Effects of growth hormone (GH) administration on homocyst(e)ine levels in men with GH deficiency: a randomized controlled trial.
GH deficiency is associated with increased cardiovascular mortality and early manifestations of atherosclerosis. Elevated serum homocyst(e)ine levels have been found to be associated with increased cardiovascular risk. The effect of GH replacement on homocyst(e)ine has not been investigated to date. We evaluated the effect of GH replacement on fasting homocyst(e)inemia in a group of men with adult-onset GH deficiency in a randomized, single blind, placebo-controlled trial. Forty men with adult-onset GH deficiency were randomized to GH or placebo for 18 months, with dose adjustments made according to serum insulin-like growth factor I (IGF-I) levels. Fasting serum homocyst(e)ine, folate, vitamin B12, and total T(3) levels were determined at baseline and 6 and 18 months. Anthropometry, IGF-I levels, insulin, and glucose were measured at 1, 3, 6, 12, and 18 months. Nutritional assessment, body composition, total T(4), thyroid hormone binding index, and free T(4) index were assessed every 6 months. Homocyst(e)ine decreased in the GH-treated group compared with that in the placebo group (net difference, -1.2 +/- 0.6 micromol/L; confidence interval, -2.4, -0.02 micromol/L; P = 0.047). Homocyst(e)ine at baseline was negatively correlated with plasma levels of folate (r = -0.41; P = 0.0087). Total T(3) increased in the GH-treated group vs. that in the placebo group (net difference, 0.17 +/- 0.046 ng/dL; confidence interval, 0.071, 0.26 nmol/L; P = 0.0012). Folate and vitamin B12 levels did not significantly change between groups. Changes in homocyst(e)ine were negatively correlated with changes in IGF-I. For each 1 nmol/L increase in IGF-I, homocyst(e)ine decreased by 0.04 +/- 0.02 micromol/L (P = 0.029). In contrast, changes in homocyst(e)ine did not correlate with changes in folate, vitamin B12, total T(3), C-reactive protein, interleukin-6, or insulin levels. This study shows that GH replacement decreases fasting homocyst(e)ine levels compared with placebo. This may be one of the mechanisms involved in the putative modulation of atherosclerosis and cardiovascular risk by GH replacement.


Successful combination chemotherapy for metastatic inflammatory myofibroblastic tumor: A case report.
A 64-year-old male presented with increased abdo-minal fullness and fever. Radiological examination revealed moderate ascites, a tumor with a diameter of 12.5 cm in the mesenteric region, as well as multiple tumors in the thoracic and abdominal para-aortic regions and in the left supraclavicular regions. Pathohistological findings of the biopsy specimen revealed atypical spindle cells accompanied by infiltration of lymphocytes. The plasmacytes were positive for CD68, murine double minute 2 and S-100, while they were negative for α-smooth muscle actin, cyclin-dependent kinase 4 and anaplastic lymphoma kinase. Clinically, the patient presented systemic symptoms and laboratory results indicated an elevation in the inflammatory response, while the CT and MRI findings were consistent with an inflammatory myofibroblastic tumor (IMT). Based on the clinical and histological findings, the patient was diagnosed with IMT. In total, 4 cycles of combination chemotherapy with doxorubicin and ifosfamide were administered. Tumor size reduction by 50% was achieved subsequent to the 4th chemotherapy cycle. In conclusion, successful control of this rare metastatic IMT was achieved by systemic chemotherapy.


Apparent total tract energy and macronutrient digestibility of one- to three-day-old, adult ground, extruded, and canned chicken-based diets in domestic cats (Felis silvestris catus).
There has been a recent increase in the popularity of feeding unconventional diets, including whole prey diets, to domestic cats (Felis silvestris catus). Data are needed that allow animal caretakers to choose and formulate diets that meet the nutritional requirements of their cats. Our objective was to evaluate the effects of feeding 1- to 3-d-old whole chicks (WHO), ground adult chicken product (GRO), a chicken-based canned diet (CAN), and a chicken-based extruded diet (EXT) on apparent total tract energy and macronutrient digestibility, N balance, and blood metabolites of domestic cats (n = 11). Macronutrient, energy, and moisture concentrations of diets varied greatly (e.g., CP: 35 to 72% DM); however, cats fed all diets maintained BW and N balance. In general, cats fed WHO had lower nutrient digestibility than those fed CAN and EXT. Cats fed GRO had greater nutrient digestibility than cats fed commercial diets. For example, apparent OM and GE digestibility coefficients were greater (P ≤ 0.05) for cats fed CAN (86 and 88%, respectively), EXT (88 and 88%), and GRO (94 and 95%) compared with those fed WHO (83 and 83%) and greater (P ≤ 0.05) for cats fed GRO compared with those fed CAN and EXT. Many blood metabolites were modified by diet, but most remained within reference ranges for domestic cats. Serum cholesterol was elevated above the reference range for all treatments and greater (P ≤ 0.05) for cats fed WHO compared with those fed CAN, EXT, and GRO. Serum creatinine concentrations were above the reference range for all treatments and greater (P ≤ 0.05) for cats fed GRO compared with those fed CAN or WHO. These data indicate that the whole prey tested herein maintained short-term health and are adequately digestible for use in companion animal diets. Research is needed to determine the global and long-term health implications of feeding whole or ground diets to domestic cats, which may be different in terms of macronutrient, energy, and moisture profiles and nutrient digestibility.


Mss51 deletion enhances muscle metabolism and glucose homeostasis in mice.
Myostatin is a negative regulator of muscle growth and metabolism and its inhibition in mice improves insulin sensitivity, increases glucose uptake into skeletal muscle, and decreases total body fat. A recently described mammalian protein called MSS51 is significantly downregulated with myostatin inhibition. In vitro disruption of Mss51 results in increased levels of ATP, β-oxidation, glycolysis, and oxidative phosphorylation. To determine the in vivo biological function of Mss51 in mice, we disrupted the Mss51 gene by CRISPR/Cas9 and found that Mss51-KO mice have normal muscle weights and fiber-type distribution but reduced fat pads. Myofibers isolated from Mss51-KO mice showed an increased oxygen consumption rate compared with WT controls, indicating an accelerated rate of skeletal muscle metabolism. The expression of genes related to oxidative phosphorylation and fatty acid β-oxidation were enhanced in skeletal muscle of Mss51-KO mice compared with that of WT mice. We found that mice lacking Mss51 and challenged with a high-fat diet were resistant to diet-induced weight gain, had increased whole-body glucose turnover and glycolysis rate, and increased systemic insulin sensitivity and fatty acid β-oxidation. These findings demonstrate that MSS51 modulates skeletal muscle mitochondrial respiration and regulates whole-body glucose and fatty acid metabolism, making it a potential target for obesity and diabetes.


Cosmetic outcomes following appendectomy in children: a comparison of surgical techniques.
Although cosmetic superiority is widely stated as an advantage of single-incision laparoscopy, there are limited studies looking at cosmetic outcome. We sought to determine patients' cosmetic satisfaction after undergoing appendectomy by the single-incision laparoscopic appendectomy (SILA), multiport laparoscopic appendectomy (LA), or open appendectomy (OA) procedure. Five hundred eighty pediatric patients who underwent appendectomy at a single institution between February 2010 and July 2011 were identified and asked to complete the Patient Scar Assessment Scale (PSAS), a validated evaluation tool for linear scars. In addition, patients were asked the "Ultimate Question" (UQ), which correlates with a patient's overall satisfaction. Linear regression models were used to examine differences between surgical approaches with statistical significance set at P<.05. Covariates for all models included patient demographics, length of stay, and surgeon. In total, 212 surveys were returned (SILA, 122; LA, 41; OA, 49) for a response rate of 37%. Regression models demonstrated significantly higher mean total PSAS scores for patients who underwent SILA and laparoscopic appendectomy (LA) appendectomy procedures compared with the open procedure (SILA, 8.70; LA, 8.86; OA, 8.01; β=-0.21, P<.05). Patients who experienced the SILA and LA procedures reported significantly higher mean UQ scores compared with OA (SILA, 9.79; LA, 9.75; OA, 9.39; β=-0.22, P<.05). SILA patients reported a 10 on the UQ significantly more often (91.1%) compared with either LA (81%) or OA (75.5%) (P<.05). SILA or LA appendectomy was associated with significantly increased cosmetic satisfaction by patients and their families when compared with OA. This is the first study to show that pediatric patients value attempts to minimize scarring with laparoscopic surgery. Further studies are needed to determine if specific patient factors influence satisfaction with scars.


A new method for biliary tract reconstruction for primary bile duct stones.
Twelve patients with repeated episodes of jaundice and infection due to primary biliary duct stones were treated by interposing a 50-cm segment of the jejunum between the proximal common duct below the liver and the first portion of the duodenum. The interposed jejunum was positioned in a retrogastric position. There were no postoperative deaths, and laboratory data indicate no alteration in gastric secretion, gastrin levels, or barium reflux into the liver. After a mean follow-up period of 11.67 months, there was no need for further operations in these patients, all of whom had had previous multiple episodes of cholangitis and biliary colic.


Developmental changes in interstitial collagens of fetal rat genital ducts.
The distribution of interstitial collagen types I and III was studied by immunocytochemistry in the mesenchyme of progressing and regressing mesonephric and paramesonephric ducts of male and female rat fetuses from the age of 15 days until birth. Immunocytochemistry revealed a collagen-poor mesenchymal area around the genital ducts and in continuation with the coelomic epithelium on the lateral edge of the mesonephric ridge of 15-day-old fetuses. Ultrastructurally, collagen fibrils were accumulated along the continuous lamina densa of the mesonephric ducts, whereas they were absent on the medial side of the male and female paramesonephric ducts. In males, the amount of collagen fibrils increased with the histological maturation of the mesenchyme around the mesonephric duct, whereas around the regressing paramesonephric duct collagens disappeared from the basement membrane region and the surrounding mesenchyme of the 16-day-old male duct. After the completion of the paramesonephric regression, the mesenchyme acquired a uniformly collagen containing interstitial matrix. In females, the collagens increased in the mesenchyme around the progressing paramesonephric duct, and the original site of the regressing mesonephric duct became occupied with a collagen-containing mesenchyme by the age of 19 days. The results suggest a close structural linkage between the mesonephric duct and the established early paramesonephric duct. The differences in the developmental maturation of the periductal mesenchyme and the observed changes in the composition of the interstitial matrix probably reflect the functional differences in the regulatory factors acting on the progression and regression of the male and female genital ducts.


Innate mucosal-associated invariant T (MAIT) cells are activated in inflammatory bowel diseases.
Inflammatory bowel diseases are characterized by a deregulated immune response targeting the gut bacterial flora. Mucosal-associated invariant T (MAIT) cells are major histocompatibility complex (MHC) class Ib-restricted innate-like lymphocytes with anti-bacterial functions. They display an effector/memory phenotype and are found in large numbers in the blood, mucosae and liver. They have also been implicated in inflammatory diseases such as multiple sclerosis. Therefore, we aimed to analyse the possible involvement of MAIT cells in Crohn's disease (CD) and ulcerative colitis (UC). To this end, a phenotypical and functional analysis of MAIT cells isolated from the blood of healthy subjects, CD and UC patients was undertaken. MAIT cells were also quantified in ileal biopsies of CD patients. The frequency of blood MAIT cells was specifically reduced in IBD patients compared with healthy donors, whereas it was dramatically greater in the inflamed versus healthy tissue. MAIT cells were activated as they expressed significantly more the Ki67 antigen, and this was accompanied by phenotypical changes such as increased expression of natural killer (NK)G2D and B and T lymphocyte attenuator (BTLA). Finally, in-vitro-activated MAIT cells from CD and UC patients secreted significantly more interleukin (IL)-17, together with a decreased interferon (IFN)-γ in CD but an increased IL-22 in UC. These data show that MAIT cells are activated in IBD, which results in an increased recruitment towards the inflamed tissues, an altered phenotype and a switch in the pattern of cytokine secretion. This is the first demonstration that MAIT cells are immune players in IBD, whose precise functions in this context need to be addressed.


Survey of patient and physician influences and decision-making regarding CT utilization for minor head injury.
Assess factors that influence both the patient and the physician in the setting of minor head injury in adults and the decision-making process around CT utilization. This is a convenience sample survey study of adult minor head injury patients (GCS 15) and their physicians regarding factors influencing the decision to use CT to evaluate for intra-cranial haemorrhage. Once a head CT was ordered and before the results were known, both the patient and physician were given a one-page survey asking questions about their concern for injury and rationale for CT use. CT results and surveys were then recorded in a centralized database and analyzed. 584 subjects were enrolled over the 27-month study period. The rate of any intra-cranial haemorrhage was 3.3%. Both the physicians (6% pre-test estimate) and the patients (22% pre-test estimate) over-estimated risk for haemorrhage. Clinical decision rules were not met in 46% of cases where CT was used. Physicians listed an average of 5 factors from a list of 9 that influenced their decision to order CT. Patients listed an average of 1.7 factors influencing their decision to present to the Emergency Department for evaluation. Many patients felt cost (45%) and low risk stratification (34%) should weigh heavily in the decision to use CT. If asked to limit CT utilization, physicians were able to identify a group with less than 2% risk of injury. Patients with low risk of intra-cranial injury continue to be evaluated by CT. Physician decision-making around the use of CT to evaluate minor head injury is multi-factorial. Shared decision-making between the patient and the physician in a low risk minor head injury encounter shows promise as a method to reduce CT utilization in this low risk cohort.


Tumor-primed, in vitro-activated CD4+ effector T cells establish long-term memory without exogenous cytokine support or ongoing antigen exposure.
Tumor-reactive T cells can be primed in vivo, then activated in vitro to provide numerical expansion and uniform acquisiton of effector phenotype and function. Adoptive transfer of effector T cells mediates complete regression of established tumors in animal models. Some experimental models indicate that extensive in vitro proliferation of T cells inhibits efficacy and that central memory T cells (T(CM)) provide greater activity than effector memory T cells (T(EM)). Clinical studies also demonstrate that persistence of adoptively transferred T cells is associated with therapeutic response, thus identifying that conditions to maximize effector cell numbers yet retain memory function are important. In this article, we demonstrate that adoptive transfer of in vitro activated effector CD4(+) T cells into tumor-free congenic mice mediates rejection of tumor challenge 9 mo later, at which time T cells re-express activation markers and undergo rapid proliferation at tumor sites. Analysis of the phenotype of memory cells in lymphoid tissues following adoptive transfer shows high CD44 expression with heterogeneous expression of CD62L, indicating a mixture of T(EM) and T(CM) phenotypes. Memory cells were sorted into two subsets based on CD62L expression levels and then activated in vitro. Although T(EM) cells proliferated more rapidly, T(EM) and T(CM) cells acquired effector phenotype and function. These data indicate that controlled in vitro expansion of tumor-reactive T cells for adoptive immunotherapy also provides a competent memory response.


Manganese induces oxidative stress, redox state unbalance and disrupts membrane bound ATPases on murine neuroblastoma cells in vitro: protective role of silymarin.
Manganese (Mn) is an essential trace element required for ubiquitous enzymatic reactions. Chronic overexposure to this metal may promote potent neurotoxic effects. The mechanism of Mn toxicity is not well established, but several studies indicate that oxidative stress play major roles in the Mn-induced neurodegenerative processes. Silymarin (SIL) has antioxidant properties and stabilizes intracellular antioxidant defense systems. The aim of this study was to evaluate the toxic effects of MnCl(2) on the mouse neuroblastoma cell lines (Neuro-2A), to characterize the toxic mechanism associated with Mn exposure and to investigate whether SIL could efficiently protect against neurotoxicity induced by Mn. A significant increase in LDH release activity was observed in Neuro-2A cells associated with a significant decrease in cellular viability upon 24 h exposure to MnCl(2) at concentrations of 200 and 800 μM (P < 0.05) when compared with control unexposed cells. In addition, exposure cells to MnCl(2) (200 and 800 μM), increases oxidant biomarkers and alters enzymatic and non enzymatic antioxidant systems. SIL treatment significantly reduced the levels of LDH, nitric oxide, reactive oxygen species and the oxidants/antioxidants balance in Neuro-2A cells as compared to Mn-exposed cells. These results suggested that silymarin is a powerful antioxidant through a mechanism related to its antioxidant activity, able to interfere with radical-mediated cell death. SIL may be useful in diseases known to be aggravated by reactive oxygen species and in the development of novel treatments for neurodegenerative disorders such as Alzheimer or Parkinson diseases.


In silico screening of drug-membrane thermodynamics reveals linear relations between bulk partitioning and the potential of mean force.
The partitioning of small molecules in cell membranes-a key parameter for pharmaceutical applications-typically relies on experimentally available bulk partitioning coefficients. Computer simulations provide a structural resolution of the insertion thermodynamics via the potential of mean force but require significant sampling at the atomistic level. Here, we introduce high-throughput coarse-grained molecular dynamics simulations to screen thermodynamic properties. This application of physics-based models in a large-scale study of small molecules establishes linear relationships between partitioning coefficients and key features of the potential of mean force. This allows us to predict the structure of the insertion from bulk experimental measurements for more than 400 000 compounds. The potential of mean force hereby becomes an easily accessible quantity-already recognized for its high predictability of certain properties, e.g., passive permeation. Further, we demonstrate how coarse graining helps reduce the size of chemical space, enabling a hierarchical approach to screening small molecules.


Structural basis for elastolytic substrate specificity in rodent alpha-chymases.
Divergence of substrate specificity within the context of a common structural framework represents an important mechanism by which new enzyme activity naturally evolves. We present enzymological and x-ray structural data for hamster chymase-2 (HAM2) that provides a detailed explanation for the unusual hydrolytic specificity of this rodent alpha-chymase. In enzymatic characterization, hamster chymase-1 (HAM1) showed typical chymase proteolytic activity. In contrast, HAM2 exhibited atypical substrate specificity, cleaving on the carboxyl side of the P1 substrate residues Ala and Val, characteristic of elastolytic rather than chymotryptic specificity. The 2.5-A resolution crystal structure of HAM2 complexed to the peptidyl inhibitor MeOSuc-Ala-Ala-Pro-Ala-chloromethylketone revealed a narrow and shallow S1 substrate binding pocket that accommodated only a small hydrophobic residue (e.g. Ala or Val). The different substrate specificities of HAM2 and HAM1 are explained by changes in four S1 substrate site residues (positions 189, 190, 216, and 226). Of these, Asn(189), Val(190), and Val(216) form an easily identifiable triplet in all known rodent alpha-chymases that can be used to predict elastolytic specificity for novel chymase-like sequences. Phylogenetic comparison defines guinea pig and rabbit chymases as the closest orthologs to rodent alpha-chymases.


Congenital bifurcation of the intratemporal facial nerve.
Anomalies of the course of the facial nerve have been reported in association with middle and inner ear malformations. Bifurcation of its intratemporal portion is a rare malformation in which focal splitting of one or more facial nerve segments occurs. We describe the CT appearance of this anomaly and discuss its possible embryology. Facial nerve bifurcation is important to recognize in patients undergoing evaluation for congenital hearing loss and other congenital ear malformations.


Sex differences in geometry of the femoral neck with aging: a structural analysis of bone mineral data.
The greater hip fracture rate among elderly women is generally ascribed to differences in femoral neck strength between the sexes. Strength of a given bone is a function of both its material properties and the magnitudes of mechanical stresses within it. This study examined the hypothesis that these apparent strength differences between the sexes are due to dissimilarities in the restructuring of the femoral neck with age, which result in higher stresses in elderly women. Using Hip Strength Analysis, a computer program developed by the authors, femoral neck cross-sectional geometric properties for stress analyses were derived from bone mineral image data of 409 community living, white subjects ranging from 19 to 93 years of age. Though both sexes show declines in femoral neck bone mineral density (BMD) and cross-sectional area with age, only females show a decline in the cross-sectional moment of inertia (CSMI, a geometric index of bone rigidity). The lack of decline in male CSMI appears to be a result of a small but significant increase in femoral neck girth. Similar age-related changes have been observed in the femoral shaft by others. The net effect of these observed changes is that mechanical stresses in the femoral neck of females appear to increase at three times the rate per decade of those of males. These results lend support to the hypothesis that the higher fracture rate in elderly women is due, at least in part, to elevated levels of mechanical stress, resulting from a combination of greater bone loss and less compensatory geometric restructuring with age.


Application of newer clearance techniques for the determination of glomerular filtration rate.
Glomerular filtration rate (GFR) is the standard measure of renal function and is critical for the management of renal diseases. Rigorous assessment of GFR requires the measurement of renal clearance of a filtration marker, such as inulin. This method, however, is not suitable for routine clinical practice. Labelled compounds as alternative filtration markers provide accurate and precise GFR measurement, but their use may be limited for safety reasons. Thus investigators have proposed clearance procedures using minute doses of non-radioactive contrast agents, including iothalamate and iohexol. Their renal clearance provides similar accuracy as inulin clearance in GFR estimation, but the need of urine collection again poses certain limitations to the procedure. Thus, plasma clearance of suitable exogenous markers, such X-ray contrast media, has been suggested for measuring renal function, in which the elimination rate of the tracer after a single intravenous injection is evaluated. Plasma clearance of these markers estimated by multiple blood samples provides precise information, but repeated sampling makes this method cumbersome. Abbreviated kinetic profiles have been proposed to predict GFR from the plasma disappearance curve. The simplified method that uses a one-compartment model corrected by the Bröchner-Mortensen formula gives an excellent correlation with inulin clearance and is currently employed for measuring GFR in multi-centre clinical trials.


High-performance switchable grating based on pre-transitional effect of antiferroelectric liquid crystals.
An optical phase grating prototype based on the homeotropic aligned antiferroelectric liquid crystal (AFLC) is demonstrated. By applying an in-plane electric field using comb-like electrodes, the helical structure of AFLC is deformed with the molecules rotating parallel to the electric field because of dielectric anisotropy. This deformation is called the pre-transitional effect of AFLC and induces biaxiality. By using this effect, a switchable phase grating is constructed using a 40μm thick cell filled with (S)-MHPOBC at 85°C. For 532nm TM polarized incident light, the maximum diffraction efficiency of 37.0% is achieved at the electric field of 1.8V/μm for the ± 1st order diffraction. The rise and decay times for the 1st order diffraction pattern are 510μs and 210μs, respectively. The high diffraction efficiency achieved under low field makes it promising for future electro-optical applications.


Structured inhibitory activity dynamics in new virtual environments.
Inhibition plays a powerful role in regulating network excitation and plasticity; however, the activity of defined interneuron types during spatial exploration remain poorly understood. Using two-photon calcium imaging, we recorded hippocampal CA1 somatostatin- and parvalbumin-expressing interneurons as mice performed a goal-directed spatial navigation task in new visual virtual reality (VR) contexts. Activity in both interneuron classes was strongly suppressed but recovered as animals learned to adapt the previously learned task to the new spatial context. Surprisingly, although there was a range of activity suppression across the population, individual somatostatin-expressing interneurons showed consistent levels of activity modulation across exposure to multiple novel environments, suggesting context-independent, stable network roles during spatial exploration. This work reveals population-level temporally dynamic interneuron activity in new environments, within which each interneuron shows stable and consistent activity modulation.


Intraocular pressure and visual field changes in normal-tension glaucoma patients treated using either unoprostone or latanoprost: a prospective comparative study.
We conducted a prospective study in patients with normal-tension glaucoma (NTG) who received either isopropyl unoprostone or latanoprost. We compared the drugs in terms of their effects on intraocular pressure (IOP) and visual field loss progression over a 3-year period. Prospective, randomized controlled study. We enrolled 48 patients with newly diagnosed NTG at Kanazawa University Hospital. Eligible patients were randomly allocated (1:1) to receive either unoprostone or latanoprost ophthalmic solutions. The primary outcomes were IOP changes and visual field deterioration within 36 months. Visual field changes were analyzed: the cumulative survival rates were calculated in terms of mean deviation, pattern standard deviation, and total deviation of the upper or lower hemi-visual field, each visual field sector, and guided progression analysis. In addition, we evaluated the progression of glaucomatous optic disc changes using fundus photography and confocal scanning laser ophthalmoscopy. The mean pretreatment IOP was 15.0±2.4 mmHg in the Unoprostone group and 15.2±1.9 mmHg in the Latanoprost group. The mean IOP during the treatment period was 13.7±2.3 mmHg in the Unoprostone group and 13.0±1.8 mmHg in the Latanoprost group. In both groups, the IOP decreased significantly (p<0.001) from baseline after treatment. The posttreatment IOP values were significantly lower in the Latanoprost group than in the Unoprostone group (p=0.023). Regarding the 3-year cumulative survival rate of visual field loss progression, there were no significant differences between groups in any parameters of the visual field or guided progression analysis. There were no significant differences between groups in disc changes. No significant differences were found between groups with regard to the visual field and structural progression in patients with NTG, although unoprostone was less effective than latanoprost in lowering the IOP.


Use of venoactive drugs after surgery for varicose veins: a preliminary study.
The aim of this paper was to assess the use of venoactive drugs (VADs) after surgery for chronic venous disease in our operative unit in terms of patients' compliance to the therapy and a possible effect on the postoperative pain and quality of life (QoL). Data of consecutive patients who underwent surgery were retrospectively analyzed. All patients, through telephone interview 90 days after the operation, were asked about taking the VAD (either sulodexide or MPFF) which was recommended during the postoperative period. Data were collected about the duration of therapy, the intensity of perceived pain (0-10 scale) at 1st, 7th and 30th postoperative days (POD), the length of rest from their daily activities and QoL during the first postoperative month (through Italian SF-12 questionnaire). P values <0.05 were considered significant. Results of patients who took the VAD were compared to those of patients who did not take the VAD (case-controlled study). A total of 132 patients were operated on (43 with endovenous radiofrequency ablation, RFA; 43 with stripping or crossectomy; 46 with phlebectomies). The proportion of patients who took VADs was two thirds, similar among the three groups. Of those, 24% took VADs for less than 30 days. No significant differences were recorded between those who took and those who didn't take any drugs in terms of intensity of pain at 1st, 7th and 30th POD, days of rest from daily activities and QoL. Irrespectively of the groups, about one third of the patients did not take the recommended VAD postoperatively. No significant difference was recorded between those who took the therapy and those who did not in terms of intensity of postoperative pain, length of rest from daily activities and QoL.


[Effects of vitamin C administration on cholesterol gallstone formation].
Biliary cholesterol is transported by vesicles and micelles. Cholesterol microcrystals are derived from thermodynamically unstable vesicles. In experimental animals vitamin C deficiency leads to a super-saturation of biliary cholesterol and to the formation of gallstones. To search for a possible relationship between serum levels of vitamin C and the formation of cholesterol gallstones in patients with cholelithiasis. Thirteen patients with cholelithiasis and a programmed surgical intervention were treated with 2 g/day of vitamin C per os for two weeks before surgery. Forty nine patients subjected to a cholecystectomy not supplemented with vitamin C were studied as controls. Plasma concentrations of vitamin C and lipid profiles were measured. The cholesterol saturation index, crystallization time, cholesterol and phospholipid content in vesicles and micelles, separated by gel filtration chromatography, were studied in bile samples obtained from the gallbladder. Vitamin C supplementation did not change significantly plasma lipids and bile lipid concentrations. However, in supplemented patients, significant reductions in vesicular cholesterol content (6.5 ± 4.8% compared to 17.9 ± 14.0% in the control group; p < 0.05) and vesicular cholesterol/phospholipid ratio (0.71 ± 0.53 compared to 1.36 ± 1.15 in controls; p < 0.05), were observed. Vitamin C administration may modify bile cholesterol crystallization process, the first step in cholesterol gallstone formation.


Correlates of genetic attributions among parents of children in the USA with developmental disabilities.
As technologies for identifying causal genetic variants in children with autism spectrum disorders (ASD) and other developmental conditions continue to advance, there is a need to understand the factors that influence parental beliefs about the causes of their child's disabilities. This study assessed the correlates of etiologic attributions among US parents of children with ASD, intellectual disability (ID), and/or developmental delay (DD). Data were obtained from the Centers for Disease Control and Prevention's nationally representative Survey of Pathways to Diagnosis and Services. Respondents were classified according to whether their child had ASD without ID or DD (ASD-only), ASD with ID and/or DD (ASD+ID/DD), or ID and/or DD without ASD (ID/DD-only). Respondents rated the extent to which they believed that genetics/heredity and environmental exposures (prenatal and/or postnatal) had contributed to their child's condition. Logistic regression analyses and chi-square tests were used to assess the relationship between parental beliefs and child characteristics. The parents of children with comorbid ASD and ID/DD were found to be significantly less likely than those in the other condition groups to attribute their child's condition to genetics. Within the ASD+ID/DD group, parental endorsement of genetics was lower among those who reported a history of language regression (p=0.006). Further research is needed to evaluate the impact of parental genetic attributions on medical decision-making.


The role of biological therapy in metastatic colorectal cancer after first-line treatment: a meta-analysis of randomised trials.
Biologic agents have achieved variable results in relapsed metastatic colorectal cancer (mCRC). Systematic meta-analysis was undertaken to determine the efficacy of biological therapy. Major databases were searched for randomised studies of mCRC after first-line treatment comparing (1) standard treatment plus biologic agent with standard treatment or (2) standard treatment with biologic agent with the same treatment with different biologic agent(s). Data were extracted on study design, participants, interventions and outcomes. Study quality was assessed using the MERGE criteria. Comparable data were pooled for meta-analysis. Twenty eligible studies with 8225 patients were identified. The use of any biologic therapy improved overall survival with hazard ratio (HR) 0.87 (95% confidence interval (CI) 0.82-0.91, P<0.00001), progression-free survival (PFS) with HR 0.71 (95% CI 0.67-0.74, P<0.0001) and overall response rate (ORR) with odds ratio (OR) 2.38 (95% CI 2.03-2.78, P<0.00001). Grade 3/4 toxicity was increased with OR 2.34. Considering by subgroups, EGFR inhibitors (EGFR-I) in the second-line setting and anti-angiogenic therapies (both in second-line and third-line and beyond settings) all improved overall survival, PFS and ORR. EGFR-I in third-line settings improved PFS and ORR but not OS. The use of biologic agents in mCRC after first-line treatment is associated with improved outcomes but increased toxicity.


[Rehabilitation integrated in acute medical treatment].
Rehabilitation integrated in acute medical treatment is of great importance to patients with acute cerebral stroke and to frail elderly people admitted to hospital with acute medical conditions or fractures. We will focus on the latter group, which receives the least attention, but steadily increases. MEDLINE-search for relevant literature published during the last 15 years, and own clinical experience. Results from randomized clinical studies indicate that early geriatric rehabilitation, integrated in the acute treatment of elderly frail patients with acute diseases or hip fractures, is more effective than treatment in general medical or orthopedic wards. Geriatric intervention does not seem to increase costs. The beneficial effects consist of reduced incidence, duration and severity of delirium; fewer iatrogenic complications, better functional capacity and in some studies reduced mortality without increasing the need for institutionalization. Prerequisites for success are adequate patient selection and dedicated geriatric and rehabilitation units with full treatment responsibility. Up to 2050, there will be a dramatic increase in the number of elderly in Norway. Restructuring and reorganization of medical and orthopedic hospital departments are some of the measures required to meet this challenge.


Quantum walks with tuneable self-avoidance in one dimension.
Quantum walks exhibit many unique characteristics compared to classical random walks. In the classical setting, self-avoiding random walks have been studied as a variation on the usual classical random walk. Here the walker has memory of its previous locations and preferentially avoids stepping back to locations where it has previously resided. Classical self-avoiding random walks have found numerous algorithmic applications, most notably in the modelling of protein folding. We consider the analogous problem in the quantum setting - a quantum walk in one dimension with tunable levels of self-avoidance. We complement a quantum walk with a memory register that records where the walker has previously resided. The walker is then able to avoid returning back to previously visited sites or apply more general memory conditioned operations to control the walk. We characterise this walk by examining the variance of the walker's distribution against time, the standard metric for quantifying how quantum or classical a walk is. We parameterise the strength of the memory recording and the strength of the memory back-action on the walker, and investigate their effect on the dynamics of the walk. We find that by manipulating these parameters, which dictate the degree of self-avoidance, the walk can be made to reproduce ideal quantum or classical random walk statistics, or a plethora of more elaborate diffusive phenomena. In some parameter regimes we observe a close correspondence between classical self-avoiding random walks and the quantum self-avoiding walk.


Biomechanics of the first ray part V: The effect of equinus deformity. A 3-dimensional kinematic study on a cadaver model.
The positional change of the medial column of the foot in closed kinetic chain with variable Achilles tendon tension was investigated in seven fresh frozen cadaver specimens using a 3-dimensional radio wave tracking system. The distal tibia and fibula and the intact ankle and foot and were mounted on a non-metallic loading frame. The frame allowed positioning of the foot to simulate midstance phase of gait while the tibia and fibula were axially loaded to 400 N. To record osseous motion, receiving transducers were attached to the first metatarsal, medial cuneiform, navicular, and talus. Movements of these bones in 3-dimensional space were measured as specimens were axially loaded and midstance motor function was simulated using pneumatic actuators. To simulate a progressive equinus influence, force was applied to the Achilles tendon at tensile loads of 0%, 30%, and 60% of predicted maximum strength during each test trial. Osseous positions and orientations were collected and analyzed in all three cardinal planes utilizing data recorded. As Achilles load increased, the position of the first metatarsal became significantly more inverted ( P < .05). Although not statistically significant, remarkable trends of arch flattening motion were detected in the distal segments of the medial column with varied Achilles load. Increased Achilles load reduced the influence of peroneus longus on the medial column.


Is plasminogen deployed as a Streptococcus pyogenes virulence factor?
Streptococcus pyogenes (group A streptococcus) causes human skin and throat infections as well as highly invasive diseases including necrotizing fasciitis. Group A streptococcal infections and invasive disease have made a resurgence in developed countries during the past two decades. S. pyogenes use multiple pathways for the acquisition and activation of human plasminogen, securing potent proteolytic activity on the bacterial cell surface. Recent experimental evidence using a humanized transgenic mouse model suggests a crucial role for human plasminogen in the dissemination of S. pyogenes in vivo.


Clinical experience of galantamine in dementia: a series of case reports.
To use case studies to add the benefit of personal experience with galantamine to published literature and to demonstrate the type of patients that may benefit from this treatment. We describe eleven patients, aged 57-90 years, fulfilling the consensus diagnostic criteria for probable Alzheimer's disease, mixed dementia, vascular dementia, Lewy body dementia or Parkinson's dementia. All patients were treated with galantamine that may enhance cholinergic function in the brain by inhibiting acetylcholinesterase and potentiating the effects of acetylcholine at nicotinic acetylcholine receptors. Clinical features were rated according to eight assessment scales in old age psychiatry and additional information was obtained from family and other carers. In some cases caregiver distress was measured. All patients described showed a general improvement in cognition and neuropsychiatric symptoms, although observed improvements and effects were not always reflected by the results of formal assessments. Several patients became more independent, particularly in their activities of daily living, and treatment was felt to have helped maintain independence in their home environment, either alone or with their family or carers. One man continued in employment. Adverse events included nausea and vomiting. Outcomes in this case series indicate that galantamine is well tolerated and highlight aspects of the different side-effect profiles of the anticholinesterase inhibitors. Subjective benefits were not always apparent from objective measures. These case studies demonstrate the type of patients that may benefit from galantamine.


Comparison of the value of immature retyculocyte and immature platelet in the diagnosıs of sepsis.
Sepsis is one of the causes of pre-treatment morbidity and mortality in the pediatric age group. In the present study, we investigated the place of the immature granulocyte percentage, (IG) immature reticulocyte fraction (IRF), and immature platelet fraction (IPF) in the diagnosis of sepsis. Complete blood count, C-reactive protein, (CRP) procalcitonin (PCT) and blood cultures were measured in 125 critical patients who were followed-up in the intensive care unit with the suspicion of sepsis and 65 healthy children between 2017 and 2019. In addition to the complete blood counts and routine parameters, IG, IRF, and IPF were examined in the patients. When the critical patient group and the healthy control group were compared, it was found that the total number of leukocytes (white blood cells), neutrophil count, platelet count, CRP, PCT, IG, IRF, and IPF values were higher at statistically significant levels. When septic and non-septic patients were compared, it was found that the CRP, PCT,IGP, and IPF were higher at statistically significant levels in the septic patients. It was concluded that CRP, PCT, IG, and IPF were significant in determining sepsis and that PCT was the most sensitive and specific biomarker in these parameters. We believe that these parameters may be suitable for practical use in determining sepsis because they give faster results and suggest the diagnosis of sepsis.


Synthesis of guanidinoacetate and creatine from amino acids by rat pancreas.
Creatine is an important molecule involved in cellular energy metabolism. Creatine is spontaneously converted to creatinine at a rate of 1·7% per d; creatinine is lost in the urine. Creatine can be obtained from the diet or synthesised from endogenous amino acids via the enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate N-methyltransferase (GAMT). The liver has high GAMT activity and the kidney has high AGAT activity. Although the pancreas has both AGAT and GAMT activities, its possible role in creatine synthesis has not been characterised. In the present study, we examined the enzymes involved in creatine synthesis in the pancreas as well as the synthesis of guanidinoacetate (GAA) and creatine by isolated pancreatic acini. We found significant AGAT activity and somewhat lower GAMT activity in the pancreas and that pancreatic acini had measurable activities of both AGAT and GAMT and the capacity to synthesise GAA and creatine from amino acids. Creatine supplementation led to a decrease in AGAT activity in the pancreas, though it did not affect its mRNA or protein abundance. This was in contrast with the reduction of AGAT activity and mRNA and protein abundance in the kidney, suggesting that the regulatory mechanisms that control the expression of this enzyme in the pancreas are different from those in the kidney. Dietary creatine increased the concentrations of GAA, creatine and phosphocreatine in the pancreas. Unexpectedly, creatine supplementation decreased the concentrations of S-adenosylmethionine, while those of S-adenosylhomocysteine were not altered significantly.


Iodine status of adolescent girls in a population changing from high to lower fish consumption.
During the last decades, fish and milk consumption has decreased considerably in Iceland, especially among adolescents. As these food items are important dietary iodine (I) sources, the aim of the study was to assess the iodine status and dietary pattern of adolescent girls in a population changing from a high to lower consumption of milk and fish. Subjects were randomly selected adolescent girls (16-20 years old, n=112). A validated Food Frequency Questionnaire (FFQ) was used to evaluate food consumption and compare it with food-based dietary guidelines for milk and dairy products (2-3 portions/day) and fish (> or =2 times/week). Urine samples were collected for measuring urinary iodine (U-I) and creatinine (Cr) and blood samples for measuring serum thyroid-stimulating hormone (TSH). Milk and dairy products provided 43% and fish provided 24% of the total dietary I. More than 65% of the girls consumed fish less than twice a week, and 40% consumed less than two portions of milk and dairy products per day. The median U-I concentration was 200 microg/l and the U-I/Cr ratio 138 microg I/g Cr. High intake of milk was associated with higher urinary iodine concentration, but fish intake was not found to be directly associated with urinary iodine concentration. Iodine status of Icelandic adolescent girls is within the optimal range defined by the World Health Organization. It is important to monitor both iodine status and the iodine concentration of important sources of iodine, as both dietary habits and composition of food might change with time.


[Research and development. The value of patents].
The goal of innovative basic applied research is the award of patents for products and processes. Patents protect the exclusive use of these products and processes. Because of the high cost of research, it is important for governments to stimulate the creativity of researchers and provide economic incentives for them to develop patentable intellectual property. In the United States, an exchange program exists between the academic researchers and industry. This easy exchange of ideas is not adequately supported in Europe, especially in Italy. To further hinder researchers, the European Union has not yet passed legislation on patents.


R-plasmid transfer in vivo in the absence of antibiotic selection pressure.
The persistence of an O18 Escherichia coli strain resistant to tetracycline, streptomycin, and sulfonamide has been followed in the fecal flora of a single individual over a period of 9 months. The strain in question carrying an R plasmid was detectable from the beginning of the survey, but it was only after a 10-day period of tetracycline therapy that it reached an all but permanent dominance in the fecal flora. No transfer of the R plasmid carried by the strain to any other coliform could be detected for 202 days after the end of tetracycline treatment. At this point, however, an O88 E. coli carrying the same plasmid as the O18 strain appeared briefly as a predominant component of the flora. The two plasmids isolated from the O18 and the O88 E. coli strains have been characterized in molecular terms and found to be similar. This suggests that R-plasmid transfer between two E. coli strains occurred in an individual who was living a normal daily life and who was not receiving antibiotics.


Nutrient sensitive protein O-GlcNAcylation modulates the transcriptome through epigenetic mechanisms during embryonic neurogenesis.
Protein O-GlcNAcylation is a dynamic, nutrient-sensitive mono-glycosylation deposited on numerous nucleo-cytoplasmic and mitochondrial proteins, including transcription factors, epigenetic regulators, and histones. However, the role of protein O-GlcNAcylation on epigenome regulation in response to nutrient perturbations during development is not well understood. Herein we recapitulated early human embryonic neurogenesis in cell culture and found that pharmacological up-regulation of O-GlcNAc levels during human embryonic stem cells' neuronal differentiation leads to up-regulation of key neurogenic transcription factor genes. This transcriptional de-repression is associated with reduced H3K27me3 and increased H3K4me3 levels on the promoters of these genes, perturbing promoter bivalency possibly through increased EZH2-Thr311 phosphorylation. Elevated O-GlcNAc levels also lead to increased Pol II-Ser5 phosphorylation and affect H2BS112O-GlcNAc and H2BK120Ub1 on promoters. Using an in vivo rat model of maternal hyperglycemia, we show similarly elevated O-GlcNAc levels and epigenetic dysregulations in the developing embryo brains because of hyperglycemia, whereas pharmacological inhibition of O-GlcNAc transferase (OGT) restored these molecular changes. Together, our results demonstrate O-GlcNAc mediated sensitivity of chromatin to nutrient status, and indicate how metabolic perturbations could affect gene expression during neurodevelopment.


[Electrophysiological study of the mechanism of mexidol action].
It has been found that mexidol (5 mM) significantly (96 +/- 2%) depressed excitatory postsynaptic current caused by step depolarization in neurons of medial vestibular nucleus of medulla oblongata slices in young (aged 13 - 17 days) male albino rats. In addition, mexidol (2,5 - 5 mM) depressed by 94 +/- 3% excitatory postsynaptic current caused by Shaffer collaterals stimulation of CA1 pyramidal neurons of hippocampal slices in young rats. Complex MK-801 (non-competitive antagonist of NMDA receptors), in contrast to CNQX (competitive AMPA receptor antagonist), considerably decreased the depressant effect of the drug in both brain structures. Therefore, the central favorable effect of mexidol can be mediated by ion mechanisms with glutamate- and GABA-ergic components, primarily by the inhibition of ion currents through NMDA receptor complex.


Life systems of polyphagous arthropod pests in temporally unstable cropping systems.
Annual cropping systems consist of a shifting mosaic of habitats that vary through time in their availability and suitability to insect pests. Agroecosystem instability results from changes that occur within a season with crop planting, development, and harvest. Further instability results from continuous alterations in biotic and abiotic insect life system components and from agricultural inputs. Changes to agroecosystems occur across seasons with changing agricultural practices, changing cropping patterns, and technological innovations. Much of this instability is a result of events unconnected with pest management. The abilities of polyphagous pest species to move among and utilize different habitat patches in response to changes in suitability enable the pests to exploit unstable cropping systems. These pest characteristics determine the location and timing of damaging populations. Habitat suitability is influenced by plant species and cultivar, crop phenology, and agricultural inputs. Pest movement is affected by a suite of intrinsic factors, such as population age structure and mobility, and extrinsic factors, including weather systems and habitat distribution. The life systems of three selected polyphagous pests are presented to demonstrate how an understanding of such systems in agricultural ecosystems improves our ability to predict and hence manage these populations.


H2-EB1 Molecule Alleviates Allergic Rhinitis Symptoms of H2-Eb1 Knockout Mice.
H2-EB1 molecule which is the homolog of Human HLA-DRB1 is proposed to be associated with allergic rhinitis (AR). Construction of H2-Eb1 knockout animal models provides a tool to elucidate the role of H2-EB1 and AR pathogenesis. To establish the H2-Eb1 knockout model and investigate the H2-EB1 functions in H2-Eb1 knockout mice as a model of AR. The Cre/LoxP system and ES gene knockout technology were applied to create heterozygous H2-Eb1 (+/-) knockout mice and their offspring of knockout homozygous(-/-), heterozygous (+/-) and wild type (+/+) H2-Eb1 mice. After identification, offspring of heterozygous (+/-) and homozygous (-/-) H2-Eb1 knockout mice were randomly selected to establish AR models to demonstrate the role of H2-Eb1 in AR pathogenesis. The H2-Eb1 knockout mice model was successfully established. The reproduction and feeding of the homozygous (-/-) H2-Eb1 knockout mice were successful. Compared with the control group, the serum OVA-IgE and IL-4 levels significantly increased, while IFN-γ levels significantly dropped (p<0.05) in the experimental groups. For the two experimental groups, the homozygous (-/-) mice group had lower serum OVA-IgE and IL-4 levels, and higher IFN-γ levels than their heterozygous (+/-) counterparts (p<0.05), concomitant with slighter allergic symptoms (gentle behavior and less eosinophils in nasal mucosa). Our study demonstrated that knockout of H2-Eb1 gene could alleviate mouse AR Symptoms, indicating H2-Eb1 may play an important role in regulating Th1/Th2 balance during the pathogenesis of AR.


A randomised controlled trial of placebo, droperidol or ondansetron to prevent nausea and vomiting after tonsillectomy in children receiving dexamethasone.
We tested whether prophylactic droperidol and ondansetron, in combination with a moderate dose of dexamethasone, were equally effective in reducing nausea and vomiting after tonsillectomy in children and that both were superior to saline with dexamethasone. We randomly allocated 300 children to intravenous saline, droperidol 10 μg.kg-1 or ondansetron 150 μg.kg-1 , after induction of anaesthesia and the administration of intravenous dexamethasone 250 μg.kg-1 . The rates (95%CI) of nausea or vomiting within 24 postoperative hours were: 42/91 after saline, 46% (36%-57%); 43/87 after droperidol, 49% (39%-60%); reduced to 18/84 by ondansetron, 21% (13%-32%), p < 0.001. There were no differences in the rates of side-effects between groups. We conclude that ondansetron is more effective than saline in preventing nausea or vomiting after paediatric tonsillectomy when given with a moderate dose of dexamethasone, whereas droperidol was not.


Antiglycating potential of Zingiber officinalis and delay of diabetic cataract in rats.
Advanced glycation end products (AGE) are associated in the development of several pathophysiologies including diabetic cataract. Earlier we have reported that some common dietary agents have antiglycating activity and ginger (Zingiber officinalis) was one of the few prominent agents that effectively prevented AGE formation in vitro. In this study we investigated the potential of ginger to prevent diabetic cataract in rats. Diabetes was induced in Wistar-NIN rats by intraperitoneal injection of streptozotocin (35 mg/kg bodyweight) and the control rats received vehicle alone. While a set of diabetic animals received AIN-93 diet, another set received either 0.5 or 3% ginger in their diet for a period of two months. Cataract progression was monitored by slit-lamp biomicroscope. At the end of two months, the animals were sacrificed to evaluate non-enzymatic glycation and osmotic stress in the eye lens. Slit-lamp examination revealed that feeding of ginger not only delayed the onset but also the progression of cataract in rats. Molecular analyses indicated that feeding of ginger significantly inhibited the formation of various AGE products including carboxymethyl lysine in the eye lens. In addition, ginger also countered hyperglycemia-induced osmotic stress in the lens. The results indicated that ginger was effective against the development of diabetic cataract in rats mainly through its antiglycating potential and to a lesser extent by inhibition of the polyol pathway. Thus, ingredients of dietary sources, such as ginger, may be explored for the prevention or delay of diabetic complications.


RNA-binding protein RNPC1: acting as a tumor suppressor in breast cancer.
RNA binding proteins (RBPs) play a fundamental role in posttranscriptional control of gene expression. Different RBPs have oncogenic or tumor-suppressive functions on human cancers. RNPC1 belongs to the RNA recognition motif (RRM) family of RBPs, which could regulate expression of diverse targets by mRNA stability in human cancer cells. Several studies reported that RNPC1 played an important role in cancer, mostly acting as an oncogene or up-regulating in tumors. However, its role in human breast cancer remains unclear. In the present study, we investigated the functional and mechanistic roles of RNPC1 in attenuating invasive signal including reverse epithelial-mesenchymal transition (EMT) to inhibit breast cancer cells aggressiveness in vitro. Moreover, RNPC1 suppress tumorigenicity in vivo. Further, we studied the expression of RNPC1 in breast cancer tissue and adjacent normal breast tissue by quantitative RT-PCR (qRT-PCR) and Western blot. We observed that RNPC1 expression was silenced in breast cancer cell lines compared to breast epithelial cells. More important, RNPC1 was frequently silenced in breast cancer tissue compared to adjacent normal breast tissue. Low RNPC1 mRNA expression was associated with higher clinical stages and mutp53, while low level of RNPC1 protein was associated with higher lymph node metastasis, mutp53 and lower progesterone receptor (PR). Functional assays showed ectopic expression of RNPC1 could inhibit breast tumor cell proliferation in vivo and in vitro through inducing cell cycle arrest, and further suppress tumor cell migration and invasion partly through repressing mutant p53 (mutp53) induced EMT. Overall, our findings indicated that RNPC1 had a potential function to play a tumor-suppressor role which may be a potential marker in the therapeutic and prognostic of breast cancer.


Gene prediction and verification in a compact genome with numerous small introns.
The genomes of clusters of related eukaryotes are now being sequenced at an increasing rate, creating a need for accurate, low-cost annotation of exon-intron structures. In this paper, we demonstrate that reverse transcription-polymerase chain reaction (RT-PCR) and direct sequencing based on predicted gene structures satisfy this need, at least for single-celled eukaryotes. The TWINSCAN gene prediction algorithm was adapted for the fungal pathogen Cryptococcus neoformans by using a precise model of intron lengths in combination with ungapped alignments between the genome sequences of the two closely related Cryptococcus varieties. This approach resulted in approximately 60% of known genes being predicted exactly right at every coding base and splice site. When previously unannotated TWINSCAN predictions were tested by RT-PCR and direct sequencing, 75% of targets spanning two predicted introns were amplified and produced high-quality sequence. When targets spanning the complete predicted open reading frame were tested, 72% of them amplified and produced high-quality sequence. We conclude that sequencing a small number of expressed sequence tags (ESTs) to provide training data, running TWINSCAN on an entire genome, and then performing RT-PCR and direct sequencing on all of its predictions would be a cost-effective method for obtaining an experimentally verified genome annotation.


Impact of geographic distance on appraisal delay for active TB treatment seeking in Uganda: a network analysis of the Kawempe Community Health Cohort Study.
Appraisal delay is the time a patient takes to consider a symptom as not only noticeable, but a sign of illness. The study's objective was to determine the association between appraisal delay in seeking tuberculosis (TB) treatment and geographic distance measured by network travel (driving and pedestrian) time (in minutes) and distance (Euclidean and self-reported) (in kilometers) and to identify other risk factors from selected covariates and how they modify the core association between delay and distance. This was part of a longitudinal cohort study known as the Kawempe Community Health Study based in Kampala, Uganda. The study enrolled households from April 2002 to July 2012. Multivariable interval regression with multiplicative heteroscedasticity was used to assess the impact of time and distance on delay. The delay interval outcome was defined using a comprehensive set of 28 possible self-reported symptoms. The main independent variables were network travel time (in minutes) and Euclidean distance (in kilometers). Other covariates were organized according to the Andersen utilization conceptual framework. A total of 838 patients with both distance and delay data were included in the network analysis. Bivariate analyses did not reveal a significant association of any distance metric with the delay outcome. However, adjusting for patient characteristics and cavitary disease status, the multivariable model indicated that each minute of driving time to the clinic significantly (p = 0.02) and positively predicted 0.25 days' delay. At the median distance value of 47 min, this represented an additional delay of about 12 (95% CI: [3, 21]) days to the mean of 40 days (95% CI: [25, 56]). Increasing Euclidean distance significantly predicted (p = 0.02) reduced variance in the delay outcome, thereby increasing precision of the mean delay estimate. At the median Euclidean distance of 2.8 km, the variance in the delay was reduced by more than 25%. Of the four geographic distance measures, network travel driving time was a better and more robust predictor of mean delay in this setting. Including network travel driving time with other risk factors may be important in identifying populations especially vulnerable to delay.


Some genetic consequences of changes in the level of recA gene function in Escherichia coli K-12.
Genetic recombination was studied in E. coli mutants that carry lesions in the recA gene but retain some capacity for generating recombinant progeny. We observed that recombination was detectable only at a very low level during the incubation of leaky RecA- merozygotes in broth. However, recombination appeared to occur at much higher frequencies when recombinant progeny were assayed by selection on minimal agar. Analysis of the recombinants obtained with Hfr donors revealed a deficiency of multiple exchanges per unit length of DNA in leaky RecA- strains. In many of these crosses recombinants that inherited donor alleles close to the transfer origin were much reduced in frequency, except when the recipient was also RecB-.


[Effect of liposomally entrapped insulin administered per os on the blood glucose level in normal and diabetic rats].
The article deals with the effect of insulin which was incorporated into lecithin-cholesterol (molar ratio 9 : 2) liposomes, administered per os to normal and diabetic Wistar rats on the blood glucose level. The blood glucose level 1.5 h after the administration of insulin is shown to decrease significantly in diabetic rats. The maximum effect is observed 3 h after and then the blood glucose level gradually increases, being considerably lower than the control one 20 h after as well. Insulin in liposomes when given orally has no hypoglycaemic effect in the normal rats. A slight but statistically significant decrease in the blood glucose level is determined in the diabetic rats after administration per os of liposome-absorbed insulin. The blood glucose level is practically the same as in the control when insulin is administered to the normal rats. Possible mechanisms of the insulin action in liposomes are discussed.


Neurologic outcome after emergency room thoracotomy for trauma.
The charts of 168 patients undergoing resuscitative thoracotomy for trauma in the emergency room at the San Francisco General Hospital from 1972 through 1978 were reviewed to assess factors affecting neurologic recovery after cardiac arrest. Forty-nine patients survived resuscitation and definitive operation, but 8 of them died in the first 24 hours postoperatively. Four patients in this group made some neurologic recovery (two good recoveries, two severe disabilities) but died later (12 to 44 days postoperatively) of septic complications. Thirteen nonsurvivors made no neurologic recovery before death. There were 33 long-term survivors (19.6 percent), 10 of whom were agonal or had no vital signs when first admitted to the emergency room. A persistent vegetative state developed in two patients who later died of sepsis (10 days and 14 months postoperatively). The remaining 32 patients all made good neurologic recovery that was apparent within 12 hours postoperatively. Transient amnesia was present during recovery in three patients. Wakefulness was the best prognostic sign of full neurologic recovery. In conclusion, emergency room thoracotomy can save a substantial number of moribund trauma patients who can be expected to sustain full neurologic recovery if they awaken within 12 hours.


The accessory soleus muscle as a cause of persistent equinus in clubfeet treated by the Ponseti method : A report of 16 cases.
Encountering an accessory soleus muscle in children undergoing surgical release for clubfeet is not a frequent occurrence and only a few reports could be traced in literature. The purpose of this study is to report a series of 20 observations in 16 patients with idiopathic clubfeet treated by the Ponseti technique where the accessory soleus muscle was responsible in preventing full ankle dorsiflexion after Achilles tendon tenotomy. Following its division, adequate dorsiflexion could be achieved. To our knowledge this is the largest series published to date on this topic. In addition, we discuss the frequency and epidemiology, as well as the anatomy of the accessory soleus muscle, its innervation and embryology. The mean age at presentation was 40.7 days (range : 6 to 210 days). The accessory soleus tendon was observed in 6 right and 6 left feet, 4 feet had bilateral involvement. The average ankle dorsiflexion after complete tendo Achilles tenotomy was 2.50 (SD: 638), and after sectioning of the accessory soleus tendon, it was 19.50 (SD: 559) (p < 0.001). Correction was obtained in all patients, after 3 to 10 casts. In conclusion, the recognition of an accessory soleus muscle, in patients with clubfeet, is important, and its release is necessary to fully correct the deformity. Failure to recognize this muscle may lead to persistent hindfoot deformity.


Light regulates attachment, exopolysaccharide production, and nodulation in Rhizobium leguminosarum through a LOV-histidine kinase photoreceptor.
Rhizobium leguminosarum is a soil bacterium that infects root hairs and induces the formation of nitrogen-fixing nodules on leguminous plants. Light, oxygen, and voltage (LOV)-domain proteins are blue-light receptors found in higher plants and many algae, fungi, and bacteria. The genome of R. leguminosarum bv. viciae 3841, a pea-nodulating endosymbiont, encodes a sensor histidine kinase containing a LOV domain at the N-terminal end (R-LOV-HK). R-LOV-HK has a typical LOV domain absorption spectrum with broad bands in the blue and UV-A regions and shows a truncated photocycle. Here we show that the R-LOV-HK protein regulates attachment to an abiotic surface and production of flagellar proteins and exopolysaccharide in response to light. Also, illumination of bacterial cultures before inoculation of pea roots increases the number of nodules per plant and the number of intranodular bacteroids. The effects of light on nodulation are dependent on a functional lov gene. The results presented in this work suggest that light, sensed by R-LOV-HK, is an important environmental factor that controls adaptive responses and the symbiotic efficiency of R. leguminosarum.


Costs and Benefits of Transgenerational Induced Resistance in Arabidopsis.
Recent evidence suggests that stressed plants employ epigenetic mechanisms to transmit acquired resistance traits to their progeny. However, the evolutionary and ecological significance of transgenerational induced resistance (t-IR) is poorly understood because a clear understanding of how parents interpret environmental cues in relation to the effectiveness, stability, and anticipated ecological costs of t-IR is lacking. Here, we have used a full factorial design to study the specificity, costs, and transgenerational stability of t-IR following exposure of Arabidopsis thaliana to increasing stress intensities by a biotrophic pathogen, a necrotrophic pathogen, and salinity. We show that t-IR in response to infection by biotrophic or necrotrophic pathogens is effective against pathogens of the same lifestyle. This pathogen-mediated t-IR is associated with ecological costs, since progeny from biotroph-infected parents were more susceptible to both necrotrophic pathogens and salt stress, whereas progeny from necrotroph-infected parents were more susceptible to biotrophic pathogens. Hence, pathogen-mediated t-IR provides benefits when parents and progeny are in matched environments but is associated with costs that become apparent in mismatched environments. By contrast, soil salinity failed to mediate t-IR against salt stress in matched environments but caused non-specific t-IR against both biotrophic and necrotrophic pathogens in mismatched environments. However, the ecological relevance of this non-specific t-IR response remains questionable as its induction was offset by major reproductive costs arising from dramatically reduced seed production and viability. Finally, we show that the costs and transgenerational stability of pathogen-mediated t-IR are proportional to disease pressure experienced by the parents, suggesting that plants use disease severity as an environmental proxy to adjust investment in t-IR.


Computers and nursing diagnoses. Issues in implementation.
In summary, the issue of using computerized systems for nursing diagnosis is really a question of when and how, not if, because we look to technology to simplify our information processing requirements. In a society that is moving quickly to increase applications of computers, there are still many technical as well as professional issues that need to be addressed. How we define computerized information systems can define how we practice. It is critical then to recognize nursing's responsibility to use technology to emphasize a commitment to care that is both individualized and humanistic. As we look to technology to simplify our information processing requirements, the process of developing computer applications for nursing holds great promise.


Quantitative Decomposition of Dynamics of Mathematical Cell Models: Method and Application to Ventricular Myocyte Models.
Mathematical cell models are effective tools to understand cellular physiological functions precisely. For detailed analysis of model dynamics in order to investigate how much each component affects cellular behaviour, mathematical approaches are essential. This article presents a numerical analysis technique, which is applicable to any complicated cell model formulated as a system of ordinary differential equations, to quantitatively evaluate contributions of respective model components to the model dynamics in the intact situation. The present technique employs a novel mathematical index for decomposed dynamics with respect to each differential variable, along with a concept named instantaneous equilibrium point, which represents the trend of a model variable at some instant. This article also illustrates applications of the method to comprehensive myocardial cell models for analysing insights into the mechanisms of action potential generation and calcium transient. The analysis results exhibit quantitative contributions of individual channel gating mechanisms and ion exchanger activities to membrane repolarization and of calcium fluxes and buffers to raising and descending of the cytosolic calcium level. These analyses quantitatively explicate principle of the model, which leads to a better understanding of cellular dynamics.


Women's representation in emergency medicine journals across two decades: 2000-2019.
The primary aim was to determine women's representation as authors in emergency medicine journals in various authorship positions over the last 20 years. The secondary aim was to compare the two decades to analyze the development over time. We conducted a retrospective bibliometric analysis of three emergency medicine journals from the online archives of 2000-2019. We analyzed a total of 7939 original research and review articles. Female authorships at the first (25,8%), last (18,7%), and corresponding (21,6%) positions were limited, despite the relatively high presence rate (72,5%). Women authored 13,1% of all single-authored publications. When the number of authors increased, the odds for women as co-authors increased. However, the odds for last and corresponding authorship decreased, while the odds for the first authorship remained unchanged. When two decades were compared, we found that proportions of women as first and corresponding authorship increased ([23,8% vs. 27,0%] p = 0.001 and [20,0% vs. 22,6%] p = 0.228, respectively) while the representation as the last author remained unchanged ([19,4% vs 18,3%] p = 0.006). The presence of women in any authorship position also increased significantly ([66,1% vs. 76,5%] p = 0.000) across two decades, with similar trends for the different journals studied. However, the yearly analysis shows that women's representation follows a fluctuating pattern with a minimal increase. When analyzing specific journals, we found that the increase in female authors as first and corresponding authors was limited to Academic Emergency Medicine ([24,7% vs 34,5%] p = 0.000 and [21,4% vs 32,1%] p = 0.000). Results of this study are promising in showing that the representation of women in emergency medicine publications is rising during the recent decade. Although the academic gender gap has not been closed, steps taken for gender equality in academic emergency medicine are clearly notable.


Roadmap Out of COVID-19.
The recent coronavirus disease (COVID-19) was declared as a public health emergency by the World Health Organisation on 30th January 2020, and has now affected more than 100 countries. Healthcare institutions and governments worldwide have raced to contain the disease, albeit to varying degrees of success. Containment strategies adopted range from complete lockdowns to remaining open with public advisories regarding social distancing. However, general principles adopted by most countries remain the same, mainly to avoid gatherings in large numbers and limit social interactions to curb the spread of disease. In Singapore, this disease had a very different progression. The first wave of the disease started with the confirmation of the first COVID-19 positive patient in Singapore on 23rd January 2020. Initially, the daily number of confirmed cases were low and manageable. With a rise in unlinked cases, the Disease Outbreak Response System Condition (DORSCON) status was raised from yellow to orange. New cluster outbreaks in foreign worker dormitories led to the rampant spread of disease, with daily spikes of COVID-19 cases. As of 7th June 2020, we have a total of 37,910 confirmed cases of COVID-19 infections, the highest in Southeast Asia, 12,999 active cases and a manageable mortality count of 25 deaths. This details our unique method for dealing with a pandemic, including a brief demographic of trauma patients during this period. We were able to conserve sufficient resources to ensure that our essential services can still continue. Moving on, we have to ensure the continued protection of our population, especially the vulnerable groups such as the elderly and the immunocompromised, as we reopen.


Transcriptomic profiling of tissue environments critical for post-embryonic patterning and morphogenesis of zebrafish skin.
Pigment patterns and skin appendages are prominent features of vertebrate skin. In zebrafish, regularly patterned pigment stripes and an array of calcified scales form simultaneously in the skin during post-embryonic development. Understanding the mechanisms that regulate stripe patterning and scale morphogenesis may lead to the discovery of fundamental mechanisms that govern the development of animal form. To learn about cell types and signaling interactions that govern skin patterning and morphogenesis, we generated and analyzed single-cell transcriptomes of skin from wild-type fish as well as fish having genetic or transgenically induced defects in squamation or pigmentation. These data reveal a previously undescribed population of epidermal cells that express transcripts encoding enamel matrix proteins, suggest hormonal control of epithelial-mesenchymal signaling, clarify the signaling network that governs scale papillae development, and identify a critical role for the hypodermis in supporting pigment cell development. Additionally, these comprehensive single-cell transcriptomic data representing skin phenotypes of biomedical relevance should provide a useful resource for accelerating the discovery of mechanisms that govern skin development and homeostasis.


Mu opioid receptor involvement in enkephalin activation of dopamine neurons in the ventral tegmental area.
Many lines of evidence suggest that opioids act in the A10 dopamine (DA) region to activate DA neurons projecting to limbic terminal areas. Thus, injection of morphine and enkephalin analogs into the ventral tegmental area (a major subnucleus of the A10 DA region) produces an increase in spontaneous motor activity that is blocked by DA receptor antagonists and increases DA metabolism in the nucleus accumbens. The present study utilized enkephalin analogs specific for either the mu or delta opioid receptor to evaluate which receptor subtype(s) is activating the A10 DA neurons. It was found that the specific mu agonist, Try-D-Ala-Gly-NMe-Phe-Gly-ol, was significantly more potent than the specific delta agonist, [D-Pen2,5]-enkephalin, at increasing spontaneous motor activity or DA metabolism in the nucleus accumbens, septum, striatum and prefrontal cortex. Further, naloxonazine, a putative antagonist of the mu-1 isoreceptor, significantly attenuated the motor-stimulant effect and increase in DA metabolism produced by intra-ventral tegmental area injection of Tyr-D-Ala-Gly-NMe-Phe-Gly-ol. It was found that the disposition of microinjected Tyr-D-Ala-Gly-NMe-Phe-Gly-ol or [D-Pen2,5]-enkephalin was not responsible for the difference in their potency. It is concluded that the mu receptor and, perhaps, the mu-1 isoreceptor mediate a major portion of the activation of A10 DA neurons previously demonstrated with mixed mu and delta opioid agonists.


S100s and HMGB1 Crosstalk in Pancreatic Cancer Tumors.
Pancreatic cancer remains a disease that is very difficult to treat. S100 proteins are small calcium binding proteins with diverse intra- and extracellular functions that modulate different aspects of tumorigenesis, including tumor growth and metastasis. High mobility group box 1 (HMGB1) protein is a multifaceted protein that also actively influences the development and progression of tumors. In this study, we investigate the possible correlations, at the transcript level, between S100s and HMGB1 in pancreatic cancer. For this purpose, we calculated Pearson's correlations between the transcript levels of 13 cancer-related S100 genes and HMGB1 in a cDNA array containing 19 pancreatic cancer tumor samples, and in 8 human pancreatic cancer cell lines. Statistically significant positive correlations were found in 5.5% (5 out of 91) and 37.4% (34 of 91) of the possible S100/S100 or S100/HMGB1 pairs in cells and tumors, respectively. Our data suggest that many S100 proteins crosstalk in pancreatic tumors either with other members of the S100 family, or with HMGB1. These newly observed interdependencies may be used to further the characterization of pancreatic tumors based on S100 and HMGB1 transcription profiles.


Numerical taxonomy of aquatic Acinetobacter isolates.
Two hundred and seventy Gram-negative strains, representing aquatic members of the genus acinetobacter, were isolated and compared with 48 related clinical isolates and reference strains from a variety of genera. For each isolate, a total of 96 coded characters derived from 89 characteristics was determined using morphological, physiological, nutritional and biochemical features, in addition to sensitivities to several antibiotics and inhibitory agents. The data were analysed by computer to obtain a simple matching coefficient for each pair of strains. Clustering was performed by the unweighted pair-group method of association. Two major phenons were formed which excluded the oxidase-positive, motile or facultatively anaerobic strains. Within each phenon, three 'subphenons' were delimited. The two phenons, comprising 291 isolates, were tentatively differentiated at the species level, while their shared characteristics indicated that both phenons should be included in the genus Acinetobacter. Phenon 2 contained most of the clinical isolates and corresponded to the type species Aci. calcoaceticus as described originally by Baumann, Doudoroff & Stanier (1968). Phenon 1 was composed almost entirely of aquatic isolates and may prove to represent a second species of a less biochemically-active nature. Distinguishing characters have been suggested as diagnostic criteria for the differentiation of these two phenons.


Instabilities of the harmonic oscillator with fluctuating damping.
We investigate the instabilities of a linear damped oscillator due to fluctuations of the damping parameter. The fluctuations are driven either by Gaussian white noise or Poisson white noise (white shot noise). We consider three notions of stability. The first two are the well-known notions of stability in the mean and stability in the mean square. We introduce the concept of thermodynamic stability, corresponding to a nonpositive rate of energy dissipation at all times. We derive analytical results for the various instability thresholds, confirm the validity of our approach for white shot noise by numerical simulations, and obtain the unexpected result that mean-square and thermodynamic stability coincide for the two types of white noise.


Emerging roles of sortilin in affecting the metabolism of glucose and lipid profiles.
Dyslipidemia has recently been identified as an important factor in modulating the progression of several health conditions, grouped as cardio-metabolic syndrome and including obesity,insulin resistance, and atherosclerosis. Among multiple factors which regulate the development of cardio-metabolic syndrome, sortilin has been found in multiple cell types, such as adipocyte, hepatocyte, and macrophage, suggesting that sortilin is correlated to the development and the severity of cardio-metabolic syndrome. Consistently, several genome-wide association (GWAS) and basic experimental research studies are being conducted to find novel gene loci involved in regulating the pathological progression of cardio-metabolic syndrome. According to these data, both SORT1 gene and sortilin protein have an important function in regulating the circulating lipid and glucose metabolism resulting in modulation of disease progression. In this comprehensive review, we summarize the recent research results in regards to sortilin function in modulating the circulating lipid and glucose metabolism. Moreover, we also discuss and analyze the emerging evidence elucidating the potential mechanisms by which sortilin affects synthesis and secretion of lipid and glucose.


Hyoidthyroidpexia as a treatment in multilevel surgery for obstructive sleep apnea.
This type of surgery is effective in patients with obstructive sleep apnea syndrome (OSAS), but may not be effective in obese patients or those with a preoperative apnea hypopnea index (AHI)>35. For these reasons, the careful study and selection of patients is fundamental in the surgical treatment of OSAS. Evaluation of the efficacy of hyoid surgery combined with oropharynx and nose surgery in the treatment of OSAS. A total of 109 OSAS patients underwent hyoidthyroidpexia as a treatment in multilevel surgery. Before surgery all patients were treated with continuous positive airway pressure (CPAP) therapy for at least 6 months and underwent preoperative and postoperative polysomnography. The preoperative examination was composed of upper airways endoscopy, lateral cephalometric radiograph, calculation of body mass index (BMI), and subjective analysis of daytime sleepiness. In all, 67/109 patients (61.5%) with postoperative AHI<20 were defined as 'responders', while the other 42 patients (38.5%) were defined as 'non-responders'. The correlation between preoperative BMI and postoperative AHI revealed that non-responders had a much higher average BMI compared with responders. Moreover, when analyzing median preoperative and postoperative AHI, it emerged that non-responders had a much higher preoperative AHI compared with responders.


A differential operator technique for restoring degraded signals and images.
A technique is described for restoring signals, images, and other physical quantities that have been distorted or degraded by an imperfect measurement system. This technique is based upon the application of a specific differential operator to the measured quantity. For digital implementation, its advantages compared to other restoration techniques are simplicity, computational efficiency, and reduced core memory requirements. Calculations for a one-dimensional example indicate that restorations comparable in quality to Wiener-filter restorations are obtained with better than an order of magnitude decrease in computation time.


Female mate fidelity in a Lek mating system and its implications for the evolution of cooperative lekking behavior.
The extent and importance of female mate fidelity in polygynous mating systems are poorly known. Fidelity may contribute to high variance in male reproductive success when it favors attractive mates or may stabilize social interactions if females are faithful to mating sites rather than males. Using 12 years of data on genetic mate choice in the cooperatively lekking lance-tailed manakin (Chiroxiphia lanceolata), I investigated the frequency of fidelity within and between years, whether females were faithful to individual males or to mating sites across years, and whether fidelity favored attractive males. Mate fidelity occurred in 41.7% of 120 between-year comparisons and was observed for 41.1% of 73 individual females that had the opportunity to mate faithfully. Females were not more likely to mate at prior mating sites when previous mates were replaced. Faithful females mated with the same male in up to four consecutive years but were not disproportionately faithful to attractive partners. Mating history influences current mate choice, and fidelity in this lekking system apparently represents active mate choice by females but little is not cited in the text. Please provide a citation or mark this reference for deletion.consensus in mate choices among faithful females. This study underscores the prevalence of mate fidelity in polygynous mating systems and emphasizes the need to consider the larger context of lifetime reproductive behavior when interpreting patterns of female choice.


O-demethylation, dehydroxylation, ring-reduction and cleavage of aromatic substrates by Enterobacteriaceae under anaerobic conditions.
Four fermentative facultative anaerobes, members of the genera Enterobacter and Escherichia, were tested for their ability to transform an aromatic lignin derivative, 3-methoxy-4-hydroxy-cinnamic acid (ferulic acid), under anaerobic (fermentative) conditions. The pure cultures studied were shown to O-demethylate, dehydroxylate, reduce the double bond in the side-chain, decarboxylate the aromatic ring to the stage of benzoate and to reduce the ring to an alicyclic acid. Aromatic hydrocarbons (toluene, ethylbenzene and propylbenzene), as well as phenols (phenol, o-cresol, p-cresol, 2-ethylphenol and 3-hydroxy-4-ethylphenol) were also produced. In addition, during 3 months incubation, the cleavage of the aromatic ring occurred, whereby a small fraction of the substrate was converted to straight-chain and branched (methylated, ethylated) five- to eight-carbon aliphatic acids. The results indicate that pure cultures of fermentative facultative anaerobes might be capable of degrading substituted aromatic acids to aliphatic products under strictly anaerobic (fermentative) conditions. These abilities, which have so far been found only in denitrifying pseudomonads among facultative anaerobes, might be common in Enterobacteriaceae. It is conceivable that these bacteria are important as degraders of aromatic compounds in anaerobic ecosystems.


The novel antipsychotic drug lurasidone enhances N-methyl-D-aspartate receptor-mediated synaptic responses.
N-Methyl-D-aspartate (NMDA) receptor (NMDAR) hypofunction has been postulated to contribute to the cognitive deficit of schizophrenia. In this study, we examined the effect of lurasidone (Latuda; Dainippon Sumitomo Pharma Co. Ltd., Tokyo, Japan), a newly approved atypical antipsychotic drug (APD), on NMDAR synaptic function in rat frontal cortical pyramidal neurons. In vivo administration of lurasidone produced a significant and selective enhancement of NMDAR-mediated synaptic responses and surface expression of NR2A and NR2B subunits. Lurasidone has high affinity for serotonin 5-HT(1A), 5-HT(2A), and 5-HT(7) receptors and dopamine D(2) receptors. In vivo administration of the 5-HT(7) receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2 -(2-(4-methyl-1-piperidinyl)ethyl)pyrrolidine (SB-269970) mimicked the enhancing effect of lurasidone on NMDAR responses, whereas the D(2) receptor antagonist haloperidol failed to do so. Previous studies have found that short-term administration of lurasidone reverses the cognitive impairment induced by subchronic administration of phencyclidine (PCP), an NMDAR noncompetitive antagonist. In this study, we found that lurasidone, as well as the prototypical atypical APD clozapine, restored NMDAR-mediated synaptic responses to normal levels in the PCP model of schizophrenia. These results suggest that NMDAR is the potential key molecular target of lurasidone, possibility via antagonizing 5-HT(7) receptors, which is consistent with evidence that 5-HT(7) receptor antagonism contributes to cognitive enhancement by atypical APDs in patients with schizophrenia.


Characteristic odor components of Citrus reticulata Blanco (ponkan) cold-pressed oil.
Citrus reticulata Blanco (ponkan) cold-pressed oil and its oxygenated fraction were studied by analytical (GC and GC/MS) and sensory analyses. The monoterpene group was predominant, accounting for more than 89.6% (w/w), of which limonene was the most abundant (80.3%). Among the oxygenated compounds, octanal and decanal were the major ones among 12 aldehydes accounting for >1.5%; six alcohols were identified with a total concentration of >0.7%, while oxides, ketones and esters did not quantitatively or qualitatively contribute to the oil. Sniffing the ponkan cold-pressed oil and its oxygenated fraction demonstrated that octanal and decanal were the characteristic odor components of ponkan. Reconstruction of the ponkan aroma model and its sensory evaluation by a hedonic test were performed, showing that, in addition to octanal and decanal which played important roles, (R)-(+)-limonene contributed to the aroma model as a background component, making the aroma model very similar to that of the original.


Decreased Triple Network Connectivity in Patients with Recent Onset Post-Traumatic Stress Disorder after a Single Prolonged Trauma Exposure.
The triple network model provides a common framework for understanding affective and neurocognitive dysfunctions across multiple disorders, including central executive network (CEN), default mode network (DMN), and salience network (SN). Considering the effect of traumatic experience on post-traumatic stress disorder (PTSD), this study aims to explore the alteration of triple network connectivity in a specific PTSD induced by a single prolonged trauma exposure. With an arterial spin labeling sequence, three networks were first identified using independent component analysis among 10 PTSD patients and 10 healthy survivors, who experienced the same coal mining flood disaster. Then, the triple network connectivity was analyzed and compared between PTSD and non-PTSD groups. In PTSD patients, decreased connectivity was identified in left middle frontal gyrus of CEN, left precuneus and bilateral superior frontal gyrus of DMN, and right anterior insula of SN. The decreased connectivity in left middle frontal gyrus of CEN was associated with clinical severity. Furthermore, no significant connection of SN with CEN and DMN was found in PTSD patients. The decreased triple network connectivity was found in this study, which not only supports the triple network model, but also suggests a possible neurobiological mechanism for cognitive dysfunction of this type of PTSD.


Oxidative stress and induction of heme oxygenase-1 in the kidney in sickle cell disease.
Chronic nephropathy is a recognized complication of sickle cell disease. Using a transgenic sickle mouse, we examined whether oxidative stress occurs in the sickle kidney, the origins and functional significance of such oxidant stress, and the expression of the oxidant-inducible, potentially protective gene, heme oxygenase-1 (HO-1); we also examined the expression of HO-1 in the kidney and in circulating endothelial cells in sickle patients. We demonstrate that this transgenic sickle mouse exhibits renal enlargement, medullary congestion, and a reduced plasma creatinine concentration. Oxidative stress is present in the kidney as indicated by increased amounts of lipid peroxidation; heme content is markedly increased in the kidney. Exacerbation of oxidative stress by inhibiting glutathione synthesis with buthionine-sulfoximine dramatically increased red blood cell sickling in the sickle kidney: in buthionine-sulfoximine-treated sickle mice, red blood cell sickling extended from the medulla into the cortical capillaries and glomeruli. HO activity is increased in the sickle mouse kidney, and is due to induction of HO-1. In the human sickle kidney, HO-1 is induced in renal tubules, interstitial cells, and in the vasculature. Expression of HO-1 is increased in circulating endothelial cells in patients with sickle cell disease. These results provide the novel demonstration that oxidative stress occurs in the sickle kidney, and that acute exacerbation of oxidative stress in the sickle mouse precipitates acute vaso-occlusive disease. Additionally, the oxidant-inducible, heme-degrading enzyme, HO-1, is induced regionally in the murine and human sickle kidney, and systemically, in circulating endothelial cells in sickle patients.


The weather affects air conditioner purchases to fill the energy efficiency gap.
Energy efficiency improvement is often hindered by the energy efficiency gap. This paper examines the effect of short-run temperature fluctuations on the Energy Star air conditioner purchases in the United States from 2006 to 2019 using transaction-level data. Results show that the probability of purchasing an Energy Star air conditioner increases as the weekly temperature before the transaction deviates from 20-22 °C. A larger response is related to fewer cooling degree days in the previous years, higher electricity prices/income/educational levels/age/rate of owners, more common use of electricity, and stronger concern about climate change. 1 °C increase and decrease from 21 °C would lead to a reduction of total energy expenditure by 35.46 and 17.73 million dollars nationwide (0.13% and 0.06% of the annual total energy expenditure on air conditioning), respectively. Our findings have important policy implications for demand-end interventions to incorporate the potential impact of the ambient physical environment.