[Control of tuberculosis in Denmark].
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Communicable Disease Control↗
Biomedical subjects
E Smith
Publications and source records attributed to E Smith.
STAT1 affects lymphocyte survival and proliferation partially independent of its role downstream of IFN-gamma.
Lymphocytes derived from mice deficient in STAT1 showed reduced apoptosis and enhanced proliferation in vitro. To understand the involvement of STAT1 in the observed reduction in apoptosis, we examined the levels of caspase and bcl-2 family genes that are involved in cell survival and/or apoptosis. The levels of caspase 1 and 11, two enzymes involved in both cytokine protein processing and induction of apoptosis, were reduced in STAT1-/- cells compared with wild-type. However, the levels of bcl-2 genes were comparable in both mice. STAT1-/- cells also displayed an enhanced proliferation following TCR stimulation. This hyperproliferation could not be ascribed completely to the loss of IFN-gamma-mediated antiproliferation. First, similar phenotypes were also observed in fibroblasts and pre-B cells derived from STAT1-/- mice, which do not produce IFN-gamma. Second, comparisons with cells lacking the gene for IFN-gamma or with cells treated with neutralizing Abs to IFN-gamma only partially mimicked the STAT1-/- phenotype. Interestingly, the kinetics of degradation of p27kip1, a CDK inhibitor, following TCR ligation were faster, and, concomitantly, the up-regulation of CDK2 kinase activity and protein levels were increased in stimulated T cells of STAT1-/- mice relative to those of wild-type mice. Furthermore, STAT1-/- animals were more susceptible to carcinogen-induced thymic tumors, a possible consequence of altered T cell growth and/or survival. These results demonstrate an essential role for STAT1 for lymphocyte survival and proliferation that is only partially dependent on IFN-gamma signaling.
Animals↗
The regulation of radiology in the United States.
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Delivery of Health Care↗
Development and characterization of expressed sequence tags for the turkey (Meleagris gallopavo) genome and comparative sequence analysis with other birds.
Twenty-one randomly selected clones from a turkey (Meleagris gallopavo) pituitary complementary DNA (cDNA) library were sequenced to develop expressed sequence tags (ESTs) for this economically important avian species whose genome is among the least understood. Primers specific for the ESTs were used to produce amplicons from the genomic DNA of turkey, chicken (Gallus gallus), guinea fowl (Numidia meleagris), pigeon (Columba domestica), and quail (Corturnix japonica). The amplicons were sequenced and analyzed for sequence variation within- and similarity among-species and with GenBank database sequences. The proportion of shared bases between the turkey sequence and the consensus sequence from each of the other species ranged from 72% to 93% between turkey and pigeon and quail and between turkey and chicken, respectively. The total number of single nucleotide polymorphisms (SNPs) observed ranged from 3 in quail to 18 in chicken out of 4898 and 5265 bases analyzed, respectively. The most frequent nucleotide variation observed was a C-->T transition. Linkage analysis of one such SNP in the backcross progeny of the East Lansing reference DNA panel, localized TUS0005, the chicken sequence derived from primers specific for turkey TUT2E EST, to chromosome 4. The ESTs reported, as well as the SNPs may provide a useful resource for ongoing efforts to develop high utility genome maps for the turkey and chicken. The primers described can also be used as a tool in future investigations directed at further understanding the biology of the guinea fowl, pigeon and quail and their relatedness to the turkey.
Animals↗
Effect of hospital asthma nurse appointment on inpatient asthma care.
While asthma nurses are funded by many health authorities within the U.K. National Health Service, for the improvement of clinical management in both inpatient and outpatient settings in secondary care, the effect of asthma nurse appointment on acute asthma care in hospitalized children has been inadequately studied. Here, we test the hypothesis that the employment of a full-time hospital asthma nurse improves quality of care for children admitted to hospital with acute asthma. Prospective in design, the study compares analyses of indicators of good clinical practice for hospitalized asthmatic children (2-16 yrs) before and after the appointment of a hospital asthma nurse. Both management [oxygen saturation check (35/106 vs. 111/126, P<0.05)] and discharge planning [self management plan/asthma education (17/106 vs. 49/126, P<0.05), follow-up arrangements with general practice (8/106 vs. 25/126, P<0.05)] improved. There was, however, no significant change in oral steroid administration, peak flow check, inhaler technique assessment, inhaled drug prophylaxis or arrangements for hospital follow-up at discharge. Employment of a hospital-based children's asthma nurse leads to significant improvement in aspects of routine in-patient asthma management. However, other important areas of in-patient asthma care did not improve following nurse-led interventions. A clearer evidence base may improve compliance with asthma management guidelines, and could make the role of hospital asthma nurse more effective.
Adolescent↗
Phosphorylation-induced dimerization of interferon regulatory factor 7 unmasks DNA binding and a bipartite transactivation domain.
Interferon regulatory factor 7 (IRF7) is an interferon (IFN)-inducible transcription factor required for activation of a subset of IFN-alpha genes that are expressed with delayed kinetics following viral infection. IRF7 is synthesized as a latent protein and is posttranslationally modified by protein phosphorylation in infected cells. Phosphorylation required a carboxyl-terminal regulatory domain that controlled the retention of the active protein exclusively in the nucleus, as well as its binding to specific DNA target sequences, multimerization, and ability to induce target gene expression. Transcriptional activation by IRF7 mapped to two distinct regions, both of which were required for full activity, while all functions were masked in latent IRF7 by an autoinhibitory domain mapping to an internal region. A conditionally active form of IRF7 was constructed by fusing IRF7 with the ligand-binding and dimerization domain of estrogen receptor (ER). Hormone-dependent dimerization of chimeric IRF7-ER stimulated DNA binding and transcriptional transactivation of endogenous target genes. These studies demonstrate the regulation of IRF7 activity by phosphorylation-dependent allosteric changes that result in dimerization and that facilitate nuclear retention, derepress transactivation, and allow specific DNA binding.
Animals↗
Exposure to hazardous substances and male reproductive health: a research framework.
The discovery in the mid-1970s that occupational exposures to pesticides could diminish or destroy the fertility of workers sparked concern about the effects of hazardous substances on male reproductive health. More recently, there is evidence that sperm quantity and quality may have declined worldwide, that the incidence of testicular cancer has progressively increased in many countries, and that other disorders of the male reproductive tract such as hypospadias and cryptorchidism may have also increased. There is growing concern that occupational factors and environmental chemical exposures, including in utero and childhood exposures to compounds with estrogenic activity, may be correlated with these observed changes in male reproductive health and fertility. We review the evidence and methodologies that have contributed to our current understanding of environmental effects on male reproductive health and fertility and discuss the methodologic issues which confront investigators in this area. One of the greatest challenges confronting researchers in this area is assessing and comparing results from existing studies. We elaborate recommendations for future research. Researchers in the field of male reproductive health should continue working to prioritize hazardous substances; elucidate the magnitude of male reproductive health effects, particularly in the areas of testicular cancer, hypospadias, and cryptorchidism; develop biomarkers of exposure to reproductive toxins and of reproductive health effects for research and clinical use; foster collaborative interdisciplinary research; and recognize the importance of standardized laboratory methods and sample archiving.
Biomarkers↗
Autologous stem-cell transplantation for poor-risk and relapsed intermediate- and high-grade non-Hodgkin's lymphoma.
The primary objective of this study was to evaluate the outcome of patients treated with high-dose chemo-/radiotherapy or high-dose chemotherapy and autologous stem-cell transplant (ASCT) for relapsed, refractory, or poor-risk intermediate-grade (IG) and high-grade (HG) non-Hodgkin's lymphoma (NHL). The secondary objectives were to determine prognostic factors for relapse and survival. Between February 1987 and August 1998, 264 patients, 169 (64%) IG and 95 (36%) HG, underwent high-dose therapy and ASCT at City of Hope National Medical Center (COHNMC). There were 157 (59%) males and 107 (41%) females with a median age of 44 years (range, 5-69 years). The median number of prior chemotherapy regimens was 2 (range, 1-4), and 71 (27%) had received prior radiation as part of induction or as salvage therapy. The median time from diagnosis to ASCT was 10.8 months (range, 3-158 months). Ninety-four patients (36%) underwent transplantation in first complete/partial remission (CR/PR), 40 (15%) in induction failure, and 130 (49%) in relapse or subsequent remission. Two preparative regimens were used: total body irradiation/high-dose etoposide/cyclophosphamide (TBI/VP/CY) in 208 patients (79%) and carmustine/etoposide/cyclophosphamide (BCNU/VP/CY) in 56 patients (21%). One hundred sixty-three patients (62%) received peripheral blood stem cells (PBSC) and 101 (38%) received bone marrow (BM) alone or BM plus PBSC. At a median follow-up of 4.43 years for surviving patients (range, 1-12.8 years), the 5-year Kaplan-Meier estimates of probability of overall survival (OS), progression-free survival (PFS), and relapse for all patients are 55% (95% confidence interval [CI]: 49%-61%), 47% (95% CI: 40%-53%), and 47% (95% CI: 40%-54%), respectively. There were 27 deaths (10%) from nonrelapse mortality, including seven (3%) patients who developed second malignancies (five with myelodysplasia/acute myelogenous leukemia and two with solid tumors). By stepwise Cox regression analysis, disease status at ASCT was the only prognostic factor that predicted for both relapse and survival. The 5-year probability of PFS for patients transplanted in first CR/PR was 73% (95% CI: 62%-81%) as compared to 30% (95% CI: 16%-45%) for induction failure and 34% (95% CI: 26%-42%) for relapsed patients. Our results further support the role of high-dose therapy and ASCT during first CR/PR for patients with poor-risk intermediate- and high-grade NHL. Early transplant is recommended for patients failing initial induction therapy or relapsing after chemotherapy-induced remission. Relapse continues to be the most common cause of treatment failure. An alternative approach to prevent relapse, the incorporation of radioimmunotherapy into the high-dose regimen, is being investigated. The development of a second malignancy is a serious complication of high-dose therapy, which requires close surveillance.
Adolescent↗
Special kids, special care. Emergency management of children with special health-care needs.
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Caregivers↗
Back-calculation based on HIV and AIDS registers in Denmark, Norway and Sweden 1977-95 among homosexual men: estimation of absolute rates, incidence rates and prevalence of HIV.
BACKGROUND: The Scandinavian countries, Denmark, Norway and Sweden, have established both HIV and AIDS registers to monitor the HIV epidemic. Information in such registers can be used to estimate the number of new HIV infections over time, incidence rates and prevalence. Information from the HIV registers made it possible to study what kind of effects such information had in the estimation process, compared with using information about new AIDS cases only. METHODS: A Markov model back-calculation approach was used. One model incorporated data on cases of both HIV and AIDS. Another model incorporated data on cases of AIDS only. Death or emigration prior to the onset of AIDS and effects of treatment were included in both models. RESULTS: Estimates of absolute rates of HIV for men who have sex with men (MSM) showed a distinct development in each country. Significant differences in incidence rates and prevalence of HIV among MSM were found between Scandinavian countries when information on diagnosed HIV was incorporated. Precision was improved when using both HIV and AIDS diagnosed cases compared with using AIDS cases only. The epidemic in Denmark was more extensive than in the two other countries for the whole study period. DISCUSSION: The results were fairly robust against reasonable variation in the model parameters. The more extensive epidemic in Denmark may have been caused by the homosexual culture denying that HIV was a disease more relevant to them than to others, until the HIV test was publicly available in 1985.
Adult↗
[Occurrence of hepatitis B and C among mentally retarded].
The objective of this study was to examine whether the prevalence of hepatitis C, like hepatitis B, is increased among the mentally retarded in Denmark. The prevalence of serological markers of hepatitis B and C was examined in an institution for the mentally retarded. A total of 126 out of 178 inhabitants (71%) with a median age of 49 years (range 23-78) participated. All subjects were anti-HCV-negative by third generation ELISA antibody test. A total of 45 (35.7%) subjects were anti-HBc-positive and 10 (7.9%) were HBsAg-positive. Among subjects with Down's syndrome (n = 20), 55% were anti-HBc-positive and 30% were HBsAg-positive as compared to 32% and 3.8% respectively among others. In conclusion, hepatitis C infection seems to be uncommon among mentally retarded persons in Denmark and the risk of acquiring infection not significantly increased as compared to that of the general population. The prevalence of serological markers for hepatitis B was high and comparable to previous studies in this population.
Adult↗
[Changes of knowledge of HIV-positivity before development of AIDS among Danish patients with AIDS 1988-1997].
We describe the changes in the period of knowledge of HIV positivity before AIDS in the light of the new anti-retroviral treatment regime among all notified Danish AIDS patients 1988-1997. Overall, 29% of the patients were diagnosed with AIDS less than four months after the first positive HIV test, a proportion that decreased through 1988-1995, but then increased. However, the proportion with over five years between positive HIV test and AIDS diagnosis increased from 9% in 1988-1990 to 48% in 1994-1995. A similar trend was seen among men, who have sex with men (MSM). Relatively more heterosexually infected than MSM had less than four months between first positive HIV test and AIDS (44% vs. 25%, p < 0.00001). Among persons known as HIV infected less than four months before AIDS, 51% were notified with Pneumocystis carinii pneumonia, a proportion that was 25% (p < 0.00001) among those known over five years before AIDS. We conclude, that the proportion of Danish AIDS patients known as HIV-infected for less than four months before AIDS recently has increased after several years of decrease, probably due to anti-retroviral treatment.
Acquired Immunodeficiency Syndrome↗
Biosynthesis of osteogenic growth peptide via alternative translational initiation at AUG85 of histone H4 mRNA.
The osteogenic growth peptide (OGP) is an extracellular mitogen identical to the histone H4 (H4) COOH-terminal residues 90-103, which regulates osteogenesis and hematopoiesis. By Northern analysis, OGP mRNA is indistinguishable from H4 mRNA. Indeed, cells transfected with a construct encoding [His102]H4 secreted the corresponding [His13]OGP. These results suggest production of OGP from H4 genes. Cells transfected with H4-chloramphenicol acetyltransferase (CAT) fusion genes expressed both "long" and "short" CAT proteins. The short CAT was retained following an ATG --> TTG mutation of the H4 ATG initiation codon, but not following mutation of the in-frame internal ATG85 codon, which, unlike ATG1, resides within a perfect context for translational initiation. These results suggest that a PreOGP is translated starting at AUG85. The translational initiation at AUG85 could be inhibited by optimizing the nucleotide sequence surrounding ATG1 to maximally support upstream translational initiation, thus implicating leaky ribosomal scanning in usage of the internal AUG. Conversion of the predicted PreOGP to OGP was shown in a cell lysate system using synthetic [His102]H4-(85-103) as substrate. Together, our results demonstrate that H4 gene expression diverges at the translational level into the simultaneous parallel production of both H4, a nuclear structural protein, and OGP, an extracellular regulatory peptide.
Animals↗
The representation of pleasant touch in the brain and its relationship with taste and olfactory areas.
Although there has been much investigation of brain pathways involved in pain, little is known about the brain mechanisms involved in processing somatosensory stimuli which feel pleasant. Employing fMRI it was shown that pleasant touch to the hand with velvet produced stronger activation of the orbitofrontal cortex than affectively neutral touch of the hand with wood. In contrast, the affectively neutral but more intense touch produced more activation of the primary somatosensory cortex than the pleasant stimulus. This indicates that part of the orbitofrontal cortex is concerned with representing the positively affective aspects of somatosensory stimuli, and in further experiments it was shown that this orbitofrontal area is different from that activated by taste and smell. The finding that three different primary or unlearned types of reinforcer (touch, taste, and smell) are represented in the orbitofrontal cortex helps to provide a firm foundation for understanding the neural basis of emotions, which can be understood in terms of states elicited by stimuli which are rewarding or punishing.
Brain↗
Cerebral vasculopathy in sickle cell anemia: diagnostic contribution of positron emission tomography.
Children with sickle cell anemia (SS) have an increased risk for cerebral vasculopathy with stroke (CVA) and cognitive impairment. The present study examines the extent to which adding positron emission tomography (PET) to magnetic resonance imaging (MRI) can improve the detection of cerebral vasculopathy. Whereas MRI has been the prime modality for showing anatomical lesions, PET excels at assessing the functional metabolic state through glucose utilization 2-deoxy-2 [18F] fluoro-D-glucose (FDG) and microvascular blood flow ([15O]H2O). Forty-nine SS children were studied. Among them, 19 had clinically overt CVA, 20 had life-threatening hypoxic episodes or soft neurologic signs, and 10 were normal based on neurological history and examination. For the entire sample of 49 subjects, 30 (61%) had abnormal MRI findings, 36 (73%) had abnormal PET findings, and 44 (90%) showed abnormalities on either the MRI or the PET or both. Of the 19 subjects with overt CVA, 17 had abnormal MRI (89%), 17 had abnormal PET (89%), and 19 (100%) had either abnormal MRI or PET or both. Among the 20 subjects with soft neurologic signs, 10 (50%) had abnormal MRI, 13 (65%) had abnormal PET, and 17 (85%) had abnormal MRI and/or PET. Six (60%) of the 10 neurologically normal subjects had abnormal PET. Among the 30 subjects with no overt CVA, 25 (83%) demonstrated imaging abnormalities based on either MRI or PET or both, thus, silent ischemia. Lower than average full-scale intelligence quotient (FSIQ) was associated with either overt CVA or silent ischemic lesions. Four subjects who received chronic red blood cell transfusion showed improved metabolic and perfusion status on repeat PET scans. In conclusion, (1) the addition of PET to MRI identified a much greater proportion of SS children with neuroimaging abnormalities, particularly in those who had no history of overt neurologic events. (2) PET lesions are more extensive, often bihemispheric, as compared with MRI abnormalities. (3) PET may be useful in management as a tool to evaluate metabolic improvement after therapeutic interventions, and (4) the correlation of PET abnormalities to subsequent stroke or progressive neurologic dysfunction requires further study.
Adolescent↗
Phase II trial of intraperitoneal cisplatin with intravenous doxorubicin and cyclophosphamide in previously untreated patients with advanced ovarian cancer-long-term follow-up.
Forty-three patients with ovarian cancer were entered on this trial and treated with intravenous (iv) cyclophosphamide (C) and doxorubicin (A), and intraperitoneal (ip) cisplatin (DDP), every 21 days for eight cycles. Following iv hydration, the cisplatin was administered through an intraperitoneal catheter in 2 L of 0.9% normal saline with a 4-h dwell. All patients are evaluable for overall and progression-free survival with a median follow-up of 70 months (range: 3-162 months); 39 patients are evaluable for response. All complete responses were surgically confirmed. The median age was 59 (range 28-82 years); 3 patients were stage IC, 5 were IIC, 14 patients were stage III (optimally debulked), 14 patients were stage III (suboptimally debulked), and 7 patients were stage IV. Two patients had received prior alkylator therapy. Six of 8 patients with Stage IC or II remain without evidence of disease at a mean of 12 years following chemotherapy. Of 14 optimally debulked stage III patients, there were 7 complete responses, 3 partial responses, 1 patient with stable disease, and 3 inevaluable patients. Of 14 suboptimally debulked stage III patients there were 4 complete responses, 4 partial responses, 3 with stable disease, 2 progressions on treatment, and 1 inevaluable patient. Five-year progression-free and overall survivals for stage III optimally debulked patients are 21 and 64%, respectively. At 10 years, progression-free and overall survivals for this group are 21 and 29%, respectively. Toxicity included neutropenia (complicated by sepsis in 2 patients), infrequent thrombocytopenia, and mild anemia. Three patients developed transient serum creatinine elevations >2.0 mg/dl; however, decreased creatinine clearance was noted in 93/258 (36%) of evaluable courses which required a cisplatin dose reduction per protocol. Controllable hypomagnesemia, nausea, and emesis were also observed. We conclude that the combination of iv CA and ip DDP is an effective regimen with long-term progression-free and overall survivals that compare favorably with those of other published studies of intravenous or intraperitoneal chemotherapy. This report is unusual in terms of the prolonged follow-up for all patients enrolled. These long-term results lend further support to recently published trials documenting the efficacy of intraperitoneal chemotherapy for patients with this disease.
Adult↗
Optimization of the growth conditions of the extremely thermophilic microorganisms Thermococcus celer and Pyrococcus woesei.
Growth medium components and cultivation conditions for the extremely thermophilic Archaea Thermococcus celer and Pyrococcus woesei were optimized. A culture media based in marine water was formulated. Both Archaea demonstrated to be strictly anaerobic with optimal growth temperature of 85 degrees and 95 degrees C, respectively. Sodium sulfide, but not cysteine, was used as a sulfur and reductive capacity source. It was observed that hydrogen sulfide could be replaced by 30 microM titanium (III) nitrile acetate. The addition of elemental S(o) enhanced growth of both microorganisms, with T. celer far more sensitive than P. woesei to the absence of S(o). P. woesei utilized maltose as a carbon source, while T. celer was able to use only peptides from yeast extract, peptone and tryptone as its carbon source. Optimum carbon source concentrations were 1.25 g/L for T. celer and 5 g/L for P. woesei. Although both Archaea required peptides as a nitrogen source, the addition of ammonia chloride to a nitrogen-limited media did not stimulate growth, which suggests that neither Archaea appear to metabolize ammonia. The growth of P. woesei, but not T. celer, was stimulated considerably in the presence of iron. Co, Ni, Zn, Mo. Mn and Mg were essential trace elements needed for optimal growth of both bacteria.
Bacteriological Techniques↗