Multiple germ cell tumors: reports of 3 cases, 1 with 3 primary lesions.
Tumors may develop in both testes, either concomitantly or sequentially. We herein report 3 cases of bilateral testicular neoplasms. One patient had concomitant seminomas of the testes and another had sequential germ cell tumors separated by an 11-year interval. The third patient is an unusual case in that he had bilateral testicular germ cell tumors diagnosed concomitantly 8 years after irradiation of an extragonadal, histologically proved, seminoma in the mediastinum. Evidence suggests that all 3 sites, each testis and the mediastinum, were primary lesions. Standard methods of therapy should be used in the treatment of malignancies.


Chemical profiling and functional properties of dietary fibre rich inner and outer bracts of culinary banana flower.
The present study endeavoured to evaluate the nutritional, phytochemical and functional properties of outer and inner bracts of culinary banana flower which is a by-product of banana production. Both outer and inner bracts were found to be rich in dietary fibre (61.13 and 66.22%, respectively) along with other chemical compositions including proximate, minerals, and antioxidant-rich phenolics both free and bound. In addition, the functional properties including glucose dialysis retardation index (GDRI) of outer and inner bracts were also studied. The outer and inner bracts exhibited total polyphenols 7.56 and 9.44 mg phenols/g dry sample, respectively. The polyphenol profile by HPLC, revealed the presence of significant amount of free and bound phenolics in both outer and inner bracts. Functional properties of these dietary fibres-rich fractions of culinary banana flower exhibited lower bulk density, higher water-holding capacity, oil-holding capacity, and water-swelling capacity in outer and inner bracts than cellulose. The outer and inner bracts showed relatively higher GDRI compared to control and cellulose. The results revealed that both the outer and inner bracts of culinary banana flower are rich source of dietary fibre along with high antioxidant activity and could be one of the promising functional ingredients for low-calorie and high-fibre food product.


Relationship between antipyrine metabolism and acetylation phenotype in health and chronic liver diseases.
The authors examined the activity of N-acetyltransferase and that of microsomal P-450 isoenzymes in health and hepatic disease state by determining the acetylation phenotype and the total (CLAP) and metabolic clearances of antipyrine to form norantipyrine or N-demethylantipyrine (MCLnora), 3-hydroxymethylantipyrine (MCLhma), and 4-hydroxyantipyrine (MCLha) in 21 healthy subjects and in 33 patients with chronic liver diseases (CLD) and investigated the relationship between the activities of these two enzyme systems. The acetylation phenotype was determined according to the urinary caffeine metabolites test. The mean and (SEM) of CLAP, MCLhma, MCLha, and MCLnora in healthy subjects were 2.42 (0.264), 0.193 (0.031), 0.322 (0.045), and 0.288 (0.04) L/h, and those observed in patients with CLD were 0.98 (0.1), 0.076 (0.015), 0.131 (0.026), 0.103 (0.022) L/h, respectively. The prevalence of fast acetylation among the healthy subjects and patients with CLD was 38% and 39%, respectively. Although all metabolic clearances appear to be reduced in healthy slow acetylators, the reduction was only significant in MCLnora, indicating a direct association between the activity of N-acetyltransferase and that of P-450 IIIA3 responsible for the N-demethylation of antipyrine. Conversely, slow acetylators with CLD exhibited significantly higher CLAP and near-significantly larger metabolic clearances including MCLnora, which suggests that P-450 activity in fast acetylators is more sensitive to chronic liver diseases than in slow acetylators.


Discovery of a series of 2-(1H-pyrazol-1-yl)pyridines as ALK5 inhibitors with potential utility in the prevention of dermal scarring.
A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFβ receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFβ induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.


Narrative review of mathematical and psychological studies of staff scheduling for holidays as applicable to anesthesiologists and nurse anesthetists.
We performed a narrative review of articles applicable to anesthesiologists' and nurse anesthetists' choices of who works each statutory holiday for operating room and non-operating room anesthesia. We include search protocols and detailed supplementary annotated comments. Studies showed that holiday staff scheduling is emotional. Working on holidays often is more stressful and undesirable than comparable workdays. Intrinsic motivation may overall, among practitioners, be greater by preferentially scheduling practitioners who choose to work on holidays, for compensation, before mandating that practitioners who would prefer to be off must work on holidays. Granting each practitioner (who so desires) at least one major holiday off can depend on identifying and scheduling other clinicians who want to work holidays for monetary compensation or extra compensatory time off. Scheduling holidays by random priority (i.e., a lottery choosing who gets to pick their holiday[s] first, second, etc.) is inefficient, resulting in fewer practitioners having their preferences satisfied, especially for small departments or divisions (e.g., cardiac anesthesia). No article that we reviewed implemented a random priority mechanism for staff scheduling. The selection of practitioners to take turns in choosing their holidays is perceived to have less fairness than a selection process that collects each participants' preferences. Although holidays often are scheduled separately from regular workdays and weekends, doing so will not increase efficiency or fairness. Holidays can, in practice, be scheduled simultaneously with non-holidays. Models can explicitly include fairness as an objective. For example, fairness can be based on the difference between the maximum and minimum number of holidays for which practitioners of the same division are scheduled. Holidays can be given greater weights than other shifts when estimating fairness. Staff scheduling for holidays, when done simultaneously with regular workdays, nights, and weekends, can also use personalized weights, specifying practitioners' preferences to be satisfied if possible.


Naproxen suppository for perineal pain after vaginal delivery.
To assess the effectiveness of rectal naproxen for reducing perineal pain after vaginal delivery. A double-blind randomized controlled trial of 142 post partum women randomly allocated to receive either naproxen (71 patients) or placebo (71 patients) suppositories. The first dose was given immediately after complete perineal suturing, while the second dose was given 6 hours post partum. The validated Thai short-form McGill pain questionnaire was used to evaluate perineal pain at 0, 6, and 24 hours post partum. Pain scores were analyzed using the unpaired t test. Pain scores at 6 and 24 hours for women in the naproxen group were significantly lower compared with women in the placebo group (6.4 and 2.3 vs 18.4 and 5.5; P<0.001). No side effects with naproxen were found. Rectal naproxen is effective and safe for reducing perineal pain after vaginal delivery.


Synthesis and biological evaluation of methoxylated analogs of the newer generation taxoids IDN5109 and IDN5390.
Starting from 10-deacetylbaccatin III (7), the 2-debenzoyl-2-m-methoxybenzoyl analogs of the newer generation taxoids IDN5109 (3) and IDN5390 (4) were synthesized. The biological evaluation of these compounds (5 and 6, respectively) showed a general increase of cytotoxicity, as observed in first-generation anticancer taxanes.


Histological evaluation of the response to interferon-alpha therapy in chronic hepatitis C.
The response rate of interferon-alpha (IFN-alpha), recently introduced in the treatment of chronic hepatitis C, is merely 25-50%. The aims of this follow-up study were to compare the efficacy of 6 and 12-month IFN-alpha treatment via liver biopsy scores and to evaluate the correlation with the biochemical response. Twenty chronic hepatitis C patients were studied; 10 received IFN-alpha therapy for 6 months and 10 for 12 months. Liver biopsy material was taken before and after therapy. There was a significant serum alanine aminotransferase (ALT) level improvement in both groups, but a significant histological improvement in necroinflammatory activity (grade) only in the 12-month group. The Chevallier stage scores demonstrated a significant progression in both groups. Twelve-month IFN-alpha treatment affords a better response in the liver histology grade and serum ALT level, but does not influence the staging; a normal ALT does not guarantee hepatitis inactivity. Liver biopsies appear indispensable for monitoring.


Isolation and characterization of tightly coupled mitochondria from wild type and nap mutant Neurospora crassa.
A fast and reproducible procedure was elaborated for isolation of tightly coupled mitochondria from wild type and nap-mutant Neurospora crassa cells harvested at different growth stages. The isolated mitochondrial preparations had controlled metabolic states and were tightly coupled, i.e., displayed good respiratory control and had close to the theoretically expected maximal ADP/O ratios upon oxidation of Krebs cycle intermediates and exogenous NADH. They contained the fully competent respiratory chain with all three points of energy conservation. Oxidation of all examined substrates by mitochondria from both wild type and mutant cells was mediated by two alternative terminal oxidative systems, albeit to varying extent, with the more pronounced engagement of the alternative oxidase in the stationary growth phase and with a minor contribution of this non-phosphorylating pathway in the substrate oxidation by mutant mitochondria. Oxidation of NAD-dependent substrates by mitochondria from the two cell types was accommodated via both rotenone-sensitive and rotenone-insensitive pathways, while the level of rotenone-insensitive pathway in mutant cells was lower than in wild type cells. It is suggested that a more limited contribution of alternative non-phosphorylating oxidative pathways to the total respiration in mutant cells, as compared with wild type cells, could, at least partially, explain an elevated ATP level in these cells. However, the absence of principal differences in the arrangement of the respiratory chain in mitochondria of wild type and mutant cells implies that the elevated ATP level in the nap mutant is largely related to reduced ATP expenses for transport processes in these cells.


Aseptic loosening rates in distal femoral endoprostheses: does stem size matter?
Long-term survival of distal femoral endoprosthetic replacements is largely affected by aseptic loosening. It is unclear whether and to what degree surgical technique and component selection influence the risk of loosening. We (1) established the overall failure and aseptic loosening rates in a tumor population and asked (2) whether stem diameter and specifically the diaphysis-to-stem ratio predicts loosening, and (3) whether resection percentage correlates with failure. We retrospectively reviewed the charts of all 93 patients in whom 104 distal femoral replacements had been performed from 1985 to 2008. We extracted the following data: age, need for revision surgeries, tumor diagnosis, adjunct treatment, and implant characteristics. We reviewed radiographs and determined stem size, bone diaphyseal width, and resection percentage of the femur. Kaplan-Meier survivorship was calculated for all implant failures and failures resulting from aseptic loosening. We evaluated radiolucent lines in patients with radiographic followup over 5 years. We identified independent risk factors for loosening. The minimum followup for radiographic evaluation was 5 years (mean, 12.7 years; range, 5.4-23.5 years). Overall implant survival for 104 stems in 93 patients was 73.3% at 10 years, 62.8% at 15 years, and 46.1% at 20 years. Survival from aseptic loosening was 94.6% at 10 and 15 years and 86.5% at 20 years. Of the variables analyzed, only bone:stem ratio independently predicted aseptic failure. Patients with stable implants had larger stem sizes and lower bone:stem ratios than those with loose implants (14.5 mm versus 10.7 mm and 2.02 versus 2.81, respectively). Our data suggest durability relates to selecting stems that fill the canal. Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.


Estimating Gestational Age With Sonography: Regression-Derived Formula Versus the Fetal Biometric Average.
To compare the accuracy of a new regression-derived formula developed from the National Fetal Growth Studies data to the common alternative method that uses the average of the gestational ages (GAs) calculated for each fetal biometric measurement (biparietal diameter, head circumference, abdominal circumference, and femur length). This retrospective cross-sectional study identified nonanomalous singleton pregnancies that had a crown-rump length plus at least 1 additional sonographic examination with complete fetal biometric measurements. With the use of the crown-rump length to establish the referent estimated date of delivery, each method's (National Institute of Child Health and Human Development regression versus Hadlock average [Radiology 1984; 152:497-501]), error at every examination was computed. Error, defined as the difference between the crown-rump length-derived GA and each method's predicted GA (weeks), was compared in 3 GA intervals: 1 (14 weeks-20 weeks 6 days), 2 (21 weeks-28 weeks 6 days), and 3 (≥29 weeks). In addition, the proportion of each method's examinations that had errors outside prespecified (±) day ranges was computed by using odds ratios. A total of 16,904 sonograms were identified. The overall and prespecified GA range subset mean errors were significantly smaller for the regression compared to the average (P < .01), and the regression had significantly lower odds of observing examinations outside the specified range of error in GA intervals 2 (odds ratio, 1.15; 95% confidence interval, 1.01-1.31) and 3 (odds ratio, 1.24; 95% confidence interval, 1.17-1.32) than the average method. In a contemporary unselected population of women dated by a crown-rump length-derived GA, the National Institute of Child Health and Human Development regression formula produced fewer estimates outside a prespecified margin of error than the commonly used Hadlock average; the differences were most pronounced for GA estimates at 29 weeks and later.


Accurate measurements of the acoustical physical constants of synthetic alpha-quartz for SAW devices.
Accurate measurements of the acoustical physical constants (elastic constants, piezoelectric constants, dielectric constants, and density) of commercially available and widely used surface acoustic wave (SAW)-grade synthetic a-quartz are reported. The propagation directions and modes of bulk waves optimal for accurately determining the constants were selected through numerical calculations, and three principal X-, Y-, and Z-cut specimens and several rotated Y-cut specimens were prepared from a single crystal ingot to determine the constants and to confirm their accuracy. All of the constants were determined through highly accurate measurements of the longitudinal velocities, shear velocities, dielectric constants, and density. The velocity values measured for the specimens that were not used to determine the constants agreed well with those calculated from the determined constants, within a difference of +/- 0.20 m/s (+/- 0.004%).


Bupi Yichang Pill alleviates dextran sulfate sodium-induced ulcerative colitis in mice by regulating the homeostasis of follicular helper T cells.
Follicular helper T (Tfh) cells-based therapy represents a new treatment option for inflammatory bowel disease. Bupi Yichang Pill (BPYCP), a traditional Chinese formula for the treatment of dysentery and diarrhea, exhibits potential anti-inflammatory activities in treating various kinds of inflammation. However, its anti-inflammatory effect on colitis and the underlying mechanisms remain unknown. To explore the protective role and underlying immunomodulatory effects of BPYCP in the treatment of UC. The dextran sodium sulfate (DSS) free-drinking method induced UC in C57BL/6 mice, and BPYCP was orally administrated at a dosage of 1.5, 3.0, or 6.0 g/kg/day. Throughout the experimental period, the effects of BPYCP on DSS-induced clinical symptoms and disease activity index (DAI) were monitored and analyzed. Hematoxylin-eosin staining was used to observe the histopathological injury of the colon. Flow cytometry was used to detect the levels of Tfh cells, Tfh cell subpopulations, and memory Tfh cells. ELISA, Western blot, and qRT-PCR were used to detect the expression of inflammatory cytokines and Tfh cell-related biomarkers. Medium and high dosages of BPYCP effectively alleviated DSS-induced experimental colitis with increased body weight, survival rate and colonic length, and decreased DAI, colonic weight, and colonic index, as well as less ulcer formation and inflammatory cell infiltration, increased anti-inflammatory cytokine IL-10, and decreased pro-inflammatory cytokines IL-17A, IL-6, and TNF-ɑ. Moreover, BPYCP administration significantly decreased the percentage of Tfh cells and the expression of Tfh markers ICOS, PD-1 and Bcl-6 in the mesenteric lymph nodes of colitis mice. In addition, BPYCP treatment obviously decreased the percentages of Tfh1, Tfh17 and Tem-Tfh cells and upregulated Tfr cells in colitis mice. However, there were no significant regulatory effects of BPYCP on Tfh cell response in normal mice. Taken together, these results demonstrated a protective effect of BPYCP against DSS-induced experimental colitis by regulating Tfh cell homeostasis.


Broadening the repertoire of microbial aldo-keto reductases: cloning and characterization of AKR3B4 from Rhodotorula mucilaginosa LSL strain.
Aldo-keto reductases (AKRs) are nicotinamide-dependent enzymes that catalyze the transformation of aldehydes and ketones into alcohols. They are spread across all phyla, and those from microbial origin have proved to be highly robust and versatile biocatalysts. In this work, we have discovered and characterized a microbial AKR from the yeast Rhodotorula mucilaginosa by combining genome-mining and expression assays. The new enzyme, named AKR3B4, was expressed by a simple protocol in very good amounts. It displays a selective substrate profile exclusively transforming aldehydes into alcohols. Also, AKR3B4 shows very good stability at medium temperatures, in a broad range of pH values and in the presence of green organic solvents. Conversion assays demonstrate it is an excellent biocatalyst to be used in the synthesis of aromatic alcohols, and also to produce furan-3-ylmethanol and the valuable sweetener xylitol. These results show that AKR3B4 displays attractive features so as to be used in chemoenzymatic processes.


Metabolite shift in Medicago truncatula occurs in phosphorus deprivation.
Symbiotic nitrogen (N) fixation entails successful interaction between legume hosts and rhizobia that occur in specialized organs called nodules. N-fixing legumes have a higher demand for phosphorus (P) than legumes grown on mineral N. Medicago truncatula is an important model plant for characterization of effects of P deficiency at the molecular level. Hence, a study was carried out to address the alteration in metabolite levels of M. truncatula grown aeroponically and subjected to 4 weeks of P stress. First, GC-MS-based untargeted metabolomics initially revealed changes in the metabolic profile of nodules, with increased levels of amino acids and sugars and a decline in amounts of organic acids. Subsequently, LC-MS/MS was used to quantify these compounds including phosphorylated metabolites in the whole plant. Our results showed a drastic reduction in levels of organic acids and phosphorylated compounds in -P leaves, with a moderate reduction in -P roots and nodules. Additionally, sugars and amino acids were elevated in the whole plant under P deprivation. These findings provide evidence that N fixation in M. truncatula is mediated through a N feedback mechanism that in parallel is related to carbon and P metabolism.


The amino acid sequence of dog (Canis familiaris) hemoglobin.
The manual sequencing of the tryptic peptic from the alpha and beta chains of dog hemoglobin is described, including evidence for the existence of two alphaT-13 peptides and thus 2 alpha chains, one with threonine and one with alanine at position 130. Although the actual sequence was published in 1970, the evidence on which it was based has not previously appeared.


Nonmetal clasp dentures: What is the evidence about their use?
The aim was to discuss the indications, contraindications, advantages, and disadvantages of Nonmetal clasp dentures (NMCDs), as well as the most relevant properties of its constituent materials. A search was conducted using the keywords: "nonmetal clasp dentures," "thermoplastic resin," "flexible resin removable partial denture," "polyamide," and "nylon" in databases PubMed/Medline, Lilacs, SciELO, and textbooks between 1955 and 2020. Theses and texts without reliable sources of publication were excluded. Once the analysis instruments were determined, the data were analyzed and discussed. NMCDs present high flexibility, easy adaptation to the abutments, color compatibility and biocompatibility with the oral mucosa, and absence of visible metal clasps. However, they need laboratory relining, grinding, and polishing, do not have criteria for its planning, become rougher and stained over time, and are able to traumatize supporting tissues. The association with metal components seems to be an alternative to increase the success of NMCDs by combining esthetics and biomechanical principles of conventional removable partial dentures. The lack of long-term clinical studies makes the professionals to rely solely on previous experiences or on the manufacturers' recommendations. It suggested that NMCDs must be indicated with caution when not used temporarily.


The processing of ultrafine-grained Mg tubes for biodegradable stents.
An investigation was carried out on equal-channel angular pressing (ECAP) and extrusion processing of a ZM21 Mg alloy to obtain an improved candidate material for the manufacturing of biodegradable Mg stents. Ultrafine-grain size billets of the ZM21 alloy were obtained by two-stage ECAP aimed at achieving an initial refining of the structure at 200°C and then reaching the submicrometer grain size range by lowering the processing temperature down to 150°C. The investigation revealed a significant improvement in the properties of the ECAP-treated samples compared with the starting coarse-grained ZM21 alloy. The 0.2% yield strength rose from 180 to 340 MPa after 150°C ECAP processing, while maintaining a fairly high tensile ductility. The ultrafine ZM21 alloy billets were then used for the extrusion of stent precursors having the form of small-size tubes. The grain size after extrusion remained in the submicrometer range while the hardness was revealed to be significantly higher than that of the coarse-grained ZM21 Mg alloy. It was demonstrated that processing of biodegradable Mg stent having an ultrafine-grained microstructure by ECAP and low-temperature extrusion is feasible and that the obtained products feature promising properties.


Measurement of insulin in human sera using a new RIA kit. 1. Insulin determination in the absence of insulin antibodies--conventional assay and micro modification.
A sensitive and versatile radioimmunoassay (RIA) for insulin was established using human insulin standard, a specific guinea pig anti-insulin antiserum and rabbit anti-guinea pig serum. Radioiodination was performed according to a modified chloramine T method. Tracer preparations were used for as long as 6 weeks after iodination. The standard curve ranges from 0.044 to 1.2 nmol/l. The intra-assay coefficient of variation (CV) was 3-5% and the inter-assay CV was 6-9% in the optimal range between 0.4 and 0.9 nmol/l. The average recovery of human insulin added to plasma or serum samples was 100.2 +/- 2.0% (n = 38) and 100.1 +/- 1.9% (n = 42), respectively. In addition to human insulin, porcine, canine, rabbit and bovine insulin can also be determined but not rat or mouse insulin. The cross-reactivity of the antiserum with porcine proinsulin was found to be 40% on the molar basis. The range of mean fasting plasma insulin concentrations in healthy subjects and under various pathological conditions were estimated.


Candida fungemia in neonates treated with fluconazole: report of forty cases, including eight with meningitis.
To assess efficacy and safety of fluconazole in neonates with Candida fungemia. Multicenter prospective protocol of all fungemias appearing between January 1, 1993, and December 31, 1997, in four major university hospitals. Forty neonates, 28 of them with very low birth weight (<1500 g; 30.5 median gestation week), with documented Candida albicans fungemia were treated with intravenous fluconazole in a daily dosage of 6 mg/kg once daily for 6 to 48 days. Thirty-four received fluconazole as monotherapy and 6 received it in combination with amphotericin B. Thirty-two (80%) were cured; 4 of them relapsed despite at least 14 days of therapy, but they were ultimately cured without sequelae. Eight other neonates died, 4 because of fungal infection and 4 because of prematurity or hemorrhage or lung failure, with fungemia (20% overall and 10% attributable mortality). Two neonates had elevated liver enzymes during fluconazole therapy and 2 others had elevated serum creatinine during fluconazole monotherapy. In none of them did these abnormalities necessitate discontinuation of antifungal therapy. In 8 neonates fungal meningitis developed as a complication of fungemia. All but 3 fungemias were C. albicans; 3 were Candida parapsilosis. Fluconazole was safe and effective antifungal therapy even in complicated or Candida fungemia in neonates and in infants with very low birth weight.


Giant hydronephrosis complicated by multiple uroepithelial carcinomas.
Giant hydronephrosis is uncommon, and malignant hydronephrosis of unknown origin is even rarer. We report a case of a 43-year-old male patient with giant hydronephrosis without painless carnivorous hematuria. Preoperative imaging and urinary search for exfoliated cells revealed no evidence of renal pelvic cancer. The patient underwent simple nephrectomy and pathology confirmed the diagnosis of multifocal high-grade papillary uroepithelial carcinoma of the renal pelvis.


Breast conservation in women with multifocal-multicentric breast cancer: is it feasible?
The incidence of preoperatively identified multifocal and multicentric breast cancer is rising with improved sensitivity of imaging modalities. Based on retrospective, historic data, breast conservation in women with multiple tumors has been discouraged because of high rates of local regional recurrence (LRR). These studies, however, do not extrapolate to contemporary practice as they do not incorporate the use of modern therapies and surgical techniques. This study is designed to evaluate the feasibility of breast conservation in women with multiple breast primaries. We retrospectively reviewed the charts of 22 women who underwent breast conservation surgery for 2 or more synchronous, ipsilateral cancers between 1998 and 2008. We extracted data including tumor size, nodal staging, receptor status, adjuvant therapies administered, and local-regional recurrence. A total of 22 patients were identified. Average follow up is 3.5 years. One patient (4.5%) experienced an in-breast recurrence. Both initial tumors in this patient were invasive ductal carcinoma, ER/PR, negative and HER2 positive. Time to LRR was 2.5 years. Our data are consistent with those of recent studies in which multifocal/multicentric local regional recurrence in multicentric/multifocal breast is equivalent to that seen in women with unifocal cancer. The single local recurrence in this study occurred in a premenopausal women with ER/PR- disease who were HER2+. Prior retrospective studies have identified ER/PR- and HER2 overexpression as independent risk factors for recurrence following breast conservation. Additional prospective trials are warranted to better assess the oncologic safety of breast conservation in this population.


Targets and mechanisms of sulforaphane derivatives obtained from cruciferous plants with special focus on breast cancer - contradictory effects and future perspectives.
Breast cancer is the most common type of cancer among women. Therefore, discovery of new and effective drugs with fewer side effects is necessary to treat it. Sulforaphane (SFN) is an organosulfur compound obtained from cruciferous plants, such as broccoli and mustard, and it has the potential to treat breast cancer. Hence, it is vital to find out how SFN targets certain genes and cellular pathways in treating breast cancer. In this review, molecular targets and cellular pathways of SFN are described. Studies have shown SFN inhibits cell proliferation, causes apoptosis, stops cell cycle and has anti-oxidant activities. Increasing reactive oxygen species (ROS) produces oxidative stress, activates inflammatory transcription factors, and these result in inflammation leading to cancer. Increasing anti-oxidant potential of cells and discovering new targets to reduce ROS creation reduces oxidative stress and it eventually reduces cancer risks. In short, SFN effectively affects histone deacetylases involved in chromatin remodeling, gene expression, and Nrf2 anti-oxidant signaling. This review points to the potential of SFN to treat breast cancer as well as the importance of other new cruciferous compounds, derived from and isolated from mustard, to target Keap1 and Akt, two key regulators of cellular homeostasis.


Prognosis-predicting system based on factors related to survival of cervical carcinoma.
To establish a different category system based on grouping of the risk factors in patients with cervical smear. Univariate and multivariate analyses of factors associated with survival time were performed in 443 patients with stage Ib-IIa squamous cell carcinoma (SCC) from 1985 to 1989. Univariate analysis showed that parametrial extension, bulky tumor size (> or = 4 cm), uterine body involvement, poor differentiation and pelvic lymph node (LN) metastasis were prognostically significant. However, by multiple regression method, only LN metastasis, deep stromal invasion (DSI), and poor differentiation (PD) were significantly related to the patient's survival time with risk ratios of 2.78, 2.61 and 1.52, respectively. A prognosis-predicting system was established on the basis of these simplified factors: groups of high, intermediate, low and very low-risks, obtained survival rates of 93-96%, 77%, 51% and 25-37%, respectively. Using this simple model, cervical carcinomas can be classified prognostically for predicting 5-year-survival rates, and for risk-guided therapy in the future.


Welding fumes composition and their effects on blood heavy metals in albino rats.
Toxic substances produced during welding include heavy metals, carbon monoxide, carbon dioxide, and nitrogen oxides. The study aims to evaluate the heavy metals concentration in welding fumes and the blood of the animals exposed to welding fumes. The fumes were collected from a welding site by a skilled welder and part of it was subjected to metals analysis. A total of 130 rats were divided into 13 groups. 12 groups were given doses calculated to correspond to real-life workers exposure regimes and 1 group served as control. The dosages were administered intratracheally after anesthetization weekly for 12 weeks. The animals were sacrificed and whole blood samples were collected for atomic absorption spectrophotometry. The metals in fumes analyzed were decreasing in order of Fe > K > Pb > Co > Cd > Ca > Ni > Mn > Zn > Cr > Al > Cu > Mg. Changes were observed in the behaviour of the test animals compared to the control indicating probable toxicity. The values of Pb, Cr, Fe, Mn, and Ni in the exposed animal's blood were higher than the control and increased relatively across the treatment groups. However, the values of Al and Zn were not significantly different from the control. These indicate that exposure to welding fumes having contained a significant amount of heavy metals has caused noticeable toxicity symptoms with simultaneous elevation in blood metal levels. Monitoring and regulation of these activities should be enforced by relevant authorities in Kano and Nigeria in general.


Ancient origins of the Mediterranean trap-door spiders of the family Ctenizidae (Araneae, Mygalomorphae).
The family Ctenizidae is a worldwide-distributed trapdoor spider group, with a modest number of genera and species but interesting biogeography. Its monophyly has been questioned on the basis of both morphological and molecular evidence. The family is represented in the Mediterranean Basin by three genera and nine species: Cteniza and Cyrtocarenum, mostly endemic to the region, and Ummidia, long considered an anthropogenic introduction to the Mediterranean because the bulk of its diversity is in the New World. The taxonomic status of some of the species and genera (e.g. Mediterranean Ummidia species or Cteniza and Cyrtocarenum) has been called into question due to their close morphological affinities. Here, we use a multilocus approach that combines DNA sequence data from three nuclear genes 28S rRNA, EF1γ and H3 to investigate the origins and phylogenetic position of the Mediterranean taxa within the context of ctenizid generic-level diversity. For the first time, all known ctenizid genera are included in a phylogenetic analysis. Additionally, Bayesian relaxed clock methods and specific substitution rates are used to infer the timing of the group's diversification. Our results disagree with the traditional division of the family Ctenizidae into two subfamilies finding them polyphyletic and stress the need for re-evaluating the morphological characters that have been used in the group's classification. Time estimates indicate an ancient origin and long history of Mediterranean ctenizids. The present day disjunct distribution of Ummidia seems to be the result of the opening of the Atlantic Ocean, suggesting a former Laurasian distribution of the genus that is further supported by Baltic amber fossils. Similarly, the opening of the western Mediterranean Basin has likely played a key role in the diversification of both Ummidia and Cteniza, whereas the origin of Cyrtocarenum species preceded the breakup of the former continuous landmass that formed the Aegean region. Deep divergence times and reciprocal monophyly support the status of Cteniza and Cyrtocarenum as independent evolutionary lineages. Alternatively, the taxonomic status of Ummidia with regard to the closely related genus Conothele remains unclear; a more thorough sampling of the latter is needed to evaluate whether the synonymy of the two genera is necessary.


Short-Chain Polyselenosulfide Copolymers as Cathode Materials for Lithium-Sulfur Batteries.
Copolymerization of sulfur, which forms sulfur-rich polymers, has recently opened a new era in the lithium-sulfur (Li-S) battery research as improved battery performances could be achieved compared to pure sulfur (S8). By means of organic chemistry, sulfur copolymers with desired features and chemical structures could be rationally designed and synthesized. In this study, sulfur-rich polymers consisting of short-chain tetrasulfide (R-S4-R) (PTS) and selenotrisulfide (R-SeS3-R) (PTSeS) bonds are suggested as cathode materials for Li-S batteries. Intrinsically short poly(seleno)sulfide bonds along with covalent anchoring effect effectively suppress the parasitic shuttle effect originating from soluble long-chain lithium polysulfides formed from pure S8. Furthermore, a comparative study demonstrates the indisputable advantage of the selenium doping, which enhances the electrical conductivity of the polymer and following battery performances. In terms of cycling performance, both PTSeS and PTS with ∼2 mg cm-2 polymer loading exhibit small capacity decays of 0.078 and 0.052% per cycle until 500 cycles at 0.5C, respectively. However, active material utilization and high rate performance are substantially superior in PTSeS due to the enhanced electron transfer kinetics. This work would provide useful design principles for fabrication of sulfur-based polymers with even greater applicability in future Li-S batteries.


Statistical issues and methods for meta-analysis of microarray data: a case study in prostate cancer.
With the proliferation of related microarray studies by independent groups, a natural step in the analysis of these gene expression data is to combine the results across these studies. However, this raises a variety of issues in the analysis of such data. In this article, we discuss the statistical issues of combining data from multiple gene expression studies. This leads to more complications than those in standard meta-analyses, including different experimental platforms, duplicate spots and complex data structures. We illustrate these ideas using data from four prostate cancer profiling studies. In addition, we develop a simple approach for assessing differential expression using the LASSO method. A combination of the results and the pathway databases are then used to generate candidate biological pathways for cancer.


Inhibition of Survival Pathways MAPK and NF-kB Triggers Apoptosis in Pancreatic Ductal Adenocarcinoma Cells via Suppression of Autophagy.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a survival rate of 4-6 months from diagnosis. PDAC is the fourth leading cause of cancer-related death in the Western world, with a mortality rate of 10 cases per 100,000 population. Chemotherapy constitutes only a palliative strategy, with limited effects on life expectancy. To investigate the biological response of PDAC to mitogen-activated protein kinase (MAPK) and NF-kappaB (NF-kB) inhibitors and the role of autophagy in the modulation of these signaling pathways in order to address the challenge of developing improved medical protocols for patients with PDAC. Two ATCC cell lines, MIAPaCa-2 and PANC-1, were used as PDAC models. Cells were exposed to inhibitors of MAPK or NF-kB survival pathways alone or after autophagy inhibition. Several aspects were analyzed, as follows: cell proliferation, by [(3)H]TdR incorporation; cell death, by TUNEL assay, regulation of autophagy by LC3-II expression level and modulation of pro-and anti-apoptotic proteins by Western blot. We demonstrated that the inhibition of the MAPK and NF-kB survival pathways with U0126 and caffeic acid phenethyl ester (CAPE), respectively, produced strong inhibition of pancreatic tumor cell growth without inducing apoptotic death. Interestingly, U0126 and CAPE induced apoptosis after autophagy inhibition in a caspase-dependent manner in MIA PaCa-2 cells and in a caspase-independent manner in PANC-1 cells. Here we present evidence that allows us to consider a combined therapy regimen comprising an autophagy inhibitor and a MAPK or NF-kB pathway inhibitor as a possible treatment strategy for pancreatic cancer.


Impact of short-term meditation and expectation on executive brain functions.
Meditation improves executive functions such as attention and working memory processes. However, it remains unclear to what extent contextual effects contribute to these improvements, since the role of meditation-associated expectations has not been investigated so far. In a randomized, single-blind, deceptive, between-subject design we compared the impact of short-term meditation (MG) on executive functioning with an expectation (ECG) and a passive control group (CG) as well as the effect of positive and negative outcome expectations. Fifty-nine healthy meditation-naïve volunteers participated on three consecutive days (20 min/session). Five groups were examined: 2 MGs, 2 ECGs and 1 CG. While one MG and one ECG were given positive suggestions concerning the effect of meditation on attention, the other two groups were given negative suggestions. MGs practised a focused attention meditation technique; ECGs were told that they were practising meditation but were given instructions for a sham meditation. CG participants sat in silence with their eyes closed. Interference control (Stroop task), selective sustained attention (d2 task), figural and verbal fluency measures of executive functions were assessed. Results indicate that suggestions have a substantial impact on interference control and verbal fluency, with positive suggestions leading to an increase in performance, whereas negative suggestions impeded improvement. This proof of concept study demonstrates the importance of the implementation of a credible ECG to elucidate context effects in meditation processes. It also indicates that suggestions can modulate the small effect of meditation on verbal fluency.


Retinal vascular patterns in domestic animals.
In this paper a morphological study of the retinal vascular patterns in various species of domestic animals is reported. A classification of these patterns into four well-defined groups is described. In the domestic ruminants, pigs and carnivores the retina contains a compact plexus of blood vessels located in the major part of the light-sensitive portion of the retina (euangiotic or holangiotic pattern). In other domestic animals blood vessels are present only in a smaller part of the retina. In the rabbit, vessels are confined to a broad horizontal band coincident with the area of dispersion of the myelinated nerve fibres. The larger of these vessels are readily visible macroscopically (merangiotic pattern). In the horse and the guinea pig the retinal blood vessels are minute and restricted to the direct neighbourhood of the optic disc (paurangiotic pattern). The avian retina is completely avascular (anangiotic pattern), but a densely vascularised pecten oculi is attached to the linear optic nerve head and protrudes far into the inferior part of the vitreous body.


Disposition of fluvoxamine in humans is determined by the polymorphic CYP2D6 and also by the CYP1A2 activity.
Fluvoxamine is a selective serotonin reuptake inhibitor used widely in the treatment of depression and other psychiatric diseases, but little is known about the specific isozymes involved in its metabolism. This study investigated the relationship between fluvoxamine disposition and the polymorphic CYP2D6 and the polycyclic aromatic hydrocarbon (as contained in cigarette smoke) inducible CYP1A2. Fluvoxamine (50 mg orally) was given to 10 extensive metabolizers and four poor metabolizers of debrisoquin, and concentrations were assessed in plasma by high performance liquid chromatography. Five of the extensive metabolizers and one of the poor metabolizers were smokers of more than 10 cigarettes per day. The CYP1A2 activity was determined by means of a urinary caffeine test. Compared with nonsmoking extensive metabolizers, nonsmoking poor metabolizers had a statistically significant (p = 0.02, Mann-Whitney U test) about twofold higher maximum plasma concentration, longer half-life, and fivefold lower oral clearance of fluvoxamine. The oral clearance of fluvoxamine correlated to the CYP1A2 index in the 14 subjects (rs = 0.58; p < 0.05; Spearman rank correlation). The disposition of fluvoxamine in humans is associated with the polymorphic CYP2D6 activity, but CYP1A2 also seems to be involved.


Natural killer cells contribute to 'hot' tumor regression in the allergic inflammatory environment.
Systemic immune status influences the elimination of tumor cells. However, it remains unclear how chronic inflammation in allergic diseases affects the tumor microenvironment and tumorigenesis. To investigate tumor progression in a state of heightened allergic inflammation, we established a mouse model of allergic inflammation. We used house dust mite extract to induce a hyper-reactive systemic immune response. Additionally, we subcutaneously inoculated two types of cancer cells (CT26 and 4T1 tumors). We conducted immune profiling of the ex-vivo tumor mass using multicolor flow cytometry staining and performed dynamic analysis of peripheral cytokines to explore the significant relationship between the development of allergic inflammation and tumorigenesis. We found that mice in a state of allergic inflammation were more susceptible to developing tumors. Interestingly, the growth of T cell-inflamed was inhibited in the allergic state, while growth of non-T cell-inflamed was promoted. Further research revealed that natural killer (NK) cells with enhanced tumor-killing or immune-regulating abilities were more active in " hot " tumors. Inhibiting NK cell activity can partially alleviate the impact of allergic inflammation on tumor growth. In summary, our results suggest that NK cells play significant role in suppressing tumor growth in an allergic inflammation mouse model. This phenomenon seems to be closely linked to both the inherent characteristics of the tumor and its interaction with the immune system. The innate immune system can be mobilized to synergize with the adaptive immune system to inhibit tumor growth, which opens a new way for a tumor immunotherapy.


Recommendations for cervical cancer prevention in Latin America and the Caribbean.
Cervical cancer control in the Latin America and Caribbean (LAC) region has been, and remains, a priority and a major public health challenge. It also provides the opportunity for the advancement of research into novel cervical cancer preventative tools including the use of prophylactic human papillomavirus (HPV) vaccines, HPV-based screening options and low technology visual inspection methods. The challenges for prevention are compounded because cervical cancer cases continue to cluster in the low socio-economic and rural populations, thus requiring strong political and social commitments to ensure effective implementation in the region. Although cytology-based screening activities exist in the majority of LAC countries, these have been largely based on opportunistic screening services. Evaluation of the impact of screening is often focused on assessing coverage of the population with Pap smears. However, regardless of the chosen technology a screening program requires a complex set of activities that must also be of high quality such us ensuring access of the underserved populations to the program, maintaining routine quality controls of the screening procedures and organizing the proper follow-up of women with abnormal screening results. The cost of the HPV vaccine and of the delivery infrastructure required is currently a significant obstacle for widespread introduction that will require collaborative resolve between public health organizations, governments and vaccine manufacturers. It is important to ensure that HPV vaccines are made available to the wider public, not only to those who can afford it. This monograph and the associated regional reports have carefully identified and discussed the many challenges and opportunities to be considered for policy decisions, in particular the complex interplay between vaccination strategies and subsequent screening requirements. An advanced cost-benefit analysis, using models calibrated to specific countries in the region, presents the range of options and relative costs thus providing evidence-based scientific guidance to governments and providers in the context of a significant and systematic international review effort.


Prevalence and degrees of myopia and hyperopia at Gondar University Hospital Tertiary Eye Care and Training Center, Northwest Ethiopia.
Refractive errors are the second and third leading cause of visual impairment and blindness in Ethiopia, respectively. The situation is worse where accessing spectacles, which are the only management option in developing countries, is a major issue. Gondar University Hospital Tertiary Eye Care and Training Center is the only referral eye care center, and it lacks published evidence on the prevalence and degrees of refractive errors (myopia and hyperopia). The purpose of this study was to determine the prevalence and degrees of myopia and hyperopia at Gondar University Tertiary Eye Care and Training Center. Records of 1,921 patients presented to refraction service at Gondar University Hospital Tertiary Eye Care and Training Center from January 2010 to January 2014 were reviewed. All cases of refractive errors (with visual improvement of at least one line) were converted into spherical equivalents (SE = sphere + ½ cylinder). Myopia was defined as SE ≤ -0.25 D and hyperopia ≥ +0.25 D. The study comprised of 61.1% males and 38.9% females; the patients had an average age of 40±17 years. The overall prevalence of refractive errors (myopia and hyperopia) was 76.3% (95% confidence interval: 75%-77%). Myopia was present in 34.5% patients and hyperopia in 38.3%. Low-degree hyperopia (86%) and low-degree myopia (49.5%) were the most frequent refractive errors. Myopia and hyperopia are major reasons for patients to visit Gondar University Hospital Tertiary Eye Care and Training Center. Low-degree myopia and hyperopia were the most common refractive errors. Stocking appropriate power lenses is needed at this tertiary eye care center in order to alleviate this problem in Ethiopia.


Neural basis of in-group bias and prejudices: A systematic meta-analysis.
In-group favoritism and prejudices relate to discriminatory behaviors but, despite decades of research, understanding of their neural correlates has been limited. A systematic coordinate-based meta-analysis of functional magnetic resonance imaging (fMRI) studies (altogether 87 original datasets, n = 2328) was conducted to investigate neural inter-group biases, i.e., responses toward in-group vs. out-group in different contexts. We found inter-group biases in some previously identified brain regions (e.g., the medial prefrontal cortex, insula) but also in many previously non-identified brain regions (e.g., the cerebellum, precentral gyrus). Sub-group analyses indicated that neural correlates of inter-group biases may be mostly context-specific. Regarding different types of group memberships, inter-group bias toward trivial groups was evident only in the cingulate cortex, while inter-group biases toward "real" groups (ethnic, national, or political groups) involved broader sets of brain regions. Additionally, there were heightened neural threat responses toward out-groups' faces and stronger neural empathic responses toward in-groups' suffering. We did not obtain significant publication bias. Overall, the findings provide novel implications for theory and prejudice-reduction interventions.


CircHULC accelerates the growth of human liver cancer stem cells by enhancing chromatin reprogramming and chromosomal instability via autophagy.
Although CircHULC was overexpressed in several cancers, the role of CircHULC in malignancies has yet to be elucidated. Gene infection, tumorigenesis test in vitro and in vivo and the signaling pathway analysis were performed. our results indicate that CircHULC promotes growth of human liver cancer stem cells and the malignant differentiation of hepatocyte-like cells. Mechanistically, CircHULC enhances the methylation modification of PKM2 via CARM1 and the deacetylase Sirt1. Moreover, CircHULC enhances the binding ability of TP53INP2/DOR with LC3 and LC3 with ATG4, ATG3, ATG5, ATG12. Therefore, CircHULC promotes the formation of autophagosomes. In particular, the binding ability of phosphorylated Beclin1 (Ser14) to Vps15, Vps34, ATG14L were significantly increased after CircHULC was overexpressed. Strikingly, CircHULC affects the expression of chromatin reprogramming factors and oncogenes through autophagy. Thereafter, Oct4, Sox2, KLF4, Nanog, and GADD45 were significantly decreased and C-myc was increased after CircHULC was overexpressed. Thus, CircHULC promotes the expression of H-Ras, SGK, P70S6K, 4E-BP1, Jun, and AKT. Interestingly, both CARM1 and Sirt1 determine the cancerous function of CircHULC dependent on autophagy. we shed light on the fact that the targeted attenuation of deregulated functioning of CircHULC could be a viable approach for cancer treatment, and CircHULC may acts as the potential biomarker and therapeutic target for liver cancer.


Fertility-Sparing Treatment for Endometrial Cancer: Oncological and Obstetric Outcomes in Combined Therapies with Levonorgestrel Intrauterine Device.
The prevalence of reaches up to 5% in women younger than 40 years. Therefore, the fertility preservation should be the goal of the clinical practice in women with desire of pregnancy and low-risk features. The aim of this study is to compare oncological and reproductive outcomes of different hormonal therapies in FST of EC. A retrospective single-center study recruiting patients with presumed FIGO STAGE IA endometrioid G1 EC from 2005 to 2020 was performed. We assessed outcomes for three different therapeutic options: GnRHa + LNG-IUD vs. MA + LNG-IUD vs. MA + LNG-IUD + MET. In total, 75 patients were enrolled and followed up for a median of 45 months. Complete response (CR) was achieved in 75% of patients at 12 months. Although not statistically significant, we reported an increasing rate of CR from the regimen with GnRHa to the one with MA + MET (65% vs. 83%). We showed a statistically significant lower risk of recurrence in women treated with MA + LNG-IUD + MET, when compared to GnRHa + LNG-IUD regimen. The pregnancy rate was 74% and live birth rate was 42%, with no differences among regimens. FST is a safe and effective option in women who desire to preserve fertility.


Neutral microprotein, a novel human plasma and urinary protein associated with a yellow-brown chromophore. Isolation from protein HC preparations and partial characterization.
An apparently novel human plasma and urinary protein of low molecular weight was isolated from several highly purified preparations of protein HC by gel chromatography and high voltage electrophoresis with a yield of about 8 mg/g. The protein has a molecular weight of about 20,000, neutral electrophoretic mobility at pH 6.5 and a high content of half-cystine. It is associated with a yellow-brown chromophore like protein HC and could be demonstrated in all investigated preparations of isolated human, rabbit and guinea-pig protein HC and alpha 1-microglobulin.


A retrospective study of length of hospital stay in infants treated for neonatal abstinence syndrome with methadone versus oral morphine preparations.
Length of hospital stay (LOS) of infants treated for neonatal abstinence syndrome (NAS) with methadone was compared to LOS of those treated with an oral morphine preparation (OMP, neonatal morphine solution, or deodorized tincture of opium). A retrospective review of medical records of infants treated for NAS due to in utero exposure to methadone and/or illicit drugs such as heroin or morphine was performed for birthweight, neonatal abstinence scores, infant and maternal illicit drug exposure history, maternal methadone dose (if any), and details of treatment. Length of stay was the primary outcome measure. Forty-six infants met the inclusion criteria. The median LOS of infants treated with methadone versus OMP was not significant (P > 0.05). Prolonged LOS was associated with larger pharmacological treatment doses required to control withdrawal symptoms, larger maternal methadone dose, and increased birthweight. After adjusting for these factors, exposure to opioids in utero, maternal nicotine use, hospital of treatment, severity of withdrawal symptoms, and foster care placement were not significantly associated with LOS in univariate or multivariate analyses. These results suggest that infants treated with OMP or methadone have similar LOS. Longer LOS is associated with both higher maternal methadone doses and higher opioid treatment dose requirements after birth. The potential effect of maternal methadone dose on neonatal LOS should be considered when treating expectant mothers on methadone maintenance therapy.


ATP regulates muscarine-sensitive potassium current in dissociated bull-frog primary afferent neurones.
1. Bull-frog dorsal root ganglion cells in primary culture were voltage clamped in the whole-cell configuration. The pipette solution contained ATP (5 mM). 2. Step depolarizations (5-70 mV, 0.1-1 s) from a holding potential close to the resting potential (range, -64 to -79 mV) evoked a non-inactivating potassium current with properties indistinguishable from those which have been reported for the M-current of bull-frog sympathetic neurones. 3. An unhydrolysable ATP analogue APP(NH)P (5 mM), substitute with ATP in the pipette solution, did not support the M-current activation. 4. Bath application of ATP (30 nM-30 microM) reduced the amplitude of the M-current in a concentration-dependent manner, congruent to 50% inhibition of the current occurring with 1 microM-ATP. The main effect of ATP was to reduce the maximum M-conductance without changing the activation and deactivation kinetics of the M-current. 5. Essentially the same results were obtained with ADP (0.1-30 microM) and alpha, beta-methylene-ATP (10-30 microM). AMP (10-100 microM) and adenosine (10-30 microM) were without effect on the M-current. 6. The ATP-induced inhibition of the M-current was irreversible when an unhydrolysable GTP analogue GTP-gamma-S (10-30 microM) was present in the pipette solution. ATP (3 microM) reduced the amplitude of the M-current only by about 10% when GDP-beta-S (100 microM) was present in the pipette solution. Pre-treatment of the cells with pertussis toxin (IAP; 500 ng ml-1) for 24 h at 24 degrees C did not prevent the ATP-induced M-current inhibition. 7. Phorbol 12-myristate 13-acetate (PMA; 1-3 microM) reduced the amplitude of the M-current to about 50%. A reduction in the M-current amplitude by PMA (3 microM) and ATP (10 microM) was attenuated when staurosporine (200 nM) was present in the pipette solution. Forskolin (10 microM) was without effect on the M-current. 8. It is concluded that ATP acting at P2 receptors, associated with an IAP-insensitive GTP-binding protein, inhibits the M-current in amphibian primary afferent neurones.


GDNF family ligand immunoreactivity in the gut of teleostean fish.
Glial-derived neurotrophic factor (GDNF), neurturin (NRTN), persephin (PSPN), and artemin (ARTN) are a group of proteins belonging to the GDNF family ligands (GFLs). GDNF, NRTN, and ARTN support the survival of central, peripheral, and autonomic neuron populations, while PSPN supports the survival of only several central neuron populations. A common receptor, RET, modulates the action of this family and a co-receptor, GFRalpha, determines RET ligand specificity. GDNF and NRTN appear to be essential for enteric nervous system (ENS) development in mammals, zebrafish, and other teleostean species. GFLs are also essential for the maintenance and plasticity of adult mammalian ENS. In this study, the distribution pattern of GFLs in the intestine of five adult fish (bass, gilt-head, scorpionfish, trout, and zebrafish) was evaluated by immunochemical and immunocytochemical analysis. The results demonstrated the presence of GDNF, NRTN, and ARTN in the gut of all species studied. They appeared to be spread in the ENS and/or endocrine cells of the intestine. These findings suggest that the presence of GFLs in fish gut is not only limited to developmental period, but could be also involved in the enteric physiology of adult species.


Growth hormone treatment of idiopathic short stature: clinical studies.
The selection of short-statured children for growth hormone (GH) treatment has long been complicated by the requirement for provocative testing that is unphysiologic, difficult to administer, and potentially dangerous. The recent FDA approval of GH for the treatment of children with idiopathic short stature allows treatment decisions to be based more on the degree of short stature and the potential for attaining a normal adult height. Several studies conducted in children have shown that GH therapy can effectively and safely produce height outcomes within a normal adult range. The observed variability in height response associated with GH use in some of these studies has left the clinician with a difficult decision. Still, the availability of GH for this patient population provides a rational treatment option for patients who fail arbitrary and inaccurate assessments.


Quantitative elucidation of the transfer of the neonicotinoid pesticide clothianidin to the breast milk in mice.
Neonicotinoid pesticides (NNs) have been reported to have neurobehavioral effects on offspring after fetal and lactational exposure. In this study, clothianidin (CLO), an NN, was administered orally as a single dose (6.5 mg/kg: 1/10 of the no-observed-adverse-effect level in the current Pesticide Evaluation Report) to 10-day post-partum ICR mice, and CLO and its metabolites desmethyl-CLO (dm-CLO) were quantified using liquid chromatography-electrospray ionization/tandem mass spectrometry (LC-ESI/MS/MS) after collecting maternal breast milk and blood samples over time (1, 3, 6, 9, 12, and 24 h after administration). CLO and dm-CLO were detected in the breast milk at 1 h after the administration, and their concentrations were significantly higher than those in blood at all time points. The concentrations of CLO and dm-CLO in the breast milk were at their highest levels at 1 and 3 h, respectively, and then decreased over time to become almost undetectable at 24 h after the administration. These results show that CLO is metabolized in the mother's body and is rapidly transferred to and concentrated in the breast milk. Since CLO concentrations in breast milk are higher than those in the blood, there is concern about the effects of CLO during lactation.


Paradoxical dose- and time-dependent regulation of superoxide dismutase and antioxidant capacity by vitamin E in rat.
Previous data about the regulation of SOD activity as the key part of the endogenous antioxidant system by vitamin E is conflicting. We investigated the effect of different nontoxic doses of vitamin E on erythrocyte SOD activity and plasma total antioxidant capacity in rats, receiving 0 (control group), 100, 300 and 600 mg vitamin E/kilogram of body weight intramuscularly twice a week over 6-weeks. We observed a linear increase in SOD activity in the first dosing group, which was significant (p<0.05) after 6th week compared to the control level. There was an increase in SOD activity at the end of 2nd and significant increase after 4th weeks, which was followed by a significant decrease at the end of 6th week in the second dosing group. In the third dosing group, there was a significant increase at the end of 2nd week and a significant decrease at the end of 4th and 6th weeks in the SOD activity. The changes in plasma antioxidant capacity were parallel to that of SOD activity with a significant and strong degree of correlation in the 4th and 6th weeks (r=0.7 and r=0.8, respectively). Serum levels of Vitamin E also increased in a time- and dose-dependent manner; the highest level was achieved in the 600 mg/kg dosing group after 6 weeks. Non-toxic doses of vitamin E at some levels can up-regulate SOD activity, but cumulative effect of the same doses can lead to attenuation of SOD activity and hence antioxidant defense.


Long term production of acute-phase proteins by adult rat hepatocytes co-cultured with another liver cell type in serum-free medium.
Three acute-phase proteins, haptoglobin, alpha 2-macroglobulin and hemopexin, as well as albumin, have been measured daily in the hydrocortisone-supplemented serum-free medium of pure and mixed cultures of adult rat hepatocytes for 5 and 20 days respectively. Whereas plasma protein production rapidly declined in pure culture, it remained relatively stable when hepatocytes were co-cultured with rat liver epithelial cells. In the latter cultures, an early stimulation of albumin and alpha 2-macroglobulin secretion was observed. In addition, four other plasma proteins, fibrinogen, alpha 1-acute-phase protein, alpha 1-acid glycoprotein and alpha 1-antitrypsin were shown by immunodiffusion to still be produced by day 20 of co-culture. These results suggest that hepatocyte co-cultures represent a suitable model for studying the mechanism which controls synthesis of plasma proteins, including acute-phase proteins by liver cells.


Modeling violation of Hawaii's crosswalk law.
In 2005, Hawaii strengthened its pedestrian crosswalk laws. Previously, motorists had the option yielding or slowing down at a crosswalk and had to stop "only when necessary." The new law requires drivers to stop and yield to pedestrians at crosswalks. The purpose of this study is to examine patterns of violation and compliance with the law among both pedestrians and drivers. Observational studies at crosswalks were done in the Spring of 2006. In addition to reporting on overall rates of compliance, the characteristics of both pedestrians and drivers who either violate or comply with the law are described. While pedestrian compliance is higher than that of drivers, there are interesting differences to report in terms of age, gender, type of intersection, land use, and other factors. In addition to the results of a descriptive analysis, logistic regression models predicting the likelihood of violation of the crosswalk laws by either pedestrians or drivers, as a function of their characteristics, the type of intersection, and other factors are presented. The study finds that drivers tend to commit proportionately more violations than pedestrians, and violations are committed by a broader range of drivers than pedestrians. These results suggest that education and enforcement should be directed towards drivers. Future directions for research and enhancing the safety of pedestrians are described in a concluding section.


A quantitative microiontophoretic analysis of the responses of central neurones to noradrenaline: interactions with cobalt, manganese, verapamil and dichloroisoprenaline.
1. A new experimental procedure has been devised for the study of pharmacological antagonism in the central nervous sytem using automated microiontophoresis to deliver pulses of agonists and computer-generated histograms to quantify the neuronal response. The system allows study of potential antagonists having direct depressant effects and also of neurones with irregular or slow discharge rates. 2. The histogram analysis reveals the necessity for regular, periodic delivery of agonists during the assessment of agonist-antagonist interactions. Without regular repetitive delivery, many agonists, such as noradrenaline, exhibit an apparent but artifactual decrease in inhibitory potency after an interruption of agonist pulses. Examples of this phenomenon are shown, using cerebellar Punkinje cells and cerebral cortical neurones in rats anaesthetized with halothane. 3. Preliminary results with these computer-generated drug response histograms revealed manganese, cobalt, and verapamil to be generally ineffective as antagonists of noradrenaline, despite their direct depressant effects. 4. Conversely, dichloroisoprenaline (DCI), a beta-adrenoceptor antagonist, was effective in blocking noradrenaline-induced depressions of firing in the cerebral cortex at doses which caused over 50% decrease in spontaneous discharge.


Virtual Fencing Technology Excludes Beef Cattle from an Environmentally Sensitive Area.
The eShepherd® virtual fencing system being commercialized for cattle has the potential to exclude cattle from environmentally sensitive areas. Animals are given audio cues to indicate a fence line via a neckband device. An electrical pulse is administered if the animal continues moving forward following an audio cue. A commercial trial was conducted in South Australia to assess whether virtual fencing technology could exclude 20 cattle from an area of regenerating saplings; across 44 days; using a contoured fence line. The results showed that the cattle were able to rapidly learn the virtual fencing cues; responding appropriately to the audio cue for 74.5% of 4378 audio signals; and were excluded from the regenerating area for 99.8% of the trial period with the more complex fence line (contoured; not straight) in place. IceQube R's® measuring lying time and bouts showed no consistent increasing or decreasing pattern of change. At the trial conclusion; the feed available in the protected zone was double the quantity and quality of the grazed zone. Technical issues occurred with some of the pre-commercial prototype devices; but those versions are now obsolete. This study observed a single group of cattle in one paddock; further testing of the virtual technology is warranted.


Anti-androgenic activities of diuron and its metabolites in male Nile tilapia (Oreochromis niloticus).
Diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea) is a widely used herbicide which has been frequently detected in surface waters throughout the world. In vivo bioassay guided fractionation studies indicated that diuron may have estrogenic activity augmented by biotransformation. This study evaluated the effects of diuron and three of its metabolites on plasma hormone concentrations and spermatogenesis of the freshwater fish Nile tilapia (Oreochromis niloticus). Sexually mature male fish were exposed for 25 days to diuron, as well to its metabolites 3,4-dichloroaniline (DCA), 3,4-dichlorophenylurea (DCPU) and 3,4-dichlorophenyl-N-methylurea (DCPMU), at concentrations of 200ng/L. Testosterone levels were decreased by diuron, but had limited effects on gonadal histology. Diuron metabolites, however, caused significant decreases in testosterone and in 11-ketotestosterone, gonadosomatic index, diameter of seminiferous tubules and in the mean percentages of germ cells (spermatids and spermatozoa). We conclude that these metabolites have antiandrogenic activity to male Nile tilapia, potentially causing reproductive impairment in male fish.


Transforming growth factor beta 1 modulates extracellular matrix organization and cell-cell junctional complex formation during in vitro angiogenesis.
Transforming growth factor-beta 1 (TGF-beta 1) is angiogenic in vivo. In two-dimensional (2-D) culture systems microvascular endothelial cell proliferation is inhibited up to 80% by TGF-beta 1; however, in three-dimensional (3-D) collagen gels TGF-beta 1 is found to have no effect on proliferation while eliciting the formation of calcium and magnesium dependent tube-like structures mimicking angiogenesis. DNA analyses performed on 3-D cell cultures reveal no significant difference in the amount of DNA or cell number in control versus TGF-beta 1 treated cultures. In 2-D cultures TGF-beta 1 is known to increase cellular fibronectin accumulation; however, in 3-D cultures no difference is seen between control and TGF-beta 1 treated cells as established by ELISA testing for type IV collagen, fibronectin, and laminin. In 3-D cultures there is increased synthesis and secretion of type V collagen in both control and TGF-beta 1 treated cultures over 2-D cultures. Even though an equal amount of type V collagen is seen in both 3-D conditions, there is a reorganization of the protein with concentration along an organizing basal lamina in TGF-beta 1 treated cultures. EM morphological analyses on 3-D cultures illustrate quiescent, control cells lacking cell contacts. In contrast, TGF-beta 1 treated cells show increased pseudopod formation, cell-cell contact, and organized basal lamina-like material closely apposed to the "abluminal" plasma membranes. TGF-beta 1 treated cells also appear to form junctional complexes between adjoining cells. Immunofluorescence using specific antibodies to the tight junction protein ZO-1 results in staining at apparent cell-cell junctions in the 3-D cultures. Northern blots of freshly isolated microvascular endothelium, 2-D and 3-D cultures, using cDNA and cRNA probes specific for the ZO-1 tight junction protein, reveal the presence of the 7.8 kb mRNA. Western blots of rat epididymal fat pad endothelial cells (RFC) monolayer lysates probed with anti-ZO-1 label a 220 kd band which co-migrates with the bonafide ZO-1 protein. These data confirm and support the hypothesis that TGF-beta 1 is angiogenic in vitro, eliciting microvascular endothelial cells to form tube-like structures with apparent tight junctions and abluminal basal lamina deposition in three-dimensional cultures.


The antioxidant and anti-inflammatory effects of Carica Papaya Linn. seeds extract on CCl4-induced liver injury in male rats.
Oxidative stress (OS) and inflammation are the central pathogenic events in liver diseases. In this study, the protective and therapeutic role of Carica Papaya Linn. seeds extract (SE) was evaluated against the hepatotoxicity induced by carbon tetrachloride (CCl4) in rats. The air-dried papaya seeds were powdered and extracted with distilled water. The phytochemical ingredients, minerals, and antioxidant potentials were studied. For determination of the biological role of SE against hepatotoxicity induced by CCl4, five groups of adult male Sprague-Dawley rats were prepared (8 rats per each): C: control; SE: rats were administered with SE alone; CCl4: rats were injected subcutaneously with CCl4; SE-CCl4 group: rats were administered with SE orally for 2 weeks before and 8 weeks during CCl4 injection; SE-CCl4-SE group: Rats were administered with SE and CCl4 as mentioned in SE-CCl4 group with a prolonged administration with SE for 4 weeks after the stopping of CCl4 injection. Then, the markers of OS [lipid peroxidation (LP) and antioxidant parameters; glutathione (GSH), superoxide dismutase (SOD), glutathione-S-transferase (GST), glutathione peroxidase (GPx)], inflammation [nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α, interleukin (IL)-6], fibrosis [transforming growth factor (TGF)-β], apoptosis [tumor suppressor gene (p53)], liver and kidney functions beside liver histopathology were determined. The phytochemical analyses revealed that SE contains different concentrations of phenolics, flavonoids, terpenoids, and minerals so it has potent antioxidant activities. Therefore, the treatment with SE pre, during, and/or after CCl4 administration attenuated the OS induced by CCl4 where the LP was reduced, but the antioxidants (GSH, SOD, GST, and GPx) were increased. Additionally, these treatments reduced the inflammation, fibrosis, and apoptosis induced by CCl4, since the levels of NF-κB, TNF-α, IL-6, TGF-β, and p53 were declined. Accordingly, liver and kidney functions were improved. These results were confirmed by the histopathological results. SE has protective and treatment roles against hepatotoxicity caused by CCl4 administration through the reduction of OS, inflammation, fibrosis, and apoptosis induced by CCl4 and its metabolites in the liver tissues. Administration of SE for healthy rats for 12 weeks had no adverse effects. Thus, SE can be utilized in pharmacological tools as anti-hepatotoxicity.


[Conservative therapy of cartilage defects of the upper ankle joint].
Cartilage defects of the upper ankle joint reflect the problem that great force is transmitted and balanced out over a relatively small surface area. As a pathophysiological factor, cartilage-bone contusions play a significant role in the development of cartilage defects of the upper ankle joint. Physiotherapeutic procedures belong to the standard procedures of conservative therapy. The use and selection of the type of therapy is based on empirical considerations and experience and investigations on effectiveness of particular therapies are relatively rare. At present a symptom-oriented therapy of cartilage defects of the upper ankle joint seems to be the most sensible approach. It can be assumed that it makes sense that the symptomatic treatment of cartilage defects or initial stages of arthritis also includes the subsequent symptoms of pain, irritated condition and limited function. This leads to starting points for physiotherapy with respect to pain therapy, optimisation of pressure relationships, avoidance of pressure points, improvement of diffusion and pressure release. In addition to the differential physiotherapeutic findings, the determination of a curative, preventive or rehabilitative procedure is especially important. In physical therapy special importance is placed on a scheduled serial application corresponding to the findings, employing the necessary methods, such as physiotherapy, sport therapy, medical mechanics, manual therapy, massage, electrotherapy and warmth therapy. From this the findings-related therapy is proposed as a practical therapy concept: locomotive apparatus pain therapy, optimisation of pressure relationships, improvement of diffusion and decongestion therapy. Therapy options have been selected base on the current literature and are summarised in tabular form. The art of symptomatic therapy of cartilage defects of the upper ankle joint does not lie in the multitude of sometimes speculative procedures, but in the targeted selection of a therapy regime based on the therapeutic goal, a corresponding application dose and serial design.


The impact of therapists' words on the adolescent brain: In the context of addiction treatment.
At this time, we still do not know how therapist behaviors influence adolescent brain response and related treatment outcomes. Therefore, we examined this question with 17 binge drinking youth (mean age=16.62 years; 64.3% female; 42.9% Hispanic; 28.6% bi-/multi-racial). In this within-subjects design, all youth completed a baseline assessment, two therapy sessions, an fMRI scan, and were re-evaluated for behavior change at one-month post-treatment. During the fMRI session, youth were presented with two types of responses from their treating therapist: higher-skill statements prescribed in an empirically-supported addiction treatment (complex reflections) vs. language standard within addiction treatment more broadly (closed questions). In terms of behavior change, at the one-month follow-up, youth showed significant reductions in number of drinking days and binge drinking days. Further, we found main effects for complex reflections and closed questions across the superior middle temporal gyrus and middle temporal gyrus (FWE-corrected, p<.05). Greater brain response was observed for complex reflections versus closed questions within the bilateral anterior cingulate gyrus. Greater BOLD response in the parietal lobe during closed questions was significantly associated with less post-treatment drinking. Lower BOLD response during complex reflections and closed questions in the precuneus were associated with greater post-treatment ratings of importance of changing. This study represents a first step in understanding how therapist behaviors influence the developing adolescent brain and how that neural response may be associated with youth treatment outcomes.


5-Amino-1-(4-nitro-phen-yl)-1H-pyrazole-3-carbonitrile.
The title compound, C(10)H(7)N(5)O(2), was synthesized by the reaction of 4-nitro-aniline and 2,3-dicyano-propionic acid ethyl ester. In the crystal, N-H⋯O and C-H⋯O hydrogen bonds link the mol-ecules, forming a three-dimensional network.


Progressive loss of cortical acetylcholinesterase activity in association with cognitive decline in Alzheimer's disease: a positron emission tomography study.
We measured brain acetylcholinesterase activity in 30 patients with Alzheimer's disease (AD) and 14 age-matched controls by positron emission tomography (PET) and using a carbon 11-labeled acetylcholine analogue. Seven AD patients had repeat PET scans. The k3 values were calculated as an index of acetylcholinesterase activity in a three-compartment analysis using the metabolite corrected arterial input function. Twenty-eight of the 30 AD patients (14 each in the early and late onset subgroups) were retained in the study so as to equalize the range and average severity of cognitive impairment within the early and late onset subgroups. The k3 values were significantly reduced in the neocortex, hippocampus, and amygdala in the early onset AD patients, although the k3 values were significantly reduced only in the temporoparietal cortex and amygdala in the late onset AD patients. In the longitudinal study, all 7 repeat AD patients showed further reduction of cortical k3 values in the second PET scans, with a mean interval of 2 years, suggesting a progressive loss of the ascending cholinergic system from the nucleus basalis of Meynert in AD. In 37 AD patients, there was a highly significant correlation between the cortical k3 values and Mini-Mental State Examination scores, supporting the cholinergic hypothesis in AD.


Molecular identification of Lodoicea maldivica (coco de mer) seeds.
The edible endosperm of Lodoicea maldivica with the common name of coco de mer is used in Chinese medicine for treating cough. Native to Seychelles, Lodoicea maldivica seeds have commanded high prices for centuries due to its scarcity. This study aims to develop a molecular identification method for the authentication of Lodoicea maldivica seeds. DNA was extracted from the sample. Two polymerase chain reaction (PCR) systems were developed to amplify a region of the chloroplast DNA and the nuclear phosphoribulokinase (PRK) region specific to Lodoicea maldivica respectively. DNA sequence of a sample was determined and compared with that of the Lodoicea maldivica reference material. The PRK gene of Lodoicea maldivica was successfully amplified and sequenced for identification. A new molecular method for the identification of Lodoicea maldivica seeds in fresh, frozen or dried forms was developed.


The impact of the nonpeptide corticotropin-releasing hormone antagonist antalarmin on behavioral and endocrine responses to stress.
The nonpeptide CRH antagonist antalarmin has been shown to block both behavioral and endocrine responses to CRH. However, it's potential activity in blunting behavioral and endocrine sequelae of stressor exposure has not been assessed. Because antagonism of central CRH by alpha-helical CRH attenuates conditioned fear responses, we sought to test antalarmin in this regard. In addition, it remains unclear as to whether this is a result of receptor blockade during conditioning or during testing. Thus, we explored whether CRH mediates the induction or expression of conditioned fear (freezing in a context previously associated with 2 footshocks; 1.0 mA, 5 sec each). Furthermore, because rats previously exposed to inescapable shock (IS; 100 shocks, 1.6 mA, 5 sec each), demonstrate enhanced fear conditioning, we investigated whether this effect would be blocked by antalarmin. Antalarmin (20 mg/kg x 2 ml i.p.) impaired both the induction and expression of conditioned fear. In addition, antalarmin blocked the enhancement of fear conditioning produced by prior exposure to IS. Despite the marked behavioral effects observed in antalarmin-treated rats, antalarmin had no effect on IS-induced rises in ACTH or corticosterone. However, antalarmin did block the ACTH response produced by exposure to 2 footshocks.


Pharmaceutical industry-authored preprints: scientific and social media impact.
Non-peer-reviewed manuscripts posted as preprints can be cited in peer-reviewed articles, which has both merits and demerits. International Committee of Medical Journal Editors guidelines mandate authors to declare preprints at the time of manuscript submission. We evaluated the trends in pharma-authored research published as preprints and their scientific and social media impact by analyzing citation rates and altmetrics. We searched EuroPMC, PrePubMed bioRxiv and medRxiv for preprints submitted by authors affiliated with the top 50 pharmaceutical companies from inception until 15 June 2020. Data were extracted and analyzed from the search results. The number of citations for the preprint and peer-reviewed versions (if available) were compiled using the Publish or Perish software (version 1.7). Altmetric score was calculated using the "Altmetric it" online tool. Statistical significance was analyzed by Wilcoxon rank-sum test. A total of 498 preprints were identified across bioRxiv (83%), PeerJ (5%), F1000Research (6%), Nature Precedings (3%), Preprint.org (3%), Wellcome Open Research preprint (0.2%) and medRxiv (0.2%) servers. Roche, Sanofi and Novartis contributed 56% of the retrieved preprints. The median number of citations for the included preprints was 0 (IQR = 1, Min-Max = 0-45). The median number of citations for the published preprints and unpublished preprints was 0 for both (IQR = 1, Min-Max = 0-25 and IQR = 1, Min-Max = 0-45, respectively; p = .091). The median Altmetric score of the preprints was 4 (IQR = 10.5, Min-Max = 0-160). Pharma-authored research is being increasingly published as preprints and is also being cited in other peer-reviewed publications and discussed in social media.


The short esophagus: intraoperative assessment of esophageal length.
To define the frequency and predictors of short esophagus in a case series of patients undergoing antireflux surgery. An observational prospective study from September 10, 2004, to October 31, 2006, was performed at 8 centers. The distance between the esophagogastric junction as identified by intraoperative esophagoscopy and the apex of the diaphragmatic hiatus was measured intraoperatively before and after esophageal mediastinal dissection; a distance of 1.5 cm was arbitrarily determined to categorize cases as long (>1.5 cm) or short (<or=1.5 cm). One hundred eighty patients were enrolled; the mean age of patients was 49.3 +/- 15.3 years. At the first measurement (after isolation of the esophagogastric junction), the median distance between the esophagogastric junction and the apex of the hiatus was equal to or shorter than 1.5 cm in 68 (37.7%) patients; at the second measurement (after full mediastinal isolation), the measurement of the distance was still shorter than 1.5 cm in 34 (18.8%) patients and between 1.5 and 2.5 cm in 24 (13.4%) patients. The median length of the mediastinal esophageal dissection was 6 cm (range 1-12 cm). An esophageal lengthening procedure was performed in 26 (14.4%) patients. The duration of symptoms (P = .047), the General Health domain of the SF-36 questionnaire (P = .001), and an x-ray barium swallow (P = .000) are predictive factors for a "true" short esophagus. True short esophagus is present in about 20% of patients undergoing routine antireflux surgery. Radiology, severity, and duration of symptoms are predictors of true foreshortening.


Isatuximab plus carfilzomib and dexamethasone versus carfilzomib and dexamethasone in elderly patients with relapsed multiple myeloma: IKEMA subgroup analysis.
In this subgroup analysis of the randomized, Phase 3 IKEMA study (NCT03275285), we evaluated efficacy and safety of the anti-CD38 monoclonal antibody isatuximab (Isa) in combination with carfilzomib-dexamethasone (Isa-Kd) versus Kd in older (≥70 years of age, n = 86) and younger (<70 years, n = 216) patients with relapsed multiple myeloma (MM). Patients received Isa 10 mg/kg intravenously weekly for 4 weeks, then every 2 weeks in the Isa-Kd arm, and approved schedule of carfilzomib (twice weekly) and dexamethasone in both study arms. Primary endpoint was progression-free survival (PFS); key secondary efficacy endpoints included rates of overall response (ORR), very good partial response or better (≥VGPR), minimal residual disease negativity (MRD-), and complete response (CR). Addition of Isa to Kd resulted in improved PFS in elderly patients (hazard ratio, 0.36 [95% CI, 0.18-0.75]) consistent with the significant PFS improvement observed in the overall IKEMA population. Treatment with Isa-Kd improved depth of response versus Kd, with higher rates of ≥VGPR (73.1% vs. 55.9%), MRD- (23.1% vs. 11.8%), and CR (38.5% vs. 23.5%). Although the incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was higher in Isa-Kd, the incidence of serious TEAEs was similar between arms. Fewer elderly patients definitively discontinued treatment due to TEAEs in Isa-Kd than Kd: 11.8% versus 23.5%. In conclusion, Isa-Kd provides a consistent benefit versus Kd in elderly patients, with a manageable safety profile, and represents a new treatment option for patients with relapsed MM, independent of age.


Assessment of Tumor Angiogenesis: Dynamic Contrast-enhanced MR Imaging and Beyond.
Dynamic contrast-enhanced (DCE) MR imaging is used increasingly often to evaluate tumor angiogenesis and the efficacy of antiangiogenic drugs. In clinical practice DCE-MR imaging applications are largely centered on lesion detection, characterization, and localization. In research, DCE-MR imaging helps inform decision making in early-phase clinical trials by showing efficacy and by selecting dose and schedule. However, the role of these techniques in patient selection is uncertain. Future research is required to optimize existing DCE-MR imaging methods and to fully validate these biomarkers for wider use in patient care and in drug development.


Simplified and enhanced VCD analysis of cyclic peptides guided by artificial intelligence.
Cyclic peptides are privileged structures in medicinal chemistry; however, their solution-state structure characterization is difficult. Vibrational circular dichroism (VCD) spectroscopy is a powerful alternative to NMR, but requires challenging calculations. We present a VCD approach guided by a genetic algorithm, which is simple, more effective, and has a higher conformer resolution.


Scanning too many orders at once: the result: drug orders are omitted.
Drug orders can be accidentally omitted or misread if a scanner pulls too many pages through at once.


Assessment of biofilm-forming ability of coagulase-negative staphylococci isolated from contaminated platelet preparations in Canada.
Coagulase-negative staphylococci (CoNS) are the most prevalent bacterial contaminants of platelet (PLT) preparations and have been implicated in adverse transfusion reactions worldwide. The most frequently identified contaminant is Staphylococcus epidermidis, which is noted for its ability to maintain chronic hospital-acquired infections by forming biofilms as a chief virulence mechanism. Strains of S. epidermidis isolated from contaminated PLT preparations in Canada were distinguished via gene-specific polymerase chain reaction (PCR) with divIVA as a marker. Biofilm-forming ability was assessed by the presence of the gene icaD, slime production on Congo red agar, and biofilm formation on polystyrene surfaces. Production of polysaccharide intercellular adhesin (PIA) was resolved by immunofluorescence. Eight of the 13 (62%) CoNS isolates under study were identified as S. epidermidis. Of these, four strains (50%) were classified as strong biofilm producers. Three of the four biofilm-positive strains (75%) produced slime, harbored the icaD gene, and had positive expression of PIA. Despite the presumable commensal origin of the CoNS isolates, a large proportion of S. epidermidis strains demonstrated a potential for enhanced virulence. Identification of contaminant staphylococci as biofilm producers is thus relevant and informative with regard to treatment approach in the circumstance of inadvertent infection of a PLT recipient.


Custom-made 3D-printed cup-cage implants for complex acetabular revisions: evaluation of pre-planned versus achieved positioning and 1-year migration data in 10 patients.
Background and purpose - The use of custom-made 3D-printed titanium implants for the reconstruction of large acetabular defects has been successively introduced in the last decade. In an observational cohort study we evaluated the agreement between preoperatively planned and actually achieved cup-cage position as well as 1-year follow-up migration of the cup-cage component.Patients and methods - 10 patients with Paprosky III defects underwent revision surgery using a custom-made 3D-printed cup-cage. The position of the implant on postoperative CT scan was compared with the preoperative plan and the postoperative CT scan was compared with the 1-year follow-up CT scan.Results - There was a median deviation in postoperative position versus planned in inclination of 3.6° (IQR 1.0-5.4), in anteversion of -2.8° (IQR -7.5 to 1.2), and in rotation of -1.2° (IQR -3.3 to 0.0). The median deviation in position of the center of rotation (COR) was -0.5 mm (IQR 2.9 to 0.7) in the anteroposterior (AP) plane, -0.6 mm (IQR -1.8 to -0.1) in the mediolateral (ML) plane, and 1.1 mm (IQR -1.6 to 2.8) in the superoinferior (SI) plane. The migration between postoperative and 1-year follow-up caused a mean change in inclination of 0.04° (IQR -0.06 to 0.09), in anteversion of -0.13° (IQR -0.23 to -0.06), and in rotation of 0.05° (IQR -0.46 to 1.4). The migration of COR was -0.08 mm (IQR -0.18 to -0.04) in the AP plane, 0.14 mm (IQR -0.08 to 0.22) in the ML plane, and 0.06 mm (IQR -0.02 to 0.35) in the SI plane. There was no re-revision.Interpretation - The early results show good agreement between planned and achieved cup-cage position and small measured migration values of the cup-cage component at the 1-year follow-up.


Presymptomatic genetic screening in families with multiple endocrine neoplasia type 2.
Medullary thyroid carcinoma occurs sporadically or as a part of the inherited cancer syndrome multiple endocrine neoplasia (MEN) type 2. The MEN 2 gene has been identified as the RET proto-oncogene on chromosome 10. In MEN 2A, RET mutations are detectable in one of five cysteine codons within exons 10 and 11 and in MEN 2B in codon 918 (exon 16). Direct DNA testing for RET proto-oncogene mutations is the method of first choice in presymptomatic screening of MEN 2 families. Gene carriers should be offered prophylactic thyroidectomy. The process of DNA analysis for RET proto-oncogene mutations is demonstrated in one family with hereditary medullary thyroid carcinoma. RET mutations were detectable in five of the nine family members at risk.


Correction to: Jejunal pouch reconstruction after total gastrectomy is associated with better short-term absorption capacity and quality of life in early-stage gastric cancer patients.
Following publication of the original article [1], the authors reported that one of the authors' names is spelled incorrectly.


Bacillus subtilis expressing a haemolysin gene from Listeria monocytogenes can grow in mammalian cells.
Intracellular parasites can be classified into those that reside within a host vacuole and those which grow directly in the host cytoplasm. Members of the latter group, which includes Rickettsia, Shigellae, Trypanosoma cruzi, and Listeria monocytogenes, possess haemolytic activity associated with the ability to enter the host cytoplasm. Therefore mutants of L. monocytogenes lacking a pore-forming haemolysin, listeriolysin O, do not escape from the endosomal compartment and consequently fail to become established in the cytoplasm. To examine the role of listeriolysin O, we cloned the structural gene for the L. monocytogenes haemolysin, hlyA, into an asporogenic mutant of Bacillus subtilis under the control of an IPTG-inducible promoter. After being internalized by the macrophage-like cell line J774, haemolytic B. subtilis disrupted the phagosomal membrane and grew rapidly within the macrophage cytoplasm. These results show that a single gene product is sufficient to convert a common soil bacterium into a parasite that can grow in the cytoplasm of a mammalian cell.


Natural occurrence of toxigenic fungi and mycotoxins in rice bran.
Thirty four samples of rice bran, of which 9 were from raw (untreated) rice (RR) and 25 from parboiled rice (PbR) were collected from commercial rice mills in and around Madras and analysed for storage mycoflora and mycotoxins. Fungi of the Aspergillus flavus group were present in 29 of the 34 samples (8 from RR and 21 from PbR) in quantities ranging from less than 1-432 thousand propagules/g, though not always as the dominant mycoflora. Fungal numbers were usually higher in RR than in PbR samples. Five of the 9 RR samples and 6 of the 25 PbR samples were positive for aflatoxins. Among 29 isolates of A. flavus obtained from the bran samples, 16 isolates -6 from RR bran and 10 from PbR bran - were found to be toxigenic in vitro. Some isolates of A. candidus also seemed to produce aflatoxin and other fluorescent substances.


The glycocalyx--linking albuminuria with renal and cardiovascular disease.
Albuminuria is commonly used as a marker of kidney disease progression, but some evidence suggests that albuminuria also contributes to disease progression by inducing renal injury in specific disease conditions. Studies have confirmed that in patients with cardiovascular risk factors, such as diabetes and hypertension, endothelial damage drives progression of kidney disease and cardiovascular disease. A key mechanism that contributes to this process is the loss of the glycocalyx--a polysaccharide gel that lines the luminal endothelial surface and that normally acts as a barrier against albumin filtration. Degradation of the glycocalyx in response to endothelial activation can lead to albuminuria and subsequent renal and vascular inflammation, thus providing a pathophysiological framework for the clinical association of albuminuria with renal and cardiovascular disease progression. In this Review, we examine the likely mechanisms by which glycocalyx dysfunction contributes to kidney injury and explains the link between cardiovascular disease and albuminuria. Evidence suggests that glycocalyx dysfunction is reversible, suggesting that these mechanisms could be considered as therapeutic targets to prevent the progression of renal and cardiovascular disease. This possibility enables the use of existing drugs in new ways, provides an opportunity to develop novel therapies, and indicates that albuminuria should be reconsidered as an end point in clinical trials.