Problems of priority change in kidney allocation and beyond.
Standardized and transparent priority setting in medicine, desirable as it is, will generally exacerbate inter-temporal equity problems arising from changes in treatment priorities: when can it be fair that the treatment of already waiting patients who would have had priority under an established system should be postponed (withheld) for an extended period of time to advance the treatment of others under a reformed system? The reform of the Eurotransplant system of priority setting in kidney allocation (ETKAS), which is in many respects ideal, is a case in point. To give due weight to new medical knowledge, waiting time after the onset of end state renal failure should change from a priority-enhancing to a priority-reducing factor. Since those who have gained in priority by waiting under the present system would be set back under the new, severe problems of transitional justice must be overcome when responding to advances in medical knowledge. The paper explores conceptually some possible ways of rule change and indicates their general relevance from an ethical and a practical point of view for future problems of medical resource allocation under transparent, standardized priority-setting rules.


Entrapment of nanoscale zero-valent iron in chitosan beads for hexavalent chromium removal from wastewater.
Nanoscale zero-valent iron (NZVI) was successfully entrapped in chitosan (CS) beads for reduction of Cr (VI) from wastewater. The removal mechanism may include both physical adsorption of Cr (VI) on the surface or inside of CS-NZVI beads and subsequent reduction of Cr (VI) to Cr (III). The free amino groups and hydroxyl groups on CS may contribute little to hinder the formation of Fe(III)-Cr(III) precipitate. Entrapment of NZVI in CS beads prevents the particles from aggregation and oxidation. The results indicate that there is no significant difference between the reaction rates of bare NZVI and entrapped NZVI. Cr (VI) reduction kinetics follows a pseudo-first-order rate expression. The reduction capacity for Cr (VI) increases with increasing temperature and NZVI dosage but decreases with the increase in initial concentration of Cr (VI) and pH values. This study demonstrates that entrapment of NZVI in CS beads has the potential to become a promising technique for in situ groundwater remediation.


Azithromycin downregulates ICOS (CD278) and OX40 (CD134) expression and mTOR activity of TCR-activated T cells to inhibit proliferation.
The precise mechanism of macrolide antibiotic azithromycin (AZM) mediated CD4+ T cell suppression is not fully understood. Given the crucial role of co-stimulatory signaling in T-lymphocyte function, we tested in vitro effects of AZM on two of the most extensively investigated costimulatory molecules, ICOS and OX40 in context to CD4+ T cell proliferation. Using multi-color flow cytometry approach on TCR-activated healthy donor peripheral blood mononuclear cells, we observed a marked reduction in the frequencies and surface expression of ICOS and OX40 receptors following AZM treatment. Functionally, in contrast to ICOS- and OX40- CD3+ CD4+ T cells, AZM treated ICOS+ and OX40+ displayed profound reduction in cell proliferation. Furthermore, AZM treated T cells displaying reduced levels of ICOS and OX40 found to be associated with suppressed mTOR activity as detected by phosphorylation levels of S6 ribosomal protein. This study provides new insights on potential mechanism of AZM mediated inhibition of T cell proliferation by targeting costimulatory pathways.


Food addiction, executive function and mood in adolescents with obesity seeking treatment.
The relationships between food addiction, executive functions and mood in adolescence are not well-understood. This study examines differences in executive functioning, depression symptoms and perceived stress among adolescents with obesity with- and without food addiction. A total of 110 adolescents with obesity (74 females; age = 15.59 ± 1.3 y; 67% Hispanic; 74% public insurance) completed the Behavior Rating Inventory of Executive Function-2 (BRIEF-2), the Yale Food Addiction Scale for children (YFAS-c), the Perceived Stress Scale (PSS) and the Center for Epidemiologic Studies Depression scale (CES-DC). Chi-squared and Fisher's exact tests were used to evaluate differences in BRIEF-2, CES-DC and PSS scores between participants with and without food addiction. A logistic regression model assessed the associations between executive dysfunction, depression and stress on food addiction individually. Multiple logistic regression was utilized to further examine the association between executive dysfunction and food addiction when accounting for depression and stress. More than a third of participants (34.5%) met the criteria for food addiction. Females were 2.89 times more likely than males to have food addiction (95th%CI = 1.12-7.46, p = 0.03). Participants with FA had significantly higher BRIEF-2 T-scores (all p < 0.05) and higher PSS and CES-DC scores (all p < 0.05). Multiple logistic regression analysis showed depression was strongly correlated with FA when controlling for executive dysfunction and stress (p = 0.010). Among obesity treatment-seeking adolescents, youths with food addiction displayed greater impairments in executive functioning and higher levels of stress and depressive symptoms than adolescents without food addiction. Prospective studies are needed to determine how this behavioral phenotype helps predict intervention outcomes.


Multi-institutional validation study of neural networks to predict duration of stay after laparoscopic radical/simple or partial nephrectomy.
We developed models to predict post-laparoscopic radical or simple nephrectomy (LapNx) and post-laparoscopic partial nephrectomy (LapPNx) hospital duration of stay (DOS). We performed a retrospective review (design group) of all 726 patients (July 1997 to April 2004) who underwent LapNx or LapPNx at the Cleveland Clinic Foundation (CCF). Preoperative findings were recorded. Neural network algorithms were designed to predict the DOS before surgery. The models were then tested on a separate 252 patients from 6 different institutions, namely Tulane University Medical School, University of Arkansas for Medical Sciences, Cedars-Sinai Medical Center, University of Iowa, Mayo Clinic at Scottsdale and CCF. In the CCF design groups, the LapNx model accuracy was 73% to 74% and the LapPNx model 73% to 83%. Overall accuracy in the test groups at all 6 institutions was 72% (area under ROC 0.6 to 0.7) for the LapNx model and 52% to 81% (ROC 0.5 to 0.7) for the LapPNx model. The LapNx model provides 72% accuracy in predicting the DOS at all 6 institutions. The LapPNx model provided fair accuracy only at CCF and Tulane University Medical School. These models may streamline the delivery of care and continued testing will allow for further refinement.


Lymphocyte subsets involved in tumor-activated nonspecific feedback suppression.
Cells from the spleen, lymph nodes, and peritoneum of DBA/2 mice bearing a subcutaneous tumor mediate nonspecific suppression of an in vitro antibody response to sheep red blood cells (SRBC) when cocultured with a normal T-cell subset(s). The spleen cells from the tumor-bearing mouse required for the suppression bear the Lyt 1 and Ala 1 surface markers characteristic of "inducer" T cells and activated cells, respectively. The activity of this cell population is also sensitive to irradiation. The normal T-cell subset which cooperates in the suppression bears the Qa-1 surface antigen which has been associated with suppressor cell precursors in several systems but lacks detectable surface Lyt 1 and 2 markers. Suppression of antibody responses in spleen cell cultures from tumor-bearing mice alone could also be elicited, but only when increased numbers of cells were cultured. These data are consistent with the theory that a tumor-activated, Lyt 1+ T-cell subset has the capacity to nonspecifically suppress immune responses by activating a Qa-1+ subset(s) of T suppressor cells, perhaps via feedback signals.


Application of omics technologies for a deeper insight into quali-quantitative production traits in broiler chickens: A review.
The poultry industry is continuously facing substantial and different challenges such as the increasing cost of feed ingredients, the European Union's ban of antibiotic as growth promoters, the antimicrobial resistance and the high incidence of muscle myopathies and breast meat abnormalities. In the last decade, there has been an extraordinary development of many genomic techniques able to describe global variation of genes, proteins and metabolites expression level. Proper application of these cutting-edge omics technologies (mainly transcriptomics, proteomics and metabolomics) paves the possibility to understand much useful information about the biological processes and pathways behind different complex traits of chickens. The current review aimed to highlight some important knowledge achieved through the application of omics technologies and proteo-genomics data in the field of feed efficiency, nutrition, meat quality and disease resistance in broiler chickens.


Neurodevelopmental toxicity induced by maternal PM2.5 exposure and protective effects of quercetin and Vitamin C.
Epidemiological studies show that maternal exposure to PM2.5 affects the neurodevelopment of the offspring, especially the neurocognitive function. However, no relevant experimental researches have been published on toxic mechanism and diet intervention. We evaluated the effects of exposure to different doses of PM2.5 on the behavioral development of offspring via a PM2.5 exposure model established by intratracheal instillation, explored its mechanism and the protective effects of quercetin and VC intervention, and focused on the protein expression of CREB/BDNF signaling pathway. Specifically, Exposure to PM2.5 during gestation and lactation period caused maternal oxidative stress. Maternal exposure to PM2.5 changed postnatal open-field behaviors in both gender, impaired spatial learning and memory in the female offspring, increased the level of IL-1β, IL-6, down-regulated p-CREB/CREB, BDNF, TrkB, p-CaMKII/CaMKII, p-CaMKIV/CaMKIV, up-regulated p-Akt/Akt and p-ERK1/2/ERK1/2 in the offspring. In addition, maternal supplementation with quercetin ameliorate the maternal oxidative stress, improved progeny inflammatory response, regulated BDNF, TrkB, p-Akt/Akt, p-ERK1/2/ERK1/2 in female offspring, regulated TrkB, p-CREB/CREB and p-Akt/Akt in male offspring. Maternal supplementation with VC increased the levels of CAT in maternal mice, up-regulated BDNF in female offspring, regulated p-CREB/CREB and p-ERK1/2/ERK1/2 in male offspring. Our findings indicate that PM2.5 exposure during pregnancy and lactation could impair behavioral development of offspring. Quercetin shows more protective effects than VC. The mechanism of neurodevelopmental toxicity induced by PM2.5 may be related to oxidative stress, inflammatory response and modulation of the CREB/BDNF signaling pathway.


ZnO encapsulants: Design and new view.
ZnO encapsulants with capsular configurations (e.g. a large inner cavity, sizeable pore, low density and high specific surface area) have attracted considerable attention as effective and promising candidates in various fields owing to the merits of ZnO (e.g. UV protection, photoelectric catalysis, gas sensitivity, antibacterial effect). However, the research on ZnO encapsulants has not yet reached the eruptive stage. This probably due to their high morphological flexibility and relatively low structural strength that is not easy to control during the preparation process. In this review, the principles of cavity-generating and pore-forming are firstly discussed in depth after going through the synthesis of hollow ZnO in the past ten years. Moreover, the regulation of cavity diameter and pore size of different synthetic strategies is investigated. Then, the research progress of ZnO encapsulants is debated in detail from the loading and release of functional materials and the corresponding characterization. Finally, some potential designs and new views on the future research and development of ZnO encapsulants are concluded.


Analysis of N-acyl aminonaphthalene sulphonic acid derivatives with potential anti-human immunodeficiency virus activity by thin-layer chromatography and flame ionization detection.
A method for checking the purity of N-acyl aminonaphthalene disulphonic acid derivatives was required for a systematic study of the anti-human immunodeficiency virus activity of these agents. We describe the use of thin-layer chromatography and flame ionization detection for the separation of these compounds, which are difficult to analyse by conventional methods. All the samples were prepared in methanol solutions (1 microliter) containing 5 micrograms of aminonaphthalene derivative. These samples were applied to each type SIII Chromarod by a single injection and developed with pure methanol or a methanol-chloroform-ammonium hydroxide (35:55:10, v/v/v) solvent system.


Industry Payments to Radiologists During the Last 5 Years and Impact of COVID-19 Pandemic.
The aim of this study is to assess the trends in industry payments to radiologists and the impact of the COVID-19 pandemic, including trends in different categories of payments. The Open Payments Database from CMS was accessed and analyzed for the period from January 1, 2016, to December 31, 2021. Payments were grouped into six categories: consulting fees, education, gifts, research, speaker fees, and royalties or ownership. The total number, value, and types of industry payments to radiologists were subsequently determined and compared pre- and postpandemic from 2016 to 2021. The total number of industry payments and the number of radiologists receiving these payments dropped by 50% and 32%, respectively, between 2019 and 2020, with only partial recovery in 2021. However, the mean payment value and total payment value increased by 177% and 37%, respectively, between 2019 and 2020. Gifts and speaker fees experienced the largest decreases between 2019 and 2020 (54% and 63%, respectively). Research and education grants were also disrupted, with the number of payments decreasing by 37% and 36% and payment value decreasing by 37% and 25%, respectively. However, royalty or ownership increased during the first year of the pandemic (8% for number of payments and 345% for value of payments). There was significant decline in overall industry payments coinciding with the COVID-19 pandemic, with biggest declines in gifts and speaker fees. The impact on the different categories of payments and recovery in the last 2 years has been heterogeneous.


Rare fracture of a total hip replacement.
Material fractures in the femoral part of total hip replacements, a late complication, are usually observed in the shaft. In our case, a fatigue fracture of the ball-neck weld occurred 8 1/2 years after implantation of the prosthesis because of insufficient weld depth. Additional negative factors proved to be varus implantation and overloading of the prosthesis due to obesity. The weld represented a point of low resistance. Even if major traumatic events are responsible for the fracture or loosening of an endoprosthesis, overloading (i.e., multiple "microtrauma") is also an important contributing factor.


Frequency of juvenile fibromyalgia syndrome in children with familial Mediterranean fever: effects on depression and quality of life.
To determine the prevalence of juvenile fibromyalgia syndrome (JFMS) in children with familial Mediterranean fever (FMF) and to evaluate quality of life (QoL) and depression. Ninety-one FMF patients (M/F: 44/47) who fulfilled the Livneh criteria and 60 healthy children (M/F: 27/33) were enrolled in the study. Yunus and Masi's criteria were used for diagnosis of JFMS. Depression was assessed with Children's Depression Inventory (CDI) and QoL was evaluated with child and parent reports of Paediatric Quality of Life Inventory 4.0 (PedsQL™). While 20 (21.9%) of 91 FMF patients fulfilled JFMS criteria, 2 (3.3%) of the control group met the diagnostic criteria of JFMS (p=0.002). PedsQL™ scores (child self-report and parent-report) of the FMF patients were significantly lower and the depression scores were significantly higher than the healthy controls (p<0.001 for all). When the FMF patients were assigned to two groups as FMF with or without JFMS, patients with JFMS were found to have a higher depression score (p=0.007) and child and parent reports of PedsQL™ 4.0 were lower in the children with JFMS than in the patients without JFMS (p=0.001, p=0.003, respectively). We have determined that JFMS frequency was higher in children with FMF and patients with FMF and JFMS had a poor QoL and were more susceptible to depression. FMF patients with widespread and persistent pain should be evaluated for JFMS in order to avoid unnecessary investigations and inappropriate treatment.


Development of a recombinant nucleocapsid protein-based ELISA for the detection of IgM and IgG antibodies to SARS-CoV-2.
Coronavirus 2019 (COVID-19) is a global concern for public health. Thus, early and accurate diagnosis is a critical step in management of this infectious disease. Currently, RT-PCR is routine diagnosis test for COVID-19, but it has some limitations and false negative results. enzyme-linked immunosorbent assay (ELISA) against SARS-CoV-2 antigens seems to be an appropriate approach for serodiagnosis of COVID-19. In the current study, an ELISA system, using a recombinant nucleocapsid (N) protein, was developed for the detection of IgM and IgG antibodies to SARS-CoV-2. The related protein was expressed, purified, and used in an ELISA system. Sera samples (67) for COVID-19 patients, as well as sera samples from healthy volunteers (112), along with sera samples from non-COVID-19 patients were examined by the ELISA system. The expression and purity of the recombinant N protein were approved by SDS-PAGE and Western blotting. The sensitivity of ELISA system was 91.04 and 92.53% for the detection of IgG and IgM antibodies, respectively. Moreover, the specificity of the developed ELISA system for IgG and IgM were 98.21 and 97.32%, respectively. Our developed ELISA system showed satisfactory sensitivity and specificity for the detection of antiSARS-CoV-2 IgM and IgG antibodies and could be used as a complementary approach for proper diagnosis of COVID-19.


Increased concentrations of the oxidative DNA adduct 7,8-dihydro-8-oxo-2-deoxyguanosine in the germ-line of men with type 1 diabetes.
The effects of diabetes mellitus on male reproductive health have not been clearly defined. A previous publication from this group reported significantly higher levels of nuclear DNA fragmentation and mitochondrial DNA deletions in spermatozoa from men with type 1 diabetes. This study compared semen profiles, sperm DNA fragmentation and levels of oxidative DNA modification in spermatozoa of diabetic and non-diabetic men. Semen samples from 12 non-diabetic, fertile men and 11 type 1 diabetics were obtained and subjected to conventional light microscopic semen analysis. Nuclear DNA fragmentation was assessed using an alkaline Comet assay and concentrations of 7,8-dihydro-8-oxo-2-deoxyguanosine (8-OHdG), an oxidative adduct of the purine guanosine, were assessed by high-performance liquid chromatography. Conventional semen profiles were similar in both groups, whilst spermatozoa from type 1 diabetics showed significantly higher levels of DNA fragmentation (44% versus 27%; P < 0.05) and concentrations of 8-OHdG (3.6 versus 2.0 molecules of 8-OHdG per 10(5) molecules of deoxyguanosine; P < 0.05). Furthermore, a positive correlation was observed between DNA fragmentation and concentrations of 8-OHdG per 10(5) molecules of deoxyguanosine (rs = 0.7, P < 0.05). The genomic damage evident in spermatozoa of type 1 diabetics may have important implications for their fertility and the outcome of pregnancies fathered by these individuals.


The fifth and sixth growth factor-like domains of thrombomodulin bind to the anion-binding exosite of thrombin and alter its specificity.
The domain of thrombomodulin that binds to the anion-binding exosite of thrombin was identified by comparing the binding of fragments of thrombomodulin to thrombin with that of Hirugen, a 12-residue peptide of hirudin that is known to bind to the anion-binding exosite of thrombin. Three soluble fragments of thrombomodulin, containing (i) the six repeated growth factor-like domains of thrombomodulin (GF1-6), (ii) one-half of the second through the sixth growth factor-like repeats (GF2.5-6), or (iii) the fifth and sixth such domains (GF5-6), were examined. Hirugen was a competitive inhibitor for either GF1-6 or GF2.5-6 stimulation of thrombin activation of protein C. GF5-6, which binds to thrombin without altering its ability to activate protein C, competed with fluorescein-labeled Hirugen for binding to thrombin. Therefore, all three thrombomodulin fragments, each of which lacked the chondroitin sulfate moiety, competed with Hirugen for binding to thrombin. To determine whether GF5-6 and Hirugen were binding to overlapping sites on thrombin or were interfering allosterically with each other's binding to thrombin, the effects of each thrombomodulin fragment and of Hirugen on the active site conformation of thrombin were compared using two different approaches: fluorescence-detected changes in the structure of the active site and the hydrolysis of chromogenic substrates. The GF5-6 and Hirugen peptides affected these measures of active site conformation very similarly, and hence GF5-6 and Hirugen contact residues on the surface of thrombin that allosterically alter the active site structure to a similar extent. Full-length thrombomodulin and GF1-6 alter the active site structure to comparable extents, but the amidolytic activity of thrombin complexed to thrombomodulin or GF1-6 differs significantly from that of thrombin complexed to GF5-6 or Hirugen. Taken together, these results indicate that the GF5-6 domain of thrombomodulin binds to the anion-binding exosite of thrombin. Furthermore, the binding of GF5-6 to the anion-binding exosite alters thrombin specificity, as evidenced by GF5-6-dependent changes in both the kcat and Km of synthetic substrate hydrolysis by thrombin. The contact sites on thrombin for the GF4 domain and the chondroitin sulfate moiety of thrombomodulin are still unknown.


Aminotransferases are associated with insulin resistance and atherosclerosis in rheumatoid arthritis.
Serum aminotransferase concentrations are reportedly strongly associated with insulin resistance, an established cardiovascular risk factor that is not routinely assessed in clinical practice. We therefore explored the possibility that serum aminotransferase concentrations are as closely related to large artery disease as insulin resistance in rheumatoid arthritis (RA). Carotid artery plaque (ultrasonography), insulin resistance and liver enzymes (prior to methotrexate (MTX) were determined in 77 consecutive patients with RA (43 with and 34 without MTX). Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were associated with insulin resistance in univariate analysis (R = 0.54, p < 0.0001 and R = 0.36, p = 0.001, respectively) and after adjustment for age, gender and waist circumference (partial R = 0.43, p = 0.0001 and partial R = 0.37, p = 0.001, respectively). ALT and AST concentrations were higher in patients with plaque as compared to in those without plaque (ALT (u/l): 27 2223242526272829303132 versus 20 181920212223, p = 0.02; AST (u/l): 25 2122232425262728 versus 20 19202122, p = 0.02). The odds ratios [95% CI] for plaque were 1.92 [1.14-3.24] (p = 0.01), 1.93 [1.17-3.16] (p = 0.009) and 1.82 [1.13-2.93] (p = 0.01) for 1 SD increase in ALT (~10 u/l) and AST (approximately 6 u/l) concentrations and in logarithmically transformed homeostasis model assessment of insulin resistance (HOMA-IR) (~0.2 uU.mmol/ml.l), respectively. After adjustment for the potentially confounding characteristics of age, sex, hypertension and hypothyroidism in logistic regression models, ALT (p = 0.049) and AST concentrations (p = 0.027) remained associated with plaque whereas the HOMA-IR did not (p = 0.08). AST concentrations (p = 0.049) were associated with plaque independent of insulin resistance whereas the HOMA-IR (p = 0.1) was not associated with plaque independent of AST concentrations. Within currently recommended reference ranges, serum aminotransferase concentrations may be strongly associated with insulin resistance and atherosclerosis in patients with RA. The measurement of aminotransferase concentrations could be a useful tool in cardiovascular risk stratification in patients with RA.


Dissipation, residue, stereoselectivity and dietary risk assessment of penthiopyrad and metabolite PAM on cucumber and tomato in greenhouse and field.
Penthiopyrad is a broad-spectrum fungicide with wide application in agriculture with preferential degradation of the S (+)-stereoisomer in soil. An understanding of the stereoselective fate of penthiopyrad is crucial for accurate food safety risk assessment. In this study, the dissipation, distribution, and dietary intake risk of penthiopyrad and its main metabolite (PAM) was conducted in cucumber and tomato samples under greenhouse and open field conditions. The half-lives of penthiopyrad in cucumber and tomato samples were < 8 days and the dissipation rates were higher in the open field than in the greenhouse. Due to the enantiomeric fraction data > 0.5, S (+)-stereoisomer dissipated slightly faster than R-(-)-stereoisomer. The residues of total penthiopyrad (sum of rac-penthiopyrad and PAM) were lower than the maximum residue limits in cucumber and tomato samples (risk quotients ≪ 100%). Therefore, the recommended penthiopyrad spraying method does not threaten vegetable cultivations and has negligible dietary intake risk.


Clinical response to thalidomide in the treatment of intracranial tuberculomas: case report.
We describe a patient with multiple intracranial tuberculomas resistant to standard care with antituberculosis drugs and corticosteroids who responded well to thalidomide. Adjunctive thalidomide may have a role in the management of refractory intracranial tuberculomas, although it should be used conservatively owing to its potential adverse events.


ZnO@ZnS nanorod-array coated titanium: Good to fibroblasts but bad to bacteria.
Cell-selective toxic titanium is highly desired in clinical dental practice. Herein, based on the in situ conversion of ZnO to ZnO@ZnS, nanorod-array structured coatings with a controllable release features of zinc (Zn), has been successfully fabricated by a two-step hydrothermal method to endow titanium surface with cell-selectivity, i.e. boosting the functions (attachment and migration) of human gingival fibroblasts (HGnFs) while acting against the invasion of pathogenic bacteria. The improved functions of HGnFs over the ZnO@ZnS nanorod-array were attributed to the material's optimized zinc release, which was decreased from an order of 3.5 mg L-1 to about 0.3 mg L-1 (within the first week). But more importantly, this concentration still had a high antibacterial efficacy up to 100% (against both the S. aureus and E. coli, 107 CFU mL-1). This study demonstrated that a ZnO@ZnS nanorod-array coating could be a promising strategy to endow titanium dental implants with improved soft tissue sealing and effectively reduce peri-implantitis.


Serum somatomedin and insulin levels in tumor hypoglycemia.
Serum concentrations of somatomedin and immunoreactive insulin were measured during the hypoglycemic phase of 3 patients with tumor hypoglycemia. Normal amounts of somatomedin were detected in their fasting sera, but they may have been inappropriate (or associated with enhanced insulin-like activity) considering the degree of hypoglycemia. Fasting serum insulin levels were consistently depressed, and in two of the cases remained low even after an oral glucose load. Nevertheless, the blood glucose concentrations of these two patients fell to hypoglycemic levels again by 3 hours; the mechanism of this reactive hypoglycemia remains unclear.


A parallel evaluation of 5 indirect cost-effective methods for assessing failure of passive immunity transfer in neonatal calves.
The aim of this study was to evaluate the diagnostic accuracy of 5 indirect methods that may be used in veterinary practices to assess the success of maternal immunoglobulins transfer in neonatal calves. Blood samples (n = 245) were collected from 2- to 6-d-old calves. Serum immunoglobulin concentrations were determined by radial immunodiffusion. Serum total protein and albumin concentrations and γ-glutamyl transferase activity were determined by veterinary practitioners using their own biochemistry analyzer. Globulin concentration was calculated. Veterinary practitioners were also asked to assess serum total protein using a digital Brix refractometer (%Brix) and an optical refractometer (g/L). Test sensitivity (Se) and specificity (Sp) were calculated using radial immunodiffusion as the reference standard, with failure of transfer of passive immunity defined as IgG <10.0 g/L. Receiver operating characteristics curves were created and optimal cutoff values for each of the 5 indirect measurement methods were selected based on the maximization of the Youden's J statistic. In this study, Globulin concentration yielded the highest accuracy to identify failure of transfer of passive immunity (Se = 89.4%; Sp = 89.3% at 34 g/L). For %Brix, the optimal combination of Se and Sp was at 8.4% Brix (Se = 86.5% and Sp = 83.8%). The use of an optical refractometer was associated with the lowest diagnostic accuracy (Se = 69.7% and Sp = 81.6% at 52 g/L). For γ-glutamyl transferase activity, the optimal cut-points were different for 2- to 3-d-old calves (Se = 87.5% and Sp = 87.8% at 393 IU/L) or 4- to 6-d-old calves (Se = 90.0% and Sp = 86.4% at 254 IU/L). Because it does not require any specialized laboratory equipment, digital Brix refractometer can be a valuable and inexpensive tool for on-farm use, to help producers and veterinary practitioners in their calf health management programs.


A Detailed Clinical Course Leading to Hypoxic Ischemic Encephalopathy After Anterior Cervical Spine Surgery: A Case Report.
A 48-year-old woman underwent anterior cervical discectomy and fusion at C5/6. Extubation was performed immediately after surgery. Tachycardia, limb tremor, and panic attack developed approximately 4 hours after surgery at 16:15. Thirty minutes later, cessation of respiration occurred at 16:50. An experienced anesthesiologist attempted intubation but was unsuccessful because of laryngopharyngeal edema at the C2 level. Finally, an otolaryngologist performed tracheotomy and secured the airway at 17:20 but hypoxic encephalopathy ensued. Predicting the airway obstruction caused by laryngopharyngeal edema was very difficult; hence, to prevent critical complications, systematic perioperative management is essential in anterior cervical spine surgery.


Malic dehydrogenase isoenzymatic pattern in lung-nematode parasite species.
The malic dehydrogenase (MDH) isoenzymatic pattern of Dictyocaulus viviparus, Protostrongylus rufescens, and Slovakian and Spanish isolates of D. filaria was studied. The MDH isoenzymatic pattern in both isolates of D. filaria was characterized by the presence of three phenotypes: (1) a single, slow anodic band; (2) a single, fast anodic band; and (3) a large spot matching its migration with bands 1 and 2. These three phenotypes may be explained as the existence of only one gene locus for the MDH in D. filaria. Allelic frequencies and the Hardy-Weinberg test were determined for Slovakian and Spanish isolates of D. filaria. This test indicated that the population was not in Hardy-Weinberg equilibrium. The MDH isoenzymatic pattern of D. viviparus displayed the same phenotypes 1 and 2 observed in D. filaria. Furthermore, the MDH isoenzymatic pattern of P. rufescens was characterized by the presence of two bands with anodic and cathodic migration. The isoenzyme with anodic migration appeared more intensively stained than did that with cathodic migration. This last isoenzyme was not observed when the samples had been stored for 1 month.


Hypercalcemic-type of small cell carcinoma of the ovary: characterization of a new tumor line.
The aim of this study was to develop and characterize a mouse xenograft model for the hypercalcemic-type of small cell carcinoma of the ovary (HTSCCO). Tumor fragments were removed from a patient and cultured in six subsequent generations of nude mice. Histology, comparative genomic hybridization (CGH), electron microscopy and serum calcium levels were investigated. Morphology remained the same from the primary tumor of the patient through the 6th passage in the mouse. Serum calcium levels were significantly higher in the tumor-bearing mice compared to controls. CGH of the HTSCCO did not show evidence of a close relationship to either a germ cell tumor or an epithelial ovarian cancer. Some evidence was provided that the HTSCCO is an inhomogeneous tumor that is neither related to a germ cell tumor nor to an epithelial ovarian cancer, but is a distinct tumor entity.


The carotid web: a developmental anomaly of the brachiocephalic system.
A case of a congenital carotid web is reported. This lesion is believed to be a very rare anomaly of carotid development. The embryologic development of the brachiocephalic arteries is discussed. Anomalies of the brachiocephalic arteries including anomalies of origin from the aortic arch, atresia, and persistent communications between the carotid and vertebral system are reviewed.


A case of trisomy 22 with a probable Robertsonian translocation 21/22.
A 2-year-old girl with a prabable trisomy-22 translocation is described. The principal clinical symptoms described by the authors who have reported cases with proved trisomy 22 are presented. A probable 46,XX,-21,+t(21q;22q) karyotype was established in the patient. The proband's clinical picture is compared with other trisomy 22 cases described in the literature. The incidence of this trisomy among the human population is discussed.


Effects of aging on asynchronous left ventricular regional function and global ventricular filling in normal human subjects.
In many patients with coronary artery disease or hypertrophic cardiomyopathy, reduced left ventricular rapid diastolic filling is related to asynchronous left ventricular regional diastolic function. Because left ventricular filling also declines with aging in normal subjects, in this study the influence of regional ventricular diastolic asynchrony on global ventricular filling as a function of age was investigated in 66 normal volunteers aged 19 to 77 years (mean 42) by radionuclide angiography. No subject had systemic hypertension or left ventricular hypertrophy. Indexes of left ventricular systolic function at rest did not vary with age, but rapid diastolic filling significantly declined with age: peak filling rate decreased (r = 0.69), time to peak filling rate increased (r = 0.53) and magnitude of rapid filling (% of left ventricular end-diastolic volume) decreased (r = 0.76) with aging. Left ventricular synchrony was assessed from regional volume curves derived by dividing the global ventricular region of interest into four quadrants. Indexes of systolic synchrony were unaffected by age, but regional variation in time to peak filling rate, an index of diastolic asynchrony, increased with aging (r = 0.51, p less than 0.001). Moreover, variation in time to peak filling rate correlated with global peak filling rate and magnitude of rapid filling (r = 0.48 and 0.54, p less than 0.001 for both). Multivariate analysis indicated that these effects were independent of age-related changes in blood pressure. Thus, aging alters left ventricular diastolic function, with reduced rate and extent of the rapid filling phase related to increased regional diastolic asynchrony.(ABSTRACT TRUNCATED AT 250 WORDS)


A comparative trial of three treatment schedules for the eradication of scabies.
A trial of three treatment schedules, consisting of 1% gamma benzene hexachloride (GBH) lotion applied head to toe and left on the body for 2, 6, or 12 to 24 hours was conducted on an island of 2,076 persons, approximately 70% of whom had clinical evidence of scabies. The island is situated off the north coast of the Republic of Panama. Examination at 1 month after therapy showed that both the 6-hour and 12- to 24-hour cure rate was high (96% and 98%). There was a significantly lower cure rate in the 2-hour group, in which only 82% were cured. Eleven to twelve percent of the subjects became infested in all groups, presumably due to contact with untreated persons with scabies on the island. A single 6-hour application of 1% GBH lotion appears to be adequate therapy for scabies if properly applied. The entire population at risk should be treated at the same time if possible to reduce or eliminate the risk of infestation. No adverse reactions to 1% GBH lotion were observed.


Effect of sodium tanshinone IIA sulfonate in the rabbit myocardium and on human cardiomyocytes and vascular endothelial cells.
Sodium tanshinone IIA sulfonate (STS) is a derivative of tanshinone IIA. The latter is a pharmacologically active component isolated from the rhizome of the Chinese herb Salvia miltiorrhiza. Liquid chromatographically pure STS was found to reduce myocardial infarct size by 53.14 +/- 22.79% relative to that in the saline control in a rabbit 1 hr-ischemia and 3 hr-reperfusion model. This effect was comparable to that of Trolox (a better characterized antioxidant serving as a reference cytoprotector), which salvaged the myocardium in the same infarct model by 62.13 +/- 18.91%. Also, like Trolox, STS did not inhibit oxygen uptake by xanthine oxidase (XO), a key enzyme in free radical generation. However, in contrast to Trolox, STS significantly prolonged the survival of cultured human saphenous vein endothelial cells but not human ventricular myocytes in vitro when these cells were separately exposed to XO-generated oxyradicals. Note that the endothelium is recognized to be a key site of oxidant generation and attack. Our findings in vitro and in vivo support the interpretation that STS is a cardioprotective substance, and that it may exert a beneficial effect on the clinically important vascular endothelium.


Hematopoietic stem cell transplantation after reduced-intensity conditioning as treatment of sickle cell disease.
Sickle cell disease generates considerable morbidity and mortality. Allogeneic hematopoietic stem cell transplantation (SCT) has the potential of curing the disease and halting end-organ damage. However, in older patients this treatment is associated with a significant risk of toxicity and death. SCT after reduced-intensity conditioning (RIC) might be a safer approach for the treatment of sickle cell disease. A 22-year-old male had experienced multiple, life-threatening hemolytic crises. We treated him with G-CSF-mobilized stem cells from his heterozygote, human leukocyte antigen-matched brother after RIC with fludarabine and cyclophosphamide. GVHD prophylaxis consisted of cyclosporine (CyA) and mycophenolate mofetil (MMF). Chimerism of peripheral blood mononuclear cells was evaluated using short tandem repeat analysis and hemoglobin analysis was performed by high-performance liquid chromatography. There were no major treatment-related toxicities. At day +30 after transplantation the patient had mixed hematopoietic chimerism, which later converted to full chimerism. Hemoglobin analysis revealed 3.4% HbA(2), 1.0% HbF, and 41.2% HbS, which essentially is the same hemoglobin partition as in his brother's blood. MMF was discontinued on day +35 and CyA on day +120. After discontinuation of CyA the patient developed mild chronic GVHD, which resolved with continued CyA, low-dose steroids, and the retinoid isotretinoin. He is doing well on day +315 without evidence of GVHD. Allogeneic SCT after RIC is feasible in adult patients with sickle cell disease. Mixed chimerism is sufficient to relieve disease-related symptoms and is possibly correlated with less acute GVHD.


[Intravenous proton-pump inhibitor for acute peptic ulcer bleeding--is profound acid suppression beneficial to reduce the risk of rebleeding?].
To compare two regimens of pantoprazole administered intravenously in patients with ulcerative gastrointestinal bleeding (UGB), and a high risk of presenting with persitent or recurrent hemorrhage. Patients were randomized into two groups: group 0--treatment with a 80 mg bolus of pantoprazole administered intravenously, followed by continuous infusion of 8 mg/h for 72 hours; group 1--treatment with 40 mg of pantoprazole administered intravenously on a daily basis. The percentage of hemorrhagic persistence/recurrence in both groups was analyzed, as were transfusion requirements, need for surgery, and mortality resulting from the hemorrhagic episode. There were 20 patients in group 0 and 21 in group 1. No differences were found between groups in terms of gender, age, smoking habits, use of NSAIDs, presence of hemodynamic instability or stigmata in ulcer crater (Forrest Ia: 5 vs. 14.3%, p = 0.322; Forrest Ib: 30 vs. 33.3%, p = 0.819; Forrest IIa: 60 vs. 50.1%, p = 0.753). In group 0, 90% of patients received endoscopic treatment, versus 100% in group 1, p = 0.232. In group 0, 50% of patients had a transfusion, as compared to 52.4% in group 1, p = 0.879. In group 0, 2 patients (10.5%) presented with recurrent hemorrhage, versus 3 patients (14.3%) in group 1. Surgery was required by 1 person from each group, and 1 patient in group 0 died. Maximum acid inhibition with a bolus and then a continuous infusion of pantoprazole does not yield better results than treatment with conventional doses in acute hemorrhagic episodes.


Microbial biotechnology approaches for conversion of pineapple waste in to emerging source of healthy food for sustainable environment.
One of the most significant and difficult jobs in food sustainability, is to make use of waste in the vegetable and fruit processing sectors. The discarded fruits along with their waste materials, is anticipated to have potential use for further industrial purposes via extraction of functional ingredients, extraction of bioactive components, fermentation. As a result of its abundant availability, simplicity and safe handling, and biodegradability, pineapple waste is now the subject of extensive research. It is regarded as a resource for economic development. This vast agro-industrial waste is being investigated as a low-cost raw material to produce a variety of high-value-added goods. Researchers have concentrated on the exploitation of pineapple waste, particularly for the extraction of prebiotic oligosaccharides as well as bromelain enzyme, and as a low-cost source of fibre, biogas, organic acids, phenolic antioxidants, and ethanol. Thus, this review emphasizes on pineapple waste valorisation approaches, extraction of bioactive and functional ingredients together with the advantages of pineapple waste to be used in many areas. From the socioeconomic perspective, pineapple waste can be a new raw material source to the industries and may potentially replace the current expensive and non-renewable sources. This review summarizes various approaches used for pineapple waste processing along with several important value-added products gained which could contribute towards healthy food and a sustainable environment.


Dose-response relationships between exercise intensity, cravings, and inhibitory control in methamphetamine dependence: An ERPs study.
The present study integrated behavioral and neuroelectric approaches for determining the dose-response relationships between exercise intensity and methamphetamine (MA) craving and between exercise intensity and inhibitory control in individuals with MA dependence. Ninety-two individuals with MA dependence were randomly assigned to an exercise group (light, moderate, or vigorous intensity) or to a reading control group. The participants then completed a craving self-report at four time points: before exercise, during exercise, immediately after exercise, and 50 min after exercise. Event-related potentials were also recorded while the participants completed a standard Go/NoGo task and an MA-related Go/NoGo task approximately 20 min after exercise cessation. The reduction in self-reported MA craving scores of the moderate and vigorous intensity groups was greater than that of the light intensity and control groups during acute exercise as well as immediately and 50 min following exercise termination. Additionally, an inverted-U-shaped relationship between exercise intensity and inhibitory control was generally observed for the behavioral and neuroelectric indices, with the moderate intensity group exhibiting shorter Go reaction times, increased NoGo accuracy, and larger NoGo-N2 amplitudes. Acute exercise may provide benefits for MA-associated craving and inhibitory control in MA-dependent individuals, as revealed by behavioral and neuroelectric measures. Moderate-intensity exercise may be associated with more positive effects, providing preliminary evidence for the establishment of an exercise prescription regarding intensity for MA dependence.


Effects of lower limb segmental muscle vibration on primary motor cortex short-latency intracortical inhibition and spinal excitability in healthy humans.
We examined the effects of lower limb segmental muscle vibration (SMV) on intracortical and spinal excitability in 13 healthy participants (mean age: 34.9 ± 7.8 years, 12 males, 1 female). SMV at 30 Hz was applied to the hamstrings, gastrocnemius, and soleus muscles for 5 min. Paired-pulse transcranial magnetic stimulation protocols were used to investigate motor-evoked potential (MEP) amplitude, short-interval intracortical inhibition (SICI) and short-interval intracortical facilitation (SICF) from the abductor hallucis muscle (AbdH). These assessments were compared to the results of a control experiment (i.e., non-vibration) in the same participants. F-waves were evaluated from the AbdH on the right (vibration side) and left (non-vibration side) sides, and we calculated the ratio of the F-wave amplitude to the M-response amplitude (F/M ratio). These assessments were obtained before, immediately after, and 10, 20, and 30 min after SMV. For SICI, there was no change immediately after SMV, but there was a decrease over time (before vs. 30 min after, p = 0.021; immediately after vs. 30 min after, p = 0.015). There were no changes in test MEP amplitude, SICF, or the F/M ratio. SMV causes a gradual decrease in SICI over time perhaps owing to long-term potentiation. The present results may have implications for the treatment of spasticity.


[Bortezomib (Velcade) in relapsed/refractory multiple myeloma--the first experience in the Czech Republic].
Multiple myeloma is the second most prevalent and mostly fatal hematologic cancer. Further advances have been made in understanding the mechanisms involved in the myeloma pathogenesis and elucidation of critical signalling pathways as therapeutical targets. Proteasome inhibitors are the example of this new approach and bortezomib is the first agent in this class to enter clinical trials. In 6 hematological centers in Czech Republic 29 patients with refractory/relapsed myeloma had been treated with bortezomib (Velcade, Millennium Pharmaceuticals) in 2004. The initial dose 1.3 mg/m2 of Velcade was given, in 1 case the dose was adjusted due to pre-existing renal failure to 1 mg/m2. The response was achieved in 17 patients (59%). Four patients had complete, 11 partial and two minor responses. In 5 cases stabilization of disease was observed and 6 patients progressed during the therapy. Unfortunately, one patient died immediately after the start of therapy due to sepsis. The most common adverse events were thrombocytopenia, anaemia, neuropathy, gastrointestinal complication, renal failure and fatigue. Grade 4 adverse events occurred in 37.9% of patients (4x thrombocytopenia, 2x gastrointestinal, 2x renal failure, 1x sepsis, leucopenia, hepatopathy and anaemia, respectively). Peripheral neuropathic pain of grade 3 was reported in 4 cases, in one patient therapy had to be interrupted due to this complication. We confirmed promising results of phase II trials.


[Covid-19, impacts on the mental health of people suffering from anxiety and depression].
The Covid-19 pandemic and the resulting health protection measures have had repercussions on the mental health of the population, particularly for people already made vulnerable by mental illness. This study describes the psychological impact of the health crisis on 85 patients suffering mainly from anxiety-depressive disorders. A retrospective analysis reveals that some patients felt their mood deteriorated during the lockdown. An increase in anxiety and depression, sleep disorders and addiction issues was observed. Recommendations could be envisaged for these patients in the event of a new epidemic episode.


Continuity of Care in Swiss Cancer Patients Using Claims Data.
Continuity of care is positively associated with beneficial patient outcomes. Data on the level of continuity of care in the ambulatory setting in Switzerland are lacking. The aim of this study was to evaluate continuity of care in Swiss cancer patients based on routine data of mandatory health insurance using four established continuity scales. Retrospective analysis of Swiss claims data (N=23'515 patients with incident use of antineoplastics). The Usual Provider Continuity score, the Modified Modified Continuity Index, the Continuity of Care index, and the Sequential Continuity Index were analyzed based on consultations with general practitioners (GPs), physician specialists and ambulatory hospital wards. Using information of health insurance claims, the number of consultations and the general level of continuity of care in Swiss cancer patients are high. Continuity of care scores were significantly associated with sociodemographic and regional factors. When focusing on consultations with GPs only, all four scores consistently showed high values indicating high levels of continuity. Continuity with general practitioners was associated with lower costs and lower risks for hospitalization and death. This is the first study giving insight into continuity of care in Swiss cancer patients. The present study shows that continuity of care is measurable using health insurance claims data. It indicates that continuity with general practitioners is associated with a beneficial outcome.


Instruments for microbial identification.
Microbiology instruments can provide rapid and accurate identification of gram-negative bacilli. The three instruments currently in widespread use vary in accuracy of identification, types of organisms identified, speed of identification, cost, and degree of automation. If matched to the needs of individual laboratories, microbiology instruments can enhance the quality and efficiency of bacterial identification.


Study of the kinetics of oxidation of monophenols by tyrosinase. The effect of reducers.
Kinetics of oxidation of monophenols by tyrosinase from the fungus Aspergillus flavipes 56003 and the effect of Fe2+, serine, and ascorbic acid on this reaction were studied. The effectors were shown to accelerate the oxidation of monophenols, decreasing the lag-time of the reaction. It is assumed that the activation of the tyrosinase in the presence of Fe2+ is due to a direct reduction of the active site copper ions. Serine and ascorbic acid are supposed to affect the reaction of quinone transformation. The activation of the enzyme in the presence of Fe2+ suggests that the oxidation of monophenols is an autocatalytic process.


Increasing medium chain fatty acids production in Yarrowia lipolytica by metabolic engineering.
Oleaginous yeast Yarrowia lipolytica is an organism of choice for the development of biofuel and oleochemicals. It has become a chassis for metabolic engineering in order to produce targeted lipids. Understanding the function of key-enzymes involved in lipid metabolism is essential to design better routes for enhanced lipid production and for strains producing lipids of interest. Because medium chain fatty acids (MCFA) are valuable compounds for biokerosene production, we previously generated strains capable of producing MCFA up to 12% of total lipid content (Rigouin et al. in ACS Synth Biol 6:1870-1879, 2017). In order to improve accumulation and content of C14 fatty acid (FA), the elongation, degradation and accumulation of these MCFA in Yarrowia lipolytica were studied. We brought evidence of the role of YALI0F0654 (YlELO1) protein in the elongation of exogenous or de novo synthesized C14 FA into C16 FA and C18 FA. YlELO1 deletion into a αFAS_I1220W expressing strain leads to the sole production of C14 FA. However, because this strain does not provide the FA essential for its growth, it requires being cultivated with essential fatty acids and C14 FA yield is limited. To promote MCFA accumulation in Y. lipolytica without compromising the growth, we overexpressed a plant diglyceride acyltransferase specific for MCFA and reached an accumulation of MCFA up to 45% of total lipid content. We characterized the role of YlELO1 in Y. lipolytica by proving its involvement in Medium chain fatty acids elongation. We showed that MCFA content can be increased in Yarrowia lipolytica by promoting their accumulation into a stable storage form (triacylglycerides) to limit their elongation and their degradation.


Efficacy and safety of dupilumab with concomitant topical corticosteroids in children 6 to 11 years old with severe atopic dermatitis: A randomized, double-blinded, placebo-controlled phase 3 trial.
Children with severe atopic dermatitis (AD) have limited treatment options. We report the efficacy and safety of dupilumab + topical corticosteroids (TCS) in children aged 6-11 years with severe AD inadequately controlled with topical therapies. In this double-blind, 16-week, phase 3 trial (NCT03345914), 367 patients were randomized 1:1:1 to 300 mg dupilumab every 4 weeks (300 mg q4w), a weight-based regimen of dupilumab every 2 weeks (100 mg q2w, baseline weight <30 kg; 200 mg q2w, baseline weight ≥30 kg), or placebo; with concomitant medium-potency TCS. Both the q4w and q2w dupilumab + TCS regimens resulted in clinically meaningful and statistically significant improvement in signs, symptoms, and quality of life (QOL) versus placebo + TCS in all prespecified endpoints. For q4w, q2w, and placebo, 32.8%, 29.5%, and 11.4% of patients, respectively, achieved Investigator's Global Assessment scores of 0 or 1; 69.7%, 67.2%, and 26.8% achieved ≥75% improvement in Eczema Area and Severity Index scores; and 50.8%, 58.3%, and 12.3% achieved ≥4-point reduction in worst itch score. Response to therapy was weight-dependent: optimal dupilumab doses for efficacy and safety were 300 mg q4w in children <30 kg and 200 mg q2w in children ≥30 kg. Conjunctivitis and injection-site reactions were more common with dupilumab + TCS than with placebo + TCS. Short-term 16-week treatment period; severe AD only. Dupilumab + TCS is efficacious and well tolerated in children with severe AD, significantly improving signs, symptoms, and QOL.


Regulation of HGF-mediated cell proliferation and invasion through NF-κB, JunB, and MMP-9 cascades in stomach cancer cells.
Blocking of activator protein-1 activity leads to suppression of growth factor-induced transformation. However, the role of individual components of the Jun family in this process is unclear. Over-expression of JunB has been reported to be associated with neoplastic transformation and regulation of Matrix metalloproteinase-9 (MMP-9) expression. Using cDNA microarray, we found that JunB might be one of target genes up-regulated by hepatocyte growth factor (HGF). Therefore, we tried to investigate the role of JunB in HGF-medicated cell proliferation and cell invasion in human gastric cancer cells, NUGC3 and MKN28. We verified that HGF increased JunB in time and dose-dependent manners. The JunB levels were decreased by the treatment with an NF-κB inhibitor, pyrrolidine dithiocarbamate. Down-regulation of JunB by transfecting cells with JunB-short hairpin RNAs (shRNA) inhibited MMP-9 up-regulation induced by HGF. Furthermore, transfection with JunB-shRNA repressed HGF-mediated increases in cell proliferation and cell invasion. These data suggest that JunB might be regulated through an NF-κB pathway and up-regulation of JunB induced by HGF might play an important role in the regulation of cell proliferation and cell invasion through MMP-9 expression. In conclusion, these results may contribute to the JunB-associated malignant phenotype of gastric cancers by regulating MMP-9, and serve as a novel therapeutic target for stomach cancer therapy in the future.


Epidemiological Surveillance of Viral Hemorrhagic Fevers With Emphasis on Clinical Virology.
This article will outline surveillance approaches for viral hemorrhagic fevers. Specific methods for surveillance of clinical samples will be emphasized. Separate articles will describe methods for surveillance of rodent-borne viruses (roboviruses) and arthropod-borne viruses (arboviruses). Since the appearance of hantaviruses and arenaviruses in the Americas, more than 30 different species in each group have been established, and therefore they have become the most frequently emerging viruses. Flaviviruses such as yellow fever and dengue viruses, although easier to recognize, are also more widely spread and therefore considered a very important public health issue, particularly for under-developed countries. On the other hand, marburgviruses and ebolaviruses, previously thought to be restricted to the African continent, have recently been shown to be more global. For many of these agents virus isolation has been a challenging task: trapping the specific vectors (mosquitoes and ticks), and reservoirs (rodents and bats), or obtaining the samples from suspected clinical human cases demands special protective gear, uncommon devices (respirators), special facilities (BSL-3 and 4), and particular skills to recognize the slow and inapparent cytopathic effects in cell culture. Alternatively, serological and molecular approaches have been very helpful in discovering and describing newly emerging viruses in many areas where the previous resources are unavailable. Unfortunately, in many cases, detailed studies have been performed only after outbreaks occur, and then active surveillance is needed to prevent viral dissemination in human populations.


CCL5 and cytokine expression in the rat brain: differential modulation by chronic morphine and morphine withdrawal.
Opioids have been shown to influence the immune system and to promote the expression of pro-inflammatory cytokines in the central nervous system. However, recent data have shown that activation of opioid receptors increases the expression and release of the neuroprotective chemokine CCL5 from astrocytes in vitro. To further define the interaction between CCL5 and inflammation in response to opioids, we have examined the effect of chronic morphine and morphine withdrawal on the in vivo expression of CCL5 as well as of pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Rats undergoing a chronic morphine paradigm (10 mg/kg increasing to 30 mg/kg, twice a day for 5 days) showed a twofold increase of CCL5 protein and mRNA within the cortex and striatum. No changes were observed in the levels of IL-1β and TNF-α. Naltrexone blocked the effect of morphine. A chronic morphine paradigm with no escalating doses (10 mg/kg, twice a day) did not alter CCL5 levels compared to saline-treated animals. On the contrary, rats undergoing spontaneous morphine withdrawal exhibited lower levels of CCL5 within the cortex as well as increased levels of pro-inflammatory cytokines and Iba-1 positive cells than saline-treated rats. Overall, these data suggest that morphine withdrawal may promote cytokines and other inflammatory responses that have the potential of exacerbating neuronal damage.


EndoPil: A Magnetically Actuated Swallowable Capsule for Weight Management: Development and Trials.
Intragastric balloons (IGBs), by occupying the stomach space and prolonging satiety, is a promising method to treat obesity and consequently improves its associated comorbidities, e.g. coronary heart disease, diabetes, and cancer. However, existing IGBs are often tethered with tubes for gas or liquid delivery or require endoscopic assistance for device delivery or removal, which are usually uncomfortable, costly, and may cause complications. This paper presents a novel tetherless, magnetically actuated capsule (EndoPil) which can deploy an IGB inside the stomach after being swallowed and being activated by an external magnet. The external magnet attracts a small magnet inside the EndoPil to open a valve, triggering the chemical reaction of citric acid and potassium bicarbonate to produce carbon dioxide gas, which inflates a biocompatible balloon (around 120 mL). A prototype, 13 mm in diameter and 35 mm in length, was developed. Simulations and bench-top tests were conducted to test the force capability of the magnetic actuation mechanism, the required force to activate the valve, and the repeatability of balloon inflation. Experiments on animal and human were successfully conducted to demonstrate the safety and feasibility of inflating a balloon inside the stomach by an external magnet.


Nucleotide sequence analysis of the structural genes for Shiga-like toxin I encoded by bacteriophage 933J from Escherichia coli.
A nucleotide sequence analysis was performed on the Shiga-like toxin I genes previously cloned from the Escherichia coli bacteriophage 933J. Two structural genes designated slt-I A and slt-I B were found to be oriented on a single transcriptional unit with slt-I A preceding slt-I B. A 12 base pair gap separated the in-phase open reading frames of slt-I A and slt-I B. Putative ribosome binding sites were identified 5' to both the slt-I A and slt-I B genes. Translation of the SLT-I nucleotide sequence revealed that both the A and B subunits were synthesized with signal peptides. The molecular weight calculated for the mature A subunit was 32,211 while the molecular weight of the mature B subunit was 7690.


[Preliminary clinical investigation of coblation-assisted functional endoscopic sinus surgery for chronic sinusitis and nasal polyps].
To explore the clinical efficacy of coblation-assisted FESS (CAFESS) by observing the patients intraoperatively and postoperatively. Thirty patients with chronic sinusitis or/and with nasal polyps were selected. The subjective symptoms and objective changes were observed 6 to 9 months after CAFESS. The sense of nasal congestion, headache and face pain, purulent rhinorrhea, postnasal drip, and other symptoms were relieved. The scores of SNOT-20 reduced from preoperative (22.53 +/- 6.26) to (7.80 +/- 3.63) 6 months postoperatively, and the difference was statistically significant (t = 16.741, P < 0.05). The scores of Lund-Kennedy decreased from (4.30 +/- 1.15) preoperatively to (1.17 +/- 0.83) 6 months postoperatively, and the difference was statistically significant (t = 19.947, P < 0.05). The observation under endoscope illustrated that epithelization commenced at 6w postoperatively and completed until 12 week after CAFESS. CAFESS is a new technique for treatment of chronic sinusitis and nasal polyps, and postoperative clinical results were satisfactory. It's a good method for the treatment of chronic sinusitis and nasal polyps.


Hepatic kinetics of SCP-1 (N-[alpha-(1,2-benzisothiazol-3(2H)-ona-1, 1-dioxide-2-yl)-acetyl]-p-aminophenol) compared with acetaminophen in isolated rat liver.
The hepatic disposition of a new analgesic, SCP-1, a derivative of acetaminophen, was studied in the isolated perfused rat liver using a recirculating system. The aim of this study was to compare the kinetic parameters of this molecule with those of acetaminophen. Sprague-Dawley rat (230-330 g) livers were perfused for 2 h with 250 ml Krebs-Henseleit bicarbonate buffer containing SCP-1 or acetaminophen, 0.07 mmol l(-1) (n=4), 0.28 mmol l(-1) (n=4), and 0.8 mmol l(-1) (n=4) (approximately one, four and ten times the therapeutic doses in man, respectively). Perfusate samples were collected from the efflux at various times. The SCP-1 and acetaminophen perfusate concentrations were assayed by a HPLC method. Pharmacokinetic analysis was carried out using a computer program. There were significant differences between the hepatic kinetics of SCP-1 and those of acetaminophen. Thus, SCP-1 elimination half-life (mean 14.8+/-10.0 min) was shorter than that of the acetaminophen (186.1+/-27.7 min) (t=11.6, P=0.0001). While the half-life of SCP-1 increases with concentration, the half-life of acetaminophen remains constant as the concentration increases. The hepatic clearance was higher for SCP-1 than acetaminophen (mean 19.01+/-14.5 ml min(-1) vs. 1.29+/-0.08 ml min(-1), respectively) (t=2.44, P<0.05), and it behaved according to dose-dependent kinetics. The SCP-1 extraction ratio was higher (mean 0.63+/-0.49) than for acetaminophen (0.04+/-0.01) (t=2.41, P<0.05) and this parameter tended to decrease as the perfusate concentrations of SCP-1 increased. It was concluded that the hepatic kinetics of SCP-1 behaved according to dose-dependent kinetics, and statistically significant differences were found between pharmacokinetics parameters of both drugs studied.


The reproducibility of cardiac and liver T2* measurement in thalassemia major using two different software packages.
In b-thalassemia major (TM) multiple blood transfusions are needed for survival. As a consequence these patients present iron overload in different organs, including heart and liver. Magnetic resonance imaging using a bright blood gradient echo sequence has been successfully used for the quantification of tissue iron. The aim is to evaluate of the accuracy and precision in the evaluation of liver and myocardial T2* values in TM using two different analytical software solutions. Thirty TM patients aged 20-56 years (mean age 37, 11M/19F) were scanned in a GE 1.5 T CVI system. Each scan included the measurement of heart and liver T2* and the left ventricular ejection fraction using standard techniques. The analysis of T2* of heart and liver was done using the two different analytical software solutions: the "Functool" protocol by GE and the T2* module of QMassMR v7.4 by Medis medical imaging systems bv, Leiden, The Netherlands. The cardiac and liver T2* measurements showed that both software solutions allow reproducible measurements with low intra-observer variations (accuracy < 0.3 ms, precision < 2 ms). There is a small but significant difference between the two solutions of 2.4 ms in cardiac and of 1.5 ms in liver measurements. However, from the clinical point of view these differences (<2 ms) are small with negligible impact on the patient's treatment management. The comparison of the T2* measurements using the two analytical software solutions proved that both techniques enable reproducible measurements for the evaluation of iron overload in heart and liver.


Can a biologic mesh survive a Candida krusei infection? A case report of infection of a biologic mesh following repair of abdominal wall hernia.
The use of biologic mesh, which is considered resistant to infection, has become common. It is preferred over synthetic mesh for use in contaminated fields. Fungal infection with infiltration of biologic mesh is rare and has not been reported. In this paper, we report a case of a patient who underwent multiple laparotomies and received multiple antibiotics and an azole antifungal. Biologic mesh was used, but it ultimately required removal because of chronic infection with Candida krusei. On biopsy, the yeast was found to have infiltrated the mesh.


Poor diagnostic value of colonic CD44v6 expression and serum concentrations of its soluble form in the differentiation of ulcerative colitis from Crohn's disease.
Increased expression of CD44v6 on colonic crypt epithelial cells in ulcerative colitis has been suggested as a diagnostic tool to distinguish ulcerative colitis from colonic Crohn's disease. To investigate colonic CD44v6 expression and serum concentrations of soluble CD44v6 (sCD44v6) in patients with ulcerative colitis and Crohn's disease. Colonic biopsy samples were obtained from 16 patients with ulcerative colitis, 13 with ileocolonic Crohn's disease, and 10 undergoing polypectomy. Serum samples were obtained from 15 patients with active ulcerative colitis, 20 with active Crohn's disease, and 20 healthy donors. Colonic CD44v6 expression was evaluated immunohistochemically by monoclonal antibody 2F10 and the higher affinity monoclonal antibody VFF18. Serum sCD44v6 concentrations were measured by ELISA. 2F10 stained colonic epithelium of inflamed ulcerative colitis and Crohn's disease samples in 80% and 40% of cases, respectively, and VFF18 in 95% and 87%, respectively. Both monoclonal antibodies displayed a sensitivity and specificity of 60% and 87% to differentiate ulcerative colitis from colonic Crohn's disease. Serum concentrations of sCD44v6 were lower in patients with ulcerative colitis (median 153 ng/ml; interquartile range (IQR) 122-211) compared with Crohn's disease (219; IQR 180-243) and healthy donors (221; IQR 197-241 (p = 0.002)). Its sensitivity and specificity to discriminate ulcerative colitis from Crohn's disease was 75% and 71%, respectively. Colonic CD44v6 and serum sCD44v6 concentrations do not facilitate reliable differential diagnosis between ulcerative colitis and Crohn's disease.


A Statewide Analysis of Self-Inflicted Injuries During COVID-19 Pandemic: Is There Adequate Access to Mental Health?
Many social and behavioral changes occurred during the COVID-19 pandemic. Our objective was to identify changes in incidence of self-inflicted injuries during COVID-19 compared to prepandemic years. Further, we aimed to identify risk factors associated with self-inflicted injuries before and during the pandemic. A retrospective cohort study of patients aged ≥18 y with self-inflicted injuries from 2018 to 2021 was performed using the Pennsylvania Trauma Outcome Study registry. Patients were grouped into pre-COVID Era (pre-CE, 2018-2019) and COVID Era (CE, 2020-2021). Statistical comparisons were accomplished using Wilcoxon rank-sum tests and chi-square or Fisher's exact tests. There were a total of 1075 self-inflicted injuries in the pre-CE cohort and 482 during the CE. There were no differences in age, gender, race or ethnicity between the two cohorts. Among preexisting conditions, those within the pre-CE cohort had a higher incidence of mental/personality disorder (59.2% versus 52.3%, P = 0.01). There were no significant differences in the mechanism of self-inflicted injuries or place of injury between the two periods. Additionally, there were no differences in discharge destinations or mortality between the two cohorts. During the height of social isolation in Pennsylvania, there were no associated increases in self-inflicted injuries. However, there were increased incidences of self-inflicted injuries among those with a prior diagnosis of mental or personality disorder in the pre-CE group. Further investigations are required to study the access to mental health services in future pandemics or public health disasters.


Unplanned hospital readmissions after kidney transplantation among patients in Hefei, China: Incidence, causes and risk factors.
Unplanned readmissions severely affect a patient's physical and mental well-being after kidney transplantation (KT), which is also independently associated with morbidity. A retrospective study was conducted to identify the incidence, causes and risk factors for unplanned readmission after KT among Chinese patients. Patients who underwent KT were admitted to the organ transplant center of the Affiliated Hospital of University of Science and Technology of China (2017-2018). Medical records for these patients were obtained through the hospital information system (HIS). In 518 patients, the incidence of unplanned readmissions within 30 days (n = 9) was 1.74%, and 90 days (n = 64) was 12.35%. The one-year unplanned readmission rate was 22.59% (n = 122). Overall, 122 patients were readmitted because of infection, renal events, metabolic disturbances, surgical complications, etc. Hemodialysis (OR = 10.462, 95% CI: 1.355-80.748), peritoneal dialysis (OR = 8.746, 95% CI: 1.074-71.238) and length of stay (OR = 1.023, 95% CI: 1.006-1.040) were independent risk factors for unplanned readmissions. Unplanned readmission rates increased with time after KT. Certain risk factors related to unplanned readmissions should be deeply excavated. Targeted interventions for controllable factors to alleviate the rate of unplanned readmissions should be identified.


Predictive value of serum CRH/5-HT ratio for postpartum depression.
To analyze the changes in the serum levels of CRH and 5-HT in women with postpartum depression (PPD) and to study the value of the CRH/5-HT ratio for the prediction of PPD. This prospective study recruited pregnant women from the Fourth Affiliated Hospital, China Medical University between January 2017 and October 2019. Women were considered for inclusion if they had no history, or no current evidence, of a psychiatric disorder. All women were assessed at postpartum day 10 with the Edinburgh Postnatal Depression Scale (EPDS). Blood samples were obtained at 20 weeks of pregnancy and the levels of CRH and 5-HT were determined by radioimmunoassay and ELISA. Associations between EPDS score, the demographic variables, and hormone levels were identified using bivariate logistic regression models. A total of 185 women were included. We found that the serum level of both CRH and 5-HT was significantly correlated with EPDS score; the AUC for CRH was 0.79, and 5-HT was 0.85, which indicated that both CRH and 5-HT are a reliable biomarker for PPD. The AUC, specificity, and sensitivity of CRH/5-HT were 0.92, 0.86, and 0.95, respectively, which were better than those of CRH or 5-HT individually. We believe that the serum CRH/5-HT ratio is an excellent biomarker for the prediction of PPD.


The auditory brain stem response in five vertebrate classes.
In representative elasmobranchs, osteichthyans, amphibians, reptiles and birds, average evoked potentials in response to acoustic clicks and tone bursts were recorded intracranially, but outside the brain, or extracranially. Controls against artifacts and tests after transections show that these potentials conform to criteria for auditory brain stem responses (ABRs). Brief waves in a 10-15 msec sequence originate successively in the eighth nerve, medulla and midbrain; there is little contribution to the latter waves from the lower levels. This response pattern appears to be consistent within each species and is similar to that extensively studied in mammals. Some of its features are remarkably alike in all the vertebrate classes tested, implying a generality in the existence of a subset of auditory neurons at several brain levels that are highly synchronous in activity, even after several synapses, and geometrically oriented to add their macroscopic, open, dipole fields. The intensity, repetition rate and the power spectrum of the click stimuli have little effect on the ABR pattern, except when the peak energy is in the low frequency range. In the range below ca. 700 Hz frequency content has a considerable effect; lower frequencies broaden certain waves. Cooling has marked and differential effects on component processes. Reversing click phase, e.g. from initial compression to initial rarefaction, can show no effect or any of several effects, depending on the species. Tone bursts evoke onset ABRs and in some cases after a transitional period a sustained frequency following response. The ABR resembles a click evoked potential even when stimulus rise time is slow. Background tones of particular frequency are most efficient in masking click evoked ABRs; white noise is less efficient. The ABR should be useful in neuroethology since it can be studied without invading the brain. It can tell that the brain is sensitive to a sound. In an immobilized animal it can be recorded in a single sweep, or it can be averaged from an awake tethered animal. It shows good sensitivity and at least some correspondence with behavioral measures of hearing.


The superiority of ratio-based lymph node staging in gastric carcinoma.
The need for a precise lymph node staging without stage migration is of paramount importance when comparing and evaluating international treatment results. We reviewed 1019 patients who underwent R0 resection at Kansai Medical University between 1980 and 1997. The patients were classified according to the 1997 International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) pN classification or the N staging depending on the ratio between the number of excised and the number of involved lymph nodes (pN1, < or = 25%; pN2, < or = 50%; pN3, >50%). Among the 1997 UICC/AJCC pN subgroups, prognosis worsened with an increase in lymph node ratio. In contrast, the ratio-based classification showed more homogenous survival according to the number of involved lymph nodes. Multiple stepwise regression analysis showed that the ratio-based classification was the most significant prognostic factor, whereas the 1997 UICC/AJCC classification was not found to be an independent predictor of survival. In addition, the ratio-based classification showed a superiority to the 1997 UICC/AJCC classification with respect to stage migration. Ratio-based lymph node staging is simple and gives more precise information for prognosis with fewer problems related to stage migration than the 1997 UICC/AJCC staging system.


Cotton thread-based multi-channel photothermal biosensor for simultaneous detection of multiple microRNAs.
The abnormal expression of microRNAs (miRNAs) is associated with various diseases. Developing simple and portable methods for sensitive, rapid and simultaneous detection of multiple miRNAs is critical to achieve accurate and timely diagnosis. Herein, a cotton thread-based multi-channel photothermal biosensor was proposed for simultaneous detection of three breast cancer-related miRNAs including miRNA-10b, miRNA-27a and miRNA-let-7a. Three cotton thread-based channels with one input were designed and the capture probes for detecting different miRNAs were immobilized on the test zones of the corresponding channels. Cu2-xS nanostrings prepared on the basis of hybridization chain reaction (HCR) were taken as the photothermal agents for signal transduction and amplification. The formation of a sandwich structure among the capture probe, target miRNA, and Cu2-xS nanostrings led to the accumulation of the Cu2-xS nanostrings on the test zones and transformed the concentration of miRNA into temperature signal under 808 nm laser irradiation. The temperature changes were quantified by a portable thermal camera and directly reflected the concentration of miRNAs. Under the optimal conditions, the developed multi-channel photothermal biosensor showed excellent specificity and sensitivity with the detection limits of 37 pM, 38 pM and 38 pM for miRNA-10b, miRNA-27a and miRNA-let-7a, respectively. Furthermore, a simultaneous detection of the three miRNAs in cell lysates were achieved and the results were in accordance with that obtained by the quantitative reverse transcription polymerase chain reaction (qRT-PCR), indicating its excellent capacity for practical applications. The developed biosensor provided an important tool for analysis of multiple targets and showed great potential in clinical diagnosis.


Pathological findings in the human auditory system following long-standing gentamicin ototoxicity.
The clinical, audiovestibular and histopathological findings in a patient who suffered from a long-standing gentamicin-induced deafness are reported. In both temporal bones, the organ of Corti was completely absent, with only a few nerve fibres remaining in the apical part of the cochlea. Regenerative ingrowth of nerve fibers into the area of the degenerative organ of Corti was present apically in both ears. The stria vascularis exhibited considerable degeneration in all turns and loss of microvasculature was found in the basilar membrane. The spiral ganglion cells, the cochlear nerve and the central auditory pathways and nuclei appeared to be unaffected.


Molecular modeling of the piezoelectric properties of ferroelectric composites containing polyvinylidene fluoride (PVDF) and either graphene or graphene oxide.
Molecular modeling of ferroelectric composites containing polyvinylidene fluoride (PVDF) and either graphene (G) or graphene oxide (GO) were performed using the semi-empirical quantum approximation PM3 in HyperChem. The piezo properties of the composites were analyzed and compared with experimental data obtained for P(VDF-TrFE)-GO films. Qualitative agreement was obtained between the results of the modeling and the experimental results in terms of the properties of the measured effective piezoelectric coefficient d 33eff and its decrease in the presence of G/GO in comparison with the average computed piezoelectric coefficient <d 33>. When models incorporating one or several G layers with 54 carbon atoms were investigated, the average piezoelectric coefficient <d 33> was found to decrease to -9.8 pm/V for the one-sided model PVDF/G and to -18.98 pm/V for the sandwich model G/PVDF/G as compared with the calculated piezoelectric coefficient for pure PVDF (<d 33> = -42.2 pm/V computed in present work, and <d33> = -38.5 pm/V, obtained from J Mol Model 35 (2013) 19:3591-3602). When models incorporating one or several GO layers with 98 carbon atoms were considered, the piezoelectric coefficient was found to decrease to -14.6 pm/V for the one-sided PVDF/GO model and to -29.8 pm/V for the sandwich GO/PVDF/GO model as compared with the same calculated piezoelectric coefficient for pure PVDF.


Effect of postnatal hypoxia on the energy homeostasis of the newborn rat during the early neonatal period.
Newborn rats breathing a low-oxygen mixture showed similar rates of glycogenolysis to newborns breathing air. However, hypoxia prevented the decrease of plasma glucose and lactate concentrations which occurred in newborns breathing air immediately after delivery. The time-course of plasma alanine was not affected by experimental hypoxia. The decrease in the liver lactate/pyruvate ratio observed in control newborns immediately after delivery was prevented by hypoxia. Lower blood oxygen concentrations were observed in hypoxic animals throughout the observation period. Lower ATP concentrations were observed in hypoxic newborns during the first hour after delivery but similar values were observed in both groups thereafter.


Neurologic outcomes of thymectomy in myasthenia gravis: comparative analysis of the effect of thymoma.
The objectives of this study were to compare the clinical features and the outcomes after thymectomy between patients with and without thymoma and to evaluate the influence of thymectomy on the subsequent clinical course of myasthenia gravis. Between 1995 and 2003, 64 consecutive patients underwent thymectomy, and of these, 60 patients were followed up for at least 12 months postoperatively. The study population was divided into 2 groups based on the presence of thymoma. We performed a retrospective analysis to compare the neurologic outcomes of thymectomy between patients with thymomatous myasthenia gravis and those with nonthymomatous myasthenia gravis. Twenty-four patients had a thymoma. No significant differences were observed between the 2 groups regarding the preoperative severity of myasthenia gravis. There was no significant difference in the follow-up duration between the 2 groups. There was no significant difference in the overall remission rate between the 2 groups (P = .064). The mean time required to reach a remission was 10.6 months and 23.5 months in the thymoma and nonthymoma groups, respectively. The mean duration of remission was 43.1 months and 30.8 months in the thymoma and nonthymoma groups, respectively. In the early phase of follow-up, more patients reached remission in the thymoma group than those in the nonthymoma group (P = .040). Neurologic outcomes of the thymoma group were no worse than those of the nonthymoma group. It is expected that earlier thymectomy is likely to result in a better prognosis by shortening the disease period, even for patients with nonthymomatous myasthenia gravis.


Repeated transient neurological symptoms after spinal anaesthesia with hyperbaric 5% lidocaine.
We report a case of repeated delayed pain after cystoscopy under spinal lidocaine anaesthesia, which may be caused by transient radicular irritation. The possible aetiology of the symptoms is discussed.


Digital Waveform Technology and the Next Generation of Mass Spectrometers.
Ion traps and guides are integral parts of current commercial mass spectrometers. They are currently operated with sinusoidal waveform technology that has been developed over many years. Recently, digital waveform technology has begun to emerge and promises to supplant its older cousin because it presents new capabilities that result from the ability to instantaneously switch the frequency and duty cycle of the waveforms. This manuscript examines these capabilities and reveals their uses and effects on instrumentation. Graphical Abstract .


Potential pharmacokinetic basis for zolpidem dosing in children with sleep difficulties.
The pharmacokinetics of zolpidem was assessed in this open-label, dose-escalation study in children with insomnia. Twenty-one children, seven per age group (2-6, >6 to 12, >12 to 18 years), received a single dose of zolpidem at one of the three dose levels (0.125, 0.25, or 0.50 mg/kg (20 mg maximum dose)). Multiple pharmacokinetic measures were assessed at nine post-dose intervals and pharmacodynamics was assessed by polysomnography and actigraphy. Significant pharmacokinetic effects by dose were observed only as linear increases in maximum concentration (C(max), P<0.001) and area under the plasma concentration-time curve (AUC, P<0.001). Significant pharmacokinetic effects by age group included an increase in AUC (P=0.02), half-life (P=0.04), and mean residence time (P=0.01), whereas total body clearance decreased (P=0.01) and steady-state volume of distribution was variable. Pharmacodynamic measures were independent of the pharmacokinetic estimates. Overall, zolpidem was well tolerated and a pediatric dose of 0.25 mg/kg is recommended for future efficacy studies.


Comparison of Estrogen and Progesterone Receptor Status in Tumor Mass and Axillary Lymph Node Metastasis in Patients with Carcinoma Breast.
Breast malignancy is a hormone-dependent tumor. The hormone receptor status in the primary tumor is required while taking decision for starting adjuvant therapy. The estrogen receptor (ER) and progesterone receptor (PR) status is also an important prognostic marker. All modified radical mastectomy cases with axillary lymph node dissection were taken. H and E staining was done. All lymph node-positive breast cancer cases were subjected to immunohistochemistry using ER and PR antibodies. In the study of 60 cases, the level of concordance between the primary tumor and the metastatic lymph node was 98.33% for ER and 96.66% for PR. There exists a positive correlation between the hormone receptor status of the primary tumor and the paired axillary lymph nodes.


Long-term follow-up of idiopathic mitral valve prolapse in 300 patients: a prospective study.
A prospective long-term follow-up study was made of 300 patients with idiopathic mitral valve prolapse, diagnosed by clinical, cineangiographic and echocardiographic criteria. There were 136 male and 164 female patients, ranging in age from 10 to 87 years (mean 42.2). The study included all patients with primary mitral valve prolapse, irrespective of clinical condition at the onset, and excluded only those patients with "secondary" mitral valve prolapse attributable to an accompanying established disorder. The average follow-up period was 6.1 years (range 6 months to 20 years). Two patients died of a noncardiac cause. The clinical condition of 153 patients remained stable. In 27 patients a supraventricular tachycardia occurred that was readily controlled with medication and caused no serious clinical complications. In 20 patients signs of mitral regurgitation appeared, but the patients remained clinically asymptomatic. Serious complications developed in 100 patients. Sudden death, most likely due to ventricular fibrillation, occurred in three patients; documented ventricular fibrillation was seen in two. Ventricular tachycardia developed in 56 patients, but in all instances the rhythm disorder was managed effectively and durably with medication. Infective endocarditis occurred in 18 patients, 4 of whom died during treatment and 6 of whom needed mitral valve replacement. The remaining eight patients suffer from severe mitral regurgitation that will require surgery in the near future. Twenty-eight patients underwent mitral valve operation because of progressive regurgitation. Cerebrovascular accidents occurred in 11 patients, but lifelong treatment with coumarin derivatives or antiplatelet aggregation agents was not considered necessary.(ABSTRACT TRUNCATED AT 250 WORDS)


Developmental maturation of intestinal and renal thiamin uptake: studies in wild-type and transgenic mice carrying human THTR-1 and 2 promoters.
Thiamin (B1) is an essential micronutrient for normal growth and development. Mammals obtain thiamin through intestinal absorption, while in the kidney thiamin is reabsorbed to prevent its loss in the urine, both processes are specialized, carrier-mediated and involve thiamin transporters-1 and 2 (THTR-1 and THTR-2, respectively; products of the SLC19A2 and SLC19A3 genes). Although thiamin appears to play an important role in neonatal growth, little is currently known about the possible regulation of intestinal and renal thiamin uptake during developmental maturation. We addressed these issues by examining intestinal and renal thiamin uptake and expression of THTR-1 and THTR-2 during early stages of life. We utilized wild-type mice (mice express orthologues of both thiamin transporters) and transgenic mice expressing human SLC19A2 or SLC19A3 promoter-reporter transgenes as a model system and examined carrier-mediated thiamin uptake, mTHTR-1 and 2 protein and mRNA levels and luciferase activity in suckling (13 days), weanling (25-27 days), and adult (60-65 days) mice. Carrier-mediated thiamin uptake by jejunal and renal brush border membrane vesicles (BBMV) both decreased with maturation (suckling>weanling>adult) and were associated with a reduction in mTHTR-1 and mTHTR-2 protein, mRNA levels, and the activity of human SLC19A2 and SLC19A3 promoter-reporter constructs in the intestines and kidneys of transgenic mice. These results are the first to demonstrate that intestinal and renal thiamin uptake are developmentally regulated during early stages of life, mediated through mTHTR-1 and mTHTR-2, and suggest the possible involvement of transcriptional regulatory mechanism(s) in this regulation.


Chemical speciation of size-segregated floor dusts and airborne magnetic particles collected at underground subway stations in Seoul, Korea.
Previous studies have reported the major chemical species of underground subway particles to be Fe-containing species that are generated from wear and friction processes at rail-wheel-brake and catenaries-pantographs interfaces. To examine chemical composition of Fe-containing particles in more details, floor dusts were collected at five sampling locations of an underground subway station. Size-segregated floor dusts were separated into magnetic and non-magnetic fractions using a permanent magnet. Using X-ray diffraction (XRD) and scanning electron microscopy/energy dispersive X-ray spectrometry (SEM/EDX), iron metal, which is relatively harmless, was found to be the dominating chemical species in the floor dusts of the <25 μm size fractions with minor fractions of Mg, Al, Si, Ca, S, and C. From SEM analysis, the floor dusts of the <25 μm size fractions collected on railroad ties appeared to be smaller than 10 μm, indicating that their characteristics should somewhat reflect the characteristics of airborne particles in the tunnel and the platform. As most floor dusts are magnetic, PM levels at underground subway stations can be controlled by removing magnetic indoor particles using magnets. In addition, airborne subway particles, most of which were smaller than 10 μm, were collected using permanent magnets at two underground subway stations, namely Jegi and Yangjae stations, in Seoul, Korea. XRD and SEM/EDX analyses showed that most of the magnetic aerosol particles collected at Jegi station was iron metal, whereas those at Yangjae station contained a small amount of Fe mixed with Na, Mg, Al, Si, S, Ca, and C. The difference in composition of the Fe-containing particles between the two subway stations was attributed to the different ballast tracks used.


Reporting guidelines for population pharmacokinetic analyses.
The purpose of this work was to develop a consolidated set of guiding principles for reporting of population pharmacokinetic (PK) analyses based on input from a survey of practitioners as well as discussions between industry, consulting and regulatory scientists. The survey found that identification of population covariate effects on drug exposure and support for dose selection (where population PK frequently serves as preparatory analysis to exposure-response modeling) are the main areas of influence for population PK analysis. The proposed guidelines consider two main purposes of population PK reports (1) to present key analysis findings and their impact on drug development decisions, and (2) as documentation of the analysis methods for the dual purpose of enabling review of the analysis and facilitating future use of the models. This work also identified two main audiences for the reports: (1) a technically competent group responsible for in-depth review of the data, methodology, and results, and (2) a scientifically literate, but not technically adept group, whose main interest is in the implications of the analysis for the broader drug development program. We recommend a generalized question-based approach with six questions that need to be addressed throughout the report. We recommend eight sections (Synopsis, Introduction, Data, Methods, Results, Discussion, Conclusions, Appendix) with suggestions for the target audience and level of detail for each section. A section providing general expectations regarding population PK reporting from a regulatory perspective is also included. We consider this an important step towards industrialization of the field of pharmacometrics such that non-technical audience also understands the role of pharmacometrics analyses in decision making. Population PK reports were chosen as representative reports to derive these recommendations; however, the guiding principles presented here are applicable for all pharmacometric reports including PKPD and simulation reports.


Reduced pancreatic insulin is associated with retarded growth of the pancreas in young prediabetic BB rats.
The beta-cell function in the perfused pancreas, the total pancreatic insulin content, and the weights of pancreas, kidney, spleen, and total body fat were compared at the age of 30 and 45 days in diabetes-prone and body weight-matched diabetes-resistant male BB rats. These inbred rats had an incidence rate of diabetes at 90 days of age of 80 and 0%, respectively. At day 30, the pancreatic insulin content was reduced in the diabetes-prone (n = 10) rats to 15 micrograms (range 7.7-31.8) compared with 32 micrograms (range 23.3-52.9) in the diabetes-resistant (n = 10) rats (p less than 0.01). Although the kinetics of insulin release in response to glucose was maintained, the amount of insulin released in the diabetes-prone rats was decreased (p less than 0.05) including the first peak (p less than 0.05). The weight of the spleen was less (p less than 0.05); whereas the weights of the pancreas, kidney, and total body fat did not differ from those observed in the diabetes-resistant control rats. At 45 days of age, the weight of the pancreas in the diabetes-prone rats (n = 8) was reduced to 159 mg (range 100-190) from 202 mg (range 185-214) (p less than 0.01). The body weight and body fat were identical to those observed in the diabetes-resistant controls (n = 8) and their kidney (p less than 0.05) and spleen (p less than 0.01) were larger. The insulin content was reduced to the same magnitude as the reduction of pancreatic weight.


The pediatric echocardiography Boot Camp: Four-year experience and impact on clinical performance.
We previously reported on the short-term impact of an echocardiography "Boot Camp" on a single class of cardiology fellows (CF). The impact of the Boot Camp on performance throughout fellowship is unknown. We enrolled four classes of CFs and two classes of cardiac ICU fellows (CVs) prospectively into the Boot Camp and compared CFs to a historical cohort. Experience with echocardiography was surveyed. Outcome measures included written pre- and post-Camp exams, a performance based test (PBT), self-efficacy assessments, numbers of echocardiograms performed, and echocardiogram quality during the last 3 months of fellowship. A total of 25 CFs and 7 CVs participated in the Boot Camp from July 2012-July 2015. Median experience score was 13/40 (4-23). Median self-efficacy improved from 22/147 (range 21-45) to 90/147 (range 49-133) (P=<.001), and written scores from 14/29 (8-24) to 24/29 (13-29) (P<.001). CFs who completed the Boot Camp performed more independent echocardiograms compared to controls at the end of the 1st (37.7±12.2 vs 28.2±12.1, P=.15), 2nd (71.3±24.4 vs 47.6±16.0, P=.044), and third year of fellowship (130.4±44.0 vs 100.0±29.3, P=.230), and on average achieved 150 total echocardiograms in the 4.8th quarter compared to the 7.8th quarter in controls, P=.053. 2D quality scores were higher and shortening fraction more often obtained in echocardiograms performed by Boot Camp CFs compared to controls. The pediatric echocardiography Boot Camp improved self-efficacy, acquisition, and retention of echocardiography skills and knowledge, and increased echocardiogram performance. Observed differences between Boot Camp and control CFs appear to wane across fellowship.