-implementation study.


Sirenomelia: a review on embryogenic enviromental theories, novel three-dimensional ultrasound imaging and first trimester diagnosis in a case of mosaic 69,XXX/46,XX fetus.
Sirenomelia is caused by atrophy of the lower extremities that is commonly associated with gastrointestinal and urogenital malformations. Embryogenic environmental theories and systematic review of the literature are reported. Genetic basis of the condition has been demonstrated in the animal model. In humans, association with de novo balanced translocation has only recently been documented. A case of triploidy mosaic fetus with sirenomelia and posterior fossa anomaly diagnosed at first trimester using novel three-dimensional ultrasound imaging techniques is presented.


Content of intrinsic disorder influences the outcome of cell-free protein synthesis.
Cell-free protein synthesis is used to produce proteins with various structural traits. Recent bioinformatics analyses indicate that more than half of eukaryotic proteins possess long intrinsically disordered regions. However, no systematic study concerning the connection between intrinsic disorder and expression success of cell-free protein synthesis has been presented until now. To address this issue, we examined correlations of the experimentally observed cell-free protein expression yields with the contents of intrinsic disorder bioinformatically predicted in the expressed sequences. This analysis revealed strong relationships between intrinsic disorder and protein amenability to heterologous cell-free expression. On the one hand, elevated disorder content was associated with the increased ratio of soluble expression. On the other hand, overall propensity for detectable protein expression decreased with disorder content. We further demonstrated that these tendencies are rooted in some distinct features of intrinsically disordered regions, such as low hydrophobicity, elevated surface accessibility and high abundance of sequence motifs for proteolytic degradation, including sites of ubiquitination and PEST sequences. Our findings suggest that identification of intrinsically disordered regions in the expressed amino acid sequences can be of practical use for predicting expression success and optimizing cell-free protein synthesis.


Present status of Catharanthus roseus monoterpenoid indole alkaloids engineering in homo- and hetero-logous systems.
Catharanthus roseus synthesizes one of the most structurally, chemically and biologically active phytomolecules monoterpenoids indole alkaloids (MIAs) with having a wide range of pharmaceutical activities. Being the sole source of antineoplastic MIAs vinblastine and vincristine C. roseus has become one of the most valued plant. The low in planta availability of these MIAs and unavailability of alternative chemical synthesis system has enhanced their demand and equally let to the exorbitant market cost. To bridge this gap alternative production systems have been investigated using MIAs metabolic engineering (ME) in the homologous and heterologous systems. The availability of improved recombinant technologies along with genomics and metabolomics tools has opened the door of tremendous new potentials of ME. To encash these potentials of ME for MIAs pathway, efforts were made by expressing constitutive structure biosynthesis enzymes, transporters, and transcription factors of C. roseus MIAs biosynthesis in both homologous and heterologous systems. Here we review the knowledge of C. roseus MIAs pathway metabolic engineering in homologous and heterologous systems, gained in the past 35 years of C. roseus research.


Long-term medical treatment in congenital hyperinsulinism: a descriptive analysis in a large cohort of patients from different clinical centers.
Up to now, only limited data on long-term medical treatment in congenital hyperinsulinism (CHI) is available. Moreover, most of the drugs used in CHI are therefore not approved. We aimed to assemble more objective information on medical treatment in CHI with regard to type and duration, dosage as well as side effects. We searched MEDLINE (from 1947) and EMBASE (from 1988) using the OVID interface for relevant data to evaluate medical treatment in a large cohort of patients with CHI from different clinical centers. Randomized, controlled trials were not available. We evaluated case reports and case series. No language restrictions were made. A total number of 619 patients were medically treated and information regarding conservative treatment was available. Drugs used were diazoxide (in 84% of patients), somatostatin analogues (16%), calcium channel antagonists (4%) and glucagon (1%). Mean dose of diazoxide was 12.5 (±4.3) mg/kg ⋅ d (range 2-60 mg/kg ⋅ d), mean duration of diazoxide treatment until remission was 57 months. Side effects of diazoxide were usually not severe. The causal relation between diazoxide and severe side effects, e.g. heart failure (3.7%) remains doubtful. Mean dose of octreotide was 14.9 (±7.5) μg/kg ⋅ d (range 2.3-50 μg/kg ⋅ d), of lanreotide 67.3 (±39.8) mg ⋅ month (range 10-120 mg ⋅ month). Mean duration of treatment with somatostatin analogues until remission was 49 months. Frequent side effects included tachyphylaxis and mild gastrointestinal symptoms. The risk of persistent growth deceleration was low (<5%). Severe side effects are rare and a causal relation remains disputable. We conclude that long-term conservative treatment of CHI is feasible.


Cerebral metabolism of parkinsonian primates 21 days after MPTP.
This study evaluates the changes in the local cerebral metabolic rate for glucose (LCMRg) in primates exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The LCMRg was evaluated 21 days following the last dose of MPTP. At this time, all MPTP-injected animals demonstrated parkinsonism and striatal dopamine was reduced to less than 3% of control values. The structures whose LCMRg was most affected were the motor cortex, the intermediate zone of the putamen, the external segment of the globus pallidus, the medial part of the ventrolateral nucleus of the thalamus (VLm), visual cortex, locus ceruleus, and the dorsolateral segment of the substantia nigra pars compacta. The structure whose increase in LCMRg correlated most closely to the clinical severity of parkinsonism was the external segment of the globus pallidus.


Measuring the electrical stapedius reflex with stapedius muscle electromyogram recordings.
Previous studies have demonstrated a correlation between cochlear implant recipients' comfort levels (C level, upper limit of dynamic range of stimulation) and the contralateral electrical stapedius reflex (ESR) threshold, detected by acoustic impedance change. However, the utility of the approach is limited because many recipients have no detectable impedance change. The goals of this study were to investigate the utility of the stapedial electromyogram (EMG) for estimating onset and strength of the ESR. Ketamine-anesthetized guinea pigs were implanted with Nucleus electrode arrays and stimulated with biphasic current pulse trains (250 pps) via a Cochlear Corporation CI24M stimulator. Typical EMG recordings (obtained with bipolar microwire electrodes) contained easily detectable unit potentials up to 300 microV in amplitude. Growth response curves (obtained from threshold-crossing counts or rms of the EMG signal) were typically monotonic with dynamic ranges spanning 700 microA or 8 dB. Based on adaptation and temporal properties, the stimulus protocol (500 ms duration with 4-5 s interstimulus intervals) was adequate for producing independent responses. The data presented are consistent with ESR characteristics (acoustic impedance technique) of cochlear implant recipients and with EMG properties of acoustically stimulated guinea pigs. Use of the EMG for characterizing the ESR may eventually be applied to human cochlear implant recipients as a guide in setting the upper limit of the dynamic range.


Getting it taped: the 'bad news' consultation with cancer patients.
'Not being told what is wrong' is the most frequent complaint patients make (Fletcher, 1980). In cancer a lack of information greatly increases the stress and anxiety experienced. In this report, 46 patients with cancer were given audiotape recordings of their 'bad news' consultations to take home. Analysis of subsequent questionnaire data revealed that both patients and their families benefited enormously from the opportunity to hear the details of their diagnosis and treatment again.


Dopamine-sensitive adenylate cyclase activity in the caudate nucleus and adrenal medulla in Parkinson's disease and in liver cirrhosis.
In human caudate nucleus and adrenal medulla dopamine-stimulated adenylate cyclase was measured. At a concentration of 100 microM dopamine, liver cirrhosis, carcinoma and therapy resistent parkinsonian patients showed decreased stimulation or even a reduction compared to controls. Therapy responding parkinsonian patients showed a decreased stimulation compared to controls, but this stimulation was significantly higher than in drug resistent patients.


[Contrast in static images in clinical magnetic resonance imaging. Part 2: Sequences for various contrast weightings and applications].
The second part of this educational article focuses on sequence techniques in magnetic resonance imaging (MRI) and on suitable parameter sets for different contrast weightings. The content is based on the recently published part 1 of this educational article providing a survey on tissue properties relevant for most important contrast mechanisms. Characteristics of contrast weightings are presented in exemplary images recorded from healthy volunteers. Typical clinical applications of the most commonly used contrast weightings are described and discussed. Sequences for the following contrast weightings are included: proton density (density of hydrogen in small mobile molecules), relaxation times T1 and T2, chemical shift (water and fat), effects of magnetic susceptibility, restricted diffusion of water molecules and magnetization transfer between macromolecules and water molecules.


Electrocardiographic abnormalities in patients with acute pancreatitis.
Electrocardiographic abnormalities may be associated with acute pancreatitis (AP). To describe the electrocardiographic disturbances present in patients with AP and to assess differences in electrolyte and pancreatic enzyme levels among patients with and without these abnormalities. Fifty-one consecutive patients with AP and without preexisting heart disease underwent a standard 12-lead electrocardiogram (EKG) and a serum electrolyte profile. EKG abnormalities were summarized in terms of frequencies, means, and standard deviations. Electrolyte and enzyme levels were summarized as medians. Differences were analyzed using the Mann-Whitney U test. Twenty-eight patients (55%) had an abnormal EKG. Nonspecific changes of repolarization (20%), sinus tachycardia (12%), and left anterior hemiblock (10%) were the most frequent disturbances. Patients with sinus tachycardia had lower levels of phosphorus (2.3 vs. 3.4 mEq/L, P < 0.004) and calcium (8.4 vs. 9.1 mg/dL, P < 0.02). A tendency to higher levels of potassium and lower levels of phosphorus was found in patients with sinus tachycardia and nonspecific changes of repolarization, respectively. No differences were found in amylase, pancreatic amylase, or lipase among patients with normal and abnormal EKG. More than 50% of the patients with AP had EKG abnormalities, and these changes could be related to electrolyte alterations.


Women's experiences of Group Cognitive Behaviour Therapy for hot flushes and night sweats following breast cancer treatment: an interpretative phenomenological analysis.
Many women with breast cancer experience problematic treatment-related menopausal symptoms (HF/NS). This study explores how these women experienced a Group Cognitive Behaviour Therapy (CBT) intervention to help them manage their treatment-related HF/NS. The study was conducted as part of a randomised control trial/RCT (MENOS 1) evaluating the intervention among this target group. In-depth semi-structured interviews were conducted with twenty trial participants to explore how they experienced the intervention and its effects. The interviews were analysed using interpretative phenomenological analysis. The analysis revealed four superordinate themes: Making sense of symptom change; new ways of coping and regaining control; tailoring the treatment to meet individual needs and resources; and valuing the group context, social support and social comparisons. All the women found Group CBT improved their ability to cope with their HF/NS, while also developing an appreciation of the role of psychological factors in their symptom experience. Through the knowledge and understanding acquired women developed a more accepting stance to their symptoms, as well as gaining a 'sense of control'. The results are consistent with the main RCT outcomes which showed that Group CBT led to a clinically significant reduction in 'HF/NS problem rating' relative to 'treatment as usual', as well as improvements in mood and physical and social functioning. The results complement the trial outcomes by illuminating women's experience of different components of the intervention and highlighting possible mechanisms of change.


Factors influencing the luminescence intensity of europium(III) complexes prepared via synergistic extraction.
The excitation and luminescence spectra of Eu(III) extracted with pivaloyltrifluoroacetone (HA) and/or 2,2'-bipyridyl (B) into CHCl3 were measured. The data were compared to those obtained in an HA/CHCl3 solution into which EuA3 or EuA3B was dissolved. The results are summarized as follows: (1) The degree of HA influence on the luminescence intensity differs in the two systems; in the HA/CHCl3-dissolved EuA3, the intensity abruptly decreases when the HA concentration exceeds approximately 10(-2)M, depending on EuA3 concentration. The data measuring the size of the dominant species in the CHCl3 containing EuA3 and HA via DLS indicate that the abrupt concentration quenching is due to the formation of aggregate consisting of EuA3 and HA. However, in the solvent-extracted sample, the luminescence intensity is not influenced by the HA concentration, even at 0.1M HA. This difference can be explained by the difference in water content. (2) In the synergistic extraction of Eu(III) with HA and B, the intensity is not substantially influenced by HA. The effect of HA on the luminescence intensity in the B/CHCl3-dissolved EuA3 is larger than that obtained via solvent extraction. These results suggest that synergistic extraction could be an efficient method for preparing the phosphor in solution and that, when using luminescence intensity to determine Eu(III) concentration, one should be careful for the other materials, such as HA, that are involved in the solution and serve as reference materials.


Metabolic Engineering of Escherichia coli for Production of α-Santalene, a Precursor of Sandalwood Oil.
α-Santalene belongs to a class of natural compounds with many physiological functions and medical applications. Advances in metabolic engineering enable non-native hosts (e.g., Escherichia coli) to produce α-santalene, the precursor of sandalwood oil. However, imbalances in enzymatic activity often result in a metabolic burden on hosts and repress the synthetic capacity of the desired product. In this work, we manipulated ribosome binding sites (RBSs) to optimize an α-santalene synthetic operon in E. coli, and the best engineered E. coli NA-IS3D strain could produce α-santalene at a titer of 412 mg·L-1. Concerning the observation of the inverse correlation between indole synthesis and α-santalene production, this study speculated that indole-associated amino acid metabolism would be competitive to the synthesis of α-santalene rather than indole toxicity itself. The deletion of tnaA could lead to a 1.5-fold increase in α-santalene production to a titer of 599 mg·L-1 in E. coli tnaA- NA-IS3D. Our results suggested that the optimization of RBS sets of the synthetic module and attenuation of the competitive pathway are promising approaches for improving the production of terpenoids including α-santalene.


Treatment of tyramine-induced brain edema with anion transport inhibitor L-644,711.
Tyramine induces coma in phenelzine-treated dogs. Development of coma in these animals is associated with brain edema, abnormal brain scans of Tc-99m-diethylene-triamine-penta-acetic acid (Tc-99m-DTPA), and elevated levels of CSF catecholamines. We found that the intravenous administration of 6-7 mg/kg of a single dose of L-644,711 given fifteen minutes after the oral administration of tyramine to phenelzine-pretreated animals followed by an infusion of normal saline containing 6-7 mg/kg of the drug given over a period of 2 hr caused reversal of brain injury. This was accompanied by full recovery within a period of 24 hr of all the animals tested. A follow-up study revealed that 24 hr after treatment with L-644,711 CSF levels of catecholamines and brain images of Tc-99m-DTPA were indistinguishable from normal controls. Animals that received no drug died from unresolved coma within 4 to 24 hr. Animals that had recovered due to therapy with L-644,711 were given 10-14 days rest followed by a repetition of the phenelzine and tyramine treatment but denied L-644,711 therapy. These animals also died of unresolved coma within 24 hr. This preliminary study suggest that the use of L-644,711 may constitute an important advance in treatment of brain edema of a wide range of neurological disorders.


Effects of solar radiation on hair and photoprotection.
In this paper the negative effects of solar radiation (ultraviolet, visible and infrared wavelengths) on hair properties like color, mechanical properties, luster, protein content, surface roughness, among others, will be discussed. Despite knowing that radiation damages hair, there are no consensus about the particular effect of each segment of solar radiation on the hair shaft. The hair photoprotection products are primarily targeted to dyed hair, specially auburn pigments, and gray shades. They are usually based on silicones, antioxidants and quaternary chemical UV filters that have more affinity for negatively charged hair surface and present higher efficacy. Unfortunately, there are no regulated parameters, like for skin photoprotection, for efficacy evaluation of hair care products, which makes impossible to compare the results published in the literature. Thus, it is important that researchers make an effort to apply experimental conditions similar to a real level of sun exposure, like dose, irradiance, time, temperature and relative humidity.


[Role of the duodenal and hepatic cells lysosomes in the phenomenon of gadolinium accumulation].
The behaviour of the intestinal mucosa and of the liver after an administration of a gadolinium salt has been studied in the Wistar rat using transmission electron microscopy, ion mass spectrometry, and electron probe microanalysis. Six hours after parenteral administration, gadolinium is concentrated with phosphorus in the lysosomes of hepatocytes and Küppfer cells. Six hours after its oral administration, gadolinium is detected in the duodenal enterocytes lysosomes, but never in those of the liver cells. It is suggested that this mechanism of local concentration limits the diffusion through the digestive barrier of foreign elements, some of them being toxic and none of them having a physiological function.


Expanded Azaporphyrins Consisting of Multiple BODIPY Units: Global Aromaticity and High Affinities Towards Alkali Metal Ions.
The one-pot self-coupling reaction of 3-amino-5-bromo-BODIPY 9 under Buchwald-Hartwig amination conditions gave nitrogen-bridged cyclic BODIPY tetramer 10, pentamer 11, and hexamer 12. Oxidation of 10, 11, and 12 in the presence of alkali metal ions provided 13, 15, and 16, respectively, as the first examples of expanded azaporphyrins possessing more than six pyrrole rings. Curiously, the oxidation even in the absence of alkali metal ions gave the same complexes as a result of spontaneous complexation. 10-12 showed large association constants (104 -106 M-1 ) with K+ and Na+ , but the spontaneous complexations were not observed, indicating the extremely high affinities of 13-16 toward alkali metal ions, which can be ascribed to the multiple and effective ion-dipole interaction of the alkali metal ion with the negatively polarized F atoms of the BF2 walls surrounding the cavity. Importantly, 13, 14, and 15 show diatropic ring currents as a result of global aromaticity.


Pacing threshold increase in nonthoracotomy implantable defibrillator leads: implications for battery longevity and margin of safety.
Just as a stable defibrillation threshold is required for implantable defibrillators to maintain efficacy and a margin of safety for the conversion of life-threatening ventricular arrhythmias, a stable pacing threshold is also required to provide bradycardia support and pacing to terminate ventricular tachycardias. This article reports the temporal course of pacing thresholds in patients treated with a tripolar, tined endocardial defibrillator lead capable of bipolar sensing and pacing, and defibrillation. Seventeen patients who underwent implantation of an implantable defibrillator system using an integrated bipolar pacing/sensing system were prospectively studied over 18 months. There were 16 males and one female, with a mean age of 69 +/- 5 years (range 61-75 years). At implantation, predischarge, and every 2 months thereafter, the pacing pulse-width threshold was tested at both 2.5 and 5.0 V stimulus amplitudes. After a mean follow-up of 363 +/- 173 days (range 34-597 days), the pacing threshold increased from 0.08 +/- 0.08 ms to 0.5 +/- 0.3 ms at the 2.5 V amplitude (p < or = 0.01, CI-0.57 to -0.27) and from 0.04 +/- 0.02 ms to 0.25 +/- 0.14 ms at the 5.0 V amplitude (p < or = 0.01, CI -0.28 to -0.14). Eight of the 17 patients (47%) received spontaneous implantable defibrillator shocks for clinically detected arrhythmias, and the total number of joules delivered via the leads did not correlate with the pacing threshold changes. We conclude that the pacing threshold for the nonthoracotomy implantable defibrillator lead system studied is not stable and increases with time. This finding has implications for defibrillator battery life in patients who use implantable defibrillators for bradycardia pacing.


Aromatic interactions at atom-to-atom contact and just beyond: a case study of protein interactions of NAD⁺/NADP⁺.
We probed aromatic-protein interactions based on specificity of enrichment of protein residues across a contact-based cutoff. Thus, 155 protein-NAD(+)/NADP(+) complexes were analyzed for enrichments within 10Å of centroids of aromatic groups of the ligand when the residues were contacted and not contacted with the aromatic ligand. Specifically, neutral-adenine and cationic-nicotinamide groups of the oxidized coenzymes evoked interest to know whether the contrast of charge or the shared aromaticity will manifest in the enrichments across the cutoff. We found that when in contact, the enrichments are highly specific for nicotinamide and adenine-aromatic structures, and thus possibly complex in the basis, but when not in contact, they are generic for charge and aromaticity of the structures, and thus possibly specific in the basis. The order of enrichments over the contacted residues is Tyr>Cys>Thr>His>Asn>Ser>Met>Ile>Phe against nicotinamide-π(+) structure and Asp>Ile>Thr>His>Arg>Tyr>Gly>Val against adenine-π structure, while the order over the non-contacted residues is Trp>Gly>His>Asn>Cys>Met>Tyr>Ser>Thr>Phe against nicotinamide-π(+) structure and Asn>Thr>Ser>Gly>Cys>His>Val against adenine-π structure. Neutral Trp, His, Tyr, and Phe, but not cationic Arg, are thus the non-contacted residues enriched specifically against nicotinamide-π(+) structure, while Asn, Gly, Thr, Ser, and Cys are the non-contacted residues enriched generically against both the nicotinamide-π(+) and adenine-π aromatic structures. By analyzing the enriched groups in their geometric specificities, we found that, the enrichments against nicotinamide cation manifest the specificity expected of cation-π interaction and against nicotinamide- and adenine-aromatic groups manifest the specificity expected of dipole-π interaction. The cutoff-based method is proven valuable in probing protein-ligand interactions in the physics involved.


Identification of therapeutic targets from genetic association studies using hierarchical component analysis.
Mapping disease-associated genetic variants to complex disease pathophysiology is a major challenge in translating findings from genome-wide association studies into novel therapeutic opportunities. The difficulty lies in our limited understanding of how phenotypic traits arise from non-coding genetic variants in highly organized biological systems with heterogeneous gene expression across cells and tissues. We present a novel strategy, called GWAS component analysis, for transferring disease associations from single-nucleotide polymorphisms to co-expression modules by stacking models trained using reference genome and tissue-specific gene expression data. Application of this method to genome-wide association studies of blood cell counts confirmed that it could detect gene sets enriched in expected cell types. In addition, coupling of our method with Bayesian networks enables GWAS components to be used to discover drug targets. We tested genome-wide associations of four disease phenotypes, including age-related macular degeneration, Crohn's disease, ulcerative colitis and rheumatoid arthritis, and demonstrated the proposed method could select more functional genes than S-PrediXcan, the previous single-step model for predicting gene-level associations from SNP-level associations.


Application of diatomite for sorption of Pb, Cu, Cd and Zn from aqueous solutions: kinetic, thermodynamic studies and application of response surface methodology (RSM).
Contamination of water and soil with toxic metals is a serious environmental issue. To study the Pb, Cu, Cd, and Zn sorption behavior by diatomite, batch experiments were carried out with increasing levels of initial concentration (0-200 mg/L) under different contact times (0-360 min) and temperatures (283, 293, 303, and 313 K). The effects of concentration (0-200 mg/L), pH (3-6), and ionic strength (0.01-0.06 mol/L) on the sorption were modeled using response surface methodology (RSM). Results showed that adsorption data were well-fitted by the Langmuir equation. The sorption of metals intensified by increasing initial concentration and pH but ionic strength had inverse effect. High value for R2 (0.99) and adjusted R2 (0.99) showed that the removal of ions can be described by response surface method. One-way ANOVA showed (p-value < 0.0001) that quadratic model is the best model for determining the interaction of variables. The values of the sorption energy parameter from Dubinin-Radushkevich model (E < 8 kJ K-1 mol-1 ) and negative values of ∆G showed that the sorption of the metals was physical and spontaneous. The positive values of enthalpy (ΔH) indicated that the sorption reaction of metals was endothermic at 283-313 K. PRACTITIONER POINTS: Applications of diatomite increased the sorption of Pb, Cd, Zn, and Cu from aqueous solutions. Diatomite, as low-cost adsorbent, had significant potential to sorption of ions. The sorption of heavy metals by adsorbent intensified by increasing initial concentration and pH but ionic strength had inverse effect. High value for R2 (0.99) and adj-R2 (0.99) showed that removal of metals can be described by response surface method (RSM) and the initial concentration of metal was the most significant factor.


Profiling patterns of fecal 20-oxopregnane concentrations during ovarian cycles in free-ranging southern white rhinoceros (Ceratotherium simum simum).
Unlike their wild counterparts, many white rhinoceros females in captivity fail to reproduce successfully such that current captive populations are not self-sustaining. The causes of the problem are poorly understood. Variation in cycle length and long periods of acyclicity are characteristics of the majority of these non-reproducing females in captivity but it is unknown whether these characteristics are a feature of reproductively successful free-ranging females. This study therefore aimed to monitor cyclic activity in a wild population of southern white rhinoceros at Lapalala Wilderness, South Africa, by measuring the concentrations of immunoreactive fecal progestagen metabolites (fPM). Five adult females were tracked twice per week for 20 months and if located a fresh fecal sample was collected. Reproductive events and group structural dynamics were also recorded and subsequently correlated with the fPM data. The baseline concentration of fPM was 0.69±0.20μg/g DW while concentrations during pregnancy were 30-400-fold higher. The females exhibited estrous cycle lengths of 30.6±7.7 days and, based on fPM data, gestation length in one female was 502±3 days. Year-round monitoring showed no clear evidence of seasonality in ovarian activity. During cyclic luteal activity females were often seen in the presence of a dominant bull. One female stopped cycling after removal of the local dominant bull and luteal activity only returned after a new bull was introduced. This suggests that white rhinoceros females in the wild might need external stimuli from a male to ovulate. These findings indicate that the irregular cyclicity reported for white rhinoceros housed in zoos and animal parks may result from conditions in captivity and account for reduced fertility.


Messenger RNA degradation: beginning at the end.
The mechanisms responsible for mRNA decay in mammalian cells, and how specific sequence elements accelerate decay, are unknown. Recent work indicates that 'ARE' instability elements recruit the exosome to promote rapid 3'-to-5' degradation of the mRNA.