Chromosome analyses of 16 cases of Wilms tumor: different pattern in unfavorable histology

Cytogenetic analyses of 16 cases of Wilms tumor with abnormal karyotypes were reviewed, 15 cases of unilateral tumor and 1 bilateral. Three tumors exhibited an unfavorable histology (i.e., anaplastic changes); the rest fell into the favorable histology group. Of the 17 tumors with abnormal clonal aberrations, 9 tumors were hyperdiploid (53%), 7 had pseudodiploid karyotypes (41%), and 1 was hypodiploid (6%). The most common numerical aberrations in descending order of frequency were gain of chromosomes 12, 8, and 6 and loss of chromosome 16. Structural rearrangements mostly involved chromosome 1, followed by chromosomes 7, 14, and 17. Clustering of breaks around 1p22 approximately p31-->pter resulting in partial loss of 1p was the most frequent structural aberration. Additionally, i(7q) was observed as a sole abnormality in two tumors and a 7p translocation in two other tumors. Two other recurrent abnormalities were a partial deletion of 14q, seen in three tumors, and complete loss of chromosome 14 in one tumor. All three Wilms tumors with unfavorable histology had abnormalities of 17p, resulting in TP53 gene deletion. These findings provide further support for the importance of gains of chromosomes 12, 8, and 6 and loss of 1p in the development of Wilms tumor. The results also support the association of unfavorable-histology Wilms tumors with TP53 deletion. The nonrandom losses of 16/16q, 7p, and 14q may point to the importance of genomic imbalance in the pathogenetic consequences and progression of Wilms tumor.     

Relationship between Serum 25(OH)D and Depression: Causal Evidence from a Bi-Directional Mendelian Randomization Study

The relationship between depression and vitamin D deficiency is complex, with evidence mostly from studies affected by confounding and reverse causality. We examined the causality and direction of the relationship between 25-hydroxyvitamin D (25(OH)D) and depression in bi-directional Mendelian randomization (MR) analyses using information from up to 307,618 white British participants from the UK Biobank and summary results from the SUNLIGHT (n = 79,366) and Psychiatric Genomics consortia (PGC 113,154 cases and 218,523 controls). In observational analysis, the odds of depression decreased with higher 25(OH)D concentrations (adjusted odds ratio (OR) per 50% increase 0.95, 95%CI 0.94–0.96). In MR inverse variance weighted (IVW) using the UK Biobank, there was no association between genetically determined serum 25(OH)D and depression (OR per 50% higher 0.97, 95%CI 0.90–1.05) with consistent null association across all MR approaches and in data from PGC consortium. In contrast, genetic liability to depression was associated with lower 25(OH)D concentrations (MR IVW −3.26%, −4.94%–−1.55%), with the estimates remaining generally consistent after meta-analysing with the consortia. In conclusion, we found genetic evidence for a causal effect of depression on lower 25(OH)D concentrations, however we could not confirm a beneficial effect of nutritional vitamin D status on depression risk.     

Increases in Naloxone Administrations by Emergency Medical Services Providers During the COVID-19 Pandemic: Retrospective Time Series Study

BackgroundThe opioid crisis in the United States may be exacerbated by the COVID-19 pandemic. Increases in opioid use, emergency medical services (EMS) runs for opioid-related overdoses, and opioid overdose deaths have been reported. No study has examined changes in multiple naloxone administrations, an indicator of overdose severity, during the COVID-19 pandemic.ObjectiveThis study examines changes in the occurrence of naloxone administrations and multiple naloxone administrations during EMS runs for opioid-related overdoses during the COVID-19 pandemic in Guilford County, North Carolina (NC).MethodsUsing a period-over-period approach, we compared the occurrence of opioid-related EMS runs, naloxone administrations, and multiple naloxone administrations during the 29-week period before (September 1, 2019, to March 9, 2020) and after NC’s COVID-19 state of emergency declaration (ie, the COVID-19 period of March 10 to September 30, 2020). Furthermore, historical data were used to generate a quasi-control distribution of period-over-period changes to compare the occurrence of each outcome during the COVID-19 period to each 29-week period back to January 1, 2014.ResultsAll outcomes increased during the COVID-19 period. Compared to the previous 29 weeks, the COVID-19 period experienced increases in the weekly mean number of opioid-related EMS runs (25.6, SD 5.6 vs 18.6, SD 6.6; P<.001), naloxone administrations (22.3, SD 6.2 vs 14.1, SD 6.0; P<.001), and multiple naloxone administrations (5.0, SD 1.9 vs 2.7, SD 1.9; P<.001), corresponding to proportional increases of 37.4%, 57.8%, and 84.8%, respectively. Additionally, the increases during the COVID-19 period were greater than 91% of all historical 29-week periods analyzed.ConclusionsThe occurrence of EMS runs for opioid-related overdoses, naloxone administrations, and multiple naloxone administrations during EMS runs increased during the COVID-19 pandemic in Guilford County, NC. For a host of reasons that need to be explored, the COVID-19 pandemic appears to have exacerbated the opioid crisis.     

Safety and efficacy of ultrasound-guided low-pressure perfusion mini-percutaneous nephrolithotomy in children aged 1–7 years: a retrospective observational study

International Urology and Nephrology - This article analyzed the safety and efficacy of ultrasound-guided mini-percutaneous nephrolithotomy (MPCNL) with low-pressure perfusion for the treatment of...     

Metabolism-based inactivation of neuronal nitric-oxide synthase by components of cigarette and cigarette smoke.

It has been shown that administration of cigarette smoke to rats leads to loss of neuronal nitric-oxide synthase (nNOS) activity and nNOS protein in penile tissue. The exact mechanism for this loss of activity and protein is not known. In the current study, we investigated whether extracts prepared from cigarette smoke or from the cigarette itself could directly inhibit nNOS activity. We discovered that the cigarette smoke extract and the cigarette extract cause a time-, concentration-, and calmodulin-dependent inactivation of nNOS in an in vitro system containing the purified enzyme. L-Arginine, but not D-arginine, protects nNOS from this time-dependent inactivation, suggesting an active site directed event. The kinetics of inactivation are consistent with the metabolism-based or suicide inactivation of nNOS. Based on studies with other metabolism-based inactivators, this cigarette-mediated inactivation may render nNOS more susceptible to proteasomal degradation and thereby may explain the loss of nNOS protein in vivo. The component(s) responsible for nNOS inactivation is not volatile, is not retained by a 3,000 molecular weight cut-off membrane, binds to activated charcoal, and is highly water-soluble under both acidic and basic conditions. The discovery of a direct inactivation of nNOS by an organic, cationic compound(s) present in tobacco and tobacco smoke provides a basis for further study of not only the mechanisms responsible for the biological effects of tobacco but also a search for a potentially novel inactivator of nNOS.     

ROLE OF ACULASER THERAPY IN CEREBRAL PALSY CHILDERN （INITIAL DATA ＆ RESULTS）

1　BACKGROUNDTheincidenceofCPis 0 .7per 1 0 0 0livebirths[1 ] .Becausecerebralpalsyinfluencesthewaychildrendevelop,itoftenresultsindevelop mentaldisability .Today ,more peoplehavecerebralpalsythananyotherdevelopmentaldis ability ,includingDownsyndrome,epilepsy ,andautism .Accordingtoasurveyconductedin1 986,2 .6%ofthepopulationofPakistaniaredisabled (includingbothphysicalandmentaldis abilities) .Childrenbetween 0～1 4 yearsinageconstitute 40 %ofthedisabled populationinPakistan .Routineme…     

The effect of dose increase of imatinib mesylate in patients with chronic or accelerated phase chronic myelogenous leukemia with inadequate hematologic or cytogenetic response to initial treatment.

PURPOSE: Imatinib mesylate is a tyrosine kinase inhibitor with high affinity for the BCR-ABL fusion protein expressed by the hematopoietic cells in chronic myelogenous leukemia (CML). Some patients with chronic-phase or accelerated-phase CML either relapse after an initial response or are refractory to imatinib, prompting us to evaluate the efficacy of dose increase in such patients. EXPERIMENTAL DESIGN: Twelve chronic-phase patients initially receiving 400 mg/day and 4 patients with accelerated phase initially receiving either 400 mg/day (two patients) or 600 mg/day (two patients) had their dose increased (14 to 800 mg/day and 2 to 600 mg/day) because of progressive disease (usually clonal evolution) or inadequate cytogenetic response after at least 1 year of therapy. RESULTS: Six patients had major cytogenetic responses after dose increase (3 complete and 3 partial). Two others had minor cytogenetic responses. Two patients with clonal evolution transiently lost the additional clonal aberrations. Almost all of the responses occurred within 6 months, and were typically 3-6 months in duration. However, 3 patients have continuing major cytogenetic responses of >18 months duration. Dose increase was well tolerated, with thrombocytopenia, mild leukopenia, and exacerbation of prior edema being the most common adverse events. CONCLUSIONS: Although increasing the dose of imatinib can benefit a subgroup of patients with CML with either an inadequate cytogenetic response or disease progression, our results suggest the majority will not have a sustained meaningful response, and that other options, such as allogeneic stem cell transplant or investigational therapies, also need to be considered at the time of dose increase.     

Human endometrial nuclear estrogen receptors among Norplant implant users.

Twenty-four parous women were included in this study. Sixteen cases were using the Norplant implant contraceptive system for more than 6 months (Group A) while eight cases served as matched controls in the secretory phase (Group B). Norplant implant users belonged to one of two equal subgroups according to whether they experienced regular menstrual bleeding (Subgroup A1) or prolonged episodes of amenorrhoea (Subgroup A2). Endometrial samples were processed for nuclear oestrogen receptor assay and for evaluation of the receptor's binding affinity to oestrogen. The results showed marked reduction in endometrial nuclear oestrogen receptors in Norplant users compared with controls as the majority of users had undetectable receptor levels. This down-regulation effect was significantly more pronounced among women with prolonged episodes of amenorrhoea. The affinity section of the study revealed no significant differences between groups or subgroups probably due to the small number of subjects with detectable receptor concentrations for comparison. These data may help in the understanding of contraceptive mechanisms and menstrual associated problems, and in the development of therapeutic measures.     

Time-dependent inhibition and tetrahydrobiopterin depletion of endothelial nitric-oxide synthase caused by cigarettes.

Smoking causes a dysfunction in endothelial nitric-oxide synthase (eNOS), which is ameliorated, in part, by administration of tetrahydrobiopterin (BH(4)). The exact mechanism by which the nitric oxide deficit occurs is unknown. We have previously shown that aqueous extracts of chemicals in cigarettes (CE) cause the suicide inactivation of neuronal NO synthase (nNOS) by interacting at the substrate-binding site. In the current study, we have found that CE directly inactivates eNOS by a process that is not affected by the natural substrate l-arginine and is distinct from the mechanism of inactivation of nNOS. We discovered that CE causes a time-, concentration-, and NADPH-dependent inactivation of eNOS in an in vitro system containing the purified enzyme, indicating a metabolic component to the inactivation. The CE-treated eNOS but not nNOS was nearly fully reactivated upon incubation with excess BH(4), suggesting that BH(4) depletion is a potential mechanism of inactivation. Moreover, in the presence of CE, eNOS catalyzed the oxidation of BH(4) to dihydrobiopterin and biopterin by a process attenuated by high concentrations of superoxide dismutase but not catalase. We speculate that a redox active component in CE, perhaps a quinone compound, causes oxidative uncoupling of eNOS to form superoxide, which in turn oxidizes BH(4). The discovery of a direct inactivation of eNOS by a compound(s) present in tobacco provides a basis not only for further study of the mechanisms responsible for the biological effects of tobacco but also a search for a potentially novel inactivator of eNOS.