The utility of dried blood spot monitoring of branched-chain amino acids for maple syrup urine disease: A retrospective chart review study.
Branched-chain amino acid (BCAA) concentrations must be tracked and maintained within an optimal range to minimize disease phenotypes in patients with maple syrup urine disease (MSUD). In 2014, the Hospital for Sick Children (SickKids) implemented a dried blood spot (DBS) home monitoring system, allowing patients to track BCAA concentrations without the inconvenience of having to travel to the hospital. We conducted a retrospective chart review study (n = 15) to assess the impacts of DBS monitoring implementation on biochemical control. Furthermore, we explored relationships among various MSUD patient parameters, including monitoring frequency, age, biochemical control, and hospitalizations. There was a 35% increase in the proportion of LEU concentrations that met recommended targets post-DBS monitoring implementation. Monitoring frequency was positively associated with better biochemical control in the newborn period (r = 0.68, p = 0.046). Frequency of hospital visits decreased steadily throughout life. DBS monitoring has resulted in a sharp increase in monitoring frequency, which is further correlated with biochemical control. Younger patients are more likely to visit the hospital and respond better to increased monitoring efforts. We recommend that DBS monitoring be adopted by other centers more broadly to improve metabolic control in MSUD patients.


The toxicology of gallium oxide in comparison with gallium arsenide and indium oxide.
Gallium arsenide (GaAs) and indium oxide (In2O3) are used in electronic industries at high and increasing tonnages since decades. Gallium oxide (Ga2O3) is an emerging wide-bandgap transparent conductive oxide with as yet little industrial use. Since GaAs has received critical attention due to the arsenic ion, it seemed reasonable to compare its toxicology with the respective endpoints of Ga2O3 and In2O3 toxicology in order to find out if and to what extent arsenic contributes. In addition, the toxicology of Ga2O3 has not yet been adequately reviewed, Therefore, this review provides the first evaluation of all available toxicity data on Ga2O3. The acute toxicity of all three compounds is rather low. Subchronic inhalation studies in rats and mice revealed persistent pulmonary alveolar proteinosis (PAP) and/or alveolar histiocytic infiltrates down to the lowest tested concentration in rats and mice, i.e. 0.16 mg Ga2O3/m3. These are also the predominant effects after GaAs and In2O3 exposure at similarly low levels, i.e. 0.1 mg/m3 each. Subchronic Ga2O3 exposure caused a minimal microcytic anemia with erythrocytosis in rats (at 6.4 mg/m3 and greater) and mice (at 32 and 64 mg/m3), a decrease in epididymal sperm motility and concentration as well as testicular degeneration at 64 mg/m3. At comparable concentrations the hematological effects and male fertility of GaAs were much stronger. The stronger effects of GaAs are due to its better solubility and presumed higher bioavailability. The database for In2O3 is too small and subchronic testing was at very low levels to allow conclusive judgements if blood/blood forming or degrading and male fertility organs/tissues would also be targets.


Relationship Between Expression of microRNA and Chemotherapy Resistance in Cervical Carcinoma.
Cervical cancer (CC), although being a potentially avoidable disease, is the second most often diagnose gynecological cancer, with at minimum 530,000 new instant reported each year, and optimism for CC remains poor. Nearly half of individuals with locally advanced cervical cancer have a poor pathological response to standard therapy. As a result, research into the molecular pathogenesis of cervical cancer and associated therapeutic targets is a must. MicroRNAs (miRNAs) are possible biomarkers in cervical cancer; elevations or reductions in many distinct miRNAs discovered in individuals with this illness indicate that miRNA could contain a function to play in the illness's pathogenesis. Nevertheless, little is known about their significance in detecting individuals who do not respond to traditional therapy. As a consequence, the intention of this study is to look at the relationship among the synthesis of miRNAs (miR 217 and miR-140-3p), which can be utilized as molecular biomarkers to predict pathological responses in cervical cancer patients after radiation and chemotherapy. Various analytical techniques were used to analyze the data, including quantitative real-time PCR (qRT-PCR), growth and apoptosis analysis, western blot analysis, luciferase reporter gene analysis, immunohistochemistry, and statistical analysis. The results show that such miRNAs participate a crucial responsibility in CC cell proliferation inhibition. They might be a new therapeutic target for microRNA-mediated cell proliferation inhibition in cervical cancer.


6 compared with 12 weeks treatment in the von Rosen splint is sufficient for Barlow and Ortolani positive hips: a comparative study of 237 neonates.
At our institution, newborns with Barlow or Ortolani positive hips have been treated for 12 weeks with the von Rosen abduction splint until 2012 when the treatment length was halved. We investigate whether acetabular development at 12 months of age and complications differ between hips treated with the von Rosen splint for 6 compared with 12 weeks. 99 patients were included in the 6-week program and 138 patients in the 12-week program. We measured the acetabular index (AI) on standard anteroposterior pelvic radiographs taken at 12 months of age. Medical records were reviewed for complications and additional treatments until age 12 months. We used non-inferiority testing with an equivalence margin of 1° with a 95% confidence interval (CI) to compare the 2 groups. The mean AI at 12 months in the 6-week group was 25° (CI 24-26) compared with 25° (CI 25-26) in the 12-week group. Non-inferiority was demonstrated for the 6-week program: -0.2° (CI -1.1 to 0.7). In the 6-week group, 8 patients received additional treatment, including 1 hip dislocation that occurred between 6 weeks and 3 months. There were no additional treatments or complications in the 12-week group. AI was equal at 12 months of age for patients treated for 6 compared with 12 weeks in the von Rosen splint. The hip dislocation which occurred indicates that follow-up around 3 months of age is indicated.


MiR-302b as a Combinatorial Therapeutic Approach to Improve Cisplatin Chemotherapy Efficacy in Human Triple-Negative Breast Cancer.
Introduction: Chemotherapy is still the standard of care for triple-negative breast cancers (TNBCs). Here, we investigated miR-302b as a therapeutic tool to enhance cisplatin sensitivity in vivo and unraveled the molecular mechanism. Materials and Methods: TNBC-xenografted mice were treated with miR-302b or control, alone or with cisplatin. Genome-wide transcriptome analysis and independent-validation of Integrin Subunit Alpha 6 (ITGA6) expression was assessed on mice tumor samples. Silencing of ITGA6 was performed to evaluate cisplatin response in vitro. Further, potential transcription factors of ITGA6 (E2F transcription facor 1 (E2F1), E2F transcription factor 2 (E2F2), and Yin Yang 1 (YY1)) were explored to define the miRNA molecular mechanism. The miR-302b expression was also assessed in TNBC patients treated with chemotherapy. Results: The miR-302b-cisplatin combination significantly impaired tumor growth versus the control through indirect ITGA6 downregulation. Indeed, ITGA6 was downmodulated in mice treated with miR-302b-cisplatin, and ITGA6 silencing increased drug sensitivity in TNBC cells. In silico analyses and preclinical assays pointed out the regulatory role of the E2F family and YY1 on ITGA6 expression under miR-302b-cisplatin treatment. Finally, miR-302b enrichment correlated with better overall survival in 118 TNBC patients. Conclusion: MiR-302b can be exploited as a new therapeutic tool to improve the response to chemotherapy, modulating the E2F family, YY1, and ITGA6 expression. Moreover, miR-302b could be defined as a new prognostic factor in TNBC patients.


Porphyrin-like compounds genesis under simulated abiotic conditions.
Experiments with gas mixtures intended to simulate the primaeval atmosphere of the Earth yielded many biologically important chemicals. Investigations into the synthesis of porphyrin-like compounds from methane, ammonia and water vapour were carried out by using high frequency discharges. Microanalyses of porphyrins showed that porphyrin-like pigments were formed in this way. The presence of divalent cations in the reaction system increased the yield of porphyrin-like pigments also involving the direct synthesis of their metal complexes. The ready formation of these compounds in abiotic conditions is significant, suggesting the possibility of their appearance during the early stage of chemical evolution.


Binding of recombinant fibrinogen mutants to platelets.
Platelet aggregation is mediated by the interaction of fibrinogen with platelet membrane glycoprotein IIb-IIIa, a member of the integrin family (integrin alpha IIb beta 3). Three different binding sites on fibrinogen for IIb-IIIa have been proposed, two RGD-containing sequences in the alpha chain and one dodecapeptide sequence at the carboxyl terminus of the gamma chain. However, recent evidence shows that mutations in either of the alpha chain sequences have no effect on platelet aggregation, whereas the substitution of a variant gamma chain (gamma') for the gamma chain results in a major reduction in platelet aggregation activity. The present investigation demonstrates that the gamma' chain shows decreased binding to IIb-IIIa as measured by direct binding experiments. In addition, adhesion studies indicate that the binding of both stimulated and unstimulated platelets to immobilized fibrinogens is mediated primarily through the gamma chain carboxyl terminus. Furthermore, a peptide corresponding to the carboxyl terminus of the gamma chain inhibits fibrinogen binding and platelet adhesion, whereas a peptide corresponding to the carboxyl terminus of the gamma' chain is significantly less inhibitory. These data show that the defective platelet aggregation activity of the fibrinogen gamma' chain is due to decreased binding to platelet glycoprotein IIb-IIIa.


Peptidyl beta-homo-aspartals: specific inhibitors of interleukin-1 beta converting enzyme and its homologues (caspases).
Inhibition of interleukin-1 beta converting enzyme (ICE), apopain, papain, thrombin and trypsin with substrate like peptidyl L- and D-alpha-aldehydes and their L-beta-homo-aldehyde analogues was investigated. The L-beta-homo-aspartals appear to be specific inhibitors for ICE and its homologues; the other enzymes were not inhibited with such L-beta-homo aldehydes. Papain shows tolerance for D-residues at P1 depending on their chiral stability.


Data scattering in scanning tunneling spectroscopy.
We investigated the scattering of current-voltage data obtained with scanning tunneling spectroscopy (STS) at room temperature at a solid-liquid interface on highly oriented pyrolytic graphite (HOPG) and in ultrahigh vacuum on HOPG and Au(111). For both experimental conditions, the data scattering can be described by a lognormal function for a moderate number of subsequent measurements. The lognormal distribution of the current can be explained by a normal distribution of the tip-surface distance. We give a simple empirical rule for STS data sorting.


Use of grafting materials during penile prosthesis implantation in patients with Peyronie's disease-a systematic review.
Severe Peyronie's disease (PD) and concomitant erectile dysfunction (ED) may require plaque incision/excision and grafting (PIG) as an adjunct to penile prosthesis implantation (IPP). Currently, there is no available consensus on the best graft material to use. Our aim was to systematically review graft materials used as patches following PIG + IPP. Literature search was performed in March 2021. Only original articles in English with a series of 10 or more patients were included. Overall, a total of 17 studies were included, corresponding to a cohort of 662 patients. The mean age ranged from 45 to 65 years and most patients had curvatures >45°. Average penile lengthening ranged from 1 to 3.5 cm, average residual curvatures from 0 to 20% and decreased glans sensitivity from 0 to 20%. Eighty to 100% of patients were satisfied with cosmetic and functional results. PIG + IPP with the use of various grafts offers promising results for the treatment of patients suffering from severe PD with concomitant ED. Unfortunately, the absence of high quality and comparative studies makes it difficult to establish the optimum graft. Therefore, the level of experience of the surgical team with one or more methods should guide their choice.


On the characteristics of the inward tail current induced by calcium overload.
The characterization of an inward tail current (Iex) induced by calcium overload and often associated with the oscillatory current (Ios) was studied by means of a two-microelectrode voltage clamp method in sheep cardiac Purkinje fibers. It was found that: (1) the inward tail current requires a prior depolarization to about -25 mV (or less negative values) in order to appear; (2) after depolarization to those values, the membrane needs to be repolarized to about -45 mV (or to more negative values) for the inward tail current to be initiated; (3) the inward tail current becomes larger after larger or longer clamp steps and increases progressively at more negative potentials; (4) the inward tail current can be separated from other known currents, notably from the pacemaker current; (5) the inward tail current is reduced by quinacrine, a blocker of Na-Ca exchange; (6) the inward tail current does not reverse at less negative potentials; (7) the membrane conductance does not increase during the inward tail current. Thus, the inward tail current shows similarities and dissimilarities with the oscillatory current, probably in relation to a common final pathway and to a different mode of onset of the two currents, respectively.


Hematopoietic MyD88-adaptor protein acts as a natural defense mechanism for cognitive deficits in Alzheimer's disease.
Accumulating evidence supports a critical role of Toll-like receptors in the clearance of Amyloid beta (Aβ) by microglial cells. Myeloid differentiation factor 88 (MyD88) is an adaptor protein that bridges the intracellular signal to nucleus for most of these innate immune receptors. We investigated here the role of competent MyD88 hematopoietic stem cells on the cognitive decline of a mouse model of Alzheimer's disease (AD). We generated classical chimeric mouse models using irradiation and transplantation of wild type GFP cells and MyD88-deficient cells. Transplantation of GFP cells essentially rescued the cognitive impairment, whereas MyD88-deficient cells significantly accelerated memory deficits of APP(swe)/PS1 mice. Moreover, we found that monocytes and microglia deficient for MyD88 exhibit a functionally impaired phagocytic reaction to Aβ.


Chicken telomerase reverse transcriptase mediates LMH cell pyroptosis by regulating the nuclear factor-kappa B signaling pathway.
The activation of human telomerase reverse transcriptase is regulated by the nuclear factor kappa B (NF-κB) signaling pathway to various degrees to promote the occurrence and development of tumors. However, the regulatory roles of chicken telomerase reverse transcriptase (chTERT) and the NF-κB signaling pathway in chickens are still elusive, particularly in respect to the regulation of cell pyroptosis. In this study, we found that chTERT upregulated the expression of p65 and p50, downregulated the expression of IκBα, promoted the phosphorylation of p65, p50, and IκBα, and significantly increased the transcript levels of the inflammatory cytokines IFNγ, TNFα, and IL-6 in LMH cells. The activity of NF-κB was significantly decreased after siRNA-mediated chTERT silencing. The expression of chTERT and telomerase activity were also significantly decreased when the NF-κB signaling pathway was blocked by p65 siRNA, MG132 or BAY 11-7082. In cells treated with LPS, the activity of NF-κB signaling pathway and the expression of chTERT were significantly upregulated. All of the results suggested that chTERT and the NF-κB pathway could regulate each other, reciprocally. Moreover, the expression of Caspase-1, NLRP3, GSDMA, IL-18, and IL-1β and caused membrane perforation, suggesting the development of pyroptosis by chTERT in LMH cells. And the expression of caspase-11 did not significantly increased in chTERT overexpression group. Genetic silence of NF-κB p65 or chTERT gene by siRNA suppressed the expression of these proinflammatory cytokines, indicating that chTERT mediates pyroptosis by regulating the NF-κB signaling pathway in LMH cells.


Application of a long-term enhanced xanthine oxidase-induced luminescence in solid-phase immunoassays.
The use of xanthine oxidase (XO) as a label in immunoanalysis has not been previously reported. This can be explained by the difficulties encountered in XO assays (poor sensitivity and versatility) and the competitive inhibition of the enzyme by allopurinol, a widely used hypouricemic agent. We demonstrate here that both difficulties can be circumvented. (i) The XO-dependent luminescent signal related to the oxidation of luminol is dramatically enhanced in the presence of iron-EDTA complex and sodium perborate in alkaline buffer. The mechanism of this enhancement is consistent with an O2-driven Fenton reaction, leading to the production of highly reactive OH radical. (ii) Residual inhibition of solid-phase bound XO by serum allopurinol and its metabolites is spontaneously reversible and can be prevented by the presence of folic acid or azahypoxanthine in the incubation buffer. With these two problems solved, XO can be classified as a choice label in immunoanalysis with the following properties: (i) high detection sensitivity (3 amol label), (ii) long-term luminescent signal (several days), (iii) versatile preparation and stability of conjugates, and (iv) long-term stability of the luminescence reagent. As an example of application, some data concerning total IgE and direct 17 beta-estradiol assays are described. Several other luminescent immunoassays of large and small molecules have been developed using XO conjugates as tracer (free and total T4, ultrasensitive thyroid stimulating hormone, CA 19.9, prolactin, hCG, specific IgE, anti-toxoplasma, and anti-chlamydia IgG), thus proving that XO can be classified as a universal label.


A review of wipes used to disinfect hard surfaces in health care facilities.
Despite a plethora of wipes available for use in health care facilities, there is a paucity of articles describing wipe composition, potential interactions between wipes and disinfectants, the manner in which wipes are used, and their relative efficacy. The purpose of this article is to provide an in-depth review of wipes used for disinfection of hard surfaces in health care settings. Comprehensive searches of the Pubmed database and Internet were conducted, and articles published from 1953 through September 2019 and pertinent on-line documents were reviewed. Bibliographies of relevant articles were reviewed. Wipes vary considerably in their composition, and the disinfectants with which they are used. With reusable dry wipes, the ratio of wipe material to disinfectant and the amount of disinfectant absorbed by the wipe and delivered to surfaces is difficult to standardize, which may affect their efficacy. The manner in which wipes are used by health care personnel is highly variable, due in part to insufficient instructions for use and inadequate education of relevant personnel. Additional research is needed regarding the best practices for using different types of wipes, improved methods for educating staff, and establishing the relative efficacy of wipes in reducing environmental contamination and health care-associated infections.


Modulation of Microglia by Voluntary Exercise or CSF1R Inhibition Prevents Age-Related Loss of Functional Motor Units.
Age-related loss of skeletal muscle innervation by motor neurons leads to impaired neuromuscular function and is a well-established clinical phenomenon. However, the underlying pathogenesis remains unclear. Studying mice, we find that the number of motor units (MUs) can be maintained by counteracting neurotoxic microglia in the aged spinal cord. We observe that marked innervation changes, detected by motor unit number estimation (MUNE), occur prior to loss of muscle function in aged mice. This coincides with gene expression changes indicative of neuronal remodeling and microglial activation in aged spinal cord. Voluntary exercise prevents loss of MUs and reverses microglia activation. Depleting microglia by CSF1R inhibition also prevents the age-related decline in MUNE and neuromuscular junction disruption, implying a causal link. Our results suggest that age-related changes in spinal cord microglia contribute to neuromuscular decline in aged mice and demonstrate that removal of aged neurotoxic microglia can prevent or reverse MU loss.


Lighting up silica nanotubes transcribed from the submicron structure of a metal-peptide hybrid.
Fluorescent silica nanotubes are attracting increasing interest because of their versatile applicability in a range of diverse fields. By using sol-gel transcription of tetraethylorthosilicate (TEOS) from various soft templates, silica nanotubes can be conveniently prepared. Metal-peptide hybrids with well-defined nanostructures and outstanding functionalities are very interesting candidates to serve as templates. Herein, we demonstrate that glutathione (GSH) can act as a building block for a bioinspired structure with dimensions down to the nanoscale, based on specific interactions between metal ions and the peptide. Congo red is able to selectively stain the nanofibres obtained, and appears apple-green in colour, implying that Congo red is promising to serve as an effective and convenient probe for determining the self-assembly of GSH and copper ions. Furthermore, silica nanotubes are synthesized using the nanofibres as a template in a very simple way. The silica nanotubes can be lit up by biomolecule-templated metal nanoparticles or nanoclusters and emit bright fluorescence. This work will certainly open up new opportunities in fabricating a broad range of nanostructured materials with versatile functionalities.


A comparative in vivo assessment of the long-term failure rate of 2 self-etching primers.
The purpose of this study was to comparatively assess the failure rate of brackets bonded with 2 self-etching adhesives after 14 months of treatment. Twenty-two patients with complete permanent dentitions, and similar treatment plans and mechanotherapies, were selected for the study. Four hundred twenty-three brackets were bonded by using a split-mouth design, with Transbond Plus Self-Etching Primer (3M Unitek, Monrovia, Calif) or One-Step Self-Etching Primer (Reliance, Itasca, Ill). These self-etching primers were applied alternately so that they were equally distributed on the maxillary and mandibular right and left quadrants. Failure rates were recorded for 14 months and analyzed with the chi-square test at alpha = 0.05 level of significance. Overall total failure rates were 0.94%, for Transbond Plus and 8.10% for One-Step. Although significantly more failures were found for the mandibular arch, no difference was identified in failure rate between anterior and posterior teeth. The results of this study suggest that care should be taken in ensuring the compatibility of retainers with adhesives.


A neutropenic child with a purple lesion on the thigh.
Zygomycosis is an aggressive infection by an angioinvasive fungus seen in patients with defects in phagocytosis. We describe a neutropenic child with primary cutaneous Rhizopus infection presenting with a bull's-eye appearance. The patient was treated with aggressive surgical debridement along with amphotericin B followed by skin grafting, with full recovery.


Reaction heat variation with pH in formation of the trypsin-soybean inhibitor complex.
The heat of reaction between beta-trypsin and Kunitz soybean inhibitor (STI) hasbeen measured at 5 degrees and 25 degrees from pH 4 to 8.5. Corresponding measuremenportion of tRNA-Gly2-GGA/G molecules isolated from E. coli cells. The missense suppressor mutation, glyTsuA36(HA), results in a C yields U base substitution at the 3' end of the anticodon of tRNA-Gly2-GGA/G(nucleotide position 38). Asecondary effect of this base substitution is the modification of the A residue directly adjacent to the 3' end of the anticodon of tRNA-Gly2-suA36(HA), suggesting that the enzymes responsible for this modification recognize the anticodon sequencesof prospective tRNA substrates. The creation of a missense-suppressing tRNA, tRNA-Gly2-suA36(HA), by an alteration of the anticodon sequence of tRNA-Gly2-GGA/G is analogous to mechanisms whereby other suppressor tRNAs have arisen. The high degree of nucleotide sequence homology between the amino acid acceptor stems and anticodon regions may be recognized by the glycyl-tRNA synthetase; the involvement of theanticodon region in the synthetase recognition process is supported by the greatly decreased rate of aminoacylation of tRNA-Gly2-suA36(HA).


Violations of human rights: health practitioners as witnesses.
For humanitarian health-care practitioners bearing witness to violations of human dignity has become synonymous with denunciations, human rights advocacy, or lobbying for political change. A strict reliance on legal interpretations of humanitarianism and human rights is inadequate for fully understanding the problems inherent in political change. With examples from the HIV/AIDS epidemic in the USA, the Rwandan genocide, and physician-led political activism in Nepal, we describe three cases in which health practitioners bearing witness to humanitarian and human-rights issues have had imperfect outcomes. However these acts of bearing witness have been central to the promotion of humanitarianism and human rights, to the pursuit of justice that they have inevitably and implicitly endorsed, and thus to the politics that have or might yet address these issues. Despite the imperfections, bearing witness, having first-hand knowledge of humanitarian and human-rights principles and their limitations, and systematically collecting evidence of abuse, can be instrumental in tackling the forces that constrain the realisation of human health and dignity.


Peripherally inserted central catheters in the patient with cardiomyopathy. The most cost-effective venous acess.
While waiting for a heart transplant, patients with cardiomyopathy receive positive inotropic agents and other medications that require ongoing venous access. To evaluate the cost effectiveness of bedside peripherally inserted central catheter (PICC) placement, a retrospective analysis was conducted comparing four types of venous access. Almost 4000 dwell days support the premise that bedside PICC placement is the most cost-effective method of providing ongoing venous access to the patient with cardiomyopathy.


The reproductive strategy of the gregarious parasitoid, Pteromalus puparum (Hymenoptera: Pteromalidae) : 1. Optimal number of eggs in a single host.
Pteromalus puparum is a gregarious parasitoid of many butterfly pupae. Adult size, mortality, and sex ratio of P. puparum, as a parasitoid of Papilio xuthus, were unit weight of the host. Effects of female size on fecundity, wing load, and longevity were also examined.The highest total weight of progeny from the host was attained when the number of eggs per gram of the host was approximately 150. Positive correlations were observed between the size of the females and their fecundity and wing load. The maximum longevity of the female kept with honey but without hosts was attained when the initial number of parasitoids per g of the host was 150.Considering the total fecundity of all female progeny, the reproductively most efficient number of eggs to be deposited per g of the host was estimated to be approximately 300. However, as shortage of food for the adult females strongly affects their fecundity, the reproductively most efficient number of eggs to be deposited per g of the host was about 70 when the adult female progeny was not provided with food.The optimal number of eggs to be deposited when the emale oviposits in the host under field conditions is discussed.


Dexmedetomidine Postconditioning Reduces Brain Injury after Brain Hypoxia-Ischemia in Neonatal Rats.
Perinatal asphyxia can lead to death and severe disability. Brain hypoxia-ischemia (HI) injury is the major pathophysiology contributing to death and severe disability after perinatal asphyxia. Here, seven-day old Sprague-Dawley rats were subjected to left brain HI. Dexmedetomidine was given intraperitoneally after the brain HI. Yohimbine or atipamezole, two α2 adrenergic receptor antagonists, were given 10 min before the dexmedetomidine injection. Neurological outcome was evaluated 7 or 28 days after the brain HI. Frontal cerebral cortex was harvested 6 h after the brain HI. Left brain HI reduced the left cerebral hemisphere weight assessed 7 days after the brain HI. This brain tissue loss was dose-dependently attenuated by dexmedetomidine. Dexmedetomidine applied within 1 h after the brain HI produced this effect. Dexmedetomidine attenuated the brain HI-induced brain tissue and cell loss as well as neurological and cognitive dysfunction assessed from 28 days after the brain HI. Dexmedetomidine postconditioning-induced neuroprotection was abolished by yohimbine or atipamezole. Brain HI increased tumor necrosis factor α and interleukin 1β in the brain tissues. This increase was attenuated by dexmedetomidine. Atipamezole inhibited this dexmedetomidine effect. Our results suggest that dexmedetomidine postconditioning reduces HI-induced brain injury in the neonatal rats. This effect may be mediated by α2 adrenergic receptor activation that inhibits inflammation in the ischemic brain tissues.


Publishing scientifically sound papers in Traditional and Complementary Medicine.
Non-conventional medical practices that make use of dietary supplements, herbal extracts, physical manipulations, and other practices typically associated with folk and Traditional Medicine are increasingly becoming popular in Western Countries. These practices are commonly referred to by the generic, all-inclusive term "Complementary and Alternative Medicine." Scientists, practitioners, and medical institutions bear the responsibility of testing and proving the effectiveness of these non-conventional medical practices in the interest of patients. In this context, the number of peer-reviewed journals and published articles on this topic has greatly increased in the recent decades. In this editorial article, we illustrate the policy of the Journal of Traditional and Complementary Medicine for publishing solid and scientifically sound papers in the field of Traditional and Complementary Medicine.


Emerging resistance to ceftriaxone treatment owing to different ampD mutations in Enterobacter roggenkampii.
The Enterobacter cloacae complex is responsible for a variety of infections in hospitalized patients and is resistant to β-lactam antibiotics owing to the expression of AmpC β-lactamase. We report emerging resistance in Enterobacter roggenkampii exposed to ceftriaxone and explore the mechanism underlying mutations responsible for this resistance. Three strains were derived from different samples from one patient (blood and liver abscess fluid). Antimicrobial susceptibility was evaluated by standard broth microdilution, while ampC expression was determined via RT-PCR. Genetic relatedness was evaluated via pulsed-field gel electrophoresis (PFGE). Species identification and comparative genome analysis were performed via genome sequencing. Mutation rate testing and selection of AmpC-derepressed mutants were conducted to explore the mutation mechanism. E. roggenkampii F1247 was susceptible to third-generation cephalosporins (3GCs); F95 and F1057, found in blood sample on day 11 and liver abscess drainage fluid on day 25, were resistant. ampC expression was 341- and 642-fold higher in F95 and F1057, respectively, than in F1247. Three isolates were the same PFGE and sequence types (ST1778) and were highly homologous (2 and 4 core genome single nucleotide polymorphism differences). Compared to F1247, F95 possessed a 575 bp deletion, including 537 bp of ampD, whereas F1057 harbored only one amino acid mutation (Leu140Pro in ampD). The mutation rates from F1247 exposure to cefotaxime, ceftazidime, ceftriaxone, piperacillin-tazobactam, and cefepime were (1.90 ± 0.21) × 10-8, (3.18 ± 0.43) × 10-8, (2.00 ± 0.20) × 10-8, (2.92 ± 0.29) × 10-9, and zero, respectively. In vitro-selected mutations responsible for resistance were identified in ampD, ampR, and dacB. E. roggenkampii may develop resistance in vivo and in vitro upon exposure to 3GCs and to a lesser extent to piperacillin-tazobactam. 3GCs should not be used as a monotherapy for E. roggenkampii infections. Therapy using cefepime or carbapenems may be preferred to piperacillin-tazobactam in the treatment of E. roggenkampii, especially if source control is difficult.


Retention of Campylobacter (Campylobacterales: Campylobacteraceae) in the house fly (Diptera: Muscidae).
The house fly (Musca domestica L.) may transmit Campylobacter to broiler flocks. We assessed the retention time of house flies for Campylobacter jejuni at five temperatures and three doses. Flies were inoculated individually at their proboscis with 1.6 x 10(7) CFU (colony forming units) of C. jejuni and incubated at 15, 20, 25, 30, and 35 degrees C. Furthermore, a dose experiment was conducted at 25 degrees C where individual flies were inoculated in three series: 6.5 x 10(6), 6.0 x 10(4), and 8.2 x 10(2) C.jejuni CFU. Whole flies were tested for C. jejuni carriage at 0, 6, 12, 18, and 24 h by initial preenrichment in Bolton broth, which afterwards was streaked on modified mCCDA agar plates and incubated under micro-aerobic conditions. The results showed that the time C. jejuni remained in flies declined over time with ascending temperatures and when reducing the inoculation dose. All flies stayed Campylobacter positive 24 h postinoculation at 15 degrees C whereas only one-third of the flies were positive at 20 degrees C and few to none at 25, 30, and 35 degrees C. When combinations of temperature and retention time were expressed as accumulated day-degrees, data could be adequately fitted using a generalized linear mixed model that included a linear effect of day-degrees and the difference between the lowest and the two highest doses. Based on model predictions of selected combinations of temperature and dose, the time for 50% and 1% of flies containing Campylobacter was calculated. It is suggested that house flies are mainly short distance carriers of C. jejuni.


Angiotensin AT2 receptor deficiency after myocardial infarction: its effects on cardiac function and fibrosis depend on the stimulus.
Hearts of normotensive angiotensin II type 2 receptor (AT2)-deficient mice do not develop fibrosis after angiotensin II-induced chronic hypertension. Thus, the goal of our study was to clarify whether AT2 knockouts (KOs) are also characterized by altered left ventricular (LV) function and modified remodeling of the extracellular matrix (ECM) after induction of myocardial infarction (MI). MI was induced in 5-mo-old female AT2-deficient mice and controls by occlusion of the left coronary artery. Time-matched sham-operated animals served as controls. After 48 h, the first sets of mice were hemodynamically characterized using a pressure-tip catheter (n = 8/group). We also obtained pressure volume loops using a microconductance catheter in additional sets of animals 3 wk after induction of MI (n = 7/group). Finally, the collagen index was illustrated by Sirius red staining and quantified by digital analysis. Whereas the LV function of sham-operated animals did not differ between both genotypes, the collagen index was 44% lower in KO animals. Forty-eight hours and 3 wk post-MI, systolic and diastolic LV function were impaired in both AT2-deficient and wild-type (WT) animals to the same extent by approx 45%. No differences were found between the two genotypes with respect to LV hypertrophy and the fibrosis index in the infarcted and noninfarcted areas 3 wk post-MI. While AT2-KO mice had less cardiac collagen content under basal conditions, the receptor deficiency had no significant influence on LV function at the two investigated time points after induction of MI or on the remodeling of ECM at the latter time point. Thus, hypertension-induced fibrosis is probably triggered by other control mechanisms than fibrosis induced by MI.


The effect of zinc oxide nanoparticles on mouse spermatogenesis.
To evaluate the effects of zinc oxide nanoparticles on mouse spermatogenesis. Thirty two adult male NMRI mice were used. Experimental Groups (ZNP-1-ZNP-3) received one of the following treatments daily for 35 days: 5, 50 and 300 mg/kg zinc oxide nanoparticles respectively. Control group received only distilled water. Epididymal sperm parameters, testicular histopathology, morphometric analysis and spermatogenesis assessments were performed for evaluation of the zinc oxide nanoparticles effects on testis. Epididymal sperm parameters including sperm number, motility and percentage of abnormality were significantly changed in 50 and 300 mg/kg zinc oxide nanoparticles treated mice (p < 0.01). Histopathological criteria such as epithelial vacuolization, sloughing of germ and detachment were significantly increased in 50 and 300 mg/kg zinc oxide nanoparticles treated mice (p < 0.001). 300 mg/kg zinc oxide nanoparticles induced formation of multinucleated giant cells in the germinal epithelium. 50 and 300 mg/kg zinc oxide nanoparticles also caused a significant decrease in seminiferous tubule diameter, seminiferous epithelium height and maturation arrest (p < 0.001). Zinc oxide nanoparticles act as testicular toxicant and further studies are needed to establish its mechanism of action upon spermatogenesis.


Developmental plasticity of the hypoxic ventilatory response after perinatal hyperoxia and hypoxia.
Both genetic and environmental factors influence the normal development of the respiratory control system. This review examines the role perinatal O2 plays in the development of normoxic breathing and the hypoxic ventilatory response in mammals. Hyperoxia and hypoxia elicit plasticity in respiratory control that is unique to development and may persist weeks to years after return to normoxia. Specifically, both hyperoxia and hypoxia during early postnatal development attenuate the adult hypoxic ventilatory response, but the underlying mechanisms for this plasticity differ. Hyperoxia attenuates the hypoxic ventilatory response through potentially life-long changes in carotid body function. Neonatal hypoxia appears to have short-term effects on carotid body function, but persistent changes in the hypoxic ventilatory response may instead reflect changes in respiratory mechanics or related neural pathways. Overall, it appears that a relatively narrow range of environmental O2 is consistent with "normal" postnatal respiratory control development, predisposing animals to potentially maladaptive plasticity in the face of disease or atypical environmental conditions.


Occurrence of arsenic contamination in Canada: sources, behavior and distribution.
Recently there has been increasing anxieties concerning arsenic related problems. Occurrence of arsenic contamination has been reported worldwide. In Canada, the main natural arsenic sources are weathering and erosion of arsenic-containing rocks and soil, while tailings from historic and recent gold mine operations and wood preservative facilities are the principal anthropogenic sources. Across Canada, the 24-h average concentration of arsenic in the atmosphere is generally less than 0.3 microg/m3. Arsenic concentrations in natural uncontaminated soil and sediments range from 4 to 150 mg/kg. In uncontaminated surface and ground waters, the arsenic concentration ranges from 0.001 to 0.005 mg/L. As a result of anthropogenic inputs, elevated arsenic levels, above ten to thousand times the Interim Maximum Acceptable Concentration (IMAC), have been reported in air, soil and sediment, surface water and groundwater, and biota in several regions. Most arsenic is of toxic inorganic forms. It is critical to recognize that such contamination imposes serious harmful effects on various aquatic and terrestrial organisms and human health ultimately. Serious incidences of acute and chronic arsenic poisonings have been revealed. Through examination of the available literature, screening and selecting existing data, this paper provides an analysis of the currently available information on recognized problem areas, and an overview of current knowledge of the principal hydrogeochemical processes of arsenic transportation and transformation. However, a more detailed understanding of local sources of arsenic and mechanisms of arsenic release is required. More extensive studies will be required for building practical guidance on avoiding and reducing arsenic contamination. Bioremediation and hyperaccumulation are emerging innovative technologies for the remediation of arsenic contaminated sites. Natural attenuation may be utilized as a potential in situ remedial option. Further investigations are needed to evaluate its applicability.


Multi heart-cutting two-dimensional liquid chromatography-atmospheric pressure photoionization-tandem mass spectrometry method for the determination of endocrine disrupting compounds in water.
The multi-heart-cutting two-dimensional liquid chromatography-tandem mass spectrometry method using atmospheric pressure photoionization has been developed and successfully validated for the determination of nine endocrine disrupting compounds in river water. The method is based on the use of two different reverse-phase columns connected through a six-port two-position switching valve equipped with a 200 μl loop. An orthogonal separation was achieved by proper selection of stationary phases, mobile phases, and the use of a gradient elution in both dimensions. The method shows excellent performance in terms of accuracy (86.2-111.1%), precision (intra-batch: 6.7-11.2%, inter-batch: 7.2-13.5%), and sensitivity (1.2-7.1 ng l(-1)). Twenty real samples collected from the Loučka and the Svratka rivers were analyzed, the studied compounds were found in all Svratka samples (9.7-11.2 ng l(-1) for β-estradiol, 7.6-9.3 ng l(-1) for estrone, and 24.6-38.7 ng l(-1) for bisphenol A).


Bovine lactoferricin on non-specific immunity of giant freshwater prawns, Macrobrachium rosenbergii.
This study aimed to investigate the effects of dietary Bovine lactoferricin (LFcinB) on the growth performance and non-specific immunity in Macrobrachium rosenbergii. Five experimental diets were 1.0‰ Bovine lactoferricin (LCB1); 1.5‰ Bovine lactoferricin (LCB1.5); 2.0‰ Bovine lactoferricin (LCB2); 2.5‰ Bovine lactoferricin (LCB2.5); the control group, basal diet without Bovine lactoferricin. A total of 600 prawns were randomly assigned to 5 groups in triplicate in 15 tanks for an 8-week feeding trial. The results showed the final weight, weight gain rate, specific growth rate and survival rate of prawns in the treatment groups were significantly improved versus the control (P < 0.05). The feed conversion ratio was reduced significantly in treatment groups compared to the control (P < 0.05). Compared with the control, alkaline phosphatase (AKP), acid phosphatase (ACP), lysozyme (LZM), catalase (CAT), superoxide dismutase (SOD) activities in the hepatopancreas of the treatment groups were significantly enhanced, and malondialdehyde (MDA) content was reduced significantly (P < 0.05). Compared with the control, the relative expression levels of AKP, ACP, LZM, CAT, SOD, Hsp70, peroxiredoxin-5, Toll, dorsal and relish genes were significantly higher among treatment groups, except for the AKP gene in the LCB1 group and the Hsp70 gene in the LCB1.5 group (P < 0.05). Compared with the control, the relative expression levels of TOR, 4E-BP, eIF4E1α and eIF4E2 genes were significantly enhanced in the LCB1.5 group (P < 0.05). When resistance against Vibrio parahaemolyticus in prawn is considered, higher doses of Bovine lactoferricin show better antibacterial ability. The present study indicated that dietary Bovine lactoferricin could significantly improve the growth performance and improve the antioxidative status of M. rosenbergii. The suitable addition level is 1.5 g/kg. LFcinB has great potential as a new feed additive without the threat of drug resistance.


Capecitabine and irinotecan with bevacizumab 2-weekly for metastatic colorectal cancer: the phase II AVAXIRI study.
The optimal sequence of chemotherapeutic agents is not firmly established for the treatment of metastatic colorectal cancer (mCRC). This phase II multi-centre study investigated the efficacy and tolerability of a standard capecitabine plus irinotecan (XELIRI) regimen with bevacizumab in previously untreated patients with mCRC. Patients received intravenous irinotecan 175 mg/m(2) on day 1 and oral capecitabine 1000 mg/m(2) (800 mg/m(2) for patients >65 years of age) twice daily on days 2-8, followed by a 1-week rest, and bevacizumab 5 mg/kg as an intravenous infusion on day 1 every 2 weeks. Seventy-seven patients were included in the intention-to-treat and safety populations. Progression-free survival at 9 months was 61%. The overall response and disease control rates were 51% and 84%, respectively. Median progression-free and overall survival times were 11.9 and 24.8 months, respectively. 48 patients (62%) had at least one grade 3/4 adverse event, the most common being asthenia, diarrhoea and neutropenia. Quality of life varied little over the study period with mean visual analogue scale general health scores ranging from 71 to 76 over cycles 1-11. Our study found irinotecan and capecitabine administered fortnightly with bevacizumab in patients with mCRC to be an effective and tolerable regimen. clinicaltrials.gov identifier NCT00875771. Trial registration date: 04/02/2009.


Rapidly progressing bilateral cataracts in a patient with beta thalassemia and pellagra.
Soon after the diagnosis of pellagra in a 20-year-old patient with beta thalassemia, bilateral intumescent cataracts rapidly developed. We believe the patient's crystalline lenses were at an increased oxidative state due to iron overload from the thalassemia. Depletion of the lens epithelial cells of an important antioxidative agent (glutathione) as a result of niacin (vitamin B3) deficiency due to pellagra reduced the antioxidative capacity of the lenses. The oxidative damage led to rapid development of cataracts.


Pediatric constipation therapy using guidelines and polyethylene glycol 3350.
To review current guidelines on the treatment of functional constipation in pediatric patients, with an emphasis on the role of polyethylene glycol 3350 (PEG 3350). Primary medical literature published in English was identified by MEDLINE search (1980-May 2003). Recently published treatment guidelines relating to pediatric functional constipation and its pharmacotherapy are assessed and compared. Published trials evaluating PEG 3350 in pediatric subjects are discussed and their results applied to the clinical role and use of this new agent. Constipation is a common disorder among children. A number of factors may play a role. A variety of medications are commonly used for this disorder, although few treatments have undergone evaluation by controlled clinical trials. Consensus guidelines recommend either osmotic laxatives, mineral oil, or their combination for maintenance treatment in concert with patient and parental education and behavioral training. PEG 3350 solution (MiraLax) has been shown in recent clinical studies to be an effective maintenance treatment for pediatric constipation. PEG 3350 is an effective and well-tolerated treatment choice for pediatric constipation, especially as an adjunct to education and behavioral training. PEG 3350 is an option for children with constipation who have failed or are intolerant of other pharmacotherapies.


Evaluation and development of diagnostic tools for rapid detection of Riemerella anatipestifer and Pasteurella multocida in ducks.
Ducks suffer a huge economic loss as a result of infections with Pasteurella multocida and Riemerella anatipestifer, which cause high morbidity and mortality. Because these pathogens induce similar clinical symptoms when coinfections occur, it is very difficult to differentiate between them based just on clinical signs. Hence, these major pathogens must be quickly and accurately detected. A total of 104 birds ranging from 2 days to 4 weeks old were collected from Egyptian farms, and the outcomes were compared statistically. Conventional cultural identification procedures and a direct multiplex polymerase chain reaction assay were utilized to recognize both pathogens in a single tube reaction simultaneously. Then, the obtained isolates were characterized phenotypically and genotypically. Clinical signs appear at 2-4 weeks of age with respiratory distress (dyspnea), white fluid feces, and stunting. The scrutinized data demonstrated a significantly higher detection rate by PCR directly compared to classical culture procedures. Pasteurella multocida was detected only by PCR. The disc diffusion technique against ten antibiotics showed absolute susceptibilities to amikacin, doxycycline, and florfenicol. High levels of beta-lactam resistance were observed. Riemerella anatipestifer isolates were screened for pathogenicity and plasmid-borne blaTEM genes. All six isolates harbored five virulence genes: aspC, RA46, m28, pstS, and Nlp/P60. Moreover, blaTEM was identified into four isolates and deposited to GenBank with accession numbers OP347083, OP347084, OP347085, and OP347086. These results suggest advanced PCR assays can be applied to the field for rapid and valuable diagnosis of two significant pathogens and focus on the worth of ducks in the propagation of transferable antibiotic resistance genes into the environment.


Recovery of motor function and dopaminergic parameters in a mouse model of Parkinson's disease induced by co-administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and diethyldithiocarbamate.
Diethyldithiocarbamate (DDC) enhances the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We studied the time course of dopaminergic parameters and motor function of MPTP+DDC-lesioned C57BL/6 mice, a model of Parkinson's disease. MPTP+DDC-lesioned mice showed a decrease in dopamine (DA) and its metabolites contents in their striata 1, 3 and 6 weeks after MPTP+DDC-treatment, compared with those of each control group. The partial and significant recoveries in DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid contents were also observed after 6 weeks, compared with those at 1 week after treatment. In addition, bradykinesia due to DA depletion was observed in mice 1 week after MPTP+DDC-treatment, but it was not significant 3 weeks after the treatment. l-DOPA alone and a co-administration of l-DOPA and a monoamine oxidase-B inhibitor selegiline improved bradykinesia of this model, also suggesting that bradykinesia observed in the model was mediated to dopaminergic deficiency. On the other hand, the serotonin content increased slightly but significantly after 3 or 6 weeks, suggesting compensatory activation of the serotonergic system against DA depletion. Thus, the partial recovery of dopaminergic parameters, the recovery of motor function and the compensatory activation of the serotonergic system were observed in this model 3-6 weeks after MPTP+DDC treatment.


Luteal phase serum cell-free DNA as a marker of failed pregnancy after assisted reproductive technology.
DNA-damaging factors have been reported in patients that failed to achieve pregnancy after assisted reproductive technologies (ART). The hypothesis was that increased circulating cell-free DNA released by damaged cells could predict unfavorable conditions leading to failed ART treatment. The objective was to compare the relative concentrations of cell-free DNA in the luteal phase sera of nonpregnant versus pregnant patients. Frozen-thawed sera (30 IVF cases) were obtained 1 week after embryo transfer. There were 16 pregnant and 14 nonpregnant cases and controls consisting of male sera (n = 8 cases). Modified isocratic capillary electrophoresis was performed and the images analyzed for cell-free DNA. Circulating cell-free DNA were identified in the sera of all patients. The serum concentrations of high (12 kb) and low (1 kb) molecular weight cell-free DNA were similar for both nonpregnant and pregnant patients. Male control sera had higher cell-free DNA concentrations compared with females. Evaluation of sera from a control case showed no fluctuations in cell-free DNA concentrations throughout specific days of the menstrual cycle. The results do not support the use of the luteal phase cell-free DNA concentration as a marker for failed pregnancies. The equal concentrations of high and low molecular weight cell-free DNA and ladder band-like gel patterns suggested cell apoptosis as the source of DNA.


CREPT-MCNP code for efficiency calibration of HPGe detectors with the representative point method.
The representative point method for the efficiency calibration of volume samples has been previously proposed. For smoothly implementing the method, a calculation code named CREPT-MCNP has been developed. The code estimates the position of a representative point which is intrinsic to each shape of volume sample. The self-absorption correction factors are also given to make correction on the efficiencies measured at the representative point with a standard point source. Features of the CREPT-MCNP code are presented.


The nutritional status of plants from high altitudes : A worldwide comparison.
Are plants at high altitudes short in nutrients? In order to answer this question the mineral nutrient content of leaves from over 150 plant species from 9 different mountain areas of all major climatic zones were analyzed (Kjeldahl nitrogen in all, phosphate in half of the samples, K, Mg, Mn, Ca in the Alps only). The majority of data are from herbaceous perennials, but shrubs and trees were studied as well. N-partitioning was studied in 45 herbaceous species from contrasting altitudes in the Alps. The survey falls into three categories: (1) comparisons of whole communities of species from contrasting altitudes, (2) analysis of altitudinal gradients, and (3) additional collections from high altitude sites alone. Unlike the other mineral nutrients, nitrogen content follows consistent altitudinal and latitudinal trends. The higher altitude sample always had higher N content per unit leaf area, irrespective of life form, wherever comparable plants (the same or related species) were investigated at contrasting altitudes. N content per unit dry weight (%) increased with altitude in herbaceous plants (in some species >4%), but was remarkably stable in evergreen woody plants (around 1%). The mean fraction of total plant N allocated to leaves of herbaceous plants in the Alps was the same at low and high altitude (1/3 of total). Leaf N (%) from the regional upper limits of higher plant life reveals a latitudinal decrease from subarctic to equatorial mountains, which may be related to the duration of annual leaf activity. Since mean N content per leaf area hardly differs between the uppermost sites, life span expectation (sink-duration) seems to control carbon investments rather than N input per leaf area. The growth of leaves at high altitude seems to be controlled in a way that leads to comparatively high nutrient contents, which in turn support high metabolic activity. Inherent developmental growth constraints inhibit nutrient dilution in the plant body and thus defy the application of classical concepts of plant-nutrient versus soil-nutrient relations developed for lowlands and in particular for cultivated plants. The results re-emphasize the global significance of links between nitrogen content, leaf sclerophylly, leaf longevity and photosynthetic capacity.


Effect of dextran and aspirin on platelet adherence after transluminal angioplasty of normal canine coronary arteries.
The effect of low-molecular-weight dextran and aspirin on platelet deposition after transluminal coronary angioplasty was studied in a normal canine model. Eighteen anesthetized, open-chest dogs were separated into 4 groups. All dogs received 3,000 units of intravenous heparin 10 to 20 minutes before the procedure. Dogs in Group 1 served as controls and were given no further treatment. Dogs in Group 2 received low-molecular-weight dextran by continuous intravenous infusion at a rate of 20 ml/hour for 1 hour before balloon inflation. Dogs in Group 3 were given 500 ml of low-molecular-weight dextran as an intravenous bolus over 1 hour, beginning 4 hours before the procedure. Dogs in Group 4 were fed 20 mg/kg of aspirin 3 hours before angioplasty. The dogs were killed 10 minutes after angioplasty and the arterial segments subjected to balloon inflation submitted for electron microscopic analysis. An additional group of 10 dogs was used to assess the bleeding times and platelet counts from control and drug-treated dogs. Drug treatment was associated with significant prolongation of the bleeding time and reduction in platelet number. Extensive endothelial desquamation in the area of balloon angioplasty was observed in all dogs. However, no appreciable qualitative difference in either the degree or extent of rapid platelet deposition to the exposed subendothelium was discernible between the control and any of the treatment groups. These results do not confirm previous observations with low-molecular-weight dextran. Further work on the initial and long-term platelet response after endothelial injury should be undertaken in a primate atherosclerotic model.


Comparison of external beam treatment techniques for T1-2, N0, M0 glottic cancers.
The purpose of this study was to compare 4 different external beam radiation therapy treatment techniques for the treatment of T1-2, N0, M0 glottic cancers: traditional lateral beams with wedges (3D), 5-field intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), and proton therapy. Treatment plans in each technique were created for 10 patients using consistent planning parameters. The photon treatment plans were optimized using Philips Pinnacle(3) v.9 and the IMRT and VMAT plans used the Direct Machine Parameter Optimization algorithm. The proton treatment plans were optimized using Varian Eclipse Proton v.8.9. The prescription used for each plan was 63 Gy in 28 fractions. The contours for spinal cord, right carotid artery, left carotid artery, and normal tissue were created with respect to the patient's bony anatomy so that proper comparisons of doses could be made with respect to volume. An example of the different isodose distributions will be shown. The data collection for comparison purposes includes: clinical treatment volume coverage, dose to spinal cord, dose to carotid arteries, and dose to normal tissue. Data comparisons will be displayed graphically showing the maximum, mean, median, and ranges of doses.


Epidemiology and management of appendicular fractures occurring in neonatal intensive care patients.
To describe the epidemiology and management of appendicular fractures occurring in the neonatal ICU in a large series of patients treated a single, quaternary care neonatal intensive care unit. Patients <1 years old with appendicular fractures treated from 2012 to 2016 at a quaternary-level NICU were identified. Bivariate testing compared fractures, work-up and management based on designated mechanism (presumed birth-related vs unknown). In patients with unknown mechanism, factors with potential fracture association were analysed in a descriptive fashion. Eighty-five fractures (54 patients) were included. Mechanistic cohorts differed by birthweight (P < .001) and gestational age at birth (P < .001). Presumed birth-related fractures were more commonly upper extremity (P < .001), solitary (P = .001) and radiographically diagnosed in the acute state (<.001). The biochemical profile of the cohorts differed significantly. The prevalence of factors with potential fracture association was high in patients with unknown mechanism. Only one patient required surgery, while all others resolved with minimal orthopaedic intervention. Findings indicate these injuries rarely require operative intervention and that two distinct injury profiles appear to exist based on fracture mechanism. Steroid use, ventilation use, diuretic use, nutritional supplementation and recent bedside procedures were common among patients without known fracture mechanism. Level III-Retrospective Cohort Study.


Extending infection prevention and control nursing (IPCN) provision to weekends at one National Health Service hospital in the United Kingdom: A feasibility and acceptability study.
Hospital Infection Prevention and Control Teams (IPCTs) provide clinical cover during weekdays with on call support at weekends. We report the results of a 6-month pilot of extending infection prevention and control nursing (IPCN) clinical cover to weekends at one National Health Service trust in the United Kingdom. We examined daily episodes of infection prevention and control (IPC) clinical advice given before and during the pilot of extended IPCN to weekends. Stakeholders rated the value, impact, and their awareness of the new extended IPCN cover. Episodes of clinical advice given were more evenly distributed across the weeks during the pilot. Advantages for infection management, patient flow, and clinical workload were seen. IPCN clinical cover at weekends is feasible and valued by stakeholders.


Progression of renal insufficiency: role of blood pressure.
The effect of blood pressure on progression of renal insufficiency was examined in a large group of patients who eventually required dialysis. Out of 198 consecutive new chronic dialysis patients, 86 had sufficient data predialysis to determine rates of progression of renal insufficiency by reciprocal creatinine versus time plots. Average plasma creatinine at first contact was 3.8 +/- 0.2 mg/dl and at the time of dialysis was 11.4 +/- 0.4 mg/dl. Mean duration of follow-up was 33.4 +/- 2.5 months and the average rate of decline in reciprocal creatinine was -0.009 +/- 0.001 dl/mg month. Patients were stratified by average value of diastolic blood pressure measured in clinic. Patients in the lowest quartile had a rate of decline in reciprocal creatinine of -0.007 +/- 0.001 dl/mg month, which was slower than that of patients in the third and fourth quartiles, -0.010 +/- 0.001 and -0.011 +/- -0.002 dl/mg month, respectively (P less than 0.05). In individual patients, a mean diastolic BP of less than 90 mm Hg was associated with a rate of decline in reciprocal creatinine of -0.006 +/- 0.001 dl/mg month which was significantly less than the rate of -0.009 +/- 0.001 when the diastolic BP was greater than 90 mm Hg. Thus, in a large group of patients who have progressed to ESRD, there is an association between control of diastolic blood pressure and a slower rate of decline in renal function.


Immunohistochemical and electron microscopic demonstration of nerve fibres in relation to gingiva, tooth germs and functional teeth in the lower jaw of the cichlid Tilapia mariae.
Immunohistochemistry revealed the presence of numerous neurofilament (NF)-like immunoreactive axons in relation to gingiva and dental follicles surrounding mineralizing tooth germs. The gingival nerve fibres frequently approached the prospective papilla of early tooth primordia. Electron microscopic (EM) analysis revealed the presence of bundles of unmyelinated axons immediately below the epithelial-proprial junction of the gingiva. Bundles of nerve fibres were also present in the border zone between the prospective papilla of bud-stage tooth germs and surrounding mesenchyme and in close proximity to blood vessels of the follicles surrounding older tooth germs, but no axons were observed within the emerging dental papilla. In the individual functional tooth, a bundle of NF-like immunoreactive nerve fibres entered the apical part of the pulp forming a subodontoblastic plexus at mid-pulpal levels. EM analysis showed that the apical bundle consisted of many unmyelinated and a few myelinated axons invested by Schwann cell processes. The subodontoblastic plexus contained unmyelinated axons only. Thin, axon-like profiles were also seen in predentinal tubules. Nerve fibres were not observed at pulpal horn levels and in the ligamentous attachment. It is concluded that both immature and mature parts of the lower-jaw dentition of the cichlid T. mariae are innervated and that the microscopic anatomy of this innervation is partly similar to the pattern seen in developing and adult mammals.


Immunocytochemical study of myelin-associated glycoprotein (MAG) and basic protein (BP) in acute experimental allergic encephalomyelitis (EAE).
To compare distributions of oligodendroglial myelin-associated glycoprotein (MAG) and myelin basic protein (BP) during demyelination in acute experimental allergic encephalomyelitis (EAE). Lewis rats were sensitized with an emulsion containing guinea pig spinal cord and complete Freund's adjuvant. The rats were examined clinically and groups were perfused with fixative before symptoms appeared (7d), within 48 h of symptom onset (10d) and during more severe illness (14d, 21d). Paraffin sections of cerebrum, brainstem, and spinal cord were immunostained with antisera to MAG and BP. Other sections in each serially mounted series were stained with luxol fast blue, hematoxylin and eosin or with the Bodian method to correlate MAG and BP results with histological changes. No abnormalities were detected 7d after sensitization. After 10d, small perivenular inflammatory cell infiltrates were present in white matter, displaced myelinated fibers, but their MAG stained periaxonal regions and BP-stained myelin sheaths appeared normal. In pontine grey matter lesions, there were focal abnormalities in a few myelin sheaths. After 21d, demyelinating lesions were present that were largest in pontine grey matter. Decreased MAG staining was present in areas of myelin sheath loss. MAG-stained fragments were found in zones of active myelin breakdown but no decrease or other change in MAG staining extended beyond the margins of demyelinating lesions into areas with normally stained myelin sheaths. Thus, in contrast to multiple sclerosis (Itoyama et al. 1980), changes in periaxonal oligodendroglial MAG are not present in acute EAE before inflammatory cell infiltrates or myelin sheath changes appear. Our findings suggest that myelin sheaths are the primary targets in EAE-induced demyelination. Oligodendroglia appear to be relatively unaffected and are available to remyelinate axons.


Phosphorylation of ribosomal proteins in rat cerebral cortex in vitro.
Incubation of cerebral cortical tissue from immature rats in the presence of [32P]orthophosphate resulted in similar rates of incorporation of radioactivity into the proteins of free and membrane-bound ribosomes. Incorporation of label into ribosomal proteins of both species continued actively for at least 3 hours. Since recovery of membrane-bound ribosomes from rat cerebral cortex is quite low, further analyses of the radioactive phosphoproteins were restricted to the free ribosome population. A significant fraction of the radioactivity which was precipitated with trichloroacetic acid was not removed by heating in trichloroacetic acid at 90 degrees or extracted with organic solvents and therefore was presumed to be covalently bound to protein. The radioactive phosphoryl groups present in the ribosomal proteins were mainly in ester linkages since they were readily removed by exposure to 1 N NaOH, relatively unaltered by 1N HCl, and unaffected by hydroxylamine. This conclusion was supported by the isolation of labeled o-phosphoserine and o-phosphothreonine residues from hydrolysates of ribosomal proteins. A significant fraction of the labeled phosphoproteins in the purified ribosomes appeared to be bound tightly to the ribosome structure since only 40% of the radioactivity could be removed by extraction of these ribosomes with 1 M KCl. Phosphorylation of proteins of cerebral monoribosomes was more rapid than the same process in polyribosomes from the same source. Eight radioactive phosphoprotein bands could be detected by electrophoresis of proteins obtained from unfractionated cerebral ribosomes on unidimensional polyacrylamide gels containing sodium dodecyl sulfate. The protein nature of these materials was confirmed by pronase digestion. Proteins of subribosomal particles isolated from the total free ribosomal population were labeled differentially. When dissociation was carried out in the presence of EDTA, the small subunit contained four radioactive phosphoprotein bands, whereas the large subunit contained five. Three of the radioactive phosphoprotein components of the small subunit were removed when dissociation of cerebral ribosomes which were previously washed with high salt media was carried out in the presence of puromycin and high salt. However, only the largest labeled phosphoprotein band of the large subunit was removed by this procedure. This component exhibited the same electrophoretic mobility as one of the radioactive phosphoprotein bands which was removed from the small subunit by high salt treatment..


Changes in whole body lipid composition in a murine model of insulin-dependent diabetes mellitus.
To assess the effect of experimentally induced insulin-dependent diabetes mellitus (IDDM) on total body lipid composition, homogenates of neonatal (0-day) and 6-day Sprague-Dawley rat pups treated on day 0 with 65 mg/kg body weight of streptozotocin (STZ) or citrate buffer alone were compared using thin-layer and gas-liquid chromatographic techniques. STZ-treated littermates in a parallel study were markedly hyperglycemic, hypoinsulinemic and attained only 50% of the gain in weight of citrate-treated controls. Although both groups were similar in protein to body weight ratios, STZ-treated pups exhibited 60% of the total lipid content of citrate-treated littermates when compared by weight. The decrease in total lipid content in the STZ-treated group resulted specifically from decreased neutral and not phospholipid content, although a small increase in phosphatidic acid and sphigomyelin was observed in this group. The changes in relative whole body lipids with short-term, high-dose STZ parallel those reported in human IDDM.


Symmetrical bithalamic hyperdensities in asphyxiated full-term newborns: an early indicator of status marmoratus.
Three severely asphyxiated full-term newborns showed tomographic findings of bilateral symmetrical hyperdensities restricted to the thalamic region. All these patients had a strikingly similar poor neurological outcome characterized by dystonia, severe mental retardation and acquired microcephaly. We presume that these bithalamic hyperdensities could be an early predictor of the later status marmoratus.


GNPAT p.D519G is independently associated with markedly increased iron stores in HFE p.C282Y homozygotes.
GNPAT p.D519G positivity is significantly increased in HFE p.C282Y homozygotes with markedly increased iron stores. We sought to determine associations of p.D519G and iron-related variables with iron stores in p.C282Y homozygotes. We defined markedly increased iron stores as serum ferritin >2247pmol/L (>1000μg/L) and either hepatic iron >236μmol/g dry weight or iron >10g by induction phlebotomy (men and women). We defined normal or mildly elevated iron stores as serum ferritin <674.1pmol/L (<300μg/L) or either age≥40y with iron ≤2.5g iron by induction phlebotomy or age≥50y with ≤3.0g iron by induction phlebotomy (men only). We compared participant subgroups using univariate methods. Using multivariable logistic regression, we evaluated associations of markedly increased iron stores with these variables: age; iron supplement use (dichotomous); whole blood units donated; erythrocyte units received as transfusion; daily alcohol consumption, g; and p.D519G positivity (heterozygosity or homozygosity). The mean age of 56 participants (94.6% men) was 55±10 (SD) y; 41 had markedly increased iron stores. Prevalences of swollen/tender 2nd/3rd metacarpophalangeal joints and elevated aspartate or alanine aminotransferase were significantly greater in participants with markedly increased iron stores. Only participants with markedly increased iron stores had cirrhosis. In multivariable analyses, p.D519G positivity was the only exposure variable significantly associated with markedly increased iron stores (odds ratio 9.9, 95% CI [1.6, 60.3], p=0.0126). GNPAT p.D519G is strongly associated with markedly increased iron stores in p.C282Y homozygotes after correction for age, iron-related variables, and alcohol consumption.


Comparative analysis of the anticoagulant activities and immunogenicity of HSC70 and HSC70TKD of Haemaphysalis flava.
Haemaphysalis flava is a hematophagous ectoparasite that acquires the nutrition needed for development and reproduction by sucking blood and digesting the blood meal. During blood-sucking and blood-meal digestion, the prevention of blood coagulation is important for this tick. Previous studies have shown that heat shock cognate 70 (HSC70) protein has certain anticoagulant activities, but its immunogenicity remains unclear. Also, whether the mutation of individual bases of the TKD-like peptide of HSC70 through the overlap extension method can change its anticoagulant activities and immunogenicity remains to be investigated. The gene encoding the HSC70 protein was cloned from a complementary DNA library synthesized from H. flava. The coding gene of the TKD-like peptide of HSC70 was mutated into a TKD peptide coding gene (HSC70TKD) using the overlap extension method. Escherichia coli prokaryotic expression plasmids were constructed to obtain the recombinant proteins of HSC70 (rHSC70) and HSC70TKD (rHSC70TKD). The purified rHSC70 and rHSC70TKD were evaluated at different concentrations for anticoagulant activities using four in vitro clotting assays. Emulsifying recombinant proteins with complete and incomplete Freund's adjuvants were subcutaneously immunized in Sprague Dawley rats. The serum antibody titers and serum concentrations of interferon-gamma (IFN-γ) and interleukin-4 (IL-4) were detected using an indirect enzyme-linked immunosorbent assay to assess the immunogenicity of rHSC70 and rHSC70TKD. The open reading frame of HSC70 was successfully amplified and found to have a length of 1958 bp. The gene encoding the TKD-like peptide of HSC70 was artificially mutated, with the 1373-position adenine (A) of the original sequence mutated into guanine (G), the 1385-position cytosine (C) mutated into G and the 1386-position G mutated into C. rHSC70 and rHSC70TKD that fused with His-tag were obtained using the expression plasmids pET-28a-HSC70 and pET-28a-HSC70TKD, respectively. rHSC70 and rHSC70TKD prolonged the thrombin time (TT) and reduced the fibrinogen (FIB) content in the plasma, but did not affect the prothrombin time (PT) or activated partial thromboplastin time (APTT) when compared to the negative control. Interestingly, the ability of rHSC70TKD to prolong the TT and reduce the FIB content in the plasma was better than that of rHSC70. The specific antibody titers of both rHSC70 and rHSC70TKD in rat serum reached 1:124,000 14 days after the third immunization. The serum concentration of IFN-γ in the rHSC70TKD group was higher than that in the rHSC70 group. The rHSC70 group has the highest serum concentration of IL-4, and the serum concentration of IL-4 in the rHSC70TKD group was higher than that in the negative group. rHSC70 and rHSC70TKD exhibited anticoagulant activities by prolonging the TT and reducing the FIB content in vitro. rHSC70TKD had better anticoagulant activities than rHSC70. Both rHSC70 and rHSC70TKD had good immunogenicity and induced humoral and cellular immunity.


A New Integrated GDL with Wavy Channel and Tunneled Rib for High Power Density PEMFC at Low Back Pressure and Wide Humidity.
Proton exchange membrane fuel cells (PEMFCs) have garnered significant attention due to their high efficiency and low emissions. However, PEMFC always suffers mass transfer and water management in performance improvement. Herein, an integrated gas diffusion layer (GDL) with wavy channel and micro-tunneled rib is designed and prepared to achieve faster and gentler mass transfer and excellent water management capability by laser engraving. Outstandingly, the new integrated GDL can use the back pressure of air as low as 0 and 50 kPa to respectively achieve 80% and 90% of fuel cell performance realized under pure oxygen. Such high performance is mainly due to the turbulent flow caused by wavy channel and express removing pathway of liquid water provided by micro-tunneled rib. Moreover, the new integrated GDL also shows wide humidity tolerance from 40% to 100% and a very high specific volume power density of 16,300 W L-1 due to the thin thickness of new integrated GDL. This new integrated GDL is expected to be widely used in PEMFC and other energy conversion devices.


Diet consistency modification improves postprandial glycemic and gastroparesis symptoms.
Diabetic gastroparesis (DGP) is an autonomic neuropathy resulting from long-standing poorly controlled diabetes, and it is also linked to fluctuations in glycemic control due to variability on nutrient absorption. Considering the scarcity of information, the aim of this study was to identify the impact of modifications on diet consistency on post-prandial glucose variability using a continuous glucose monitoring (CGM) and its effect on the perception and severity of gastrointestinal symptoms. This proof-of-concept study was carried out in a cross-sectional cohort of six individuals with type 1 diabetes mellitus with confirmed diagnosis of DGP. Two types of diet were used to evaluate glycemic control and DGP symptoms, general consistency standard meal (SD) and modified consistency test diet (MD), associated with an application of rapid acting insulin at the time of food intake. Glycemic control was evaluated by CGM, and the Gastroparesis Cardinal Symptom Index (GCSI) was applied after meals. The CGM curve was different for MD + insulin and SD + insulin. There was a smaller increment of interstitial glucose with 2 h after MD + insulin, returning almost to the basal level 4 h later. Patients scored significantly lower GCSI after MD + insulin compared to the same index after they received SD + insulin. Moreover, there was a decrease in important clinical scores present in the index, like: "Not able to finish meal", "Loss of appetite" and "Stomach or belly feels larger". This study showed that a modified diet can improve postprandial glycemic excursion and the perception and severity of gastroparesis symptoms. The online version contains supplementary material available at 10.1007/s40200-022-01117-w.


Does partial nephrectomy at an academic institution result in better outcomes?
Partial nephrectomy (PN) outcomes may be better at academic institutions than at non-academic centers. Peer-review, sub-specialized practice profile, higher individual surgeon and institutional caseload may explain this observation. To the best of our knowledge, the role of institutional academic affiliation has not been examined with regard to PN postoperative outcomes. Within the Health Care Utilization Project Nationwide Inpatient Sample (NIS), we focused on PNs performed within the 10 most contemporary years (1998-2007). We explored the effect of academic status on three short-term PN outcomes (intraoperative and postoperative complications, as well as in-hospital mortality). Multivariable logistic regression analyses further adjusted for age, race, gender, Charlson Comorbidity Index (CCI), surgical approach, hospital region, annual hospital caseload and insurance status. Overall, 8,513 PNs were identified. Of those, 5,906 (69.4%) were recorded at academic institutions. Academic institution patients had lower CCI, were less frequently Caucasian and more frequently had private insurance (all P < 0.001). Academic institution PNs were associated with fewer postoperative complications (14.6% vs. 16.6%, P = 0.018). In multivariable analyses, institutional academic status did not affect the three short-term PN outcomes. Patient selection explains better PN postoperative outcomes at academic institutions. Control for these biases removes the outcome differences, at least when the three short-term PN outcomes are considered. However, the interpretation of these findings needs to take into account the lack of adjustment for case complexity.


Antioxidant activities potential of tea polysaccharide fractions obtained by ultra filtration.
Three polysaccharide fractions (TPS1, TPS2 and TPS3) with different molecular weights were obtained using ultra filtration membranes from crude tea polysaccharide (CTPS) extracted from abandoned lower grade tea leaves. Each fraction contained different contents of neutral sugar, uronic acid, protein, and total polyphenols. These differences provided basis for the antioxidant and free radical scavenging activity of these polysaccharide fractions. The molecular weights of TPS1, TPS2, and TPS3 were around 2.40×10(5) Da, 2.14×10(4) Da, and 2.46×10(3) Da, respectively. In general, TPS1 and CTPS had stronger antioxidant activity, TPS2 and TPS3 had lower antioxidant activity. TPS1 had higher activity for DPPH and lipid per oxidation inhibition. But it had lower capacity for reducing power and metal chelating. This might be due to its higher content of hexuronic acid and larger molecular weight. The order of inhibition activity of lipid per oxidation of various polysaccharide fractions was the same as DPPH radical scavenging activity, as well as the order of metal chelating activity of various polysaccharide fractions similar to hydroxyl radical scavenging activity, which demonstrated that hydroxyl radical scavenging activity of polysaccharide relied heavily on the Fe(2+) metal chelating to decrease the generation of hydroxyl radical.


Flow injection analysis system for the supervision of industrial chromatographic downstream processing in biotechnology.
Sugar beet molasses is a natural resource for various products used in daily life, ranging from sucrose to amino acids for pharmaceutical industry. The separation of molasses into these high value components is performed on a large scale by ion exchange/exclusion chromatography. A biosensor system was set up for the "in time" analysis of serine and sucrose during molasses desugarisation. D-Serine was analysed with the multi-enzyme system D-serine dehydratase/lactic dehydrogenase and photometric detection of the NADH consumed. Sucrose was determined with invertase/mutarotase/glucose oxidase and the oxygen consumed was monitored amperometrically. An analysis could be performed within 2-5 min by directly injecting samples from the chromatographic process into the flow injection analysis system. The determination range for the sucrose analysis was 0-2.5 gl-1 and for the analysis of D-serine 0-0.5 gl-1. The standard deviation for the measurement of D-serine was 1.7%.


Continuation of postpartum antiretroviral therapy in a cohort of women infected with human immunodeficiency virus.
A common dilemma for HIV-positive pregnant women is the issue of continuation or cessation of antiretroviral therapy (ART) postpartum. Current guidelines for ART during pregnancy offer no specific recommendations for postpartum ART care. The objective of this study was to ascertain characteristics that would predict cessation or continuation of ART postpartum. In this study, prenatal and medical clinic records were reviewed retrospectively for a cohort of 29 HIV-infected pregnant women who were seen in the Temple University High Risk obstetrics practice from 1997 to 1998. All women took ART during pregnancy, except for one who received i.v. AZT and nevirapine during labor. HIV-specific medical care was provided concurrently during the time of the woman's obstetrics visit by a nurse practitioner and a clinical nurse specialist in consultation with the physician. Factors that were included for review included race, age, use of ART at the time of pregnancy diagnosis, type of ART during pregnancy, CD4 count, HIV-1 ribonucleic acid polymerase chain reaction (RNA PCR) levels, current substance use, disclosure of HIV status to current partner, years of HIV infection, prior HIV infected child, and whether this was a first pregnancy. The two groups of women were divided between those who discontinued ART postpartum and those who continued ART. The data were analyzed with the Kruskal-Wallis test for two groups, or calculations of risk ratios with Fisher's exact test. Study results indicated that 15 out of 29 women (51%) continued ART postpartum. The significant factors for continuation included Latina ethnicity (risk ratio = 0.24, confidence interval = 0.06-0.87), CD4 < 200 mm3 (p = .04), and a greater number of drugs in the antiretroviral regimen 3 versus 2 (p = .05). This study showed that postpartum continuation of ART was associated with identified Latina ethnicity, lower CD4 counts, and a greater number of drugs in the pregnancy regimen. Further study is recommended to understand the clinical impact of intermittent ART, the strategies for postpartum therapy adherence, and clinical follow-up.


Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women.
The pharmacokinetics and behavioral effects of isoallopregnanolone (3beta-hydoxy-5alpha-pregnan-20-one) in women are not known. Allopregnanolone (3alpha-hydoxy-5alpha-pregnan-20-one) is a well-known neurosteroid, acting via the GABA(A) receptor in the human brain. The naturally occurring progesterone metabolite isoallopregnanolone is the 3beta-stereoisomer of allopregnanolone. Prior studies have concluded that isoallopregnanolone has no effect on the GABA(A) receptor. However, an antagonistic effect of isoallopregnanolone to allopregnanolone on the GABA(A) receptor has been shown in animal and in vitro studies. The purpose of this study was to evaluate the pharmacokinetics and behavioral effects of isoallopregnanolone in humans. Six healthy women were given three increasing doses of isoallopregnanolone intravenously in the follicular phase. Repeated blood samples for analyses of isoallopregnanolone and allopregnanolone concentrations were drawn. Saccadic eye movement variables, self-rated sedation, and mood rating scales were used during the test day. A Likert scale for prospective symptoms was used to measure daily fluctuations during the ongoing menstrual cycle. Exogenously administered isoallopregnanolone produced a dose-dependent increase in the serum concentration of isoallopregnanolone. In parallel, there was also a rise in the allopregnanolone concentration. There was a decrease in saccadic eye movement variables, but no effect was found on self-rated sedation or mood and no changes were seen in prospective symptoms during the menstrual cycle. After administration of isoallopregnanolone at a cumulative dose of 0.20 mg/kg, no adverse effects were observed. There is a metabolism of isoallopregnanolone to allopregnanolone, most likely explaining the effects on the saccadic eye movements.


A role for endoplasmic reticulum dynamics in the cellular distribution of microtubules.
The dynamic distribution of the microtubule (MT) cytoskeleton is crucial for the shape, motility, and internal organization of eukaryotic cells. However, the basic principles that control the subcellular position of MTs in mammalian interphase cells remain largely unknown. Here we show by a combination of microscopy and computational modeling that the dynamics of the endoplasmic reticulum (ER) plays an important role in distributing MTs in the cell. Specifically, our physics-based model of the ER–MT system reveals that spatial inhomogeneity in the density of ER tubule junctions results in an overall contractile force that acts on MTs and influences their distribution. At steady state, cells rapidly compensate for local variability of ER junction density by dynamic formation, release, and movement of ER junctions across the ER. Perturbation of ER junction tethering and fusion by depleting the ER fusogens called atlastins disrupts the dynamics of junction equilibration, rendering the ER–MT system unstable and causing the formation of MT bundles. Our study points to a mechanical role of ER dynamics in cellular organization and suggests a mechanism by which cells might dynamically regulate MT distribution in, e.g., motile cells or in the formation and maintenance of neuronal axons.


Consequences of use of anabolic androgenic steroids.
Whether providing anticipatory guidance to the young adolescent patient, conducting a preparticipation examination on a young athlete, or treating a sick user of anabolic androgenic steroids (AASs), the primary care physician must be familiar with the adverse consequences of the use of these compounds. This article reviews the endocrine, cardiovascular, neuropsychiatric, musculoskeletal, hematologic, hepatic, and miscellaneous effects of AASs, highlighting effects reported in children and adolescents, and relying on consequences in adults when pediatric data is unavailable.


Genetic analysis of echovirus 11 variability in adsorption to human erythrocytes.
The frequency of nonhemagglutinating (h-) mutants was determined in hemagglutinating (HA) clones of echovirus 11. The HA clones were derived from the prototype strain Gregory and a clinical isolate of echovirus 11. The h- mutants were found at a constant frequency of 3.0 x 10(-5) (mean value) in the HA clones derived from both strains. Since the conditions of the population equilibrium of HA clones and neutrality of the mutation were satisfied, it was proposed that the observed frequency of h- mutants occurred as a result of a point mutation. The frequency of h+ revertants at the second passage of h- mutant clone was 9.1 x 10(-5). Hence the frequency of reversion suggests that the number of potential sites of back mutation was restricted.


Centrins in retinal photoreceptor cells: regulators in the connecting cilium.
Changes in the intracellular Ca2+ concentration regulate the visual signal transduction cascade directly or more often indirectly through Ca2+-binding proteins. Here we focus on centrins, which are members of a highly conserved subgroup of the EF-hand superfamily of Ca2+-binding proteins in photoreceptor cells of the vertebrate retina. Centrins are commonly associated with centrosome-related structures. In mammalian retinal photoreceptor cells, four centrin isoforms are expressed as prominent components in the connecting cilium linking the light-sensitive outer segment compartment with the metabolically active inner segment compartment. Our data indicate that Ca2+-activated centrin isoforms assemble into protein complexes with the visual heterotrimeric G-protein transducin. This interaction of centrins with transducin is mediated by binding to the betagamma-dimer of the heterotrimeric G-protein. More recent findings show that these interactions of centrins with transducin are reciprocally regulated via site-specific phosphorylations mediated by the protein kinase CK2. The assembly of centrin/G-protein complexes is a novel aspect of translocation regulation of signalling proteins in sensory cells, and represents a potential link between molecular trafficking and signal transduction in general.


Conventional versus minimal ovarian stimulation: an intra-patient comparison of ovarian response in poor-responder women according to Bologna Criteria.
Is minimal ovarian stimulation (MOS) as effective as conventional ovarian stimulation (COS) in ovarian response and embryo quality in the same 46 poor-responder patients according to the Bologna criteria? An intra-patient comparison of patients undergoing both protocols. Ovaries were stimulated with either a gonadotrophin-releasing hormone antagonist protocol and a combination of recombinant FSH and highly purified human menotrophin (HP-HMG) daily (COS), or with the use of clomiphene citrate 50 mg daily and 150 IU of HP-HMG or recombinant FSH every other day from simulation day 4 (MOS). After MOS, significantly more good-quality embryos (1.0 ± 1.2 versus 0.3 ± 0.6) (P = 0.002), oocytes (3.2 ± 1.9 versus 2.0 ± 1.8) (P = 0.002), and mature (metaphase II) oocytes (2.6 ± 1.7 versus 1.6 ± 1.7) (P = 0.001) were obtained. In COS cycles, a significantly higher total gonadotrophin dose was needed per good-quality embryo (+2194 IU; 95% CI 618 to 3170). In poor responder patients, MOS is a good alternative when COS has failed, or even as a first-line treatment. It offered a significantly greater number of good-quality embryos as well as a higher number of oocytes, using significantly lower doses of gonadotrophins per oocyte and embryo obtained.


The effects of hysterectomy with bilateral salpingectomy on ovarian reserve.
To determine whether ovarian reserve is compromised after hysterectomy with bilateral salpingectomy. A prospective longitudinal study was conducted among 84 women who underwent hysterectomy with bilateral salpingectomy at a tertiary medical center in Beijing, China, between August 2, 2015, and January 15, 2017. Serum levels of anti-Müllerian hormone (AMH) and follicle-stimulating hormone (FSH) were measured to assess ovarian function before undergoing the procedure (baseline) and at weeks 1 and 6 after surgery (postoperative period). The median age was 41.61 ± 0.62 years. Age negatively correlated with the serum AMH level at baseline (P<0.001), as well as with preoperative-to-postoperative changes in the concentration of this hormone (P<0.001). Serum AMH levels were lower in the postoperative period versus the preoperative period (P<0.001). By contrast, serum FSH levels were higher in the postoperative period than in the preoperative period (P<0.001). Moreover, no correlation was found with body mass index. Hysterectomy with bilateral salpingectomy compromised ovarian reserve, with the damage being most severe among younger patients.


Cutoff Values of Brachial-Ankle Pulse Wave Velocity for Atherosclerotic Risks by Age and Sex in the Japanese General Population.
In this study, we aim to analyze the correlation between brachial-ankle pulse wave velocity (baPWV) and Suita score or Framingham risk score and obtain the cutoff value of baPWV by sex and age for cardiovascular risk, as assessed by these scores in the large Japanese annual health checkup data. In total, 25,602 participants (14,539 men and 11,063 women), who had their annual health checkups, were included in this study. Cutoff values of baPWV for the moderate- and high-risk groups stratified by sex and age were obtained using a receiver operating characteristic (ROC) curve analysis. As per our findings, the Suita score demonstrated better correlations with baPWV than the Framingham risk score in both sexes (men, Suita score R2=0.41 and Framingham risk score R2=0.37; women, Suita score R2=0.54 and Framingham risk score R2=0.33). The ROC curve analysis demonstrated the cutoff values of baPWV for moderate- and high-risk groups estimated using the Suita score, and they are as follows: in men, the baPWV cutoff values were 1,350 cm/s in the 40s, 1,430 cm/s in the 50s, 1,520 cm/s in the 60s, and 1,880 cm/s in the 70s. In women, the baPWV cutoff values were 1,350 cm/s in the 40s, 1,430 cm/s in the 50s, 1,570 cm/s in the 60s, and 1,800 cm/s in the 70s. We demonstrated that baPWV significantly correlated with the Suita score or Framingham risk score in both men and women, with the former presenting a stronger correlation than the latter. We propose the cutoff values of baPWV for moderate- and high-risk groups estimated using the Suita score.


DOMINO: Using Machine Learning to Predict Genes Associated with Dominant Disorders.
In contrast to recessive conditions with biallelic inheritance, identification of dominant (monoallelic) mutations for Mendelian disorders is more difficult, because of the abundance of benign heterozygous variants that act as massive background noise (typically, in a 400:1 excess ratio). To reduce this overflow of false positives in next-generation sequencing (NGS) screens, we developed DOMINO, a tool assessing the likelihood for a gene to harbor dominant changes. Unlike commonly-used predictors of pathogenicity, DOMINO takes into consideration features that are the properties of genes, rather than of variants. It uses a machine-learning approach to extract discriminant information from a broad array of features (N = 432), including: genomic data, intra-, and interspecies conservation, gene expression, protein-protein interactions, protein structure, etc. DOMINO's iterative architecture includes a training process on 985 genes with well-established inheritance patterns for Mendelian conditions, and repeated cross-validation that optimizes its discriminant power. When validated on 99 newly-discovered genes with pathogenic mutations, the algorithm displays an excellent final performance, with an area under the curve (AUC) of 0.92. Furthermore, unsupervised analysis by DOMINO of real sets of NGS data from individuals with intellectual disability or epilepsy correctly recognizes known genes and predicts 9 new candidates, with very high confidence. In summary, DOMINO is a robust and reliable tool that can infer dominance of candidate genes with high sensitivity and specificity, making it a useful complement to any NGS pipeline dealing with the analysis of the morbid human genome.