Viral screening and assisted conception treatment--the Bourn Hall experience.
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Child↗
Biomedical subjects
S Marcus
Publications and source records attributed to S Marcus.
Direct binding and In vivo regulation of the fission yeast p21-activated kinase shk1 by the SH3 domain protein scd2.
The Ste20/p21-activated kinase homolog Shk1 is essential for viability and required for normal morphology, mating, and cell cycle control in the fission yeast Schizosaccharomyces pombe. Shk1 is regulated by the p21 G protein Cdc42, which has been shown to form a complex with the SH3 domain protein Scd2 (also called Ral3). In this study, we investigated whether Scd2 plays a role in regulating Shk1 function. We found that recombinant Scd2 and Shk1 interact directly in vitro and that they interact in vivo, as determined by the two-hybrid assay and genetic analyses in fission yeast. The second of two N-terminal SH3 domains of Scd2 is both necessary and sufficient for interaction with Shk1. While full-length Scd2 interacted with only the R1 N-terminal regulatory subdomain of Shk1, a C-terminal deletion mutant of Scd2 interacted with both the R1 and R3 subdomains of Shk1, suggesting that the non-SH3 C-terminal domain of Scd2 may be involved in defining specificity in SH3 binding domain recognition. Overexpression of Scd2 stimulated the autophosphorylation activity of wild-type Shk1 in fission yeast but, consistent with results of genetic analyses, did not stimulate the activity of a Shk1 protein lacking the R1 subdomain. Results of additional two-hybrid experiments suggest that Scd2 may stimulate Shk1 catalytic function, at least in part, by positively modulating protein-protein interaction between Cdc42 and Shk1. We propose that Scd2 functions as an organizing center, or scaffold, for the Cdc42 complex in fission yeast and that it acts in concert with Cdc42 to positively regulate Shk1 function.
Binding Sites↗
Risperidone use at a state hospital: a clinical audit 2 years after the first wave of risperidone prescriptions.
BACKGROUND: In spite of some inherent limitations, naturalistic data can provide information on populations that have greater heterogeneity than can controlled clinical trials and on functional outcomes that may be especially important in clinical practice. In the present retrospective naturalistic study, we evaluated key clinical outcomes among the first wave of risperidone-treated patients at a state psychiatric hospital. METHOD: Outcome data were extracted from the charts of 142 patients 2 years after initiation of treatment with risperidone. Their diagnoses included DSM-III-R schizophrenia (57%), schizoaffective disorder (22%), dementia and other organic conditions (7%), bipolar disorder (5%), and other psychiatric disorders (9%). RESULTS: During the 2-year period, 92 of 142 patients were discharged from the hospital: 61 (43%) were discharged on risperidone treatment and 31 (22%) were discharged on treatment with other drugs. At the time of the study, 50 of 142 patients were still in the hospital: of these, 18 (13%) were still receiving risperidone. The modal maximum daily dose of risperidone was 4.1 mg in patients discharged on risperidone treatment and 7.5 mg in patients still in the hospital. All groups were granted more ward privileges after starting risperidone, the most being granted to patients discharged from the hospital on risperidone treatment (p<.05 versus patients discharged on treatment with other drugs) and those still receiving risperidone in the hospital. Significantly fewer patients discharged on risperidone treatment than on treatment with other drugs were readmitted to the hospital within 2 years after discharge (p<.01). CONCLUSION: Improved privilege levels and a reduced readmission rate indicate that risperidone was an effective antipsychotic agent among a heterogeneous patient population in a state hospital. These factors may be especially important to justify use of this agent in the current fiscal climate.
Adult↗
Update of geriatric psychiatry practices among American psychiatrists: Analysis of the 1996 National Survey of Psychiatric Practice.
Using data from the 1996 National Survey of Psychiatric Practice from the American Psychiatric Association (APA), the authors updated information on psychiatrists who are high geriatric providers (HGPs). In 1996, HGPs comprised 18% of the sample. Only 23% reported no geriatric patients in their practice, a 51% reduction from 1988-89; the proportion of HGPs is increasing. HGPs were more often male, minority, international medical school graduates, certified in geriatric psychiatry, and not medical school-affiliated. HGPs worked longer hours/week in direct patient care, had more patient visits/week, and saw more new patients/month, spending more time in hospitals and nursing homes and less time in office-based practice, and seeing more patients with mood disorders, psychotic disorders, and other disorders. Medicare was a proportionally higher payment source. Older psychiatrists were likely to have more patients over age 65. Tracking practice activities of HGPs may help inform policy discussion regarding staffing needs for geriatric patients with late-life mental disorders.
Aged↗
5-Aminolevulinic acid photosensitization of dysplastic Barrett's esophagus: a pharmacokinetic study.
Photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) may have a role in the treatment of dysplastic Barrett's esophagus. Before ALA-induced PDT can be used clinically, optimum treatment parameters must be established. In this study of 35 patients, the issues of drug dosage, time interval between drug and light delivery and side effects of oral ALA administration are addressed. Spectrofluorometric analysis of tissue samples demonstrates that oral ALA administration induces porphyrin accumulation in esophageal tissues, with maximum levels at 4-6 h. High-performance liquid chromatography confirms the identity of this porphyrin as PpIX, and fluorescence microscopy analysis demonstrates that it preferentially accumulates in the esophageal mucosa, rather than in the underlying stroma. Side effects of ALA administration included malaise, headache, photosensitivity, alopecia, transient derangement of liver function, nausea and vomiting. Fewer side effects and less hepatic toxicity was seen with 30 mg/kg than 50 mg/kg ALA. In conclusion, oral ALA administration induces preferential PpIX accumulation in the esophageal mucosa, with peak PpIX fluorescence noted at 4 h and minimal systemic toxicity at a dose of 30 mg/kg.
Aminolevulinic Acid↗
Negative regulation of mitosis in fission yeast by the shk1 interacting protein skb1 and its human homolog, Skb1Hs.
We previously provided evidence that the protein encoded by the highly conserved skb1 gene is a putative regulator of Shk1, a p21(Cdc42/Rac)-activated kinase (PAK) homolog in the fission yeast Schizosaccharomyces pombe. skb1 null mutants are viable and competent for mating but less elongate than wild-type S. pombe cells, whereas cells that overexpress skb1 are hyperelongated. These phenotypes suggest a possible role for Skb1 as a mitotic inhibitor. Here we show genetic interactions of both skb1 and shk1 with genes encoding key mitotic regulators in S. pombe. Our results indicate that Skb1 negatively regulates mitosis by a mechanism that is independent of the Cdc2-activating phosphatase Cdc25 but that is at least partially dependent on Shk1 and the Cdc2 inhibitory kinase Wee1. We provide biochemical evidence for association of Skb1 and Shk1 with Cdc2 in S. pombe, suggesting that Skb1 and Shk1 inhibit mitosis through interaction with the Cdc2 complex, rather than by an indirect mechanism. These results provide evidence of a previously undescribed role for PAK-related protein kinases as mitotic inhibitors. We also describe the cloning of a human homolog of skb1, SKB1Hs, and show that it can functionally replace skb1 in S. pombe. Thus, the molecular functions of Skb1-related proteins have likely been substantially conserved through evolution.
Amino Acid Sequence↗
Cloning and characterization of shk2, a gene encoding a novel p21-activated protein kinase from fission yeast.
We describe the characterization of a novel gene, shk2, encoding a second p21(cdc42/rac)-activated protein kinase (PAK) homolog in fission yeast. Like other known PAKs, Shk2 binds to Cdc42 in vivo and in vitro. While overexpression of either shk2 or cdc42 alone does not impair growth of wild type fission yeast cells, cooverexpression of the two genes is toxic and leads to highly aberrant cell morphology, providing evidence for functional interaction between Cdc42 and Shk2 proteins in vivo. Fission yeast shk2 null mutants are viable and exhibit no obvious phenotypic defects. Overexpression of shk2 restores viability and normal morphology but not full mating competence to fission yeast cells carrying a shk1 null mutation. Additional genetic data suggest that Shk2, like Cdc42 and Shk1, participates in Ras-dependent morphological control and mating response pathways in fission yeast. We also show that overexpression of byr2, a gene encoding a Ste11/MAPK kinase kinase homolog, suppresses the mating defect of cells partially defective for Shk1 function, providing evidence of a link between PAKs and mitogen-activated protein kinase signaling in fission yeast. Taken together, our results suggest that Shk2 is partially overlapping in function with Shk1, with Shk1 being the dominant protein in function.
Amino Acid Sequence↗
Relationship between peripheral estrogen concentrations at insemination and subsequent fetal loss in cattle.
In a survey on pregnancy rate and embryonic losses in dairy cattle on 6 Israeli farms, cows (n = 78) were divided into 3 groups on the basis of ultrasonography at 21 d post insemination; pregnancy diagnosis at 40 to 50 d post insemination and blood progesterone (P4) levels at 21 d. The groups were either pregnant (P4 level > 1.0 ng/ mL); not pregnant (P4 < 0.5 ng/mL), or showed early embryo loss (P4 > 1.0 ng/mL and the presence of an embryonic vesicle on D 21 but later returned to estrus or were found not pregnant on D 40 to 50). On the day of insemination, peripheral estrogen was significantly higher (P < 0.05) in the early embryo loss group (15.3 +/- 1.1 pg/mL, n = 27) than in pregnant (9.4 +/- 0.6 pg/mL, n = 26) or not pregnant (9.6 +/- 0.7 pg/mL, n = 25) group. The cows on 3 farms which were fed 1 to 2 kg/d of vetch (Vicia sativa), an estrogenic legume, had higher estrogen concentrations on the day of insemination than cows (2 farms) fed other legumes (13.7 +/- 0.64, n = 58 vs 10.7 +/- 0.8 pg/mL, n = 42; P < 0.01). On one of the 3 farms, vetch was replaced with alfalfa after the first year. Following the cessation of vetch feeding the estrogen concentrations in the blood decreased from 32 +/- 5 pg/mL to 14 +/- 2 pg/mL (n = 9). These data suggest that high peripheral estrogen on the day of insemination is associated with early embryonic loss. These data also indicate that estrogen concentrations on the day of insemination can be influenced by diet.
Abortion, Veterinary↗
Biosafety monitoring of patients receiving intracerebral injections of murine retroviral vector producer cells.
Patients with recurrent malignant brain cancer, who were receiving gene therapy by intracerebral injection of murine retroviral vector producer cells (VPCs), were monitored for the presence of replication-competent retrovirus (RCR). RCR sequences were not detected by polymerase chain reaction (PCR) in any of the 608 peripheral blood leukocyte (PBL) samples analyzed. Vector DNA sequences were detected transiently in PBL samples from a subset of 34 patients. Humoral immune responses to a retroviral core protein p30 and murine VPC were detected in some patients, most frequently in patients receiving repeated administrations of VPC. RCR was not detected in biological assays of PBLs from 41 patients who had either anti-retroviral antibodies in sera and/or vector DNA in PBLs. Our data suggest that in situ generation of RCR was not detected following intracerebral inoculation of VPCs in any of the 128 patients evaluated.
Animals↗
Pseudomethemoglobinemia: a case report and review of sulfhemoglobinemia.
OBJECTIVES: To see if methemoglobin could potentially be misdiagnosed and the limitation of present cooximeters. PATIENT: A 17-year-old girl who overingested a combination of cimetidine, acetaminophen, ibuprofen, and naproxen in a suicide attempt. METHOD: Use of pulse co-oximeters to aid in the diagnosis of suspected sulfhemoglobinemia. RESULTS: Diagnosis of sulfhemoglobinemia achieved with final confirmation made with gas chromatography. Patient steadily improved with supportive care. CONCLUSIONS: There is a potential for the diagnosis of methemoglobin with some of the limitations of present co-oximeters. The laboratory diagnosis of sulfhemoglobinemia can be difficult to make.
Acetaminophen↗
Molecular characterization of two deletion events involving Alu-sequences, one novel base substitution and two tentative hotspot mutations in the hypoxanthine phosphoribosyltransferase (HPRT) gene in five patients with Lesch-Nyhan syndrome.
Mutations identified in the hypoxanthine phosphoribosyltransferase (HPRT) gene of patients with Lesch-Nyhan (LN) syndrome are dominated by simple base substitutions. Few hotspot positions have been identified, and only three large genomic rearrangements have been characterized at the molecular level. We have identified one novel mutation, two tentative hot spot mutations, and two deletions by direct sequencing of HPRT cDNA or genomic DNA from fibroblasts or T-lymphocytes from LN patients in five unrelated families. One is a missense mutation caused by a 610C-->T transition of the first base of HPRT exon 9. This mutation has not been described previously in an LN patient. A nonsense mutation caused by a 508C-->T transition at a CpG site in HPRT exon 7 in the second patient and his younger brother is the fifth mutation of this kind among LN patients. Another tentative hotspot mutation in the third patient, a frame shift caused by a G nucleotide insertion in a monotonous repeat of six Gs in HPRT exon 3, has been reported previously in three other LN patients. The fourth patient had a tandem deletion: a 57-bp deletion in an internally repeated Alu-sequence of intron 1 was separated by 14 bp from a 627-bp deletion that included HPRT exon 2 and was flanked by a 4-bp repeat. This complex mutation is probably caused by a combination of homologous recombination and replication slippage. Another large genomic deletion of 2969 bp in the fifth patient extended from one Alu-sequence in the promoter region to another Alu-sequence of intron 1, deleting the whole of HPRT exon 1. The breakpoints were located within two 39-bp homologous sequences, one of which overlapped with a well-conserved 26-bp Alu-core sequence previously suggested as promoting recombination. These results contribute to the establishment of a molecular spectrum of LN mutations, support previous data indicating possible mutational hotspots, and provide evidence for the involvement of Alu-mediated recombination in HPRT deletion mutagenesis.
Alu Elements↗
Coadministration of theophylline enhances diuretic response to furosemide in infants during extracorporeal membrane oxygenation: a randomized controlled pilot study.
OBJECTIVE: This pilot study evaluates the efficacy of low-dose theophylline administered before furosemide to enhance diuresis in neonates recovering from fluid retention during extracorporeal membrane oxygenation (ECMO). STUDY DESIGN: Infants receiving ECMO (n = 24) were randomized (double blind, placebo-controlled) to receive either regimen A (placebo/furosemide day 1, theophylline/furosemide day 2, placebo/furosemide day 3) or regimen B (theophylline/furosemide day 1, placebo/furosemide day 2, theophylline/furosemide day 3). Urine flows and renal functions were compared. RESULTS: Urine flow rate before initiation of diuretic therapy was not significantly different between groups A and B (2.6 +/- 1.4 vs 3.5 +/- 1.3 ml/kg/hr, respectively, p = 0.12). Infants who received theophylline/furosemide had significantly higher urine flow rates than those who received placebo/furosemide on day 1 (11.8 +/- 4.6 vs 7.2 +/- 2.4 ml/kg/hr, p < 0.01). The 24-hour fluid volumes and balances became significantly more negative with theophylline enhancement of furosemide's effect. There were no significant differences in renal function between the two groups. CONCLUSION: Low doses of theophylline given before furosemide administration significantly enhance diuretic response in infants with fluid retention during ECMO.
Diuresis↗
Combined fresh and frozen embryo transfer resulting in a twin delivery.
We report the delivery of non-identical twins resulting from the combined transfer of one fresh and one frozen embryo to a 31 year old patient. To our knowledge, this is the first reported case where both a fresh and a frozen embryo implanted in the same cycle led to non-identical twins. We conclude that supernumerary embryos after in-vitro fertilization should be frozen and used in subsequent cycles, with implantation potentials as high as fresh embryos. The possibility of mixing fresh and frozen embryos, though rarely needed, should be considered, particularly when there is only one fresh embryo available for transfer.
Adult↗
Does ovarian hyperstimulation syndrome affect the quality of oocytes?
Two wives of a Muslim with severe male factor infertility had simultaneous intracytoplasmic sperm injection (ICSI) treatments. One wife developed ovarian hyperstimulation syndrome (OHSS), and 19 of 27 oocytes retrieved were subjected to ICSI but only one fertilized; the other wife had a normal response to ovarian stimulation, normal fertilization following ICSI, successful treatment and has recently delivered a live-born infant. The wife who suffered from OHSS has since had another ICSI cycle with a normal response to ovarian stimulation, a normal fertilization rate but no pregnancy. The only variable that determined the different rate of fertilization in the simultaneous ICSI cycles appears to be oocyte quality. While the results of frozen embryo replacement cycles following the decision to freeze all embryos following OHSS is generally satisfactory, it is important to counsel couples about the possible detrimental effects of OHSS on oocyte quality.
Adult↗
Flu-like symptoms and hyperechoic foetal bowel.
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Adult↗
Use of ECT for the inpatient treatment of recurrent major depression.
OBJECTIVE: The authors' goals were to determine the frequency and distribution of ECT for general hospital inpatients with recurrent major depression and to estimate the effects of prompt ECT on the length and cost of inpatient care. METHOD: Data from the 1993 Healthcare Cost and Utilization Project were analyzed to determine the rate of ECT use for adult inpatients with a principal discharge diagnosis of major depression, recurrent. Associations between prompt initial use of ECT (in the first 5 hospital days) and length and cost of inpatient care were examined before and after control for sociodemographic, diagnostic, and hospital organizational characteristics. RESULTS: An estimated 9.4% of general hospital adult inpatients with a principal diagnosis of recurrent major depression received ECT in the survey year. A majority (59.2%) of these received their initial ECT session within the first 5 days after hospital admission. In univariate analyses, the likelihood of receiving ECT was greater for older patients, whites, privately insured individuals, and patients who lived in more affluent areas. Patients who received ECT tended to have relatively long and costly admissions. After control for several demographic, diagnostic, and hospital organizational characteristics, prompt ECT (as compared with delayed ECT or none) was associated with significantly shorter and less costly inpatient care. CONCLUSIONS: The longer stays and higher treatment costs associated with ECT may be a consequence of patient selection. When patient selection is taken into account, prompt administration of ECT is associated with shorter and less costly hospital stays. Nonetheless, economically disadvantaged patients are relatively unlikely to receive this treatment.
Adolescent↗
Open-label phase I study of combination therapy with zidovudine and interferon-beta in patients with AIDS-related Kaposi's sarcoma: AIDS Clinical Trials Group Protocol 057.
The aim of this study was to identify a safe and tolerable dose of recombinant interferon-beta (IFN-beta) used in conjunction with a fixed dose of zidovudine in patients with early-stage, good-prognosis AIDS-related Kaposi's sarcoma. We conducted a phase I, dose-escalation controlled trial of 22.5, 45 of 90 million units of IFN-beta given by daily subcutaneous injection with 500 mg per day of oral zidovudine. At the time of this study, this was standard of care for HIV infection. Patients were sequentially enrolled at three medical centers. Tumor response, drug tolerance, antiviral studies and CD4 changes were assessed. Four patients were enrolled at each dose level, and escalation proceeded when at least four patients had tolerated two weeks of therapy without dose-limiting toxicity. ACTG Kaposi's sarcoma tumor response criteria were used to assess response. Fifteen patients were enrolled. The combination of IFN-beta and zidovudine was well tolerated, and the dose-limiting toxicities were local skin necrosis and systemic symptoms. Despite generally good prognostic characteristics, only two patients achieved a clinical complete response and three addition patients had stable disease for a prolonged period of time (range 24-44 weeks). There was no correlation between baseline CD4 cell counts and tumor response, nor between the antiviral effect of IFN-beta as measured by decreases in immune-complex dissociated p24 antigen and tumor response. Higher doses of IFN-beta did not result in more tumor responses or in greater antiviral activity. The maximum tolerated dose of IFN-beta in combination with 500 mg per day of zidovudine was 45 million units by subcutaneous injection per day. IFN-beta is well tolerated in patients with AIDS-related Kaposi's sarcoma when used in conjunction with zidovudine. However, the antitumor response rate in good-prognosis patients is low. Further studies of this agent should be in the context of four-drug antiretroviral regimens where viral suppression is greatest and any antitumor activity of IFN-beta may be observed.
Anti-HIV Agents↗
"Accidental ingestion of sustained release calcium channel blockers in children".
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Accidents, Home↗