Rules of social exchange: game theory, individual differences and psychopathology.
Human social interaction is rarely guided by pure reason. Instead, in situation in which humans have the option to cooperate, to defect, or to punish non-cooperative behavior of another person, they quite uniformly tend to reciprocate "good" deeds, reject unfair proposals, and try to enforce obedience to social rules and norms in non-cooperative individuals ("free-riders"), even if the punishment incurs costs to the punisher. Abundant research using various game theoretical approaches has examined these apparently irrational human behaviors. This article reviews the evolutionary rationale of how such behavior could have been favored by selection. It explores the cognitive mechanisms required to compute possible scenarios of cooperation, defection, and the detection of cheating. Moreover, the article summarizes recent research developments into individual differences in behavior, which suggest that temperament and character as well as between- and within-sex differences in hormonal status influence behavior in social exchange. Finally, we present an overview over studies that have addressed the question of how neuropsychiatric disorders may alter performance in game theoretical paradigms, and propose how empirical approaches into this fascinating field can advance our understanding of human nature.


Species specific profiles of secondary metabolites within the genusFusarium, obtained by reversed phase high performance liquid chromatography.
Extracts of pure cultures ofFusarium species were analysed by reversed phase High Performance Liquid Chromatography. The peaks recorded by the Photodiode-Array UV-VIS detector were characterized by their alkylphenone retention time index, and by their UV-VIS spectrum (200-600 nm). The number of biosynthetic families (chemosyndromes) was counted by grouping the peaks having similar UV-VIS spectra.All the investigatedFusarium species had a specific profile of 4-13 chemosyndromes, of which some were species specific while others could be recorded in more than one species.


Situs inversus totalis associated with subaortic stenosis, restrictive ventricular septal defect, and tricuspid dysplasia in an adult dog.
A rare association between situs inversus totalis (SIT), restrictive ventricular septal defect, severe subaortic stenosis, and tricuspid dysplasia was observed in an adult mixed-breed dog. Primary ciliary dyskinesia and Kartagener's syndrome were excluded. After 15 mo the dog died suddenly. The association between SIT and congenital heart diseases is discussed.


Production of acetone and conversion of acetone to acetate in the perfused rat liver.
The utilization of millimolar concentrations of [2-14C]acetone and the production of acetone from acetoacetate were studied in perfused livers from 48-h starved rats. We devised a procedure for determining, in a perfused liver system, the first-order rate constant for the decarboxylation of acetoacetate (0.29 +/- 0.09 h-1, S.E., n = 8). After perfusion of livers with [2-14C]acetone, labeled acetate was isolated from the perfusion medium and characterized as [1-14C]acetate. No radioactivity was found in lactate or 3-hydroxybutyrate. After 90 min of perfusion with [2-14C]acetone, the specific activity of acetate was 30 +/- 4% (n = 13) of the initial specific activity of acetone. We conclude that, in perfused livers from 2-day starved rats, acetone metabolism occurs for the most part via free acetate.


Changing associations of episiotomy and anal sphincter injury across risk strata: results of a population-based register study in Finland 2004-2011.
To evaluate the changing association between lateral episiotomy and obstetric anal sphincter injury (OASIS) for women with low and high baseline risk of OASIS. A population-based register study. Data gathered from the Finnish Medical Birth Register for the years 2004-2011. All women with spontaneous vaginal or vacuum-assisted singleton births in Finland (n=384 638). OASIS incidence. During the study period, the incidence of OASIS increased from 1.3% to 1.7% in women with first vaginal births, including women admitted for first vaginal birth after a prior caesarean section and from 0.1% to 0.3% in women with at least one prior birth, whereas episiotomy rates declined from 56.7% to 45.5% and 10.1- 5.3%, respectively. At the study onset, when episiotomy was used more widely, it was negatively associated with OASIS in women with first vaginal births, but as episiotomy use declined it became positively associated with OASIS. Women with episiotomy were complicated by OASIS with clearly higher risk scores than women without episiotomy suggesting that episiotomy was clearly protective against OASIS. OASIS occurred with lower mean risk scores among women with and without episiotomy over time. However, OASIS incidences increased only among women with episiotomy, whereas it decreased or remained among women without episiotomy. The cross-over effect between episiotomy and OASIS could be explained by increasing disparity in baseline OASIS risk between treated and untreated women, since episiotomy use declined most in women at low OASIS risk. Episiotomy rate can be safely reduced in low-risk women but interestingly along with the policy change the practice to cut the episiotomy became less protective among high-risk women.


Pathological Complete Response following Neoadjuvant Chemotherapy in Invasive Ductal Carcinoma with Mammary Paget's Disease: A Case Report.
Mammary Paget's disease is a rare malignancy. Mastectomy or breast-conserving surgery has been considered as the standard treatment, while there have been few reports of neoadjuvant chemotherapy (NAC). A 53-year-old woman with erythema and skin ulceration of the left breast was admitted to our institution. Breast examinations revealed left invasive ductal carcinoma (cT1bN0M0, cStage I), and a punch biopsy of the left mammary erythema indicated Paget's disease (cTisN0M0, cStage0). The patient received NAC because of multiple lesions. Consequently, the breast tumor clinically disappeared, and the erythema improved. These outcomes made it easier to perform surgery (left mastectomy and sentinel node biopsy). Histopathological examination revealed no residual cancer cells in either the mammary gland or breast skin, and no metastasis was found in the sentinel lymph node. Therefore, NAC may be a useful treatment for mammary Paget's disease.


Prognostic factors for the outcomes of COVID-19 patients infected with SARS-CoV-2 Omicron and Delta variants.
The SARS-CoV-2 Omicron variant has replaced the previously dominant Delta variant because of high transmissibility. However, studies on the impact of the Omicron variant on the severity of COVID-19 are still limited in developing countries. Our study aimed to determine the prognostic factors for the outcomes of patients infected with SARS-CoV-2 Omicron and Delta variants, including age, sex, comorbidities, and smoking. In this retrospective cross-sectional study, we involved 352 patients with COVID-19 from Yogyakarta and Central Java provinces, Indonesia, from May 2021 to February 2022, consisting of 164 males and 188 females. We included all patients with the PCR's Ct value of less than 30 for further whole-genome sequencing. Ct value and mean age of COVID-19 patients were not significantly different between both groups (p = 0.146 and 0.273, respectively). Patients infected with Omicron (n = 139) and Delta (n = 213) variants showed similar hospitalization (p = 0.396) and mortality rates (p = 0.565). Multivariate analysis of both groups showed that older age (≥ 65 years) had a higher risk for hospitalization (OR = 3.86 [95% CI = 1.29-11.5]; p = 0.015) and fatalities (OR = 3.91 [95% CI = 1.35-11.42]; p = 0.012). In both groups, patients with cardiovascular disease had a higher risk for hospitalization (OR = 5.36 [95% CI = 1.08-26.52]; p = 0.039), whereas patients with diabetes revealed a higher risk for fatalities (OR = 9.47 [95% CI = 3.23-27.01]; p = < 0.001). Our study shows that patients infected with Omicron and Delta variants reveal similar clinical outcomes, including hospitalization and mortality. Our findings further confirm that older age, cardiovascular disease, and diabetes are substantial prognostic factors for the outcomes of COVID-19 patients. Our findings imply that COVID-19 patients with older age, cardiovascular disease, or diabetes should be treated comprehensively and cautiously to prevent further morbidity and mortality. Furthermore, incomplete data on vaccination status hampered us from analyzing further its impact on hospitalization and mortality in our patients.


Subconjunctival injection of tumor necrosis factor-α pre-stimulated bone marrow-derived mesenchymal stem cells enhances anti-inflammation and anti-fibrosis in ocular alkali burns.
To investigate the therapeutic effect of subconjunctival injection of tumor necrosis factor-α (TNF-α) pre-stimulated bone marrow-derived mesenchymal stem cells (BMMSCs) on ocular alkali burns in a rat model. After applying a 6 mm filter paper soaking in 1 N NaOH on the cornea of rats, the suspension of TNF-α pre-stimulated BMMSCs, BMMSCs and PBS were given subconjunctivally and respectively. Corneal epithelial defect, corneal opacity, inflammation as well as PTGS2 and TSG-6 expression on day 7 and fibrosis on day 14 were compared. TNF-α pre-stimulated BMMSCs group had a more predominate effect on promoting corneal epithelial repairing, decreasing corneal opacity, reducing inflammatory cells and CD68 + macrophages on day 7 and suppressing fibrosis on day 14 compared to BMMSCs group. Besides, it had significant increased expressions of PTGS2 and TSG-6 in vitro. Pre-treated with Indomethacin revealed a reverse effect on above-mentioned changes. Subconjunctival injection of TNF-α pre-stimulated BMMSCs enhanced anti-inflammatory and anti-fibrotic effect in ocular alkali burns, which was possibly though up regulation of PTGS2 and TSG-6 expression.


Cancer of unknown primary (CUP) of the head and neck: retrospective analysis of 81 patients.
The treatment of patients with cervical lymph node metastases without detectable primary tumor remains an important challenge, until today, no standard therapy is available. The present study investigated the multimodal treatment of patients with head and neck CUP syndrome (HNCUP) and their follow-up retrospectively. 81 patients with cervical lymph node metastases without a primary tumor were treated at the Departments of Otorhinolaryngology as well as Radiotherapy and Radiation Oncology at the University of Saarland in Homburg, Germany in the period between 1991 and 2013. All patients received routine work-up consisting of CUP panendoscopy and imaging. Neck dissection was then performed in 77% of the patients. The most common histology was squamous cell carcinoma (80%). Ten percent of the patients had distant metastases. All patients underwent primary or adjuvant radiation therapy, or simultaneous radiochemotherapy. After a median follow-up of 3.5 years, the 5-year survival rate was 30%. There was a local recurrence that was known in 20/63 patients (31%) and distant metastases were documented in 19/61 M0 patients (31%). Higher grade late toxicity (grade 3-4) was observed in 12% of patients. Neck dissection and radiation therapy remains an integral part of HNCUP therapy, while the use of chemotherapy could be considered in selected cases. Prospective multicenter randomized trials would be necessary to identify the best target volume and to clarify the role of chemotherapy.


Musculoskeletal health - The case for action.
Musculoskeletal health is critical for human function, enabling mobility, dexterity and the ability to work and actively participate in all aspects of life. It is essential for maintaining economic, social and functional independence as well as human capital across the life course. Action is needed and the Global Alliance for Musculoskeletal Health (G-MUSC) is working with the entire musculoskeletal community to develop a global consensus on the important components of a global strategy. This will serve to influence and accelerate the priorities and actions of countries and international agencies such as the WHO. This issue aims to provide a background for developing such a global strategy for improving musculoskeletal health.


Characterisation of a New Human Alveolar Macrophage-Like Cell Line (Daisy).
There is currently no true macrophage cell line and in vitro experiments requiring these cells currently require mitogenic stimulation of a macrophage precursor cell line (THP-1) or ex vivo maturation of circulating primary monocytes. In this study, we characterise a human macrophage cell line, derived from THP-1 cells, and compare its phenotype to the THP-1 cells. THP-1 cells with and without mitogenic stimulation were compared to the newly derived macrophage-like cell line (Daisy) using microscopy, flow cytometry, phagocytosis assays, antigen binding assays and gene microarrays. We show that the cell line grows predominantly in an adherent monolayer. A panel of antibodies were chosen to investigate the cell surface phenotype of these cells using flow cytometry. Daisy cells expressed more CD11c, CD80, CD163, CD169 and CD206, but less CD14 and CD11b compared with mitogen-stimulated THP-1 cells. Unlike stimulated THP-1 cells which were barely able to bind immune complexes, Daisy cells showed large amounts of immune complex binding. Finally, although not statistically significant, the phagocytic ability of Daisy cells was greater than mitogen-stimulated THP-1 cells, suggesting that the cell line is more similar to mature macrophages. The observed phenotype suggests that Daisy cells are a good model of human macrophages with a phenotype similar to human alveolar macrophages.


Liver enzymes as predictors of liver damage due to blunt abdominal trauma in children.
Blunt abdominal trauma in children can result in injury to the liver. In hemodynamically stable patients, initial evaluation of liver transaminase levels may be useful in determining the need for computed tomography (CT). We reviewed the medical records of 44 hemodynamically stable children who had abdominal CT and who also had liver enzyme determinations as the initial workup. Liver enzymes were found to be elevated in all but one patient with CT confirmed hepatic injury. The sensitivity and specificity of elevated liver enzyme levels were 92.9% and 100%, respectively, for predicting liver injury. When hemodynamically stable pediatric patients with blunt abdominal trauma have AST levels >400 and/or ALT levels >250 IU/L, abdominal CT is indicated. Children in this study with serum transaminase levels below these values were at decreased risk of liver injury.


Contaminants disrupt aquatic food webs via decreased consumer efficiency.
Changes in consumer-resource dynamics due to environmental stressors can alter energy flows or key interactions within food webs, with potential for cascading effects at population, community, and ecosystem levels. We conducted a meta-analysis to quantify the direction and magnitude of changes in consumption rates following exposure of consumer-resource pairs within freshwater-brackish and marine systems to anthropogenic CO2, heavy metals, microplastics, oil, pesticides, or pharmaceuticals. Across all contaminants, exposure generally decreased consumption rates, likely due to reduced consumer mobility or search efficiency. These negative effects on consumers appeared to outweigh co-occurring reductions in prey vigilance or antipredator behaviors following contaminant exposure. Consumption was particularly dampened in freshwater-brackish systems, for consumers with sedentary prey, and for lower-trophic-level consumers. This synthesis indicates that energy flow up the food web, toward larger - often ecologically and economically prized - taxa may be dampened as aquatic contaminant loads increase.


Cochlear ablation in mice lacking SHP-1 results in an extended period of cell death of anteroventral cochlear nucleus neurons.
Cochlear ablation results in the death of anteroventral cochlear nucleus (AVCN) neurons from birth to approximately postnatal day 14 (P14) in the murine brainstem. It is not known whether microglial activation contributes to AVCN neuronal death following deafferentation. In order to determine whether microglial activation helps to define the period of neuronal susceptibility within AVCN, we performed unilateral cochlear ablation on mice lacking the protein tyrosine phosphatase SHP-1 (me/me). These mice have been shown to have an exaggerated microglial response following ischemic injury. In the present study, the glial and neuronal response to deafferentation within AVCN was examined in wild-type and me/me mice at P5, P14, and P21. Lack of SHP-1 results in robust microglial but not astrocyte activation within the ablated P14 me/me AVCN. These mice also exhibit approximately 28% neuronal death at P14, a time when normal wild-type littermate controls show little cell death. Glial activation and neuronal loss at P5 and P21 were similar between the two phenotypes, suggesting a role of activated microglia in inducing neuronal death beyond P14 but not P21. These results indicate that activated microglia may participate in determining whether neurons in AVCN live or die following deafferentation.


Nonpharmacologic interventions. Exercise, fall prevention, and role of physical medicine.
Musculoskeletal changes that are related to osteoporosis can be prevented, challenged, or reduced with implementation of proper rehabilitation programs. The nonpharmacologic interventions recommended here are evidence-based and have resulted from controlled trials and studies.


Adjuvant therapy of uterine clear cell carcinoma: a review.
Uterine clear-cell carcinoma (UCCC) is a rare subset of type II endometrial carcinoma with a poor prognosis relative to the most common type of endometrioid carcinoma. Due to its rarity, there has been limited direct evidence of the efficacy of specific adjuvant therapy posthysterectomy in women with UCCC. We present a review of current literature regarding adjuvant therapy of uterine clear cell carcinoma. We searched for English-language publications through Pubmed using a combination of the following key words: endometrial carcinoma, clear cell carcinoma, recurrence, prognosis, adjuvant therapy, radiation treatment and chemotherapy. Due to the rarity of UCCC, studies were not limited by design or number of patients. There is a paucity of randomized prospective controlled studies focusing on UCCC adjuvant therapy. Findings have largely been derived from retrospective studies of type II endometrial carcinomas or all endometrial cancers as a group. Very few retrospective studies were found to focus on UCCC adjuvant therapy, although certain larger studies did have subset analyses of UCCC patients. For early stage disease, locoregional radiotherapy, especially vaginal brachytherapy, has evidence of efficacy. The therapeutic gain of radiotherapy may be further improved with the addition of systemic chemotherapy. Evidence for combined radiation therapy with systemic chemotherapy in women with advanced stage UCCC has remained debatable. UCCC-specific studies are needed to determine the best adjuvant therapy for UCCC without the confounding effects of USC and other endometrial cancers.


[Hearing in premature infants. Evoked-cochlear microphones].
This report summarizes our experience in obtaining microphonic potentials in human beings. Special studies were made to obtain microphonic potentials in premature newborns.


Informatics challenges for the impending patient information explosion.
As we move toward an era when health information is more readily accessible and transferable, there are several issues that will arise. This article addresses the challenges of information filtering, context-sensitive decision support, legal and ethical guidelines regarding obligations to obtain and use the information, aligning patient and health professionals' expectations in regard to the use and usefulness of the information, and enhancing data reliability. The authors discuss the issues and offer suggestions for addressing them.


Joint single-cell profiling resolves 5mC and 5hmC and reveals their distinct gene regulatory effects.
Oxidative modification of 5-methylcytosine (5mC) by ten-eleven translocation (TET) DNA dioxygenases generates 5-hydroxymethylcytosine (5hmC), the most abundant form of oxidized 5mC. Existing single-cell bisulfite sequencing methods cannot resolve 5mC and 5hmC, leaving the cell-type-specific regulatory mechanisms of TET and 5hmC largely unknown. Here, we present joint single-nucleus (hydroxy)methylcytosine sequencing (Joint-snhmC-seq), a scalable and quantitative approach that simultaneously profiles 5hmC and true 5mC in single cells by harnessing differential deaminase activity of APOBEC3A toward 5mC and chemically protected 5hmC. Joint-snhmC-seq profiling of single nuclei from mouse brains reveals an unprecedented level of epigenetic heterogeneity of both 5hmC and true 5mC at single-cell resolution. We show that cell-type-specific profiles of 5hmC or true 5mC improve multimodal single-cell data integration, enable accurate identification of neuronal subtypes and uncover context-specific regulatory effects on cell-type-specific genes by TET enzymes.


SAD phasing of XFEL data depends critically on the error model.
A nonlinear least-squares method for refining a parametric expression describing the estimated errors of reflection intensities in serial crystallographic (SX) data is presented. This approach, which is similar to that used in the rotation method of crystallographic data collection at synchrotrons, propagates error estimates from photon-counting statistics to the merged data. Here, it is demonstrated that the application of this approach to SX data provides better SAD phasing ability, enabling the autobuilding of a protein structure that had previously failed to be built. Estimating the error in the merged reflection intensities requires the understanding and propagation of all of the sources of error arising from the measurements. One type of error, which is well understood, is the counting error introduced when the detector counts X-ray photons. Thus, if other types of random errors (such as readout noise) as well as uncertainties in systematic corrections (such as from X-ray attenuation) are completely understood, they can be propagated along with the counting error, as appropriate. In practice, most software packages propagate as much error as they know how to model and then include error-adjustment terms that scale the error estimates until they explain the variance among the measurements. If this is performed carefully, then during SAD phasing likelihood-based approaches can make optimal use of these error estimates, increasing the chance of a successful structure solution. In serial crystallography, SAD phasing has remained challenging, with the few examples of de novo protein structure solution each requiring many thousands of diffraction patterns. Here, the effects of different methods of treating the error estimates are estimated and it is shown that using a parametric approach that includes terms proportional to the known experimental uncertainty, the reflection intensity and the squared reflection intensity to improve the error estimates can allow SAD phasing even from weak zinc anomalous signal.


[Ethical attitudes of intensive care paediatricians as regards patients with spinal muscular atrophy type 1].
Spinal muscular atrophy type 1 (SMA-1) is a progressive and fatal disease that leads to ethical problems for Paediatric professionals. Our objective was to determine the ethical options of Paediatric Intensive Care Unit (PICU) paediatricians as regards a child with SMA-1 and respiratory failure. A cross-sectional descriptive study was conducted using an anonymous questionnaire sent to PICUs in Spain (which can be accessed through the Spanish Society of Paediatric Critical Care web page). Of the 124 responses analysed, 70% were from women, 51% younger than 40 years, 54% from a PICU with more than 10 beds, 69% with prior experience in such cases, and 53% with religious beliefs. In the last patient cared for, most paediatricians opted for non-invasive mechanical ventilation (NIV) and limitation of therapeutic effort (LET) in case of NIV failure. Confronted with a future hypothetical case, half of paediatricians would opt for the same plan (NIV+LET), and 74% would support the family's decision, even in case of disagreement. Age, prior experience and sex were not related to the preferred options. Paediatricians with religious beliefs were less in favour of initial LET. Less than two-thirds (63%) scored the quality of life of a child with SMA-1 and invasive mechanical ventilation as very poor. Faced with child with SMA-1 and respiratory failure, most paediatricians are in favour of initiating NIV and LET when such support is insufficient, but they would accept the family's decision, even in case of disagreement.


Influence of Clinical pathways on treatment and outcome quality for patients undergoing pancreatoduodenectomy? A retrospective cohort study.
Pancreatic surgery demands complex multidisciplinary management. Clinical pathways (CPs) are a tool to facilitate this task, but evidence for their utility in pancreatic surgery is scarce. This study evaluated the effect of CPs on quality of care for pancreatoduodenectomy. Data of all consecutive patients who underwent pancreatoduodenectomy before (n = 147) or after (n = 148) CP introduction were evaluated regarding catheter and drain management, postoperative mobilization, pancreatic enzyme substitution, resumption of diet and length of stay. Outcome quality was assessed using glycaemia management, morbidity, mortality, reoperation and readmission rates. Catheters and abdominal drainages were removed significantly earlier in patients treated with CP (p < 0.0001). First intake of liquids, nutritional supplement and solids was significantly earlier in the CP group (p < 0.0001). Exocrine insufficiency was significantly less common after CP implementation (47.3% vs. 69.7%, p < 0.0001). The number of patients receiving intraoperative transfusion dropped significantly after CP implementation (p = 0.0005) and transfusion rate was more frequent in the pre-CP group (p = 0.05). The median number of days with maximum pain level >3 was significantly higher in the CP group (p < 0.0001). There was no significant difference in mortality, morbidity, reoperation and readmission rates. Following implementation of a CP for pancreatoduodenectomy, several indicators of process and outcome quality improved, while others such as mortality and reoperation rates remained unchanged. CPs are a promising tool to improve quality of care in pancreatic surgery.


Weight change and risk of depression in patients with diabetic kidney disease: a nationwide population-based study.
Several studies have reported that depression is prevalent in patients with diabetes or chronic kidney disease. However, the relationship between weight changes and the risk of depression has not been elucidated in patients with diabetic kidney disease (DKD). From the Korean National Health Insurance Service database, we selected 67,866 patients with DKD and body weight data from two consecutive health examinations with a 2-year interval between 2009 and 2012. Weight change over 2 years was categorized into five groups: ≥-10%, <-10% to ≥-5%, <-5% to <5%, ≥5% to <10%, and ≥10%. The occurrence of depression was monitored via the codes of International Statistical Classification of Diseases, 10th revision through the end of 2018. During the 5.24-year follow-up, 17,023 patients with DKD developed depression. Weight change and the risk of depression had a U-shaped relationship: patients with ≥-10% weight change (hazard ratio [HR], 1.12) and those with ≥10% weight change (HR, 1.11) showed higher HRs for depression than those with <-5% to <5% weight change, even after adjusting for several confounding factors. In the subgroup analyses, the risk of depression tended to increase as weight gain or weight loss increased in all subgroups. Both weight loss and weight gain increased the risk of depression in patients with DKD.


Evaluation of diagnostic accuracy of 10 serological assays for detection of SARS-CoV-2 antibodies.
Antibody detection is essential to establish exposure, infection, and immunity to SARS-CoV-2, as well as to perform epidemiological studies. The worldwide urge for new diagnostic tools to control the pandemic has led to a quick incorporation in clinical practice of the recently developed serological assays. However, as only few comparative studies have been published, there is a lack of data about the diagnostic accuracy of currently available assays. We evaluated the diagnostic accuracy to detect Ig G, Ig M+A, and/or IgA anti SARS-CoV-2 of 10 different assays: lateral flow card immunoassays, 4 enzyme-linked immunosorbent assay (ELISA), and 3 chemiluminescent particle immunoassays (CMIA). Using reverse transcriptase polymerase chain reaction (RT-PCR) for COVID-19 as gold standard, sensitivity, specificity, PPV, and NPV were determined. Each assay was tested in 2 groups, namely, positive control, formed by 50 sera from 50 patients with SARS-CoV-2 pneumonia with positive RT-PCR; and negative control, formed by 50 sera from 50 patients with respiratory infection non-COVID-19. Sensitivity range of the 10 assays evaluated for patients with positive COVID-19 RT-PCR was 40-77% (65-81% considering IgG plus IgM). Specificity ranged 83-100%. VPP and VPN were respectively 81-100% and 61.6-81%. Among the lateral flow immunoassays, the highest sensitivity and specificity results were found in Wondfo® SARS-CoV-2 Antibody Test. ELISA IgG and IgA from EUROIMMUN® were the most sensitive ELISA. However, poor results were obtained for isolated detection of IgG. We found similar sensitivity for IgG with SARS-CoV-2 for Architect by Abbott® and ELISA by Vircell®. Results obtained varied widely among the assays evaluated. Due to a better specificity, overall diagnostic accuracy of the assays evaluated was higher in case of positive result. On the other side, lack of antibody detection should be taken with care because of the low sensitivity described. Highest diagnostic accuracy was obtained with ELISA and CMIAs, but they last much longer.


LPS induces melanogenesis through p38 MAPK activation in human melanocytes.
We have observed that lipopolysaccharide (LPS) induces pigmentation in melanocytes and in this study have examined whether these responses are mediated by the p38 mitogen-activated protein kinase (MAPK) signaling pathway. LPS appears to stimulate the pigmentation of melanocytes and cultured skin. LPS was found to induce the expression of microphthalmia-associated transcription factor (MITF) and tyrosinase protein in cells. Stimulation of melanocytes with LPS led to time dependent phosphorylation of p38 MAPK. Furthermore, p38 MAPK functionally regulated the LPS-induced melanin formation in melanocytes; a p38 MAPK inhibitor, SB203580, almost completely attenuated the LPS-mediated up-regulation of melanin synthesis and induction of MITF and tyrosinase expression. These findings indicate that activation of p38 MAPK plays an important role in LPS-induced melanogenesis by up-regulating MITF and tyrosinase expression.


Sarcopenia in chronic kidney disease: prevalence by different definitions and relationship with adiposity.
This was a cross-sectional study with chronic kidney disease (CKD) patients under non-dialysis-dependent (NDD), hemodialysis (HD), and kidney transplant (KTx) treatment aimed to evaluate the prevalence of sarcopenia using the European Working Group on Sarcopenia in Older People (EWGSOP2) and the Foundation for the National Institutes of Health (FNIH) guidelines, and to analyze the relationship between sarcopenia and its components and body adiposity. Body composition was assessed by dual-energy X-ray absorptiometry and anthropometry. Bioelectrical impedance provided data on the phase angle and body water. The prevalence of sarcopenia in the total sample (n = 243; 53% men, 48 ± 10 years) was 7% according to the FNIH and 5% according to the EWGSOP2 criteria, and was low in each CKD group independently of the criteria applied (maximum 11% prevalence). Low muscle mass was present in 39% (FNIH) and 36% (EWGSOP2) and dynapenia in 10% of the patients. Patients who were sarcopenic according to the EWGSOP2 criteria presented low body adiposity. Conversely, patients who were sarcopenic according to the FNIH criteria presented high adiposity. This study suggests that in CKD (i) sarcopenia and low muscle mass prevalence varies according to the diagnostic criteria; (ii) sarcopenia and low muscle mass are common conditions; (iii) the association with body adiposity depends on the criteria used to define low muscle mass; and (iv) the FNIH criteria detected higher adiposity in individuals with sarcopenia. Novelty: Prevalence of sarcopenia and low muscle mass in CKD varied according to the diagnostic criteria. Association of excess adiposity with sarcopenia and low muscle mass depends on muscle mass index applied. FNIH criteria detected higher adiposity in individuals with sarcopenia and low muscle mass.


Novel cry gene from Paenibacillus lentimorbus strain Semadara inhibits ingestion and promotes insecticidal activity in Anomala cuprea larvae.
A positive clone was selected from a library of total cell DNA of Paenibacillus lentimorbus strain Semadara that reacted with an antiserum that was raised against parasporal crystal proteins produced by this strain. The positive clone had a DNA insert containing two whole cry genes (cry43Aa1, cry43Ba1), one partial cry gene (cry43-like), and three smaller genes located upstream. Eight blocks that are conserved in the Cry proteins of Bacillus thuringiensis [Microbiol. Mol. Biol. Rev. 62 (1998) 775] were detected in their deduced amino acid sequences. The Escherichia coli transformant expressing cry43Aa1 caused inhibition of ingestion and 90% mortality in the first stadium larvae of Anomala cuprea. A low concentration of sporangia mixed with the transformant expressing cry43Aa1 easily infected the larvae of A. cuprea. The protein of approximately 150 kDa produced by the transformants expressing the cry genes reacted with antiserum specific for the parasporal crystal proteins. Southern hybridization analysis demonstrated that the cry genes were located on the chromosomal DNA of this strain, which possessed at least four cry genes.


pH evaluation in the digestive tract of the pygmy octopus, Paractopus digueti.
This study is considered the first report on the digestive tract pH of the pygmy octopus (Paroctopus digueti). Adult octopuses obtained from the wild (mean ± SD) (42.1 ± 15.1 g), and those acclimated to captivity in a fed (25.4 ± 9.0 g, n = 15) or fasted (23.1 ± 6.1 g, n = 15) state, were studied. The digestive tract regions of buccal mass (BMA), anterior salivary glands (ASG), posterior salivary glands (PSG), crop (CRO), stomach (STO), caecum (CAE), digestive gland (DGL) and intestine (INT) were dissected. The pH of the internal part of the digestive tract regions was measured. Food intake (dry weight) per octopus was 53.8 ± 35.1 mg to 214.9 ± 157.6 mg at 15 min and 8 h, respectively. The apparent food transit time was approximately 8 h for the appearance of feces in the posterior intestine. In all cases, the pH of the digestive tract regions was lower than pH 7.0. No statistical difference was found when comparing the pH by digestive tract regions between wild octopuses and octopuses in captivity (fasting and feeding). In acclimatized octopuses, the average pH was 6.41 ± 0.22 and 6.41 ± 0.23 for fasting and fed octopuses, respectively. Although DGL had the lowest pH values relative to other digestive tract tissues (p < 0.05), pH was always >5.0 (6.04 ± 0.12 in the wild and 5.97 ± 0.17 in feeding octopuses). In conclusion, the pygmy octopus has an acidic pH in its digestive tract under fasting and feeding conditions.


The biological relevance of N-terminal neurotensin fragments in the regulation of exocrine pancreas secretion.
Stimulation of the exocrine pancreas is one of the biological effects attributed to the tridecapeptide neurotensin (NT). Only the C-terminal 8-13 fragment with its extremely short plasma half-life in the peripheral circulation was considered to be necessary for biological activity. The N-terminal fragments that are detectable in peripheral blood in much greater concentrations were considered to be of no importance. In order to elucidate the biological relevance of these N-terminal fragments, five dogs were infused with neurotensin at a rate (50 pmol/kg/h) that had been determined to give physiological plasma concentrations. Pancreatic secretions were collected from previously implanted modified Herrera pouches. The effects of the N-terminal fragments NT 1-8 and NT 1-11 on the exocrine pancreas secretion were tested in the same way. It was possible for the first time to demonstrate a biological effect of the N-terminal fragments found in the postprandial circulation in vivo. The plasma concentrations determined by radioimmunoassay remained within the physiological range (less than 40 pg/ml). These N-terminal neurotensin fragments may therefore participate in the hormonal regulation of the exocrine pancreas secretion.


Medial tibial "spackling" to lessen chronic medial tibial soft tissue irritation.
We describe a unique, utilitarian reconstructive treatment option known as tibial "spackling" for chronic, localized medial joint line pain corresponding with progressive radiographic peripheral medial tibial bone loss beneath a well-fixed revision total knee arthroplasty tibial baseplate. It is believed that this localized pain is due to chronic irritation of the medial capsule and collateral ligament from the prominent medial edge of the tibial component. In the setting of failed nonoperative treatment, our experience with utilizing bone cement to reconstruct the medial tibial bone defect and create a smooth medial tibial surface has been successful in eliminating chronic medial soft tissue irritation.


Aflatoxin contamination in insect damaged seeds of horsegram under storage.
Studies on one of the protein rich pulses, horsegram (Dolichos biflorus L.) were carried out to know how far these low risk pulses are free from aflatoxin contamination under severe insect infestation in storage. A total of 150 stored seed samples of horsegram were analyzed for the presence of aflatoxins by collecting 25 samples each of undamaged and insect damaged seeds of all the three varieties (PDM-1, PHG-1 and HG-96). More than 33% of insect damaged seed samples were contaminated with aflatoxin B1 and B2, whereas less than 8% of the undamaged seed samples contain only low levels of aflatoxin B2. Higher levels of aflatoxin B1 (up to 130 μg/kg) were reported in insect damaged seed samples of all the three varieties under study. The levels of aflatoxin B2 were always lower than aflatoxin B1 of the corresponding seed samples with insect damage. Aflatoxin B1 was reported in both the undamaged and insect damaged seed samples of all the three varieties of horsegram. It is evident from the varietal response studies that PDM-1 and HG-96 varieties of horsegram are highly vulnerable to aflatoxin contamination whereas, PHG-1 variety is relatively less susceptible to it. In general, insect infestation leads to increase in fungal invasion (including aflatoxigenic fungi) and this further enhances the levels of aflatoxin contamination in horsegram seeds.


DNA-fork displacement rates in cultured mammalian cells with mutations in ribonucleotide reductase.
DNA-replication fork displacement rates were measured in mouse S49 lymphosarcoma cell lines and in derivatives of those cell lines. One of the derivatives lacks dCMP deaminase activity and two others bear defined mutations in ribonucleotide reductase. We also examined a revertant cell line that was selected from one of the ribonucleotide reductase mutants and has regained normal ribonucleotide reductase activity. Our results show a correlation between decreased fork-displacement rates and alterations in ribonucleotide reductase, suggesting a possible involvement of this enzyme in the replication apparatus.


Metamemory, memory performance, and causal attributions in gifted and average children.
Fifth and seventh graders who had been teacher-selected as high- or average-achieving were tested on the Kognitiver Fähigkeits Test, a standardized test of intellectual abilities for German children. Children who met preestablished criteria as gifted or average were then tested on measures of metacognitive knowledge, attributional beliefs, and performance on a sort recall task. Results indicated ability-related differences in metamemory and sort recall performances. Responses to the attributional questionnaires also varied systematically according to ability: gifted children were more likely to attribute their academic successes to high ability than were average children, who showed a stronger belief in the importance of effort in determining task outcomes. Causal modeling analyses illustrated the strength of metacognitive knowledge as a performance predictor on the memory task, especially for average children. Results are discussed in terms of the value of metacognitive theory in understanding individual performance differences.


DAMIAN: an open source bioinformatics tool for fast, systematic and cohort based analysis of microorganisms in diagnostic samples.
We describe DAMIAN, an open source bioinformatics tool designed for the identification of pathogenic microorganisms in diagnostic samples. By using authentic clinical samples and comparing our results to those from established analysis pipelines as well as conventional diagnostics, we demonstrate that DAMIAN rapidly identifies pathogens in different diagnostic entities, and accurately classifies viral agents down to the strain level. We furthermore show that DAMIAN is able to assemble full-length viral genomes even in samples co-infected with multiple virus strains, an ability which is of considerable advantage for the investigation of outbreak scenarios. While DAMIAN, similar to other pipelines, analyzes single samples to perform classification of sequences according to their likely taxonomic origin, it also includes a tool for cohort-based analysis. This tool uses cross-sample comparisons to identify sequence signatures that are frequently present in a sample group of interest (e.g., a disease-associated cohort), but occur less frequently in control cohorts. As this approach does not require homology searches in databases, it principally allows the identification of not only known, but also completely novel pathogens. Using samples from a meningitis outbreak, we demonstrate the feasibility of this approach in identifying enterovirus as the causative agent.


Probiotic bacteria reduced duration and severity but not the incidence of common cold episodes in a double blind, randomized, controlled trial.
To investigate the effect of long-term consumption of probiotic bacteria on viral respiratory tract infections (common cold, influenza), a randomized, double blind, controlled intervention study was performed during two winter/spring periods (3 and 5 month). Four hundred and seventy-nine healthy adults were supplemented daily with vitamins plus minerals with or without probiotic lactobacilli and bifidobacteria. The intake of the probiotic had no effect on the incidence of common cold infections (verum=158, control=153 episodes, influenza was not observed), but significantly shortened duration of episodes by almost 2 days (7.0+/-0.5 versus 8.9+/-1.0 days, p=0.045), reduced the severity of symptoms and led to larger increases in cytotoxic T plus T suppressor cell counts and in T helper cell counts.


Thrombolytic versus fibrinogenolytic activity of rt-PA and streptokinase in patients with acute myocardial infarction.
In this study the concentration of plasma breakdown products of cross-linked fibrin (XDP), serum fibrinogen-fibrin degradation products (FDP), and plasma fibrinogen were measured before and at the end of the administration of single-chain recombinant tissue-type plasminogen activator (rt-PA, 100 mg IV over three hours) or streptokinase (1.5 million units over one hour), respectively, in two groups, each composed of 22 patients with acute myocardial infarction. The XDP concentration was not statistically different between the two groups at the end of thrombolytic treatment, whereas FDP and fibrinogen concentrations were significantly different (FDP: streptokinase 396 +/- 287 vs rt-PA 177 +/- 222 micrograms/mL, p less than 0.01; fibrinogen: streptokinase 71 +/- 43 vs rt-PA 181 +/- 49 mg/dL, p less than 0.001). These results indicate that the two drugs have equipotent thrombolytic activity at this administration regimen but that rt-PA causes a markedly more selective lysis of fibrin in comparison with streptokinase.


Dose-response effect of lower limb resistance training volume on pain and function of women with patellofemoral pain: A systematic review and meta-regression.
Analyze whether the effects of lower limb resistance training on pain and self-reported function were associated with the exercise volume prescribed for women with patellofemoral pain (PFP). A systematic search was undertaken in four databases from inception to May 2023. Eligible trials examined the effects of resistance training programs on pain (visual analogue scale or numerical pain scale) and function (Anterior Knee Pain Scale) in women with PFP. Meta-analysis was undertaken with a random-effects model. The association of resistance training volume-related variables with mean difference effects on pain and function were tested by exploratory univariable meta-regression models. From 1,404 estudies retained for screening after duplicate removals, 16 studies (579 patients) were included. Changes in knee pain were inversely associated with weekly training frequency (β = 0.5 ± 0.2, P = 0.012). No associations were found between the amount of resistance exercise prescribed per session or per week and effects on pain. Changes in function were associated with the number of sets per week (β = 0.1 ± 0.1, P = 0.044) and number of sets per session (β = 0.6 ± 0.2, P < 0.001) over the intervention. Most favorable results were achieved with 17 to 27 sets per session and >45 sets per week. The amount of prescribed resistance exercise does not seem to be critical for pain reduction in women with PFP. However, our findings support a dose-response effect in terms of improving function.


Orientation Selectivity Sharpens Motion Detection in Drosophila.
Detecting the orientation and movement of edges in a scene is critical to visually guided behaviors of many animals. What are the circuit algorithms that allow the brain to extract such behaviorally vital visual cues? Using in vivo two-photon calcium imaging in Drosophila, we describe direction selective signals in the dendrites of T4 and T5 neurons, detectors of local motion. We demonstrate that this circuit performs selective amplification of local light inputs, an observation that constrains motion detection models and confirms a core prediction of the Hassenstein-Reichardt correlator (HRC). These neurons are also orientation selective, responding strongly to static features that are orthogonal to their preferred axis of motion, a tuning property not predicted by the HRC. This coincident extraction of orientation and direction sharpens directional tuning through surround inhibition and reveals a striking parallel between visual processing in flies and vertebrate cortex, suggesting a universal strategy for motion processing.


Strain differences in change in airway responsiveness after repeated antigenic challenge in three strains of rats.
1. The strain differences in 2,4-dinitrophenylated-Ascaris antigen-induced airway hyperresponsiveness (AHR) were investigated in three strains of rats: Brown-Norway (BN), Long-Evans Cinnamon (LEC) and Wistar. 2. Fourty-eight hour-passive cutaneous anaphylaxis titers after repeated challenge were highest in BN and lowest in LEC. 3. Twenty-four hours after the last challenge, a marked AHR and significant increase in wet/dry weight ratio of the main bronchus were observed only in Wistar. 4. Only the isolated bronchus of the challenged Wistar among the strains showed hyperresponsiveness to acetylcholine. 5. Wistar may be the best strain for antigen-induced AHR.


Practicing coarse orientation discrimination improves orientation signals in macaque cortical area v4.
Practice improves the performance in visual tasks, but mechanisms underlying this adult brain plasticity are unclear. Single-cell studies reported no [1], weak [2], or moderate [3, 4] perceptual learning-related changes in macaque visual areas V1 and V4, whereas none were found in middle temporal (MT) [5]. These conflicting results and modeling of human (e.g., [6, 7]) and monkey data [8] suggested that changes in the readout of visual cortical signals underlie perceptual learning, rather than changes in these signals. In the V4 learning studies, monkeys discriminated small differences in orientation, whereas in the MT study, the animals discriminated opponent motion directions. Analogous to the latter study, we trained monkeys to discriminate static orthogonal orientations masked by noise. V4 neurons showed robust increases in their capacity to discriminate the trained orientations during the course of the training. This effect was observed during discrimination and passive fixation but specifically for the trained orientations. The improvement in neural discrimination was due to decreased response variability and an increase of the difference between the mean responses for the two trained orientations. These findings demonstrate that perceptual learning in a coarse discrimination task indeed can change the response properties of a cortical sensory area.


Parental smoke exposure and the development of nicotine craving in adolescent novice smokers: the roles of DRD2, DRD4, and OPRM1 genotypes.
Among adolescent novice smokers, craving is often the first, and is the most reported, symptom of nicotine dependence. Until now, little has been known about the development of craving symptoms in novice smokers. The aim of this study was to identify specific genetic (i.e., DRD2 Taq1A, DRD4 48 bp VNTR, and OPRM1 A118G polymorphisms) and environmental mechanisms that underlie the emergence of both cue-induced and cognitive craving among adolescent novice smokers. A five-wave longitudinal, genetically-informed survey study was conducted with intervals of four months. The sample included 376 early adolescent smokers (12-13 years of age at baseline). Self-report questionnaires were completed regarding smoking behavior, observed parental smoking behavior, and both cue-induced and cognitive craving. Data were analyzed with a latent growth curve approach. For both cue-induced and cognitive craving, significant interaction effects were found for DRD2 Taq1A with parental smoke exposure. A1-allele carriers did not seem to be influenced by the environment with regard to craving development. Adolescents who are homozygous for the A2-allele and who are more exposed to parental smoking experience the highest levels of both types of craving over time. No significant interaction effects were found between parental smoke exposure and DRD4 48 bp VNTR or OPRM1 A118G. Previous studies identified DRD2 Taq1A A1-allele carriers as vulnerable to developing nicotine dependence. However, this study showed that parental smoking increased the chances of developing dependence more rapidly for early adolescents who are considered to be less sensitive to the rewarding effects of nicotine according to their DRD2 Taq1A genotype. It is thus especially important that these young people not be exposed to smoking in their social environment.


A species comparison of the histamine H2-receptor on mast cells and basophils.
The histamine H2-agonist dimaprit was employed in experiments to investigate the role of H2-receptors in mediator release systems from the rat, guinea-pig and man. Whereas inhibition of histamine release by dimaprit was observed in all 3 species, this effect appeared not always to be related to H2-receptor occupancy. Although the data in general support previous evidence for the presence of H2-receptors on human basophils and guinea-pig mast cells, the use of dimaprit as a pure H2-agonist in these studies is questioned. No evidence for H2-receptors on rat mast cells was obtained.


Maxillary sinus detection on cone beam computed tomography images using ResNet and Swin Transformer-based UNet.
This study, which uses artificial intelligence-based methods, aims to determine the limits of pathologic conditions and infections related to the maxillary sinus in cone beam computed tomography (CBCT) images to facilitate the work of dentists. A new UNet architecture based on a state-of-the-art Swin transformer called Res-Swin-UNet was developed to detect sinus. The encoder part of the proposed network model consists of a pre-trained ResNet architecture, and the decoder part consists of Swin transformer blocks. Swin transformers achieve powerful global context properties with self-attention mechanisms. Because the output of the Swin transformer generates sectorized features, the patch expanding layer was used in this section instead of the traditional upsampling layer. In the last layer of the decoder, sinus diagnosis was conducted through classical convolution and sigmoid function. In experimental works, we used a data set including 298 CBCT images. The Res-Swin-UNet model achieved more success, with a 91.72% F1-score, 99% accuracy, and 84.71% IoU, than outperforming the state-of-the-art models. The deep learning-based model proposed in the present study can assist dentists in automatically detecting the boundaries of pathologic conditions and infections within the maxillary sinus based on CBCT images.


Tub bathing improves thermoregulation of the late preterm infant.
To compare body temperature of the late preterm infant after 24 hours of life at three time points before and after immersion tub bathing or sponge bathing. We hypothesized that late preterm infants achieve significantly improved thermoregulation when bathed by immersion tub bath compared to traditional sponge bathing. This study was a randomized controlled trial. A large metropolitan teaching hospital in the northeastern United States. Late preterm infants (100) born between 35 and 36 6/7 weeks gestation, bathed in the well-baby nursery of a 30-bed mother/baby unit. Infant participants were identified and informed consent was obtained from the parent. Infants were randomized into two groups: 50 bathed by sponge and 50 bathed by immersion tub. Infant body temperature was measured at three time points: 10 minutes prior to bathing, 10 minutes following bathing, and 30 minutes following bathing. Infants who were tub bathed experienced significantly less variability in body temperature and overall were warmer 10 minutes and 30 minutes following the bath compared to infants who were sponge bathed (p = .024). The study findings support the hypothesis that late preterm infants who are tub bathed experience significantly less body temperature variability and an overall higher body temperature following the bathing procedure.


Endothelial cells' responses to hypoxia and reperfusion.
Our results suggest that longer periods of hypoxia lead to a deficiency of high energy phosphates. Reoxygenation leads to the formation of ROS, irrespectively of the duration of hypoxia. It might be concluded that a diminished level of intracellular high energy phosphates upon hypoxia followed by oxidative stress plays a key role in the reperfusion associated cellular dysfunctions.


Expression of inflammation-related genes in aldosterone-producing adenomas with KCNJ5 mutation.
The adrenocortical cells have been shown to produce various inflammatory cytokines such as TNFα and IL-6, which could modulate steroidogenesis. However, the role of inflammatory cytokines in aldosterone-producing adenomas (APAs) is not fully understood. In the present study, we examined the relationships between mRNA expression levels of the inflammation-related genes and somatic mutations in APA tissues. We evaluated mRNA expression levels of TNFA, IL6, and NFKB1 in APA tissues obtained from 44 Japanese APA patients. We revealed that mRNA expression patterns of the inflammation-related genes depended on a KCNJ5 somatic mutation. In addition, we showed that mRNA expression levels of the inflammation-related genes correlated with those of the steroidogenic enzyme CYP11B1 in the patients with APAs. The present study documented for the first time the expression of inflammation-related genes in APAs and the correlation of their expression levels with the KCNJ5 mutation status and mRNA expression levels of steroidogenic enzymes, indicating the pathophysiological relevance of inflammation-related genes in APAs.


How Is Learning Motivation Shaped Under Different Contexts: An Ethnographic Study in the Changes of Adult Learner's Motivational Beliefs and Behaviors Within a Foreign Language Course.
There has been a burgeoning interest of students' motivational beliefs in determining their motivational behaviors in classroom activities: choice of task and persistence of task. Previous research mostly used quantitative methods to understand students' general motivation, without taking contextual factors into consideration. To fill in this gap, the present study examined the influence of changing contexts on students' motivational beliefs in a Chinese language classroom, and how those changes in motivational beliefs shaped their motivational behaviors in class activities. An ethnographic multiple-case study approach was adopted, and six adult learners were chosen from a Chinese language course in a Hong Kong university. On-going semi-structured interviews, class observations, stimulated recall and document reviews were conducted to understand student development across time. Findings show that the more proficient students were showing relatively stable motivational beliefs as well as behaviors throughout the foreign language course. In contrast, the less proficient students were demonstrating obvious changes in their motivational beliefs and hence behaviors, due to the different contexts of non-exam and high-stake exam. The study suggested students' learning motivation in class was context-dependent, and could fluctuate substantially on a weekly basis. Those dynamic within-course changes at different learning stages and the reasons shaping the changes could give pedagogical insights to the teacher with adult learners.


Evaluation of body growth in prepubertal Japanese children with obstructive sleep apnea after adenotonsillectomy over a long postoperative period.
The aim of this study was to identify changes in body growth patterns in prepubertal Japanese children with obstructive sleep apnea (OSA) after adenotonsillectomy (AT) over a long postoperative period. We retrospectively analyzed the hospital records of 69 children, aged 3-10 years with OSA, who were followed-up for a median period of 38 months (range, 24-92 months) after AT. Height and weight were measured during the preoperative period and 12, and 24 months postoperatively, data were converted to standard deviation scores (SDS) using current gender- and age-specific values for the growth parameters adopted by the National growth chart of Japan. Comparisons between the pre and postoperative SDS values for height and weight were performed. The numerical data were examined statistically. The SDS for height and weight of Japanese OSA children significantly increased 24 months post AT and continued over the entire 24-month follow-up period. Height growth acceleration after AT ended earlier in children of 6.0 ± 1.5 years at the time of AT than in children of 4.7 ± 1.3 years who could not catch-up. In prepubertal Japanese children with OSA, AT was effective for the growth of those children over a long postoperative period.


Hormonal control of ornithine decarboxylase in isolated liver cells and the effect of ethanol oxidation.
The regulation of ornithine decarboxylase activity was studied in freshly isolated rat hepatocytes incubated in a chemically defined medium for 5 h. Glucagon, dibutyryl cyclic AMP, insulin and dexamethasone produced dramatic increases in ornithine decarboxylase activity, 6--100-times the basal activity. Actinomycin D inhibited completely the stimulatory action of these substances. With glucagon, dibutyryl cyclic AMP and insulin, the rise in ornithine decarboxylase activity was rapid but transient, peaking at 200 min and then declining rapidly. By contrast, the response to dexamethasone was gradual and sustained in the 5 h incubation. The transient nature of the response to glucagon was unaltered by repeated additions of optimally effective doses of glucagon suggesting the development of 'refractoriness' to the actions of this hormone. Ethanol oxidation inhibited by 50% the stimulation of ornithine decarboxylase by glucagon and dexamethasone and this effect was blocked by 4-methylpyrazole, an inhibitor of alcohol dehydrogenase. Acetate (2.5--20 mM), the metabolic product of hepatic ethanol oxidation, was also effective. The data indicate that glucagon, insulin and glucocorticoids are all effective in stimulating the activity of ornithine decarboxylase in isolated hepatocytes but they differ in their duration and time of peak of action. Additionally, the inhibitory effect of ethanol on the hormonal stimulation of ornithine decarboxylase is dependent on its oxidation and may be mediated by acetate.


Reduced risk of peristomal infection of direct percutaneous endoscopic gastrostomy in cancer patients: comparison with the pull percutaneous endoscopic gastrostomy procedure.
Although pull percutaneous endoscopic gastrostomy (Pull-PEG) is a commonly used procedure, peristomal infection and tumor implantation are considered unavoidable complications of this procedure as the instrument passes through the oral cavity. A novel extracorporeal PEG technique, Direct-PEG, has been developed to reduce the risk of peristomal infection and implantation. The Direct-PEG procedure was performed on 87 patients from April 2006 to April 2007 in a single, high-volume cancer center in Japan. To compare the surgical outcomes of Direct-PEG and Pull-PEG, the clinical outcomes of Direct-PEG, such as peristomal infection, were retrospectively collected and compared with those of 64 patients having Pull-PEG procedures from April 2005 to March 2006. The mean operation time for the Direct-PEG group (13+/-1 minutes) was comparable to that for the Pull-PEG group (12+/-1 minutes), and the mean visual analogue pain score during surgery was lower for the Direct-PEG group (3.5+/-1.7) than for the Pull-PEG group (24.6+/-3.6; p < 0.001). The incidence of peristomal infection was lower in the Direct-PEG group (1%) than in the Pull-PEG group (9%; p=0.001). Although the most common major underlying disease in the groups was oropharyngeal or esophageal tumor, tumor implantation was not observed in either group. Direct-PEG may be superior to the Pull-PEG method for a high-volume cancer center because of reduced risks of infection.


Age-related Deficits in Voluntary Activation: A Systematic Review and Meta-analysis.
Whether there are age-related differences in neural drive during maximal effort contractions is not clear. This review determined the effect of age on voluntary activation during maximal voluntary isometric contractions. The literature was systematically reviewed for studies reporting voluntary activation quantified with the interpolated twitch technique (ITT) or central activation ratio (CAR) during isometric contractions in young (18-35 yr) and old adults (>60 yr; mean, ≥65 yr). Of the 2697 articles identified, 54 were eligible for inclusion in the meta-analysis. Voluntary activation was assessed with electrical stimulation and transcranial magnetic stimulation on five different muscle groups. Random-effects meta-analysis revealed lower activation in old compared with young adults (d = -0.45; 95% confidence interval, -0.62 to -0.29; P < 0.001), with moderate heterogeneity (52.4%). To uncover the sources of heterogeneity, subgroup analyses were conducted for muscle group, calculation method (ITT or CAR), and stimulation type (electrical stimulation or transcranial magnetic stimulation) and number (single, paired, or train stimulations). The age-related reduction in voluntary activation occurred for all muscle groups investigated except the ankle dorsiflexors. Both ITT and CAR demonstrated an age-related reduction in voluntary activation of the elbow flexors, knee extensors, and plantar flexors. ITT performed with paired and train stimulations showed lower activation for old than young adults, with no age difference for the single electrical stimulation. Together, the meta-analysis revealed that healthy older adults have a reduced capacity to activate some upper and lower limb muscles during maximal voluntary isometric contractions; however, the effect was modest and best assessed with at least paired stimulations to detect the difference.


Dual-acting diether derivatives of piperidine and homopiperidine with histamine H(3) receptor antagonistic and anticholinesterase activity.
The study presents novel biological properties of diether derivatives of homo- or substituted piperidine ligands of the histamine H(3) receptor. The compounds were evaluated for their inhibitory potency against acetylcholinesterase (AChE) from the electric eel and butyrylcholinesterase (BuChE) from horse serum. The most interesting multifunctional compound 13 displayed high affinity for the cloned hH(3) R (K(i) = 3.48 nM) and moderate inhibitory potency against both enzymes (IC(50) AChE = 7.91 µM and BuChE = 4.97 µM). Molecular modeling studies revealed interactions with key amino acid residues in the homology model of histamine H(3) receptor ligands, as well as the binding model for AChE and BuChE in the catalytic and peripheral active sites.


A comparison of six and 12 PUVA treatments in the prophylaxis of polymorphic light eruption.
Polymorphic light eruption (PLE) is a common condition for which the most effective treatment is prophylactic phototherapy. This is traditionally given in courses of approximately 12-15 exposures. We compared the effect of six and 12 treatments of psoralen-UVA (PUVA) therapy, in the prophylaxis of PLE, in a side-to-side within-patient comparison pilot study. In six out of eight patients, six treatments provided as much protection as 12 treatments. Five of these six patients had reported relatively mild disease in the previous year, in comparison to the other two patients. In view of the inconvenience and increased incidence of adverse effects associated with long treatment courses, we recommend the use of short courses, particularly in patients who are relatively mildly affected.


Three New Iridoid Glycosides from the Aerial Parts of Asperula involucrata.
Three new iridoid glycosides, named involucratosides A - C (1 - 3), were isolated from the H2 O subextract of crude MeOH extract prepared from the aerial parts of Asperula involucrata along with a known iridoid glycoside (adoxoside), three flavone glycosides (apigenin 7-O-β-glucopyranoside, luteolin 7-O-β-glucopyranoside, apigenin 7-O-rutinoside) as well as two phenolic acid derivatives (chlorogenic acid and ferulic acid 4-O-β-glucopyranoside). Their chemical structures were established by UV, IR, 1D- (1 H, 13 C and JMOD) and 2D- (COSY, HSQC, HMBC and NOESY) NMR experiments and HR-ESI-MS. In addition, the crude extract, subextracts and isolates were evaluated for their xanthine oxidase inhibitory and antioxidant activities in in vitro tests. This is the first report on the chemical composition and bioactivities of A. involucrata.


Effects of phentolamine and atropine on angina pectoris induced by handgrip test in patients with variant angina.
In 19 patients with variant angina, handgrip test as an isometric exercise was performed in 3 conditions on different successive days in the early morning: in the control, after administration of phentolamine (0.3 mg/kg) and after administration of atropine sulfate (0.04 mg/kg). Angina associated with ST-segment elevation on the electrocardiogram was induced in 5 patients (26%) in the control condition, in 14 (74%) after phentolamine and in 5 of 16 (31%) after atropine. All anginal events but 1 occurred after the cessation of the exercise and were not associated with the significant increase of rate-pressure products. These attacks were considered to be due to coronary spasm. The frequency of the induction of angina was significantly higher after phentolamine than in the other 2 conditions (p less than 0.01). It is concluded that the attack can be induced by the handgrip exercise in a sizable number of patients with variant angina, and that the administration of phentolamine increases the incidence of angina induced by handgrip exercise. The mechanism or mechanisms by which coronary spasm is induced by handgrip exercise remains to be elucidated.


Comparison of two-point discrimination testing devices.
In order to provide hand therapists and physicians with information regarding instruments for testing two-point discrimination we evaluated 20 noninjured and 18 nerve-injured patients using the three-prong Aesthesiometer, a paper clip, and a Disk-Criminator. Two-point discrimination was tested by means of a randomized order for the two different discrimination tests and the three different testing devices. The measurement for either moving or static two-point discrimination, when obtained with the three-prong Aesthesiometer, was consistently less sensitive than with the Disk-Criminator, and the correlation coefficient was the least between these two testing devices. The Disk-Criminator measurement had the smallest standard deviation among the three testing devices. In terms of desirability of the testing device tip geometry, translation of interprong distance to numerical rating scale, and facility of alternating between one- and two-prong testing techniques, the paper clip was judged to be the least favorable and the Disk-Criminator to be the most favorable test device.


Examining the Provision of School-Based Athletics in Public High Schools Among Girls in the United States.
In order to better understand some of the barriers to athletic opportunities for girls, we examined school-level characteristics to assess how they are associated with both the provision and participation in athletic opportunities for girls across US public high schools. Cross-sectional data for this study comes from the bi-annual Civil Rights Data Collection which collects school-level information for all US public schools between the 2009-2010 through 2017-2018 school years. Several important school-level characteristics were found to limit the provision of athletic opportunities, participation rates and athletic participation gender equity ratios for girls and included the percent of the student body who were eligible for free lunch and who were racial minorities. Moreover, the analysis found that greater provision of athletic opportunities for boys was associated with lower athletic participation gender equity ratios across US public high schools (ie, lower participation for girls when compared to boys). This study provides evidence that schools with fewer resources and a higher proportion of disadvantaged students tend to have the fewest opportunities to participate in school-based athletics, particularly among girls. Moreover, girls' participation rates in athletics still lag behind boys despite having similar numbers of sports and sport teams.


Attention for future reward.
When stimuli are consistently paired with reward, attention toward these stimuli becomes biased (e.g., Abrahamse, Braem, Notebaert & Verguts, et al., Psychological Bulletin 142:693-728, 2016, https://doi.org/10.1037/bul0000047). An important premise is that participants need to repeatedly experience stimulus-reward pairings to obtain these effects (e.g., Awh, Belopolsky & Theeuwes, Trends in Cognitive Sciences 16:437-443, 2012, https://doi.org/10.1016/j.tics.2012.06.010). This idea is based on associative learning theories (e.g., Pearce & Bouton, Annual Review of Psychology 52:111-139, 2001) that suggest that exposure to stimulus-reward pairings leads to the formation of stimulus-reward associations, and a transfer of salience of the reward to the neutral stimulus. However, novel learning theories (e.g., De Houwer, Learning and Motivation 53:7-23, 2009, https://doi.org/10.1016/j.lmot.2015.11.001) suggest such effects are not necessarily the result of associative learning, but can be caused by complex knowledge and expectancies as well. In the current experiment, we first instructed participants that a correct response to one centrally presented stimulus would be followed by a high reward, whereas a correct response to another centrally presented stimulus would be paired with a low reward. Before participants executed this task, they performed a visual probe task in which these stimuli were presented as distractors. We found that attention was drawn automatically toward high-reward stimuli relative to low-reward stimuli. This implies that complex inferences and expectancies can cause automatic attentional bias, challenging associative learning models of attentional control (Abrahamse et al., 2016; Awh et al., 2012).


Clinical evaluation of 40% urea and 12% ammonium lactate in the treatment of xerosis.
Urea and ammonium lactate are used for the treatment of xerosis, with different degrees of success. This study compares the clinical effectiveness of these two agents. To compare the effectiveness and tolerance of a 40% urea topical cream (Carmol 40) from Doak Dermatologics, a subsidiary of Bradley Pharmaceuticals, Inc., and 12% ammonium lactate topical lotion (Lac-Hydrin 12%) from Westwood Squibb, a division of Bristol-Myers Squibb. A randomized, double-blind, bilateral paired comparison study was conducted involving 25 men and women who were undergoing treatment for moderate to severe xerosis. The study included evaluations upon initiation of the study, after a 14-day treatment period and treatment follow-up on day 28. Eighteen study participants completed the entire 28-day evaluation period. Evaluation of treatment benefit was based on instrumental measurement of water loss from the skin surface, skin capacitance, skin desquamation, skin roughness, subject self assessment of skin and investigator evaluation. Results indicated that clinical observation ratings by patients and investigators, as well as instrument measures, show differences between the two treatments. Most measures show that improvement is achieved in less time with 40% urea cream than with 12% ammonium lactate lotion. On day 14, the 40% urea cream was superior to the 12% ammonium lactate lotion as measured by skin roughness, fissure reduction, thickness and dryness. At day 14 of treatment, 40% urea cream was superior to 12% ammonium lactate for most of the instrumental and clinical assessments.


Self-selected unrefined and refined carbohydrate diets do not affect metabolic control in pump-treated diabetic patients.
This study investigated whether unrefined or refined carbohydrate diets have any effect on metabolic control and on insulin requirement in near-normoglycaemic Type 1 (insulin-dependent) diabetic out-patients on continuous subcutaneous insulin infusion therapy. Two females and 8 males (aged 27 +/- 9 years; diabetes duration 13 +/- 8 years; duration of insulin pump therapy 22 +/- 5 months; means +/- SD) participated in a randomised cross-over study with two 6-week periods on self-selected refined and unrefined carbohydrate diets respectively. As a result, energy intake differed between the experimental diets (2372 +/- 669 kcal/day on unrefined diet vs 2757 +/- 654 kcal/day on refined diet, p = 0.04), as did the fibre intake (18 +/- 5 g/day with the refined carbohydrate diet vs 35 +/- 13 g/day with the unrefined carbohydrate diet, p = 0.02). The composition of nutrients was approximately 40% carbohydrate, 45% fat, and 13% protein with both diets. Body weight, HbA1c, daily mean blood glucose (7.2 +/- 0.6 mmol/l) and serum lipids remained virtually unchanged during the entire study. Insulin requirement varied between 40.1 +/- 7.9 U/day with the unrefined carbohydrate diet, and 42.5 +/- 10.1 U/day with the refined carbohydrate diet (NS). Thus, neither the refined nor the unrefined carbohydrate diet affected insulin requirement and metabolic control in these near-normoglycaemic, normolipaemic, non-obese, insulin-pump-treated Type 1 diabetic patients.


Computed tomography of fatty replacement in extramedullary hematopoiesis.
A case of thoracic extramedullary hematopoiesis with a large fatty component presented a unique CT appearance that has not been previously reported.


Assessment of surface water quality during different tides and an anthropogenic impact on coastal water at Gulf of Kachchh, West Coast of India.
The port-based activity is often associated with industrial growth in the hinterland and similar phenomenon reported from the Gulf of Kachchh, India. Industrialization exerts pressure on coastal water through the release of waste water or effluents which influence the entire marine ecosystem. The present paper tries to evaluate the variation in the water quality during the high tide and low tide in relation to the anthropogenic or natural influence in Gulf of Kachchh. The tidal variation is important as it reflects the influence of the land-based activity on the coastal waters. To prove this logic, a series of stations were taken along the coastal water and statistical analysis, viz., Pearson correlation, Box plot, hierarchical cluster analysis (HCA), and factor analysis (PCA/FA) were conducted. Pearson correlation and Box plot represent visual impact of parameter variations in respected tides. The chemometric analysis, i.e., HCA and PCA/FA, clearly indicates an anthropogenic impact on coastal water. The results of HCA revealed that major anthropogenic and domestic impacts were found at various stations during the low tide. The HCA points out that an anthropogenic and the tidal activity in the Gulf of Kachchh influence the physical water quality parameters like pH, salinity, dissolved solid, oxygen, turbidity, sulfate, and nutrients in the coastal ecosystem. The PCA/FA further ascertains the finding of HCA analysis that the state of the art of the water quality of coastal ecosystem has direct relevance with the land-based activities and sewage outfall points. Tide-based control on the water quality parameters was evident that the high tide nutrients like phosphates and nitrogen were high, while during the low tide, temperature, salinity, total solids, and sulfate showed higher concentrations. The findings of the paper will be useful for developing effective management strategies for policy makers or stakeholders operating in the coastal area.


A novel concept of cam-type femoroacetabular impingement treatment with patient-specific template guided osteochondral deformity ablation.
To present a novel surgical concept for the cam-type femoroacetabular impingement (FAI) treatment and to assess and report the clinical outcomes. We performed a retrospective study of a single-surgeon case series of six hips in five consecutive male patients with symptomatic cam-type FAI, treated with the mini-open anterior hip approach with a patient-specific template (PST)-guided deformity ablation between 2015 and 2018. We assessed the hip range of motion, iHOT-33, Tegner, and EQ-5D before surgery and after a minimum follow-up of 30 months. The average age was 37 ± 13.3 years, average BMI was 31.1 ± 3.3 kg/m2, and average pre-surgery Tönnis hip osteoarthritis (OA) grade was 1 ± 1. The average surgery duration was 71 ± eight minutes. The average estimated blood loss was 83 ± 26 ml. After a mean follow-up of 50 ± 12 months, we observed no OA progression with no change in Tönnis hip OA grades. Hip flexion and internal rotation significantly improved (p = 0.007; p = 0.048) from mean 98° ± 9° and 14° ± 11° to mean 113° ± 8° and 23° ± 8°, respectively. iHOT-33, Tegner, and EQ-5D improved significantly (p = < 0.001; p = 0.004; p = < 0.001) from mean 44.7 ± 12.2, 3 ± 1, and 0.513420 ± 0.101389 to mean 94 ± 2.7, 5 ± 1, and 1.000000 ± 0, respectively. One patient needed revision surgery for heterotopic ossification removal, with no sequelae at the last follow-up. Mini-open anterior hip approach with the PST-guided cam-type FAI deformity ablation presents an accurate and reproducible solution for cam-type FAI surgical treatment, with promising clinical outcomes. Using a PST in the cam-type FAI surgery may present a powerful additional tool in the existing open techniques armamentarium.


Increased transport of 3,4-dihydroxyphenylacetic acid from brain during performance of operant behavior in the rat.
Although the performance of positively reinforced operant behavior is accompanied by increased turnover of brain dopamine in the rat, the accumulation of 3,4-dihydroxyphenylacetic acid (DOPAC), the major metabolic product of dopamine in brain, is not increased during operant performance. The hypothesis that the lack of increased DOPAC accumulation stems from an increase in the rate at which DOPAC is eliminated from the brain was tested by measuring the relative rate of DOPAC transport from brain in rats performing operant behavior and in control rats. The transport of DOPAC was estimated following inhibition of monoamine oxidase with pargyline. The pargyline-induced depletions of DOPAC in the caudate putamen and amygdala were significantly greater in rats that performed operant behavior than in control rats. In the caudate putamen, the concentrations of homovanillic acid and 5-hydroxyindoleacetic acid were also depleted by pargyline to a greater extent in operant performing rats than in controls. These results suggest that in addition to the increased turnover of dopamine in central neurons during operant behavior, the rate of elimination of acidic amine metabolites from brain is also accelerated.


Cyst of the medullary conus: malformative persistence of terminal ventricle or compressive dilatation?
The ventriculus terminalis is a cavity situated at the level of the conus medullaris, enclosed by ependymal tissue and normally present as a virtual cavity or as a mere ependymal residue. In rare cases, and almost exclusively in pediatric age, the ventriculus terminalis may be visualized by radiological investigations, either by sonography or MRI, and represents a transient finding in children under 5 years of age. In pathological conditions, a cyst of the conus medullaris is probably the result of a persistent ventriculus terminalis and is usually described in children in association with a tethered cord; in a very limited number of cases, it has been described in adults whose clinical symptoms consist of neurological and/or sphincter disturbances not associated with other pathologies. The authors describe the case of a 42-year-old female with a cyst of the conus whose only symptom was imperious minction; she had been suffering from these urinary disorders for many years. The patient was not operated on because the clinical situation remained stable, without modifications of the MRI in follow-up over a 6-year period. The authors therefore suggest that in adult patients, a cyst of the conus medullaris is probably an expression of malformative persistence of the fifth ventricle and does not necessarily have a progressive evolution.


Analysis of molecular mechanisms and anti-tumoural effects of zoledronic acid in breast cancer cells.
Zoledronic acid (ZOL) is the most potent nitrogen-containing bisphosphonate (N-BPs) that strongly binds to bone mineral and acts as a powerful inhibitor of bone resorption, already clinically available for the treatment of patients with osteolytic metastases. Recent data also suggest that ZOL, used in breast cancer, may provide more than just supportive care modifying the course of the disease, though the possible molecular mechanism of action is still unclear.As breast cancer is one of the primary tumours with high propensity to metastasize to the bone, we investigated, for the first time, differential gene expression profile on Michigan Cancer Foundation-7 (MCF-7) breast cancer cells treated with low doses of ZOL (10 μM). Microarrays analysis was used to identify, describe and summarize evidence regarding the molecular basis of actions of ZOL and of their possible direct anti-tumour effects. We validated gene expression results of specific transcripts involved in major cellular process by Real Time and Western Blot analysis and we observed inhibition of proliferation and migration through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Matrigel assay. We then focused on changes in the cytoskeletal components as fibronectin 1 (FN1), actin, and anti angiogenic compounds as transforming growth factor-β1 (TGF-β1) and thrombospondin 1 (THBS1). The up-regulation of these products may have an important role in inhibiting proliferation, invasion and angiogenesis mediated by ZOL.


Factors contributing to energy loss in left ventricle during diastolic and systolic phases in elderly patients.
The change of left ventricular function deteriorated with age because of gradual increases of blood pressure may result in increased energy loss (EL) in left ventricle (LV). The present study investigated EL in LV among hypertensive elderly patients and examined factors contributing to EL. A single-center retrospective study was performed on elderly hypertensive outpatients (≥65 years) who underwent echocardiography (N = 105). EL in the LV was measured using a vector flow mapping system, and factors affecting peak EL during the early-diastolic phase (ED-EL), late-diastolic phase (LD-EL), and systolic phase (Sys-EL) were evaluated. Mean age was 79.9 ± 6.4 years (male 43%). Mean ED-EL, LD-EL, and Sys-EL were 42.1 ± 46.7, 75.6 ± 60.2, and 40.4 ± 40.2 mJ/N/s. In a stepwise regression analysis, the E/e'(lateral) (unstandardized B = 0.005, 95%CI -0.03 to 0.007, standardized β = 0.434, P < .001) was identified as factors affecting ED-EL. The factors affecting LD-EL were E/A ratio (B = -0.122, 95%CI -0.176 to -0.068, β = -0.470, P < .001) and time velocity integral (TVI) in LVOT (unstandardized B = 0.002, 95%CI 0.000 to 0.004, β = 0.247, P = .021). The factors influencing Sys-EL were TVI in LVOT (B = 0.002, 95%CI 0.001 to 0.004, β = 0.390, P < .001), E/A ratio (B = -0.054, 95%CI -0.093 to -0.015, β = -0.258, P = .008), left ventricular outflow tract (LVOT) diameter (B = -0.006, 95%CI -0.010 to -0.002, β = -0.307, P = .006), and left ventricular mass index (B = 0.000, 95%CI 0.000 to 0.001, β = 0.208, P = .039). Peak EL in the LV was higher during diastolic phase than systolic phase among elderly hypertensive patients. Peak EL both during late-diastolic phase and systolic phase was affected by systolic blood flow in LVOT and LV transmitral flow pattern.


An evaluation of the two-stage flexor tendon reconstruction technique.
The performance of 43 two-stage flexor tendon reconstructions in 39 patients was reviewed. Results were graded by comparing the preoperative passive motion of the proximal and distal interphalangeal joints after stage one to the active motion of these same joints after stage two. The procedures returned 16% excellent, 23% good, 26% fair, and 35% poor results with three graft ruptures. Following the tenolysis of 20 grafts (47%) the results for the entire group were improved to 27% excellent, 28% good, 30% fair, and 16% poor. Stage reconstruction, including tenolysis, was felt to be the best available method for restoration of digital function following flexor tendon loss in the badly scarred digit.


Importance of tumor affinity of nitroazoles in hypoxic radiosensitization.
In vitro and in vivo sensitizing activities of a variety of nitroazole derivatives including misonidazole (MISO), SR-2508, and RSU-1069 were correlated by the aid of pharmacokinetic measurements of the drug uptake in animal solid tumors. The sensitizer enhancement ratio in vivo (SERvivo) on solid tumors increased linearly with the square root of administrated dose (Ds). The specific activity (A) in vivo of nitroazoles was evaluated from the square-root empirical relationship, SERvivo = 1.00 + A D1/2S. The intratumor concentration of nitroazoles at a given time t after administration was in proportion to the DS, in which the proportional constant was defined as the tumor-affinity factor FT,t. The absolute molar activity alpha M defined by A(M/FT,t)1/2, where M is the molecular weight of nitroazoles, showed a linear relationship with the SER in vitro (SERvitro) at 1 mM of sensitizers. The sensitizer dose required to achieve an SERvivo of 1.5 (DS,1.5) decreased and thus the overall sensitizing efficiency on animal solid tumors increased as the FT,t became greater.


A novel risk score to predict deep vein thrombosis after spontaneous intracerebral hemorrhage.
Studies showed that patients with hemorrhagic stroke are at a higher risk of developing deep vein thrombosis (DVT) than those with ischemic stroke. We aimed to develop a risk score (intracerebral hemorrhage-associated deep vein thrombosis score, ICH-DVT) for predicting in-hospital DVT after ICH. The ICH-DVT was developed based on the Beijing Registration of Intracerebral Hemorrhage, in which eligible patients were randomly divided into derivation (60%) and internal validation cohorts (40%). External validation was performed using the iMCAS study (In-hospital Medical Complication after Acute Stroke). Independent predictors of in-hospital DVT after ICH were obtained using multivariable logistic regression, and β-coefficients were used to generate a scoring system of the ICH-DVT. The area under the receiver operating characteristic curve (AUROC) and the Hosmer-Lemeshow goodness-of-fit test were used to assess model discrimination and calibration, respectively. The overall in-hospital DVT after ICH was 6.3%, 6.0%, and 5.7% in the derivation (n = 1,309), internal validation (n = 655), and external validation (n = 314) cohorts, respectively. A 31-point ICH-DVT was developed from the set of independent predictors including age, hematoma volume, subarachnoid extension, pneumonia, gastrointestinal bleeding, and length of hospitalization. The ICH-DVT showed good discrimination (AUROC) in the derivation (0.81; 95%CI = 0.79-0.83), internal validation (0.83, 95%CI = 0.80-0.86), and external validation (0.88; 95%CI = 0.84-0.92) cohorts. The ICH-DVT was well calibrated (Hosmer-Lemeshow test) in the derivation (P = 0.53), internal validation (P = 0.38), and external validation (P = 0.06) cohorts. The ICH-DVT is a valid grading scale for predicting in-hospital DVT after ICH. Further studies on the effect of the ICH-DVT on clinical outcomes after ICH are warranted.


A multicenter, randomized, parallel-group, clinical trial comparing the safety and efficacy of loteprednol etabonate 0.5%/tobramycin 0.3% with dexamethasone 0.1%/tobramycin 0.3% in the treatment of Chinese patients with blepharokeratoconjunctivitis.
To compare the efficacy and safety of loteprednol etabonate 0.5%/tobramycin 0.3% (LE/T) and dexamethasone 0.1%/tobramycin 0.3% (DM/T) ophthalmic suspensions in a Chinese population with ocular inflammation associated with blepharokeratoconjunctivitis (BKC). This study was a multicenter, randomized, investigator-masked, parallel-group clinical trial. Patients aged ≥18 years with a clinical diagnosis of BKC in at least one eye received LE/T or DM/T administered 4 times daily for 2 weeks. At baseline and on days 3, 8, and 15 (visits 2, 3, and 4), clinical assessments of ocular signs and symptoms, visual acuity (VA), biomicroscopy, and intraocular pressure (IOP) were performed in both eyes. The primary efficacy endpoint was the change from baseline (CFB) to visit 4 in the signs and symptoms composite score in designated study eyes using a non-inferiority metric to compare LE/T to DM/T. Safety evaluation included adverse events, biomicroscopy findings, and changes in VA and IOP. NCT number, NCT01028027. A total of 308 patients were included in the per protocol population (n = 156 LE/T, n = 152 DM/T). A significant CFB in composite signs and symptoms was seen with both treatments at each follow-up visit (p < 0.0001). The mean (SD) CFB at visit 4 was -11.63 (4.56) and -12.41 (4.71) in the LE/T and DM/T groups, respectively, and the upper bound of the 90% confidence interval for the difference was less than the prespecified non-inferiority margin. Comparable results were found for secondary efficacy outcomes. Patients treated with DM/T experienced a significantly greater increase in mean CFB in IOP compared to those treated with LE/T at all follow-up visits (p ≤ 0.0186) and nearly twice as many IOP elevations ≥5 mmHg (p = 0.0020). Treatment with LE/T was at least as effective as DM/T in Chinese patients with BKC and had a better safety profile with respect to change in IOP.


Leveraging the use of in vitro and computational methods to support the development of enabling oral drug products: An InPharma commentary.
Due to the strong tendency towards poorly soluble drugs in modern development pipelines, enabling drug formulations such as amorphous solid dispersions, cyclodextrins, co-crystals and lipid-based formulations are frequently applied to solubilize or generate supersaturation in gastrointestinal fluids, thus enhancing oral drug absorption. Although many innovative in vitro and in silico tools have been introduced in recent years to aid development of enabling formulations, significant knowledge gaps still exist with respect to how best to implement them. As a result, the development strategy for enabling formulations varies considerably within the industry and many elements of empiricism remain. The InPharma network aims to advance a mechanistic, animal-free approach to the assessment of drug developability. This commentary focuses current status and next steps that will be taken in InPharma to identify and fully utilize 'best practice' in vitro and in silico tools for use in physiologically based biopharmaceutic models.


The absorptive viability of isolated intestine prepared from dead animals.
Glucose and water absorption rates are much lower (50%) in isolated perfused rat small intestine when the animals are killed by stunning or ether before removal of the intestine than when the animal is maintained alive under light ether anaesthesia throughout the setting-up procedure.


Meta-analysis of the efficacy of sorafenib for hepatocellular carcinoma.
By carrying out a meta-analysis of randomized controlled trials that compared sorafenib or combined chemotherapy with placebo or combined chemotherapy, the effectiveness of sorafenib in hepatocellular carcinoma was evaluated in the present study, which also provided clinical practice guidelines of evidence-based-medicine. We reviewed PubMed citations concerning sorafenib treating hepatocellular carcinoma in randomized controlled trials from Jan 2000 to July 2012. All the literature was extracted by Cochrane systematic reviews and underwent meta-analysis with RewMan 5.0 software. Finally, four papers documenting randomized controlled studies were included. Compared with controls, sorafenib was shown to significantly increase overall survival (OS), time to progression (TTP), and disease control rates (DCR), but not the time to symptom progression (TTSP) in hepatocellular carcinoma patients. The incidence of grade-III/IV adverse reactions, including hand- foot-skin reactions, diarrhea, hypertension and skin rash or desquamation, in sorafenib treatment group was higher than that in controls. However, there was no significant difference in the incidence of hypodynamia between the two groups. Sorafenib exerts significant curative effects in hepatocellular carcinoma.


The association between student body mass index and tests of flexibility assessed by the FITNESSGRAM®: New York City public school students, 2017-18.
FITNESSGRAM® is the most widely used criterion-referenced tool to assess/report on student health-related fitness across the US. Potential weight-related biases with the two most common tests of musculoskeletal fitness-the trunk extension and Back-Saver Sit-and-Reach (sit-and-reach)-have been hypothesized, though have not been studied. To determine the association between musculoskeletal fitness test performance and weight status, we use data from 571,133 New York City public school 4th-12th grade students (85% non-White; 75% qualified for free or reduced-price meals) with valid/complete 2017-18 FITNESSGRAM® data. Adjusted logistic mixed effects models with a random effect for school examined the association between weight status and whether a student was in the Healthy Fitness Zone (HFZ; met sex- and age-specific criterion-referenced standards) for the trunk extension and sit-and-reach. Compared to students with normal weight, the odds of being in the HFZ for trunk extension were lower for students with underweight (OR = 0.77; 95% CI: 0.741, 0.795) and higher for students with overweight (OR = 1.10; 95% CI: 1.081, 1.122) and obesity (OR = 1.11; 95% CI: 1.090, 1.13). The odds of being in the HFZ for sit-and-reach were lower for students with underweight OR = 0.85; 95% CI: 0.826, 0.878), overweight (OR = 0.83; 95% CI: 0.819, 0.844) and obesity (OR = 0.65; 95% CI: 0.641, 0.661). Students with overweight and obesity perform better on the trunk extension, yet worse on the sit-and-reach, compared to students with normal weight. Teachers, administrators, and researchers should be aware of the relationship of BMI with student performance in these assessments.