Left ventricular diastolic function and long-term outcomes in patients with normal exercise echocardiographic findings.
The objective of the present study was to determine whether diastolic dysfunction (DD) is associated with outcomes in the absence of myocardial ischemia. We studied 2,835 patients undergoing exercise echocardiography from January 2006 through December 2006 who had normal systolic function (ejection fraction ≥50%) and an absence of exercise-induced wall motion abnormalities. Diastolic function was graded as normal, mild DD, or moderate to severe DD. Medical records review and patient contact were undertaken to determine mortality, cardiovascular events (i.e., death, myocardial infarction, or stroke), incident heart failure (HF), and hospitalization. The mean ± SD age was 58.9 ± 12.8 years, and 54.0% were women. DD was present in 40.0% of the participants, with mild DD in 28.2% and moderate to severe DD in 11.8%. During a median follow-up of 4.4 years, 81 deaths and 114 cardiovascular events occurred, and DD was associated with greater rates of mortality, cardiovascular events, and HF events or hospitalizations (all p <0.001). On multivariate analysis, mild or moderate to severe DD (referent, normal function) was associated with HF or hospitalization (hazard ratio 1.45, 95% confidence interval 1.18 to 1.78, p <0.001 for mild DD; hazard ratio 1.75, 95% confidence interval 1.37 to 2.24, p <0.001 for moderate to severe DD) but was not independently associated with death or cardiovascular events. The diastolic index of filling pressure (E/e') was independently associated with mortality, cardiovascular events, and HF or hospitalization. In conclusion, among patients without demonstrable myocardial ischemia, left ventricular DD was associated with greater event rates during long-term follow up but did not independently predict hard end points other than HF or hospitalization. E/e' was independently associated with the clinical outcomes and might be an important echocardiographically derived parameter to identify in patients undergoing exercise echocardiography.


Novel surface display system for heterogonous proteins on Lactobacillus plantarum.
To establish a novel cell surface display system that would enable the display of target proteins on Lactobacillus plantarum. BlastP analysis of the amino acids sequence data revealed that the N-terminus of the putative muropeptidase MurO from L. plantarum contained two putative lysin motif (LysM) repeat regions, implying that the MurO was involved in bacterial cell wall binding. To investigate the potential of MurO for surface display, green fluorescent protein (GFP) was fused to MurO at its C-terminus and the resulting fusion protein was expressed in Escherichia coli. After being mixed with L. plantarum cells in vitro, GFP was successfully displayed on the surfaces of L. plantarum cells. Increases in the fluorescence intensities of chemically pretreated L. plantarum cells compared to those of nonpretreated cells suggested that the peptidoglycan was the binding ligand for MurO. SDS sensitivity assay showed that the GFP fluorescence intensity was reduced after being treated with SDS. To demonstrate the applicability of the MurO-mediated surface display system, β-galactosidase from Bifidobacterium bifidium, in place of GFP, was functionally displayed on the surface of L. plantarum cells via MurO. The MurO was a novel anchor protein for constructing a surface display system for L. plantarum. The success in surface display of GFP and β-galactosidase opened up the feasibility of employing the cell wall anchor of MurO for surface display in L. plantarum.


Tubulo-interstitial nephritis and uveitis syndrome associated with mastitis: a case report.
A new case of tubulo-interstitial nephritis and uveitis (TINU) syndrome in a 14-y-old girl is described. In this patient unilateral mastitis was an associated feature. The aetiology of this rare syndrome, the prognosis for which is usually good, is still unknown. The most common theory supports a cell-mediated immune response induced by infectious/antigenic stimuli. The presence of acute unilateral mastitis in this patient may represent an additional localization in TINU syndrome.


Transgenerational effects of maternal depression on affect recognition in children.
The association between maternal depression and adverse emotional and behavioral outcomes in children is well established. One associated factor might be altered affect recognition which may be transmitted transgenerationally. Individuals with history of depression show biased recognition of sadness. Our aim was to investigate parallels in maternal and children's affect recognition with remitted depressed mothers. 60 Mother-child dyads completed an affect recognition morphing task. We examined two groups of remitted depressed mothers, with and without history of physical or sexual abuse, and a group of healthy mothers without history of physical or sexual abuse. Children were between 5 and 12 years old. Across groups, mothers identified happy faces fastest. Mothers with remitted depression showed a higher accuracy and response bias for sadness. We found corresponding results in their children. Maternal and children's bias and accuracy for sadness were positively correlated. Effects of remitted depression were found independent of maternal history of physical or sexual abuse. Our sample size was relatively small and further longitudinal research is needed to investigate how maternal and children's affect recognition are associated with behavioral and emotional outcomes in the long term. Our data suggest a negative processing bias in mothers with remitted depression which might represent both the perpetuation of and vulnerability to depression. Children of remitted depressed mothers appear to be exposed to this processing bias outside acute depressive episodes. This may promote the development of a corresponding processing bias in the children and could make children of depressed mothers more vulnerable to depressive disorders themselves.


Noncovalent reversible binding-enabled facile fabrication of leak-free PDMS microfluidic devices without plasma treatment for convenient cell loading and retrieval.
The conventional approach for fabricating polydimethylsiloxane (PDMS) microfluidic devices is a lengthy and inconvenient procedure and may require a clean-room microfabrication facility often not readily available. Furthermore, living cells can't survive the oxygen-plasma and high-temperature-baking treatments required for covalent bonding to assemble multiple PDMS parts into a leak-free device, and it is difficult to disassemble the devices because of the irreversible covalent bonding. As a result, seeding/loading cells into and retrieving cells from the devices are challenging. Here, we discovered that decreasing the curing agent for crosslinking the PDMS prepolymer increases the noncovalent binding energy of the resultant PDMS surfaces without plasma or any other treatment. This enables convenient fabrication of leak-free microfluidic devices by noncovalent binding for various biomedical applications that require high pressure/flow rates and/or long-term cell culture, by simply hand-pressing the PDMS parts without plasma or any other treatment to bind/assemble. With this method, multiple types of cells can be conveniently loaded into specific areas of the PDMS parts before assembly and due to the reversible nature of the noncovalent bonding, the assembled device can be easily disassembled by hand peeling for retrieving cells. Combining with 3D printers that are widely available for making masters to eliminate the need of photolithography, this facile yet rigorous fabrication approach is much faster and more convenient for making PDMS microfluidic devices than the conventional oxygen plasma-baking-based irreversible covalent bonding method.


Cloning and biochemical characterization of a recombinant chitinase encoded by the CHT4 gene from Candida albicans.
As one of the major components in the fungal cell wall, chitin is a polymer of β-1,4-linked N-acetylglucosamine. Chitinases are hydrolytic enzymes that break down glycosidic bonds in the chitin. The human fungal pathogen Candida albicans has three chitinase-encoding genes, CaCHT1, CaCHT2 and CaCHT3. The CaCHT4 gene encodes a protein with the glycoside hydrolase family GH18 domain, Glyco_18, which suggests that CaCht4 might be a chitinase. In the present study, we have cloned, expressed and purified the N-terminally His6-tagged CaCht4 protein from bacterial cells. Further biochemical characterization has shown that this recombinant CaCht4 protein shows both exochitinase (chitobiosidase) and endochitinase activities, but has no N-acetylglucosaminase activity. The optimal temperature for the exochitinase activity of CaCht4 is 55 °C. Taken together, these data support that the CaCHT4 gene encodes a chitinase. Our finding provides a basis for us to understand the biological functions of the CaCHT4 gene in C. albicans.


Crucial role of aspartic acid at position 265 in the CH2 domain for murine IgG2a and IgG2b Fc-associated effector functions.
Replacement of aspartic acid by alanine at position 265 (D265A) in mouse IgG1 results in a complete loss of interaction between this isotype and low-affinity IgG Fc receptors (Fc gammaRIIB and Fc gammaRIII). However, it has not yet been defined whether the D265A substitution could exhibit similar effects on the interaction with two other Fc gammaR (Fc gammaRI and Fc gammaRIV) and on the activation of complement. To address this question, 34-3C anti-RBC IgG2a and IgG2b switch variants bearing the D265A mutation were generated, and their effector functions and in vivo pathogenicity were compared with those of the respective wild-type Abs. The introduction of the D265A mutation almost completely abolished the binding of 34-3C IgG2a and IgG2b to all four classes of Fc gammaR and the activation of complement. Consequently, these mutants were hardly pathogenic. Although oligosaccharide side chains of these mutants were found to contain higher levels of sialic acids than those of wild-type Abs, the analysis of enzymatically desialylated D265A variants ruled out the possibility that very poor Fc-associated effector functions of the D265A mutants were due to an increased level of the mutant Fc sialylation. Thus, our results demonstrate that aspartic acid at position 265 is a residue critically implicated in triggering the Fc-associated effector functions of IgG, probably by defining a crucial three-dimensional structure of the Fc region.


Inhibition by d,l-methadone of RNA and protein synthesis in neonatal mice: antagonism by naloxone or naltrexone.
Neonatal mice were injected once daily with d,l-methadone in a dosage of 2 mg/kg. The remaining half of the litter was injected with saline. After one week the incorporation of labeled uridine and labeled leucine was significantly (P less than 0.05) reduced in skeletal muscle. Longer treatment with methadone impaired RNA and protein synthesis in liver, heart, skeletal muscle and brain. The percentage reduction RNA was log-dose related. When methadone was discontinued for 1 week following 4 weeks of treatment, incorporation of precursors into RNA and protein was found to be normal. A specific opioid effect is suggested by the finding that naltrexone or in part, naloxone, given concomitantly with with the methadone prevents development of the biochemical lesion.


Evaluation of amniotic membrane transplantation as an adjunct to medical therapy as compared with medical therapy alone in acute ocular burns.
To evaluate the role of amniotic membrane transplantation (AMT) in acute ocular burns. Prospective, randomized, controlled clinical trial. Patients with grade II to IV ocular burns within 3 weeks of injury were recruited. Thirty-seven patients, 7 of whom had bilateral involvement (total, 44 eyes), participated in the trial. Twenty eyes were included in group A (AMT) and 24 eyes were included in group B (controls). The eyes in the AMT group underwent AMT in addition to conventional medical therapy. In the control group, only conventional medical therapy was instituted. The patients' subjective assessments of relief of ocular discomfort, healing of the corneal epithelial defect, visual acuity, extent of corneal vascularization, formation of symblepharon, and tear function tests. At day 1, subjective ocular discomfort scores were reduced significantly in eyes with moderate burns in the AMT group compared with controls (P = 0.05), but there was no difference between the 2 groups in eyes with severe burns. The log mean percentage reduction in size of epithelial defect by day 7 was 7.43+/-0.89 after AMT and 6.23+/-1.10 with medical treatment alone in moderate grade burns at day 7 (P = 0.01), but there was no difference between the 2 groups in eyes with severe burns. There was no overall difference in the final visual acuity, symblepharon formation, corneal vascularization, and tear function tests between the 2 groups over the next 3 months and further follow-up. There was a high dropout rate for long-term follow-up. Amniotic membrane transplantation in eyes with acute ocular burns has advantages in terms of reduction of pain and promotion of early epithelialization in patients with moderate grade burns, but not so in severe burns. There seems to be no definite advantage to AMT over medical therapy alone in terms of improvement in visual acuity, appearance of symblepharon, corneal vascularization, and results of tear function tests on short-term follow-up.


Pathogenesis of Gastric Cancer.
Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. GC is a heterogeneous disease and the endpoint of a long multistep process largely influenced by Helicobacter pylori infection, genetic susceptibility, and environmental factors. In a subset of GC cases, infection with the Epstein-Barr virus (EBV) may also be involved. The development of GC is the consequence of the accumulation of multiple epi/genetic changes during the patient's lifetime that will result in oncogenic activation and/or tumor suppressor pathways' inactivation. This review will focus on the most recent updates on the characterization of the molecular phenotypes of sporadic and hereditary GC. This article will also update the most recent findings on the relationship between H. pylori infection and stem cells at the origin of GC. The understanding of the molecular genetics underlying gastric carcinogenesis is of paramount importance to identify novel potential targets for the development of screening and prognostic markers that can be clinically valuable for the management of GC patients and for the design of clinical trials.


Lead toxicity thresholds in 17 Chinese soils based on substrate-induced nitrification assay.
The influence of soil properties on toxicity threshold values for Pb toward soil microbial processes is poorly recognized. The impact of leaching on the Pb threshold has not been assessed systematically. Lead toxicity was screened in 17 Chinese soils using a substrate-induced nitrification (SIN) assay under both leached and unleached conditions. The effective concentration of added Pb causing 50% inhibition (EC50) ranged from 185 to >2515mg/kg soil for leached soil and 130 to >2490mg/kg soil for unleached soil. These results represented >13- and >19-fold variations among leached and unleached soils, respectively. Leaching significantly reduced Pb toxicity for 70% of both alkaline and acidic soils tested, with an average leaching factor of 3.0. Soil pH and CEC were the two most useful predictors of Pb toxicity in soils, explaining over 90% of variance in the unleached EC50 value. The relationships established in the present study predicted Pb toxicity within a factor of two of measured values. These relationships between Pb toxicity and soil properties could be used to establish site-specific guidance on Pb toxicity thresholds.


[The superego or conscience. On the difference between the 2 concepts and its significance for psychotherapy of children and adolescents].
Proceeding from the matter-of-fact equation of conscience to superego in recent psychoanalytical papers the author first describes the phenomenon of conscience which is subdivided in manifestations attributed to the good and the bad conscience. By means of the Freudian conception developing from egoideal via idealego to superego Freud's reception of conscience is examined. In this connection the author demonstrates an obvious onesidedness in Freud's use of the term of conscience which leans towards the accusing, punishing, bad conscience. Among Freud's successors, on the part of the psychology of the proprium, heed is paid to those aspects of conscience neglected by Freud, the implicit total aspect of the phenomenon of conscience, however, was lost. Finally the author discusses the double aspect of conscience, the good and the bad conscience, with respect to its impact on the psychotherapy of children and adolescents.


Recognition of monovalent sialosides by influenza virus H3 hemagglutinin.
This report presents a procedure for evaluating the relative affinities of simple sialoside receptor determinants for their interaction with the receptor binding pocket of the influenza virus hemagglutinin. The virus examined was A/Memphis/102/72, previously shown to exhibit preferential binding specificity for enzymatically modified erythrocytes containing the NeuAc alpha 2,6Gal linkage. Sialosides examined included those with structures representative of terminal sequences found on carbohydrate groups of naturally occurring glycoproteins and glycolipids. Sialosides with the NeuAc alpha 2,6Gal and NeuAc alpha 2,6GlcNAc linkage were 5-30 times more potent inhibitors than those with the NeuAc alpha 2,3Gal linkage. The results provide evidence that the previously reported specificity of the A/Memphis/102/72 hemagglutinin for the NeuAc alpha 2,6Gal sequence on cell surface receptors was due to differential affinity of the receptor binding pocket for sialoside sequences, apart from contributions due to the protein or lipid portions of the cell surface receptors. A number of synthetic sialic acid glycosides were also evaluated as inhibitors of viral attachment. The differential inhibition observed with these receptor analogs may provide clues to the detailed molecular interaction of sialosides with the hemagglutinin binding pocket and aid in the design of small molecular weight inhibitors of viral adsorption to cells.


Cytomegalovirus Antibody Responses Associated With Increased Risk of Tuberculosis Disease in Ugandan Adults.
Recent evidence highlights human cytomegalovirus (HCMV) and immune activation as risk factors for tuberculosis disease. It is not known whether other herpesviruses are also implicated, nor whether a dose-response relationship exists between tuberculosis risk and herpes coinfection. This nested case-control study used stored serum samples from 25 persons with tuberculosis up to 10 years before tuberculosis diagnosis and between 3 and 6 matched controls without tuberculosis from a rural Ugandan cohort. Samples were investigated for Epstein-Barr virus, herpes simplex virus, and HCMV-specific immunoglobulin G (IgG), serum markers of inflammation, and mycobacterial antibody levels. Humoral response to HCMV, but not Epstein-Barr or herpes simplex virus, was associated with increased risk of active tuberculosis disease up to 10 years before diagnosis. Individuals with medium HCMV IgG were 2.8 times more likely to have tuberculosis (P = .055), and those with high HCMV IgG 3.4 times more likely to have tuberculosis (P = .007). Mycobacterial antibody levels were not associated with differences in odds of tuberculosis disease. Interferon-induced protein 10 was independently associated with increased odds of tuberculosis (odds ratio, 4.2; P = .009). These data provide evidence of a dose response between magnitude of HCMV IgG with risk of tuberculosis disease. An inflammatory environment, characterized by serum interferon-induced protein 10 and interleukin 1α, is independently associated with increased risk of tuberculosis disease.


Premature Birth and Large for Gestational Age Are Associated with Risk of Barrett's Esophagus in Adults.
Birth characteristics, including weight and gestational age, may be associated with risk of Barrett's esophagus (BE), the only known precursor for esophageal adenocarcinoma; however, data are limited. To examine associations between various birth characteristics and BE, and whether these associations are mediated by known risk factors for BE. Data were obtained from a cross-sectional study among eligible Veterans Affairs patients scheduled for an upper endoscopy, and a sample identified from primary care clinics. Participants underwent an esophagogastroduodenoscopy and completed a survey that captured information on sociodemographic and clinical factors, as well as birth information. We compared 263 patients with histologically confirmed BE to 1416 controls without BE on endoscopy. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated using multivariate logistic regression. Premature birth was independently associated with risk of BE after adjusted by age, sex, race, and other birth characteristics (OR 3.28, 95 % CI 1.22-8.79). On the other hand, large for gestational age was inversely associated with risk of BE (OR 0.46, 95 % CI 0.21-0.98). These effects were stronger for patients with long-segment BE than with short-segment BE. The associations were not mediated by gastroesophageal reflux disease symptoms, use of proton pump inhibitors, Helicobacter Pylori infection, waist-hip-ratio, height or the presence of hiatus hernia. Premature birth and large for gestational age may be associated with risk of BE in adults. These associations do not appear to be mediated through known risk factors for BE; however, additional studies are required to confirm our findings.


The effect of preoperative nutrition on the immune system.
In many surgical departments it has been common practice to give patients with weight loss pre-operative parenteral nutrition before major surgery. The purpose of the present study was to elucidate the value of intravenous pre-operative nutrition in relation to the immune system. The study comprised 10 patients undergoing total gastrectomy. All patients had a weight loss of 15% of body weight or more within 6 months or 10% within 3 months. Before operation they all received parenteral nutrition for 1 week. They all had 1.5 g of protein per kg per day and energy corresponding to the basal metabolic rate + 50% as Vamin, Intralipid, and carbohydrate solutions. Before and after this treatment blood samples were taken to estimate neutrophil function (the rate of oxygen consumption and superoxide liberation, phagocytosis and intracellular lysis of Candida albicans, the concentration and consumption rate of ATP during phagocytosis, and chemotaxis) and immune globulins (IgG, IgM, & IgA). Cellular immunity (CMI) was estimated by intradermal application of seven different antigens. We found a significant increase in response to the intradermal antigens (p < 0.01) but no difference in any of the parameters expressing leukocyte function or immune globulins.


The use of non-three-layer ultrasound in biopsy recommendation for premenopausal women.
To evaluate diagnostic accuracy and timing of abnormal transvaginal ultrasonography for the recommendation of endometrial biopsy among premenopausal patients with abnormal uterine bleeding. Two-hundred and thirteen transvaginal ultrasonograms of premenopausal women with abnormal uterine bleeding were retrospectively evaluated. 'Abnormal' ultrasonography was defined as either non-three-layer appearance during the proliferative phase or thickening > or =15 mm during the secretory/unknown phase. Findings were assessed on the basis of the histological diagnosis of the biopsies taken as the reference standard. Accuracy of the defined criteria with their likelihood ratio for detection of an endometrial disease was calculated. Abnormal histopathologic findings were detected in 147 (69%) of 213 patients. 'Abnormal' transvaginal ultrasonography criteria could detect disease states in 90.3% of patients with a sensitivity of 94.6% and a specificity of 77.2% (p<0.01). Sensitivity and specificity increased to 97.1 and 84.4% for ultrasonography conducted during the proliferative phase and were 60 and 61.9% for the secretory/unknown phase, respectively. Better results were clearly found for ultrasonograms obtained during the proliferative phase (p<0.01). The inclusion of post-biopsy proliferative phase transvaginal ultrasonography data of the following cycle resulted in a sensitivity of 95.2% and a specificity of 89.4%. The application of transvaginal ultrasonography using non-three-layer criteria is a highly accurate first step for the selection of premenopausal patients with abnormal uterine bleeding, which may reduce the number of unnecessary endometrial biopsies by approximately 25%. Proliferative phase evaluation is preferable.


Haloperidol disrupts Akt signalling to reveal a phosphorylation-dependent regulation of pro-apoptotic Bcl-XS function.
The antipsychotic drug haloperidol is still used to treat psychosis and "agitation", often with devastating consequences, particularly in geriatric and pre-demented patients. Cytotoxicity induced by haloperidol has been associated with induction of Bcl-XS, a pro-apoptotic member of the Bcl-2 family, as well as with modulation of the Akt pro-survival pathway. Using preneuronal PC12 and primary neuronal cultures, we show that haloperidol inactivates Akt. This induces the dephosphorylation of serine residues in Bcl-XS and promotes its association with the mitochondrial voltage-dependent anion channel (VDAC), as well as with cytochrome c- and caspase-3-dependent events. These events are sensitive to expression of constitutively active Akt. Mutation of Serine106 (Ser106), which is flanked by a putative Akt motif, hinders the association of the Bcl-XS protein with Akt, but promotes its association with VDAC. The dephosphorylation mimic, Bcl-XS(Ser106Ala), induces caspase-dependent PC12 and neuronal cell apoptosis. In contrast, Bcl-XS(Ser106Ala) induces a significant loss of VDAC expression, and cytochrome c- and caspase-independent toxicity in the non-neuronal HEK293A cells. We link haloperidol and Akt to Bcl-XS-sensitive toxicity via cell line-dependent mitochondrial events centering on VDAC. This clearly mitigates the chronic use of haloperidol in neuropsychiatric populations, but supports its use as a potential acute therapeutic in cancer, where apoptosis is desirable.


Effects of contraceptives on hemoglobin and ferritin. Task Force for Epidemiological Research on Reproductive Health, United Nations Development Programme/United Nations Population Fund/World Health Organization/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland.
The effects of combined oral contraceptives (OC), depot medroxyprogesterone acetate injections (DMPA), levonorgestrel subdermal implant (Norplant), copper-containing intrauterine devices (copper IUD), and Chinese stainless steel ring IUD on hemoglobin and ferritin were studied in 18-40-year-old, nonpregnant, and nonlactating women in seven countries (Bangladesh, Chile, China, the Dominican Republic, Pakistan, Thailand, and Tunisia). Data from 2507 women were analyzed. The study had a cross-sectional component in which 1295 current users of the contraceptive methods were compared with 1212 women initiating use of contraceptives. The results of this component showed that the current users of hormonal contraceptive methods generally had higher hemoglobin and ferritin levels than the noncontraceptors. The differences between women using hormonal contraceptive and noncontraceptors in mean values for hemoglobin varied between 3 and 6 g/L and for ferritin between 2 and 18 g/L. The current users of copper IUD had higher hemoglobin levels (difference in mean levels of 3 g/L), but lower ferritin levels (difference of 10 g/L) than noncontraceptors. Current use of the stainless steel ring had an adverse effect on both hemoglobin and ferritin. In a longitudinal component of the study, 285 anemic women (hemoglobin between 80 and 120 g/L at the time of initiation of contraception)--a subgroup of the cross-sectional component--were followed-up at 3, 6, and 12 months after initiation. In this component, significant mean increases of hemoglobin at 12 months were observed among the users of oral contraceptives and DMPA, but not among users of copper or stainless steel ring IUD. It is concluded that hemoglobin and ferritin levels are influenced by the use of contraceptives and that the hormonal contraceptives included in the present study have a beneficial effect on these parameters. The effects of copper IUD on hemoglobin and ferritin should be studied further.


Speech Perception Skills of Hindi Speaking Children with Pre-lingual Hearing Loss Using Hearing Aids and Cochlear Implants.
Very few published studies have reported auditory speech perception in Hindi children with pre-lingual hearing loss. The study is aimed at comparing the speech perception skills of Hindi speaking children with pre-lingual severe to profound hearing loss using hearing aids and cochlear implants. Forty-three 6 to 8-year old children were included as participants, of which 22 were bilateral behind-the-ear hearing aid (HA) users and 21 were unilateral cochlear implant (CI) users. Speech perception was assessed through a forced-choice, picture-pointing task using recorded stimuli presented at 70 dB HL in the sound field. The skills assessed include: (a) pattern perception, (b) bisyllabic word identification, (c) monosyllabic word identification, (d) sentence identification and (e) minimal pair identification. Children using CI consistently performed significantly better than those with HA on all tasks. For the skills assessed, best performance was seen in pattern perception and poorest performance was seen in monosyllabic word identification. One participant from the CI group obtained ceiling scores for pattern perception and bisyllabic word identification. There was no statistically significant difference in the performance of 6 to 7 and 7 to 8-year-old children for any of the tasks. Children fitted with CI have better access to the cues important for perception of speech and hence perform consistently better than those using hearing aids. Recorded speech perception test can be used with children using cochlear implants and hearing aids.


Interpersonal capitalization moderates the associations of chronic caregiving stress and depression with inflammation.
Chronic stress and depression can enhance chronic low-grade inflammation. Interpersonal factors may buffer the impact of stress and depression on inflammation. Interpersonal capitalization is a social support process in which one discloses positive personal events and experiences to close others. Greater capitalization may attenuate the deleterious impact of chronic stress and depression. The goal of the current study was to assess whether interpersonal capitalization is associated with inflammation and whether it moderates the association of chronic stress and depression with inflammation. In this cross-sectional study of chronic caregiving stress, 222 caregiving mothers of adolescents with developmental disabilities or comparison mothers of typically developing adolescents completed a self-reported daily diary assessment of capitalization, the Center for Epidemiological Study-Depression scale, and provided blood samples to assess interleukin-6, tumor necrosis factor-α, and C-reactive protein, three circulating inflammatory markers. Regression analysis indicated that there was no main effect of capitalization on inflammation, p = .24, R2 = .006. However, there was a significant three-way interaction among capitalization, chronic caregiving stress, and depressive symptoms, p = .01, R2 = .02. Among participants with lower capitalization, greater depressive symptoms were associated with higher inflammation in the caregiving group, but not in the comparison group. Among participants with higher capitalization, greater depressive symptoms were no longer significantly associated with higher inflammation among caregivers, but were marginally related to inflammation in the comparison group. Capitalization may thus be an interpersonal process mitigating the effects of chronic stress and depression on inflammation.


Non-uniform projections of granule cells to the cerebellar molecular layer. An autoradiographic tracing study in a turtle.
Injections of radioactive amino acids and wheat germ agglutinin were made into the cerebellar cortex of the turtle, Pseudemys scripta elegans. Labeled parallel fibers were always found to project along the entire mediolateral extent of the corpus cerebelli, regardless of the location of the injection site. In fact, lateral cerebellar portions of both the ipsi- and the contralateral hemisphere often appeared more heavily labeled than intermediate regions. Particularly impressive was the differential pattern of labeling throughout the depth of the molecular layer. Projections coursing towards the midline and the contralateral side were located predominantly in the basal half of the molecular layer while those oriented laterally showed a tendency to occupy primarily superficial portions of the molecular layer. Regional variations along the rostrocaudal extent of the cerebellar plate were also noted. These findings are in an apparent conflict with the reported parallel fiber organization of mammals where granule cells are commonly thought to project to basal and superficial portions of the molecular layer respectively according to a basal-superficial gradient in their location within the granular layer.


AFM nano-mechanics and calcium dynamics of prostate cancer cells with distinct metastatic potential.
Despite recent advances, it is not clear to correlate the mechanical compliances and the metastatic potential of cancer cells. In this study, we investigated combined signatures of mechanical compliances, adhesions, and calcium dynamics correlated with the metastatic potential of cancer cells. We used the lowly (LNCaP) and highly (CL-1, CL-2) metastatic human prostate cancer cells. The AFM-based nanomechanics was performed to determine the elastic moduli and the cell-to-substrate adhesion. The intracellular calcium dynamics was evaluated by fluorescence spectroscopy. Cell migration and the distribution of cytoskeleton were evaluated using the wounded monolayer model and immunofluorescence, respectively. The elastic moduli, the calcium dynamics, and the migratory ability are greater in CL-1 and CL-2 than LNCaP. CL-1 and CL-2 also display a significantly larger area of cell-to-substrate adhesions while the LNCaP displays a limited adhesion. These properties were slightly reduced in CL-2 compared with CL-1 cells. The enhanced elastic moduli and calcium dynamics found in CL-1 and CL-2 can be consistently explained by the intensified tensile stress generated by actin cytoskeletons anchored at more focal adhesion sites. Although the suppressed mechanical compliance of highly metastatic cells may not support the enhanced cancer metastasis, the enhanced adhesion and calcium dynamics are favorable for invasion and extra-vasation required for malignant progression. Our results suggest that the mechanical compliance alone may fail to indicate the metastatic progression, but the combined biomechanical signatures of mechanical compliance, adhesion, and calcium dynamics can provide critical clues to determine the metastatic potential of cells.


Development and Biomass Composition of Ephestia kuehniella (Lepidoptera: Pyralidae), Tenebrio molitor (Coleoptera: Tenebrionidae), and Hermetia illucens (Diptera: Stratiomyidae) Reared on Different Byproducts of the Agri-Food Industry.
The aim of this study was to evaluate five agro-industrial byproducts (apricots, brewer's spent grains, brewer's spent yeast, feed mill byproducts including broken cereal grains, and hatchery waste including eggshell debris, fluff, infertile eggs, dead embryos, and egg fluids) or mixtures thereof as food diets of Ephestia kuehniella (Zeller), Tenebrio molitor (L.), and Hermetia illucens (L.). Eleven out of 26 tested combinations allowed the first instar larvae to reach the adult stage. Results showed that bioconversion parameters and biomass composition can vary depending on the diet composition, especially in the case of E. kuehniella and H. illucens, whose nutritional requirements seem more complex than those of T. molitor. Tenebrio molitor was able to develop in almost all byproducts. However, only when T. molitor was fed with suitable mixtures of byproducts the development parameters were similar to those obtained with the standard diet. The best results in terms of bioconversion parameters were obtained by feeding H. illucens with a diet including dried brewer's spent grain, feed mill byproducts and brewer's spent yeast. The larvae of these three species can be considered interesting from a nutritional point of view, because of their high protein and fat content. However, the fatty acids profile of H. illucens larvae, with high proportions of saturated fatty acids, seems less healthy for human consumption compared with those of E. kuehniella and T. molitor.


An ultra-sensitive homologous chemiluminescence immunoassay to tackle penicillin allergy.
Penicillin is one of the most widely used antibiotics to treat bacterial infections in clinical practice. The antibiotic undergoes degradation under physiological conditions to produce reactive compounds that in vivo bind self-proteins. These conjugates might elicit an immune response and trigger allergic reactions challenging to diagnose due to the complex immunogenicity. Penicillin allergy delabeling initiatives are now part of antibiotic stewardship programs and include the use of invasive and risky in vivo tests. Instead, the in vitro quantification of specific IgE is highly useful to confirm immediate allergy to penicillins. However, discrepant results associated with the low sensitivity and accuracy of penicillin allergy in vitro tests have limited their routine diagnostic use for delabeling purposes. We aimed to develop a homologous chemiluminescence-based immunochemical method for the reliable determination of specific IgE to penicillin G, using unprecedented synthetic human-like standards. The synthetic standard targets the major antigenic determinant of penicillin G and the paratope of Omalizumab, acting as human-like specific IgE. It is a potent calibrator, highly stable, easy, and inexpensive to produce, overcoming the limitations of the pooled human serum preparations. The developed method achieved a good agreement and strong positive relationship, reaching a detection limit below 0.1 IU mL-1 and excellent reproducibility (RSD <9%). The clinical sensitivity of the assay significantly increased (66%), doubling the accuracy of the reference method with an overall specificity of 100%. The new diagnostic strategy compares favorably with results obtained by the standard procedure, paving the way towards the standardization of penicillin allergy testing, and enhancing the detection sensitivity of specific IgE in serum to tackle reliably β-lactam allergy delabeling.


Buprenorphine alters ethanol self-administration in rats: dose-response and time-dependent effects.
Buprenorphine is a partial opioid agonist derived from thebaine and has high affinity for mu and kappa opioid receptors. The present study investigated dose-response (0.03, 0.15, 0.3, 3 mg/kg) and time-dependent effects of buprenorphine (1.5 or 4 h post-treatment) on EtOH self-administration in outbred Sprague-Dawley rats. Freely feeding and drinking rats were trained to initiate EtOH self-administration for 1 h daily using the ascending concentration procedure, wherein they were provided with increasing concentrations of EtOH at 2, 5, 7, 9 and 11% (v/v), respectively. Water was concurrently available with each concentration. Animals were maintained on a given concentration of EtOH for 5 days. By day 21, animals began their stabilization on the 11% regimen and remained on this concentration throughout the remainder of the study. EtOH and water consumption were recorded daily at both 10- and 60-min intervals. At 1.5 h post-buprenorphine, all test doses greatly suppressed both EtOH and water intake at the 10-min interval. At the 60-min interval, all but the lowest dose (0.03 mg/kg) significantly suppressed EtOH intake, while only the highest dose (3 mg/kg) suppressed water intake. In contrast to the suppressant profile observed at 1.5 h post-buprenorphine, at 4 h post-buprenorphine the lower doses (0.03 and 0.15 mg/kg) significantly increased EtOH intake while the higher doses (0.3 and 3 mg/kg) continued to suppress intake. None of the doses of buprenorphine altered water intake 4 h post-buprenorphine. The results support previous research demonstrating the utility of low doses of buprenorphine in suppressing behavior rewarded by a non-opioid drug.


Biogeochemical cycling, tolerance mechanism and phytoremediation strategies of boron in plants: A critical review.
Boron (B) is an inimitable plant micronutrient, predominantly distinguished by super-narrow range between its deficiency and toxicity concentrations, which depends upon boron speciation in the growth media and form of living organisms. Moreover, the significant variations in its mobility amid different species, and distinctive inter and intra-species responses to extreme concentrations. Therefore, it is necessary to screen the bioavailability, speciation, biogeochemical cycling and exposure pathways of boron in the environment. The genes involved in the tolerance mechanism of boron in different plants were discussed in the current review paper. The functions related to scarcity and excess of boron concentration are assessed. The diverse plants implicated in phytoremediation of boron contaminated sites that restrict boron accumulation in food crops and health risks associated with soils containing deficit or surplus boron concentration were appraised. Ultimately, a summary of numerous strategies involved in the recovery and repair of boron-contaminated soils have been reviewed.


Serum sensitivity and cell surface hydrophobicity of Klebsiella pneumoniae treated with gentamicin, tobramycin and amikacin.
A suppression of bacterial growth of Klebsiella pneumoniae after 30 min treatment with gentamicin, tobramycin and amikacin at suprainhibitory concentrations was found (postantibiotic effect, PAE). The antibiotics at a concentration of 2 x MIC induced PAEs in the range of 0.5-1.7 h, PAEs manifested by aminoglycosides at a concentration of 4 x MIC varied between 0.8-3.3 h. Susceptibility of exposed bacteria to serum bactericidal activity was efficiently enhanced compared with controls (without antibiotics). A survival of treated bacteria was between 12.7-36.6% (2 x MIC) or 5.0-8.3% (4 x MIC). The percentage of viable nontreated bacteria moved between 70.2-83.0% at these conditions. Surface hydrophobicity of bacteria exposed to aminoglycosides was only slightly increased. The results indicate that exposure of K. pneumoniae to a suprainhibitory concentrations of aminoglycosides in vitro enhanced the susceptibility of this strain to human serum bactericidal activity. Whether this phenomenon occurs in vivo, remains to be determined.


Parathyroid gland of the freshwater snake Natrix piscator Schneider.
The structure and function of the parathyroid glands of freshwater snake, Natrix piscator, were studied. N. piscator has two pairs of parathyroid glands which are composed of cell cords of typical endocrine appearance, and follicles are absent. Parathyroidectomy was followed by significant (P less than 0.001) hypocalcemia and hyperphosphatemia throughout the 5th week of experimental period. Following parathyroidectomy, calcium and phosphate concentrations in bone were significantly (P less than 0.05) increased after 5 weeks; however, these values in muscle were not significantly changed. Tetany was also observed in parathyroidectomized snakes. Histological structure and function of the glands do not appear to vary seasonally. Administration of parathyroid gland extract of this ophidian reptile into rats caused significant (P less than 0.05) elevation of serum calcium.


Associations between self-reported diabetes mellitus, disordered eating behaviours, weight/shape overvaluation, and health-related quality of life.
Eating disorders (ED) and disordered eating behaviours (DEB) have been found to be common in people with diabetes mellitus (DM). However, findings have been inconsistent. This study investigated the association between self-reported diabetes (Type 1 or 2) with ED/DEB (binge eating, subjective binge eating or loss of control overeating, severe dieting and purging) weight/shape overvaluation, and health-related quality of life (HRQoL) in a household survey in South Australia. In 2017 2977 people aged ≥15 years, who were representative of the general population, were interviewed. Participants reported their gender, age, household income, highest educational attainment, area of residence, presence of DM, ED/DEB, level of overvaluation, current HRQoL and height and weight. For the analyses between ED/DEB, self-reported DM and HRQoL, a grouping variable was created: 1) people without ED/DEB or self-reported DM; 2) people without ED/DEB and with self-reported DM; 3) people with ED/DEB and without self-reported DM; and 4) people with ED/DEB and self-reported DM. Analyses were stratified by sex and age group. Subjective binge eating prevalence was higher in people with self-reported DM (6.6% vs 2.8%, p = 0.016), and overvaluation was lower in those with DM (36% vs 43.8%, p = 0.007). In analyses stratified by sex and age group, subjective binge eating was higher in women and in people over 45 years with self-reported DM and overvaluation was lower in men and in people over 45 years with self-reported DM. However, these differences were not significant on tests of gender and age interaction. People in both DM groups scored significantly lower than people without DM groups on physical HRQoL. In contrast, people in both ED/DEB groups scored lower than people without ED/BEB on mental HRQoL. People with self-reported DM had a higher prevalence of subjective binge eating, a lower prevalence of overvaluation and there were no significant effects of age or gender. Furthermore, participants with self-reported DM and comorbid ED or DEB had impairments of both mental and physical HRQoL. Assessing an individual's sense of control over eating along with other DEB is likely important for identification of these mental health problems.


A closed system for corporeal irrigation in the treatment of refractory priapism.
The treatment of priapism, although considered a urologic emergency, has been historically diverse and often unsuccessful. We propose a method of corporeal aspiration and irrigation in an entirely closed system for priapism refractory to conservative measures. The advantages of this system are a reduced risk of body fluid exposure and corporeal contamination and the capacity for extended irrigation without repeated corporeal puncture.


Comparative evaluation of the volume of occlusal adjustment of repositioning occlusal devices designed by using an average value digital articulator and the jaw movement analyzer.
The volume of occlusal adjustment of digital occlusal devices designed with different digital occlusal articulators is unknown. The purpose of this clinical study was to evaluate and compare the clinical efficacy and volume of occlusal adjustment of digital occlusal devices designed by using an average value digital articulator and the jaw movement analyzer (JMA). Thirty participants were randomly divided into 2 groups, an Average value group and a JMA group, with 15 participants in each group. The centric relation position of the participants was determined by an experienced investigator with the aid of a leaf gauge. An intraoral scanner (TRIOS 3) was used to obtain digital scans of the maxillary and mandibular dentition and the maxillomandibular relationship record in the centric relation position. Personalized articulator parameters of participants in the JMA group were obtained by using a JMA (JMAnalyser). Different articulator parameters were used to fabricate an occlusal device in a denture design software program (exocad DentalCAD). The surface of the occlusal device was coated with a dental optical spray and then scanned by using a laboratory scanner (Kavo LS3). The process was repeated after the occlusal device was adjusted. The files of the 2 scans were imported into a reverse engineering software program, and the root mean square (RMS) values were obtained by best-fit alignment and 3-dimensional comparison. The Shapiro-Wilk normality test and homogeneity of variance test were performed, and t tests were used to evaluate differences in the RMS values between the groups (α=.05). The experimental data were generally normally distributed (P>.05). No statistically significant difference was found between the RMS values of the Average and the JMA groups (P>.05). No significant difference in the volume of occlusal adjustment was found when using occlusal devices made by using the digital average articulator or the JMA, suggesting that either method can be used to program articulators for the fabrication of occlusal devices.


A sensitive fluorescent sensor for the detection of endogenous hydroxyl radicals in living cells and bacteria and direct imaging with respect to its ecotoxicity in living zebra fish.
We have synthesized a novel fluorescent probe, , which shown a high potential for imaging of endogenous ˙OH in living cells and various types of bacteria. In addition, it is an excellent sensor for in vivo imaging of ˙OH generated following treatment with TiO2NPs in zebra fish.


Hirudin-based peptides block the inflammatory effects of thrombin on endothelial cells.
Thrombin is a serine protease that plays an essential role in blood coagulation and also induces various responses in endothelial cells. The actions of thrombin on the conversion of fibrinogen to fibrin are inhibited by peptides based on the amino acid sequence of hirudin, a natural anticoagulant from leeches. We show in these studies that the peptides Hir45-64 and sulfated Hir53-64 block the effects of thrombin on endothelial cells. These peptides inhibited, in a concentration-dependent manner, the synthesis of prostaglandin I2 and platelet-activating factor, and the acquisition of an adhesive surface for leukocytes that occur in response to thrombin. These actions of the peptides occurred even though the catalytic site of thrombin was not blocked.


Lactic fermentation and antioxidant activity of Zingiberaceae plants in Taiwan.
The present study evaluated functional properties of lactic-fermented ginger products. Three Zingiberaceae species were used as the substrate for fermentation using three lactic acid bacteria. The fermentation process ended 35-40 h after inoculation and reached a pH value of 3.5-4.0. Total antioxidant performances were 68-75%, and were best observed using Bifidobacterium longum as the starter in three ginger samples. DPPH scavenging was on average 70%, with free radical anion scavenging and peroxide removal effects of 30.6% and 43.7%, respectively. The product acceptance survey showed that the 100% fermented juice without a mixture with non-fermented ginger juice obtained the highest score in overall performance. The lactic-fermented Vanoverberghia and Hedychium ginger species retained an antioxidant activity and DPPH scavenging activity of on average 70%. This study may suggest a new way of ginger food processing with high functionality. Also, it may help to popularize the growing and processing of endemic ginger plants in Taiwan.


[The effect of "aging" of fibrinogen molecule on the structure and properties of fibrin gel].
The effect of molecular "aging" of fibrinogen stimulated by preincubation in solution on the fibrin three-dimensional architecture, its ability to crosslink fibrin-stabilizing factor, and the sensitivity of fibrin gel to plasmin hydrolysis have been studied. The method of elastic light scattering was used to demonstrate that fibrin generated from "defective" fibrinogen had a coarser structure with a higher mean mass-length ratio of polymeric fibers compared to native fibrinogen (2.24 x 10(9) and 1.46 x 10(9) g/(mol x cm), respectively). Crosslinking had no effect on the architecture of both control and experimental fibrin samples. Spectrophotometric and electrophoretic analysis has shown a higher sensitivity of coarse fibrin gels to plasmin. A close correlation between spontaneous local conformational reconstructions in fibrinogen molecule and its functional activity is concluded.


Service evaluation of laceration risk using trainer adrenaline auto-injectors.
Anaphylaxis is a severe, potentially fatal allergic reaction best treated with intramuscular epinephrine via epinephrine auto-injectors (AAIs). Our published concerns over laceration injuries to young children associated with AAIs led to this service evaluation of the two administration methods: swing and jab (S&J) and place and press (P&P), to determine potential laceration risk. A trainer EpiPen was used with facepaint placed in the needle indentation which would record the length of movement of the AAI. The two different methods 'administered' were alternated. Children were asked to move their leg to simulate a withdrawal reaction. Age, whether they moved, and length of paint mark were recorded. Outpatients waiting area in Noah's Ark Children's Hospital, Cardiff. Children aged 5-11 with no prior knowledge of AAI use. No intervention was implemented. 135 children (mean age 8 years; range 5-11 years) were asked to participate; measurements were taken from 100 children. 50 children moved for one or both methods. For those that moved, S&J mean paint length=8.3 mm (SD 17.4, 95% CI 3.4 to 13.3), P&P mean=3.5 mm (SD 11.0, 95% CI 0.4 to 6.6). Mean difference between methods was 4.8 mm (SD 10.1, 95% CI 1.9 to 7.7). Slightly more children moved for S&J (44) compared with 38 for P&P. S&J produces more movement and longer paint marks than P&P. The risk of laceration when administering an EpiPen to young children may be lower by using the more controlled P&P. We feel it is advisable to teach P&P instead in children below 11 years of age.


The reproducibility of electronic color measurements of the marginal gingiva.
This study evaluated the reproducibility of electronic color determination system evaluations of the marginal gingiva, which could be important for adhesive cervical fillings or prosthetic restorations that imitate the gingiva. In 50 subjects, the L*, a*, and b* color coordinates were evaluated five times at a point in the marginal area of a central incisor using different electronic color determination systems: (SP) Shadepilot, (ES) Easyshade, (CE) Crystaleye, and (SV) X-Rite. The mean color difference (ΔE) and its standard deviation between the five measurements from each participant were calculated separately for each device. Further ICC for interdevice reliability was determined. The L*, a*, and b* color coordinates and ΔE values differed significantly among the systems (p < 0.001). Within each patient and measurement system, ΔE ranged from 1.4 to 3.2 (SD 1.1-2.5), L* from 2.6 to 5.7 (SD 2.6-5.7), a* from 11.9 to 21.3 (SD 3.6-3.9), and b* from 15.1 to 28.9 (SD 1.7-4.3). Interdevice reliability ranged between 0.675 and 0.807. Color determination of the marginal gingiva using the electronic tooth color determination systems tested herein showed limited reproducibility. The results obtained with the different measurement systems differed enormously. These results show that the electronic color measurement devices tested allow no high reproducible determination of color coordinates of the marginal gingiva.


ddm1 plants are sensitive to methyl methane sulfonate and NaCl stresses and are deficient in DNA repair.
Plant response to stress includes changes in gene expression and chromatin structure. Our previous work showed that Arabidopsis thaliana Dicer-like (DCL) mutants were impaired in transgenerational response to stress that included an increase in recombination frequency, cytosine methylation and stress tolerance. It can be hypothesized that changes in chromatin structure are important for an efficient stress response. To test this hypothesis, we analyzed the stress response of ddm1, a mutant impaired in DDM1, a member of the SWI/SNF family of adenosine triphosphate-dependent chromatin remodeling genes. We exposed Arabidopsis thaliana ddm1 mutants to methyl methane sulfonate (MMS) and NaCl and found that these plants were more sensitive. At the same time, ddm1 plants were similar to wild-type plants in sensitivity to temperature and bleomycin stresses. Direct comparison to met1 plants, deficient in maintenance methyltransferase MET1, showed higher sensitivity of ddm1 plants to NaCl. The level of DNA strand breaks upon exposure to MMS increased in wild-type plants but decreased in ddm1 plants. DNA methylation analysis showed that heterozygous ddm1/DDM1 plants had lower methylation as compared to fourth generation of homozygous ddm1/ddm1 plants. Exposure to MMS resulted in a decrease in methylation in wild-type plants and an increase in ddm1 plants. Finally, in vitro DNA excision repair assay showed lower capacity for ddm1 mutant. Our results provided a new example of a link between genetic genome stability and epigenetic genome stability. We demonstrate that heterozygous ddm1/DDM1 plants are more sensitive to stress and have more severe changes in methylation than homozygous ddm1/ddm1 plants.


Gender Identity and Sex Role of Patients Operated on for Bladder Exstrophy-Epispadias.
We evaluated whether genital deformity has an impact on gender identity and sex role in patients operated on for bladder exstrophy-epispadias complex. A total of 62 adolescents and adults operated on for bladder exstrophy-epispadias complex were mailed questionnaires evaluating gender identity (Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults) and sex role (Bem Sex Role Inventory). Of the patients 33 responded and the results were compared with 99 gender matched controls. On the gender identity questionnaire female patients had median scores similar to those of their gender matched controls (4.93 vs 4.89, p = 0.412) but in males the score was lower compared to controls (4.87 vs 4.96, p = 0.023), indicating somewhat more conflicted gender identity. However, no patient had gender dysphoria. Female sex role index was higher in female patients vs controls (5.9 vs 5.3, p = 0.003) but was comparable between male patients and controls (5.2 vs 5.0, p = 0.459). Masculine sex role indices were comparable between female patients and controls as well as between male patients and controls. Of 32 patients 17 were considered to have androgynous sex role, as were 24 of 97 controls (p = 0.004). The exact diagnosis (bladder exstrophy or epispadias) or dissatisfaction with appearance of the genitals had no impact on gender identity or on sex role indices. Male patients had lower gender identity scores compared to controls and female sex role was enhanced among female patients. Androgynous sex role was more common in patients vs controls. Gender dysphoria was not noted in any patient.


Association between baseline VEGF/sVEGFR-2 and VEGF/TSP-1 ratios and response to metronomic chemotherapy using cyclophosphamide and celecoxib in patients with advanced breast cancer.
Metronomic chemotherapy (MCT) with cyclophosphamide (Cy) and celecoxib (Cel) has therapeutic efficacy and low toxicity profile in advanced breast cancer patients (ABCP), but no reliable biomarkers of response have been found yet that allow patient selection for treatment. To investigate the potential role as biomarkers of pro- and antiangiogenic parameters and evaluate their response in ABCP receiving metronomic Cy 50 mg p.o./day + Cel 400 mg p.o./day. Serum levels of vascular endothelial growth factor-C (VEGF-C), soluble VEGF receptors 2 and 3 (sVEGFR-2, sVEGFR-3), were measured at different time points in 13/15 patients included in a phase II trial of MCT with Cy+Cel. Serum levels of sVEGFR-2 and sVEGFR-3 increased significantly during treatment (P = 0.0392; P = 0.0066, respectively). VEGF-C showed no significant modifications. Previous determinations of VEGF and TSP-1 in the same patients were utilized. VEGF/sVEGFR-2, VEGF/TSP-1, and VEGF-C/sVEGFR-3 ratios decreased significantly along the treatment (P = 0.0092; P = 0.0072; P = 0.0141, respectively). Nonsignificant variations were observed for VEGF-C/sVEGFR-2 ratio. Baseline values of VEGF/sVEGFR-2 and VEGF/TSP-1 ratios were associated with time to progression (TTP) (P = 0.0407; P = 0.0394, respectively) meanwhile baseline VEGF was marginally significant (P = 0.0716). Patients with values lower than the 50th percentile for both ratios showed longer TTP. We have identified the baseline VEGF/sVEGFR-2 and VEGF/TSP-1 ratios as potential biomarkers of response in ABCP treated metronomically with Cy+Cel. This finding warrants its confirmation in a higher number of patients.


Identification of a new Indian camel germplasm by microsatellite markers based genetic diversity and population structure of three camel populations.
Camel invokes fascinating chapter of Indian desert history and is integral component of its ecosystem. Camel population has reached a crisis point after three decades of decline (75%) causing major concern to the policy makers. >28% of Indian camel is not yet characterized. It is imperative to describe country's camel germplasm and its existing diversity for designing conservation plan. One such population is Sindhi, distributed along border with Pakistan. Twenty five microsatellite markers being valuable tool for estimating genetic diversity were selected to elucidate genetic variability and relationship of Sindhi with two registered camel breeds of India- Marwari and Kharai. The standard metrics of genomic diversity detected moderate variability in all the three populations. A total of 303 alleles with a mean of 8.116 ± 0.587 alleles per locus were found in total of 143 animals. Sindhi population had intermediate allelic diversity with 8.522 ± 1.063 alleles per locus. Corresponding values in Marwari and Kharai were 8.783 ± 0.962 and 7.043 ± 1.030, respectively. Genetic variability within the breeds was moderate as evidenced by the mean observed heterozygosity of 0.556 ± 0.025. Sindhi camel population harbors higher genetic variability (Ho = 0.594) as compared to the two registered camel breeds (Marwari, 0.543 and Kharai, 0.531). Mean expected heterozygosity under Hardy-Weinberg equilibrium was higher than the observed values across the three camel groups, indicating deviations from assumptions of this model. In fact, average positive F value of 0.084 to 0.206 reflected heterozygote deficiency in these populations. These Indian camel populations have not experienced serious demographic bottlenecks in the recent past. Differences among populations were medium and accounted for 7.3% of total genetic variability. Distinctness of three camel populations was supported by all the approaches utilized to study genetic relationships such as genetic distances, phylogenetic relationship, correspondence analysis, clustering method based on Bayesian approach and individual assignment. Sindhi camel population was clearly separated from two registered breeds of Indian camel. Results conclude Sindhi to be a separate genepool. Moderate genetic diversity provides an optimistic viewpoint for the survival of severely declining indigenous camel populations with appropriate planning strategies for conserving the existing genetic variation and to avoid any escalation of inbreeding.


Effect of cysteine addition and heat treatment on the properties and microstructure of a calcium-induced whey protein cold-set gel.
A model gel of whey protein isolate (WPI) was prepared by cold gelation with calcium. This system was modified by the addition of free cysteine residues (Cys) at different steps of the process. The WPI cold-set gels obtained were then subjected to heat treatment at 90°C. First, the effect of Cys addition on the heat-induced aggregation of WPI was studied through Atomic Force Microscopy (AFM) and infrared spectroscopy (ATR-FTIR), while Cys' effect on cold gelation was observed by AFM, Confocal Laser Scanning Microscopy (CLSM) and oscillatory rheology (amplitude sweeps). The impact of heating on the microstructure and the viscoelastic properties of the WPI cold-set gels were finally investigated through several techniques, including DSC, ATR-FTIR, CLSM, cryo-SEM, and rheological measurements (temperature sweeps). When added during the first step of cold gelation, Cys modified heat-induced aggregation of WPI, resulting in the formation of a denser gel network with a fractal dimension (Df) of 2.8. However, the addition of Cys during the second step of cold gelation led to the formation of highly branched clusters of WPI and a looser gel network was observed (Df = 2.4). In this regard, the use and limitations of oscillatory rheology and the "Kraus model" to determine the Df of WPI cold-set gels was discussed. The viscoelastic properties and the microstructure of the WPI cold-set gels were irreversibly modified by heating. Gels were stiffer, more brittle, and coarser after heat treatment. New disulfide bonds and calcium bridges formed, as well as H-bonded β-sheets, all contributing to the formation of the final gel network structure.


"Tear-drop augmentation mastopexy": a technique to augment superior pole hollow.
Breast ptosis classification systems focus on the inferior descent of the nipple, as well as the descent and distribution of the breast parenchyma below the inframammary fold. Common problems, such as development of a superior pole hollow and an excessive width of the superior pole, extending into the axilla, are not addressed. Few procedures specifically address these deficiencies, and even less information is available in terms of preventative maneuvers when augmentation is desired as an adjunct. Round implants worsen the problem by creating a superior pole shelf, and anatomic implants are unreliable alternatives. Here, we present a technique-"tear-drop" augmentation mastopexy-that addresses superior pole hollow, excess superior pole width, as well as breast ptosis and hypomastia. Patients with moderate to severe breast ptosis (Regnault's classification), tubular breast deformity, and deformities secondary to previous breast surgery are included in the study. Skin is deepithelialized through a circumareolar incision, and a skin-fat flap is elevated completely encircling the breast. A 2-cm area of parenchyma is left attached to the skin in the lower half of the breast. Breast parenchyma in the superior half of the breast is then advanced and plicated in a superiomedial direction to move the nipple areolar complex to the desired new position. Care is taken to redefine the pectoralis major muscle at its axillary border. A 3-cm incision is then placed in the inferior part of the parenchyma at the 6 o'clock position to create a subpectoral pocket for placement of the implant. The tunnel is then closed to separate the implant pocket from the subcutaneous dissection. Residual dermal flap is used to define, and add durability to the parenchyma reshaping procedure. A 3-0 mersiline (Ethicon, Somerville, NJ) blocking suture is used for a uniform circumareolar skin closure. Patients (n:35), ages 17-48, underwent "tear-drop" augmentation mastopexy between January 1999 and September 2002 for correction of the breast ptosis, tubular breast deformity, and deformities secondary to previous aesthetic breast surgery. The average follow-up was 2 years. All patients displayed type 1 or 2 (Baker classification) capsules. One subcutaneous hematoma and one subcutaneous seroma were seen, which were both treated by percutaneous aspiration. No submuscular hematomas, infections, skin or nipple losses, or hypertrophic scars were noted. Patient satisfaction was high. A more natural "tear-drop" breast shape was created with an improvement in the superior pole hollow and narrowing of the superior breast. The smallest breasts did not benefit from this technique for elimination of the superior pole shelf, as correction was proportional to the amount of breast tissue available for superior advancement. The "tear-drop" augmentation mastopexy is a novel technique for correction of the breast ptosis with augmentation, avoiding problematic development of superior pole hollow and excess superior width. This technique is also well applied to tubular breast deformity as well as to secondary breast procedures. Long-term follow-up demonstrates a safe and reproducible result with high patient satisfaction. This technique may solve several problems associated with breast ptosis surgery, which before were not specifically addressed, and the technique warrants further investigation.


[Preoperative determination of optimal amputation level in end-stage arterial occlusive disease].
For the preoperative determination of the amputation site in occlusive arterial disease of the lower extremity (i.e. healing by first intention in spite of a peripheral amputation level below the knee or at the knee) we developed a score by analyzing 500 patients with 523 amputations retrospectively. By means of a prospective study (100 consecutive lower limb amputations) this score has proved to be a helpful tool for realizing our therapeutic principle.


Model evaluation of plant metal content and biomass yield for the phytoextraction of heavy metals by switchgrass.
To better understand the ability of switchgrass (Panicum virgatum L.), a perennial grass often relegated to marginal agricultural areas with minimal inputs, to remove cadmium, chromium, and zinc by phytoextraction from contaminated sites, the relationship between plant metal content and biomass yield is expressed in different models to predict the amount of metals switchgrass can extract. These models are reliable in assessing the use of switchgrass for phytoremediation of heavy-metal-contaminated sites. In the present study, linear and exponential decay models are more suitable for presenting the relationship between plant cadmium and dry weight. The maximum extractions of cadmium using switchgrass, as predicted by the linear and exponential decay models, approached 40 and 34 μg pot(-1), respectively. The log normal model was superior in predicting the relationship between plant chromium and dry weight. The predicted maximum extraction of chromium by switchgrass was about 56 μg pot(-1). In addition, the exponential decay and log normal models were better than the linear model in predicting the relationship between plant zinc and dry weight. The maximum extractions of zinc by switchgrass, as predicted by the exponential decay and log normal models, were about 358 and 254 μg pot(-1), respectively. To meet the maximum removal of Cd, Cr, and Zn, one can adopt the optimal timing of harvest as plant Cd, Cr, and Zn approach 450 and 526 mg kg(-1), 266 mg kg(-1), and 3022 and 5000 mg kg(-1), respectively. Due to the well-known agronomic characteristics of cultivation and the high biomass production of switchgrass, it is practicable to use switchgrass for the phytoextraction of heavy metals in situ.


Patient "Catastrophizing" Associated with Expectations of Opioid Prescriptions for Acute Pain Control.
The prescription of opioids for acute pain may be a driving factor in chronic opioid abuse. We examined patients' characteristics associated with the expectation of the receipt of opioid prescriptions for acute pain control. A 1-time survey was administered to adult patients at family medicine clinics in the Pacific Northwest between November 2018 and January 2019. Logistic regression modeled adjusted odds of expecting an opioid prescription in ≥ 3 of the 4 dispositional acute pain scenarios by patient demographics, opioid use, past-week pain intensity and duration, past-week anxiety, and pain catastrophizing. The survey was completed by 108 patients (62% female, 48% between 30 and 49 years of age, 75% non-Hispanic Whites). Most patients (71%) expected an opioid prescription in ≥ 1 of the 4 scenarios; 26% expected a prescription in ≥ 3 scenarios. Patients with higher levels of pain catastrophizing had more than 3 times greater odds of expecting opioids than those with lower pain catastrophizing (OR, 3.73; P = .032; 95% CI, 1.12-12.46); no other characteristics were statistically significant. Higher pain catastrophizing was associated with increased odds of expecting opioids in dispositional acute pain scenarios in outpatient settings. Future studies can determine whether addressing pain catastrophizing reduces expectations of opioid prescribing for acute pain control. The finding that most patients expected opioid prescriptions in acute pain scenarios needs further exploration into other potential factors associated with these expectations. Evidence-based guidelines for condition-specific acute pain management are warranted for appropriate opioid prescribing and to guide treatment expectations.


Regression of left ventricular hypertrophy in hypertensive dialyzed uremic patients on long-term antihypertensive therapy.
There have been no studies of the possibility of reversing the left ventricular hypertrophy (LVH) of chronically hemodialyzed hypertensive uremics (HDH) with long-term antihypertensive therapy. We have measured left ventricular sizes of eight (6 male, 2 female, aged 29 to 61 years) HDH with M-mode echocardiography, before and 12, 18 and 24 months after the start of a combined antihypertensive therapy which included ACE-inhibitors, beta-blockers and calcium-antagonists. Pre-treatment values for mean blood pressure (MBP), 116.6 +/- 2.9 mm Hg, end diastolic diameter (EDD), 62.6 +/- 6.6 mm, interventricular septum (IVS), 14.2 +/- 3.0 mm, and left ventricular mass index (LVMi), 239 +/- 61 g/m2, were all significantly higher than those for nine sex- and age-matched hemodialyzed normotensive subjects (HDN) with comparable hemoglobin (Hb) levels. During the antihypertensive treatment, both the systolic and diastolic BP decreased steadily (P = 0.0001; P = 0.0003; ANOVA) and significantly by the third month (P < 0.05; P < 0.01), reaching levels comparable to those of the HDN group after 12 months. At this time the LVMi (204 +/- 67) and the IVS (13.1 +/- 2.7), although both significantly lower than baseline, were still higher than in the HDN group, while the EDD was similar. After 24 months, however, both the IVS (12.3 +/- 3.1) and the LVMi (161 +/- 65) were no longer different from those of the HDN group.(ABSTRACT TRUNCATED AT 250 WORDS)


Peripheral nerve regeneration through optic nerve grafts.
Grafts of optic nerve were placed end-to-end with the proximal stumps of severed common peroneal nerves in inbred mice. It was found that fraying the proximal end of adult optic nerve grafts to disrupt the glia limitans increased their chances of being penetrated by regenerating peripheral nerve fibres. Suturing grafts to the proximal stump also enhanced their penetration by axons. The maximum distance to which the axons grew through the CNS tissue remained about 1.5 mm from 2-12 weeks after grafting. Schwann cells were seldom identified in the grafts. Varicose and degenerating nerve fibres were often seen within the grafts. Some varicose profiles were shown to be the terminal parts of axons within the grafts. Axons containing clusters of organelles resembling synaptic vesicles became more abundant in the longer-term grafts. Immunohistochemical studies performed on sutured grafts using a polyclonal antiserum to neurofilaments confirmed the impressions given by the electron microscopical observations. Grafts of neonatal optic nerve lacked myelin debris but were not usually penetrated by regenerating peripheral axons within a 6-week period. Sixty minutes after the intravenous injection of horseradish peroxidase, reaction product could be detected in the extracellular spaces around blood vessels in all types of living optic nerve graft. This indicates that blood-borne macromolecules could penetrate the grafts. However, the profiles of axons which were found within living optic nerve grafts had no obvious relationship to blood vessels and were usually surrounded by astrocytic processes. These results suggest that living astrocytes, rather than the absence of serum-derived trophic factors or the presence of CNS myelin, constitute the major barrier to the extension of axons and the migration of Schwann cells into CNS tissue.


The p53-family members p63 and p73 inhibit insulin-like growth factor-I receptor gene expression in colon cancer cells.
The insulin-like growth factor-I receptor (IGF-IR) has a critical role in malignant transformation. Consistent with its antiapoptotic role, the IGF-IR gene is overexpressed in most types of cancer, including colorectal tumors. The recently identified p53 homologues, p63 and p73, exhibit some of the biological properties of p53, including the ability to transactivate p53-responsive genes and to induce apoptosis. In the present study, we examined the hypothesis that p63/p73 proteins may contribute to colon cancer cell proliferation via mechanism/s that involve regulation of IGF-IR gene expression. Using transient co-expression assays in colon cancer-derived HCT116 cells, we showed that both proteins inhibit IGF-IR promoter activity and endogenous IGF-IR levels in a dose-dependent manner, whereas mutant proteins are significantly impaired in their ability to suppress IGF-IR gene expression. These results are compatible with the notion that disruption of p63/p73-mediated signal transduction pathways in colon cancer may lead to increased IGF-IR gene transcription. In summary, we have identified the IGF-IR gene as a novel downstream target for p63/p73 action.


RNAi technologies in agricultural biotechnology: The Toxicology Forum 40th Annual Summer Meeting.
During the 40th Annual Meeting of The Toxicology Forum, the current and potential future science, regulations, and politics of agricultural biotechnology were presented and discussed. The meeting session described herein focused on the technology of RNA interference (RNAi) in agriculture. The general process by which RNAi works, currently registered RNAi-based plant traits, example RNAi-based traits in development, potential use of double stranded RNA (dsRNA) as topically applied pesticide active ingredients, research related to the safety of RNAi, biological barriers to ingested dsRNA, recent regulatory RNAi science reviews, and regulatory considerations related to the use of RNAi in agriculture were discussed. Participants generally agreed that the current regulatory framework is robust and appropriate for evaluating the safety of RNAi employed in agricultural biotechnology and were also supportive of the use of RNAi to develop improved crop traits. However, as with any emerging technology, the potential range of future products, potential future regulatory frameworks, and public acceptance of the technology will continue to evolve. As such, continuing dialogue was encouraged to promote education of consumers and science-based regulations.


Improved method for determination of ammonia and nitrite oxidation activities in mixed bacterial cultures.
A simple and reliable method to measure the activity of ammonia and nitrite oxidisers in mixed bacterial cultures was developed. The developed method differentiates between the ammonia and nitrite oxidisers by consecutive injection of NO2- and NH4+. The main advantage of this method is that it avoids the use of metabolic inhibitors for ammonia or nitrite oxidisers, as used by other methods. Moreover, it allows measuring of the short-term effect of an inhibitor on both the ammonia and nitrite oxidisers in one test under controlled environmental conditions (pH, temperature). The developed method was applied to determine the inhibitory effects of salt (NaCl up to 15 g Cl/l) on an enriched culture of nitrifying bacteria. The results of the method demonstrate its potential to accurately determine the individual activities of nitrite and ammonia oxidisers.


Social connectedness, depression symptoms, and health service utilization: a longitudinal study of Veterans Health Administration patients.
Our study explored whether aspects of veterans' social connectedness (social support, interpersonal conflict, loneliness, social norms, number of confidants) are associated with change in their depression symptoms and health services utilization over 1 year. We conducted a prospective, longitudinal study of 262 military veterans who obtained primary care and other services at a Veterans Health Administration (VHA) facility and screened positive for depression. Participants completed surveys at baseline and 12-month follow-up. We measured social connectedness variables using the NIH Toolbox Adult Social Relationship Scales. We used the Patient Health Questionnaire to assess depression symptoms and suicidal ideation and administrative medical record data for health services utilization. We calculated change scores to model outcomes over time using multivariable regressions. We found that higher levels of baseline loneliness were associated with decreased depression severity over 1 year (B = - 1.55, 95% CI [- 2.53, - .56], p < .01). We found a similar association for suicidal ideation. In contrast, higher baseline number of confidants was associated with increased depression (B = .55, 95% CI [.18, .92], p < .01). Higher levels of emotional support were associated with decreased mental health visits (B = - 3.88, 95% CI [- 6.80, - .96], p < .01). No significant associations were found between social connectedness variables and primary care visits. Emotional support may play an important role in reducing mental health treatment utilization among VHA-using veterans. Additional investigation as to how and why loneliness and number of confidants might be paradoxically associated with depression symptoms remains necessary.


How do physicians weigh iatrogenic complications?
To determine how physicians weigh iatrogenic complications when making clinical decisions. Physicians were mailed a questionnaire describing two simplified scenarios--one involving a patient with a cerebral embolism and the other involving a patient with a life-threatening arrhythmia. In each scenario there was one potential natural adverse outcome (which could be prevented with drug therapy) and one potential drug side effect (iatrogenic adverse outcome), which would be clinically indistinguishable from the natural adverse outcome. Half the respondents were given the probability of the natural adverse outcome (PN) and were asked to specify the probability of the iatrogenic adverse outcome (PI) at which they felt that giving and withholding the therapy were equivalent strategies. The other respondents were given the PI and asked to specify the PN at which they felt the two strategies were equivalent. Academic medical center. Staff physicians. Results are expressed as the ratio PI/PN at which the respondent felt that giving and not giving therapy were equivalent strategies. A ratio less than 1 indicates that errors of commission (iatrogenic adverse outcomes) were given more weight than were errors of omission (natural adverse outcomes when therapy was withheld). Ratios less than 1 were provided in 56% of the responses (n = 230). The mean PI/PN in the group with ratios less than 1 was 0.53 +/- 0.26 (SD; n = 129). In making decisions, some physicians appear to weigh errors of commission more heavily than they do errors of omission, while others weigh them equally. This diversity of physicians' attitudes may explain some of the variation observed in clinical practice in settings where The possibility of iatrogenic complications is of concern.


Malignancies and outcome in Takotsubo syndrome: a meta-analysis study on cancer and stress cardiomyopathy.
Takotsubo syndrome (TTS) can be induced by a large variety of physical/emotional triggers; several cases, however, are related to either an overt or occult malignancy, as shown in retrospective studies and case reports. The aim of this study was therefore to evaluate the clinical outcome of patients with TTS and cancer in a meta-analysis study. In June 2018, a Pubmed systematic research was conducted for studies assessing outcome in patients with TTS and cancer. We assessed Mantel-Haenszel pooled estimates of risk ratios (RRs) and 95% confidence intervals (CIs) for adverse events at follow-up. After paper retrieval, four studies were included in the meta-analysis, with a total of 123,563 patients. The prevalence of current or previous malignancy among patients admitted with TTS was 6.7% (8258 patients). When compared to control patients, patients with cancer showed an increased risk of clinical events (RR 3.24, 95% CI 3.04-3.45, p < 0.01). The risk of in-hospital events was significantly higher in the cancer group (RR 2.08 95% CI, 1.50-2.87, p < 0.01) and was mainly due to higher need for respiratory support (RR 1.67, 95% CI, 1.58-1.77, p < 0.01). The risk of adverse events at follow-up was also higher in the cancer group (RR 3.30, 95% CI 3.09-3.51, p < 0.01). Cancer, either history or active, is associated with an increased risk of adverse events in TTS.


Metolazone upregulates mitochondrial chaperones and extends lifespan in Caenorhabditis elegans.
Accumulating studies have argued that the mitochondrial unfolded protein response (UPRmt) is a mitochondrial stress response that promotes longevity in model organisms. In the present study, we screened an off-patent drug library to identify compounds that activate UPRmt using a mitochondrial chaperone hsp-6::GFP reporter system in Caenorhabditis elegans. Metolazone, a diuretic primarily used to treat congestive heart failure and high blood pressure, was identified as a prominent hit as it upregulated hsp-6::GFP and not the endoplasmic reticulum chaperone hsp-4::GFP. Furthermore, metolazone specifically induced the expression of mitochondrial chaperones in the HeLa cell line. Metolazone also extended the lifespan of worms in a atfs-1 and ubl-5-dependent manner. Notably, metolazone failed to increase lifespan in worms with knocked-down nkcc-1. These results suggested that metolazone activates the UPRmt across species and prolongs the lifespan of C. elegans.


Quality of death among hospice decedents: Proxy observations from a survey of community-dwelling adults in the contiguous United States.
This study examines hospice service experience and quality of death. A survey of 123 community-dwelling adults in the United States found that physical comfort, pain-free, and spiritual peace were more important to respondents reporting a personal experience with hospice. A "good death" was associated with older patients who died at home, and respondent satisfaction with hospice service. A "good death" was mapped as 29 nodes and 79 links using semantic network analysis. Three subjects (patient, family, hospice), three timeframes (end-of-life, moment of dying, death), and four central causes (home, peaceful, pain-free, and expected) were identified.


β3 adrenergic agonist treatment in chronic pulmonary hypertension associated with heart failure (SPHERE-HF): a double blind, placebo-controlled, randomized clinical trial.
Pulmonary hypertension (PH) associated with left heart disease is an increasingly prevalent problem, orphan of targeted therapies, and related to a poor prognosis, particularly when pre- and post-capillary PH combine. The current study aimed to determine whether treatment with the selective β3 adrenoreceptor agonist mirabegron improves outcomes in patients with combined pre- and post-capillary PH (CpcPH). The β3 Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure (SPHERE-HF) trial is a multicentre, randomized, parallel, placebo-controlled clinical trial that enrolled stable patients with CpcPH associated with symptomatic heart failure. A total of 80 patients were assigned to receive mirabegron (50 mg daily, titrated till 200 mg daily, n = 39) or placebo (n = 41) for 16 weeks. Of them, 66 patients successfully completed the study protocol and were valid for the main analysis. The primary endpoint was the change in pulmonary vascular resistance (PVR) on right heart catheterization. Secondary outcomes included the change in right ventricular (RV) ejection fraction by cardiac magnetic resonance or computed tomography, other haemodynamic variables, functional class, and quality of life. The trial was negative for the primary outcome (placebo-corrected mean difference of 0.62 Wood units, 95% confidence interval [CI] -0.38, 1.61, p = 0.218). Patients receiving mirabegron presented a significant improvement in RV ejection fraction as compared to placebo (placebo-corrected mean difference of 3.0%, 95% CI 0.4, 5.7%, p = 0.026), without significant differences in other pre-specified secondary outcomes. SPHERE-HF is the first clinical trial to assess the potential benefit of β3 adrenergic agonists in PH. The trial was negative since mirabegron did not reduce PVR, the primary endpoint, in patients with CpcPH. On pre-specified secondary outcomes, a significant improvement in RV ejection fraction assessed by advanced cardiac imaging was found, without differences in functional class or quality of life.


Flow cytometry as an integrative method for the evaluation of vaccine immunogenicity: A validation approach.
The applied bioanalytical assays used for the evaluation of human immune responses from samples collected during clinical trials must be well characterized, fully validated and properly documented to provide reliable results. Even though recommendations for the standardization of flow cytometry instrumentation and assay validation for its clinical application have been published by several organizations, definitive guidelines are not available yet. The aim of the present paper is to provide a validation approach for flow cytometry, examining parameters such as linearity, relative accuracy, repeatability, intermediate precision, range and detection limits and specificity, in order to demonstrate and document its applicability for clinical research purposes and its possible use as one of the methods for the evaluation of vaccine immunogenicity.


Steroid-triazole conjugates: A brief overview of synthesis and their application as anticancer agents.
Steroids are biomolecules that play pivotal roles in various physiological and drug discovery processes. Abundant research has been fuelled towards steroid-heterocycles conjugates over the last few decades as potential therapeutic agents against various diseases especially as anticancer agents. In this context various steroid-triazole conjugates have been synthesized and studied for their anticancer potential against various cancer cell lines. A thorough search of the literatures revealed that a concise review pertaining the present topic is not compiled. Therefore, in thus review we summarize the synthesis, anticancer activity against various cancer cell lines and structure activity relationship (SAR) of various steroid-triazole conjugates. This review can lay down the path towards the development of various steroid-heterocycles conjugates with lesser side effects and profound efficacy.


Weekend sleep after early and later school start times confirmed a model-predicted failure to catch up sleep missed on weekdays.
Many people believe they sleep for longer time on weekend nights to make up for sleep lost on weekdays. However, results of simulations of risetimes and bedtimes on weekdays and weekends with a sleep-wake regulating model revealed their inability to prolong weekend sleep. In particular, they predicted identical durations of weekend sleep after weeks with relatively earlier and relatively later risetime on weekdays. In the present study, this paradoxical prediction was empirically confirmed. Times in bed were calculated from weekday and weekend risetimes and bedtimes in pairs of samples of students with early and later school start time and in subsets of samples from 7 age groups with weekday risetime earlier and later than 7:00 a.m. Among 35 pairs of students, mean age ± standard deviation was 14.5 ± 2.9 years and among the age group samples, 21.6 ± 14.6 years. As predicted by the simulations, times in bed on weekends were practically identical in the samples with early and later school start time and in two subsets with earlier and later weekday risetime. The model-based simulations of sleep times can inform an individual about an amount of irrecoverable loss of sleep caused by an advance shift of wakeups on weekdays.


Composition and Long-Term Variation Characteristics of Coral Reef Fish Species in Yongle Atoll, Xisha Islands, China.
Yongle Atoll was the largest atoll in the Xisha Islands of the South China Sea, and it was a coral reef ecosystem with important ecological and economic values. In order to better protect and manage the coral reef fish resources in Yongle Atoll, we analyzed field survey data from artisanal fishery, catches, and underwater video from 2020 to 2022 and combined historical research to explore the changes in fish species composition and community structure in Yongle Atoll over the past 50 years. The results showed that a total of 336 species of fish were found on Yongle Atoll, belonging to 17 orders and 60 families. Among them, Perciformes had the most fish species with 259 species accounting for 77.08% of the total number of species. The number of fish species in the coral reef of Yongle Atoll was exponentially correlated with its corresponding maximum length and significantly decreases with its increase. The fish community structure of Yongle Atoll changed, and the proportion of large carnivorous fish decreased significantly, while the proportion of small-sized and medium-sized fish increased. At the same time, Yongle Atoll has 18 species of fish listed on the IUCN Red List, 15 of which are large fish. The average taxonomic distinctness (Delta+, Δ+) and the variation taxonomic distinctness (Lambda+, Λ+) in 2020-2022 were lower than the historical data, and the number of fish orders, families, and genera in Yongle Atoll has decreased significantly, which indicates that the current coral reef fish species in Yongle Atoll have closer relatives and higher fish species uniformity. In addition, the similarity of fish species in Yongle Atoll was relatively low at various time periods, further proving that the fish community structure has undergone significant variation. In general, due to multiple impacts, such as overfishing, fishing methods, environmental changes, and habitat degradation, the fish species composition of Yongle Atoll may have basically evolved from carnivorous to herbivorous, from large fish to small fish, and from complexity to simplicity, leaving Yongle Atoll in an unstable state. Therefore, we need to strengthen the continuous monitoring of the coral reef ecosystem in Yongle Atoll to achieve the protection and restoration of its ecological environment and fishery resources, as well as sustainable utilization and management.


Changes in the body composition after laparoscopic gastric plication: a short-term prospective case series.
While laparoscopic gastric plication (LGP) results in a rapid weight loss in the first postoperative months, changes in body composition after LGP have not been studied previously. To evaluate the body composition after LGP. A tertiary referral hospital. This is a consecutive case series. Body composition was measured using bioimpedance analysis with a Tanita BC-418 by 1 nutritionist. Weight, fat mass (FM), fat-free mass (FFM), and total body water (TBW) were measured at baseline and at 1, 3, and 6 months postoperative. Sixteen consecutive patients underwent LGP. No intraoperative or major postoperative complications occurred during the follow-up period. No patient was lost to follow-up at any point during the study period. Mean postoperative total weight loss was 31 kg after 6 months, of which 25.5 kg (83%) was due to FM reduction. %FM was decreased by 15% after 6 months, whereas %TBW increased by 11%. Most of the weight loss caused by LGP is attributable to FM loss, and FFM loss is minimal after LGP. Therefore, LGP shifts body composition toward normal.


Gastrointestinal symptoms and cardiac vagal tone in type 1 diabetes correlates with gut transit times and motility index.
Although gastrointestinal (GI) symptoms are common in diabetes, they frequently do not correlate with measurable sensorimotor abnormalities. The wireless motility capsule (WMC) measures pressure, temperature, and pH as it traverses the GI tract wherefrom transit times and motility indices are derived. The aim was to investigate whether GI symptoms correlate with changes in (a) segmental transit times, (b) segmental motility index, (c) cardiac vagal tone, or (d) presence/absence of peripheral neuropathy in type 1 diabetes. Gastrointestinal symptoms in 104 participants with type 1 diabetes were measured using Gastroparesis Cardinal Symptoms Index and Gastrointestinal Symptom Rating Scale. All underwent standardized WMC investigation measuring segmental transit time and motility. Cardiac vagal tone and presence of peripheral neuropathy were measured using electrocardiographic and nerve conduction velocity testing. Colonic transit time was correlated with postprandial fullness (P = .01) and constipation (P = .03), while decreased colonic motility index was correlated with diarrhea (P = .01) and decreased bloating (P < .05). Symptoms were not correlated with gastric or small bowel transit time or motility index. In participants with low cardiac vagal tone, gastric motility index (P < .01) and colonic transit time (P < .05) were increased, but not in those with peripheral neuropathy. Abdominal pain was decreased with both peripheral neuropathy (P = .04) and decreased cardiac vagal tone (P = .02). This study supports the rationale for whole gut investigation, using not only transit times but incorporating contractility indices as well. Furthermore, a decreased parasympathetic modulation and an increased hyposensate state appear to be present in type 1 diabetes.