The AHA guidelines on hormone replacement therapy and cardiovascular disease. American Heart Association.
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Aged↗
Biomedical subjects
H Burger
Publications and source records attributed to H Burger.
Analysis of transition from long-term nonprogressive to progressive infection identifies sequences that may attenuate HIV type 1.
Long-term nonprogressive human immunodeficiency virus type 1 (HIV-1) infection and its transition to progressive infection presents an opportunity to identify the molecular determinants of HIV-1 attenuation and pathogenesis. We studied an individual who underwent a transition from long-term nonprogressive to rapidly progressive infection. Because HIV-1 RNA genomes in plasma represent replicating virus, we developed a technique to clone full-length HIV-1 RNA genomes from plasma and used this technique to obtain clones from this individual before and during the transition. Most clones assayed were infectious, demonstrating that the RNA genomes encoded viable virus. Analysis of 20 complete HIV-1 RNA genomic sequences revealed one major difference between sequences found during the two phases of infection. During the nonprogressive phase, the predominant sequences had a large deletion in an Sp1-binding site and adjacent promoter in the U3 part of the long terminal repeat (LTR); when the infection became progressive, all viruses had intact Sp1 and promoter sequences and were derived from a minor species present earlier. Analysis of 184 clones of the LTR region obtained at five time points spanning a 7-year period confirmed this switch. In an in vitro assay, the deletion downregulated LTR-driven transcription of a reporter gene. In addition, analysis of cytotoxic T lymphocyte (CTL) epitopes predicted from the complete viral RNA genomes revealed multiple potential escape mutants that accumulated by the time of progression. These studies suggest that during the nonprogressive phase, the Sp1 enhancer-promoter deletion is likely to have played a role in decreasing replication, thereby attenuating HIV-1. The accumulation of CTL escape mutants suggests that a breakdown in immunologic surveillance may have allowed proliferation of intact virus, thus leading to rapid disease progression. These data reveal the viral and immune interactions characterizing a transition from long-term nonprogressive to rapidly progressive infection.
Base Sequence↗
SKY1 is involved in cisplatin-induced cell kill in Saccharomyces cerevisiae, and inactivation of its human homologue, SRPK1, induces cisplatin resistance in a human ovarian carcinoma cell line.
The therapeutic potential of cisplatin, one of the most active and widely used anticancer drugs, is severely limited by the occurrence of cellular resistance. In this study, using budding yeast Saccharomyces cerevisiae as a model organism to identify novel drug resistance genes, we found that disruption of the yeast gene SKY1 (serine/arginine-rich protein-specific kinase from budding yeast) by either transposon insertion or one-step gene replacement conferred cellular resistance to cisplatin. Heterologous expression of the human SKY1 homologue SRPK1 (serine/arginine-rich protein-specific kinase) in SKY1 deletion mutant yeast cells restored cisplatin sensitivity, suggesting that SRPK1 is a cisplatin sensitivity gene, the inactivation of which could lead to cisplatin resistance. Subsequently, we investigated the role of SRPK1 in cisplatin sensitivity and resistance in human ovarian carcinoma A2780 cells using antisense oligodeoxynucleotides. Treatment of A2780 cells with antisense oligodeoxynucleotides directed against the translation initiation site of SRPK1 led to down-regulation of SRPK1 protein and conferred a 4-fold resistance to cisplatin. The human SRPK1 gene has not been associated with drug resistance before. Our new findings strongly suggest that SRPK1 is involved in cisplatin-induced cell kill and indicate that SRPK1 might potentially be of importance for studying clinical drug resistance.
Antineoplastic Agents↗
Endogenous nitric oxide synthesis and vascular leakage in ischemic-reperfused rabbit lungs.
Pulmonary edema formation resulting from loss of capillary barrier properties is a prominent finding in lung ischemia/reperfusion (I/R) injury. The role of endogenous nitric oxide (NO) in this process is unresolved. We exposed buffer-perfused rabbit lungs to warm I/R and measured air space NO liberation and intravascular accumulation of NO degradation products. In lungs undergoing 210 min of ischemia with normoxic ventilation, with maintenance of positive intravascular pressure to avoid vascular collapse, NO synthesis was moderately reduced during ischemia but was fully restored upon reperfusion, and a moderate leakage response occurred during reperfusion. Pretreatment with the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) suppressed NO synthesis but did not affect the leakage. During ischemia with anoxic ventilation, NO synthesis was fully abrogated, but again promptly reappeared upon reperfusion and entrance of oxygen into the system. It was with this protocol that the most severe vascular leakage was encountered, which was markedly reduced in the presence of L-NMMA or superoxide dismutase. We conclude that endogenous NO does not play a major role in the induction or mitigation of I/R injury under conditions of normoxic ischemia, but that return of endogenous NO synthesis upon reperfusion after anoxic ischemia contributes substantially to the triggering of vascular leakage, possibly via interaction with superoxide.
Animals↗
Estrogen - a potential treatment for schizophrenia.
Estrogen has been shown in animal studies to modulate both the dopamine and serotonin neurotransmitter systems - the main neurotransmitters implicated in the pathogenesis of schizophrenia. A double blind, 28 day, placebo-controlled study was conducted with three groups of women of child-bearing age (N=12 in each group) who received standardized antipsychotic medication plus 50mcg transdermal estradiol or 100mcg transdermal estradiol or transdermal placebo. Analyses show that women receiving 100mcg of estradiol made greater improvements in the symptoms of schizophrenia than both the 50mcg estradiol and placebo groups. Women receiving 50mcg estradiol had more improvement in their symptoms compared with the placebo group. The 100mcg estradiol group had significantly lower mean lutenizing hormone (LH) and higher mean prolactin levels across the study period compared with both the 50mcg and placebo groups. The addition of 100mcg adjunctive transdermal estrogen significantly enhanced the treatment of acute, severe psychotic symptoms in women with schizophrenia. The differential response of adding 50mcg versus 100mcg estradiol on the types of symptom affected may be related to the estrogen effect on LH and prolactin. The positive impact of estrogen treatment on psychotic symptoms by a direct effect on dopamine and serotonin systems or via an indirect prolactin-mediated effect may be very useful in the overall treatment of women with schizophrenia.
Administration, Cutaneous↗
Are changes in sexual functioning during midlife due to aging or menopause?
OBJECTIVE: To determine whether changes in women's sexual functioning during midlife are due to aging or menopause. DESIGN: Prospective, observational study. SETTING: Population-based sample assessed in own homes. PATIENT(S): Four hundred thirty-eight Australian-born women aged 45-55 years and still menstruating at baseline. One hundred ninety-seven were studied for effects of the natural menopausal transition. Control group A (n = 44) remained premenopausal or early perimenopausal for 7 years. Control group B (n = 42) remained postmenopausal over 5 years. INTERVENTION(S): Nil; questionnaires and blood sampling annually. MAIN OUTCOME MEASURE(S): Shortened version of the Personal Experiences Questionnaire. RESULT(S): By the late perimenopause, there was a significant decline in the factors we had derived of sexual responsivity and total score, and there was an increase in the partner's problems factor. By the postmenopausal phase, there was a further decline in the factors sexual responsivity, frequency of sexual activities, libido, and in the total score, and a significant increase in vaginal dyspareunia and partner's problems. Sexual responsivity significantly declined in both control groups. CONCLUSION(S): Sexual responsivity is adversely affected by both aging and the menopausal transition. Other domains of female sexual functioning were significantly adversely affected when the women became postmenopausal. The relationship with the partner and his ability to perform sexually is adversely affected by the menopausal transition.
Australia↗
Functional testing of elderly subjects after lower limb amputation.
The aim of the present study was to find out if it is possible to use the same functional tests for elderly subjects after lower limb amputation who live independently at their homes as for healthy ones. Will these tests discriminate among different problems in subjects with different levels and different causes of amputation and will they discriminate between active and sedentary subjects? The study examined 83 volunteers who lived independently at their homes (55 healthy sedentary, 17 after trans-tibial amputation, 11 after trans-femoral amputation). All subjects were aged 60 or older. All subjects after lower limb amputation were found to have significantly worse results in almost all tests in comparison with the healthy sedentary men. The subjects after transfemoral amputation needed significantly more time at the "up and go" test, walked a shorter distance in 9 minutes. and performed fewer stand-ups from a chair and fewer steps in two minutes than the subjects after trans-tibial amputation. The active subjects after lower limb amputation had better balance, were quicker at the "up and go" test and walked longer in a minute than the sedentary subjects after lower limb amputation. It can be concluded that this test battery can also be used to test subjects after lower limb amputation because it discriminates among different severity of problems in subjects with different level and cause of amputation as well as between active and sedentary ones.
Aged↗
Knee muscle activity during ambulation of trans-tibial amputees.
Gait analysis of trans-tibial amputees brings to light asymmetries of different gait parameters between the amputated and sound legs. The present study investigated the activity of the vastus medialis and biceps femoris muscles during ambulation of trans-tibial amputees. Peak activities of the vastus medialis were reached similarly in both legs (6.06+/-4.9% and 8.84+/-3.6% of gait cycle, in the sound and amputated leg, respectively). Biceps femoris peak activities were reached at 92.43+/-6.6% of gait cycle in the sound leg, and significantly later (at 9.81+/-4.8% of gait cycle) in the amputated leg (p < 0.05). Integrated EMG activity ratios, between swing and stance periods, were similar for the vastus medialis (0.33 in the sound and 0.35 in the amputated leg). However, these ratios differed significantly for the biceps femoris since the amputated leg presented a substantial (p < 0.05) smaller ratio (0.22) compared with the sound leg (0.83). The use of prosthesis in trans-tibial amputees requires further activity of the biceps femoris during stance period to improve support of the amputated leg knee joint.
Adult↗
Biology of HIV-1 in women and men.
The HIV epidemic continues to spread worldwide, particularly among women and nonwhites. Development of vaccines and improved treatments depend on understanding pathogenesis. In the past few years, studies have begun to focus on HIV-1 pathogenesis in women, in whom some differences have been found in comparison with men. Attention is now focused on HIV-1 infection in reservoirs other than blood, particularly the genital tract. In addition, study of the genetic determinants of susceptibility to HIV-1 infection, including the chemokine receptors, have provided knowledge useful for the design of new treatments.
CD4 Lymphocyte Count↗
Curved reconstructions versus three-dimensional surface rendering in the demonstration of cortical lesions in patients with extratemporal epilepsy.
RATIONALE AND OBJECTIVES: To compare the visibility and localization of extratemporal cortical lesions in extratemporal epilepsy by using curved reconstruction (CR) and three-dimensional surface rendering (3D SR) of 3D-acquired MR images and to study the degree of confidence with which localizations are made, particularly at the gyral level. METHODS: Twenty patients with extratemporal epilepsy, based on seizure symptomatology and/or scalp electroencephalographic registrations, with an extratemporal structural lesion on conventional MR imaging, were selected for this study by a neuroradiologist with extensive experience in the assessment of epilepsy patients. Transverse T2 spin-echo, coronal fluid-attenuated inversion recovery, and transverse 3D-acquired/two-dimensionally reconstructed T1 MR images were used for the selection. A second neuroradiologist (observer 1) and a radiology resident (observer 2) assessed CR and 3D SR in random order. Both observers were masked to all patient data. The subjective visibility of lesions and gyral location were scored. The interobserver agreements for lesion visibility and localization and for degree of confidence were compared for CR and 3D SR. RESULTS: For both observers, the lesion was visible in 55% of 3D SRs and 95% of CRs. The proportion with "very clearly visible" lesions on 3D SR was 19% (4/20) according to observer 1 and 30% (6/20) according to observer 2. For CR, this proportion was substantially higher: 55% for both observers. This difference was significant for observer 1 but not for observer 2. The interobserver agreement was high for both methods. Agreement on gyral localization was 28% for CR and 40% for 3D SR. The percentage of similar confidence scores for the same gyral localization and for gyral localization with a maximum difference of one gyrus between the observers did not differ significantly for CR or 3D SR. The observers were more often confident in agreed cases in CR and moderately confident in 3D SR. CONCLUSIONS: These results suggest that CRs of the brain surface are superior to 3D SR for the visualization of extratemporal cortical lesions in patients with drug-resistant extratemporal epilepsy. If lesions are seen, no significant difference was found between the two techniques for localization; however, the degree of confidence appears higher for CR at the gyral level.
Adolescent↗
Minimally invasive surgery for solitary parathyroid adenomas in patients with primary hyperparathyroidism: role of US with supplemental CT.
PURPOSE: To determine the role of ultrasonography (US) with supplemental computed tomography (CT) in patients with primary hyperparathyroidism who undergo minimally invasive surgery instead of conventional neck exploration. MATERIALS AND METHODS: US and CT were performed in 61 consecutive patients with primary hyperparathyroidism (part 1) to identify and localize solitary adenomas for resection by means of minimally invasive surgery and to provide a surgical road map. In part 2, involving 33 consecutive patients, CT was performed only when no solitary adenoma was identified with US or for road map information. Minimally invasive surgery was considered successful when serum calcium levels normalized and remained stable. RESULTS: In part 1, 46 definite solitary adenomas were found with US and two additional ones with CT. Minimally invasive surgery was successful in 45 patients and failed once. In part 2, US helped identify 23 solitary adenomas, and CT helped to find one. Minimally invasive surgery was successful in 22 patients and failed in two. Combined results in 94 patients demonstrated successful minimally invasive surgery in 67 (71%), with 64 of them selected with US alone (95% CI: 61, 80). The sensitivity of US in the diagnosis of solitary adenoma was 78% (95% CI: 67%, 86%), with a positive predictive value of 96% (95% CI: 88%, 99%). CONCLUSION: US examination of patients with primary hyperparathyroidism allowed successful selection for minimally invasive surgery in more than two-thirds of the cases, with additional CT useful chiefly for surgical road mapping.
Adenoma↗
Preferential suppression of CXCR4-specific strains of HIV-1 by antiviral therapy.
To initiate infection, HIV-1 requires a primary receptor, CD4, and a secondary receptor, principally the chemokine receptor CCR5 or CXCR4. Coreceptor usage plays a critical role in HIV-1 disease progression. HIV-1 transmitted in vivo generally uses CCR5 (R5), but later CXCR4 (X4) strains may emerge; this shift heralds CD4+ cell depletion and clinical deterioration. We asked whether antiretroviral therapy can shift HIV-1 populations back to R5 viruses after X4 strains have emerged, in part because treatment has been successful in slowing disease progression without uniformly suppressing plasma viremia. We analyzed the coreceptor usage of serial primary isolates from 15 women with advanced disease who demonstrated X4 viruses. Coreceptor usage was determined by using a HOS-CD4+ cell system, biological and molecular cloning, and sequencing the envelope gene V3 region. By constructing a mathematical model to measure the proportion of virus in a specimen using each coreceptor, we demonstrated that the predominant viral population shifted from X4 at baseline to R5 strains after treatment. Multivariate analyses showed that the shift was independent of changes in plasma HIV-1 RNA level and CD4+ cell count. Hence, combination therapy may lead to a change in phenotypic character as well as in the quantity of HIV-1. Shifts in coreceptor usage may thereby contribute to the clinical efficacy of anti-HIV drugs.
Anti-HIV Agents↗
Interaction between the vitamin D receptor gene and collagen type Ialpha1 gene in susceptibility for fracture.
Osteoporosis is a common disease with a strong genetic component. Polymorphisms in the vitamin D receptor (VDR) gene have been implicated in osteoporosis but explain only a small part of the genetic effect on bone mineral density (BMD) while their effect on fractures is still uncertain. Recently, a G to T polymorphism in an Sp1 site in the collagen type Ialpha1 (COLIA1) gene was found to be associated with reduced BMD and with increased fracture risk. To analyze the combined influence of polymorphisms in the VDR gene and the COLIA1 gene in determining the susceptibility to osteoporotic fracture, we studied 1004 postmenopausal women. The "baT" VDR haplotype, constructed from three adjacent restriction fragment length polymorphisms, was found to be overrepresented among fracture cases (p = 0.009). This corresponded to an odds ratio (OR) of 1.8 (95% CI, 1.0-3.3) for heterozygous carriers and 2.6 (95% CI, 1.4-5.0) for homozygous carriers of the risk haplotype. The effect was similar for vertebral and nonvertebral fractures and, most importantly, independent of BMD. We observed significant interaction (p = 0.03) between VDR and COLIA1 genotype effects. Fracture risk was not VDR genotype-dependent in the COLIA1 "reference" group (genotype GG) while in the COLIA1 "risk" group (genotypes GT and TT) the risk of fracture was 2.1 (95% CI, 1.0-4.4) for heterozygous and 4.4 (95% CI, 2.0-9.4) for homozygous carriers of the VDR risk haplotype. We conclude that both the VDR and the COLIA1 polymorphisms are genetic markers for osteoporotic fracture in women, independent of BMD. Our data indicate that interlocus interaction is likely to be an important component of osteoporotic fracture risk.
Cohort Studies↗
Syntheses and 1H-, 13C- and 15N-NMR spectra of ethynyl isocyanide, H-C triple bond C-N triple bond C, D-C triple bond C-N triple bond C and prop-1-ynyl isocyanide, H3C-C triple bond C-N triple bond C, D3C-C triple bond C-N triple bond C: high resolution infrared specturm of prop-1-ynyl isocyanide
Ethynyl isocyanide, H-C triple bond C-N triple bond C (1a), deuteroethynyl isocyanide, D-C triple bond C-N triple bond C (1b), prop-1-ynyl isocyanide, H3C-C triple bond C-N triple bond C (1c), and trideuteroprop-1-ynyl isocyanide, D3C-C triple bond C-N triple bond C (1d) are synthesized by flash vacuum pyrolysis of suitable organometallic precursor molecules (CO)5Cr(CN-CCl triple bond CClH) (5a), (CO)5Cr(CN-CCI=CClD) (5b), (CO)5Cr(CN-CCl=CCl-CH3) (5c) and (CO)5Cr(CN-CCI=CCl-CD3) (5d), respectively. Compounds 5a-d are formed in two steps by radical alkylation of tetraethyl-ammonium pentacarbonyl(cyano)chromate, NEt4[Cr(CO)5(CN)] (2) by 1,1,2,2,-tetrachloroethane (3a), 1,1,2,2-tetrachloro-1,2-dideuteroethane (3b), 1,1,2,2,-tetrachloropropane (3c), and 1,1,2,2-tetrachloro- 1,3,3,3-tetradeutero-propane (3d) yielding [(CO)5Cr(CN-CCl2-CCl2-H)] (4a), [(CO)5Cr(CN-CCl2-CCl2D)] (4b), [(CO)5Cr(CN-CCl2-CCl2-CH3)] (4c), and [(CO)5Cr(CN-CCl2-CCl2-CD3)] (4d). Dehalogenation of 4a-d using zinc in diethylether/acetic acid gives 5a-d, respectively. A multinuclear NMR study revealed the 1H-, 13C- and 15N-NMR data of 1a and 1c. Molecular spectroscopic data of 1c were determined by high resolution infrared spectroscopy. The by-products of the pyrolysis are the E and Z isomers of the halogenated ethenyl isocyanides H(Cl)C=CCl-NC (6a) and H3C(Cl)C=CCl-NC (6c) which have been characterized by IR, MS and NMR spectroscopy.
Journal Article↗
Long-term oral contraceptive use increases breast cancer risk in women over 55 years of age: the DOM cohort.
The role of past oral contraceptive use in the development of breast cancer is unclear, particularly in postmenopausal women. The authors investigated this relationship among pre- and postmenopausal middle-aged women in a nested case-control study within the population-based DOM cohort, Utrecht, the Netherlands. Among a total population of 12,184 women followed up for an average of 7.5 years, 309 breast cancer cases aged 42 to 63 years, diagnosed from November 1982 through May 1996, and 610 controls were examined. Overall, duration of oral contraceptive use was not clearly related to breast cancer. In women older than 55 years, however, oral contraceptive use for more than 10 years was associated with a 2-fold increased risk of breast cancer (odds ratio (OR) 2.1, 95% confidence interval (CI) 1.1-4.0). We conclude that long duration of oral contraceptive use increases the risk of breast cancer in women over 55 years of age but not in younger women.
Adult↗
The influence of post-polio syndrome on independence and life satisfaction.
PURPOSE: The aim of the study was to find out the influence of the new symptoms on life satisfaction and independent living and the most frequent disabilities in patients with post-polio syndrome that are affecting the satisfaction and independence. METHOD: A questionnaire was sent to all the post-polio survivors (207) who visited the Rehabilitation Institute in Ljubljana at least once in the last ten years. We got 100 answers, which were analysed by SPSS (statistical package for social sciences). RESULTS: Sixty nine reported that they had new symptoms that may be classified as post-polio syndrome. CONCLUSIONS: We have found that the new symptoms in post-polio survivors, which may be classified as post-polio syndrome, increased their walking and climbing stairs disability, increased their disability to perform daily activities and also decreased their satisfaction with life.
Activities of Daily Living↗
A genome-wide screening in Saccharomyces cerevisiae for genes that confer resistance to the anticancer agent cisplatin.
Cisplatin is a potent DNA-damaging agent that has demonstrated anticancer activities against several tumors. However, manifestation of cellular resistance is a major obstacle in anticancer therapy that severely limits the curative potential of cisplatin. Therefore, understanding the molecular basis of cisplatin resistance could significantly improve the clinical efficacy of this anticancer agent. Here, we employed Saccharomyces cerevisiae as a model organism to study cisplatin resistance mechanisms and describe a one-step cisplatin selection to identify and characterize novel cisplatin resistance genes. Screening a multicopy yeast genomic library enabled us to isolate several yeast clones for which we could confirm that the cisplatin resistance phenotype was linked to the introduced fragment. In a first attempt, a number of open reading frames could be identified. Among these genes, PDE2 and ZDS2 were repeatedly identified as genes whose overexpression confers cellular resistance to cisplatin. PDE2, encoding cAMP-phosphodiesterase 2, is of particular interest because the overexpression of this yeast gene is known to induce cisplatin resistance in mammalian cells as well, providing proof of the principle of our experimental approach. In addition, the identification of PDE2 shows that our yeast screening system can directly be informative for drug resistance in mammalian cells.
Chromosome Mapping↗
Adjacent genes, for COL2A1 and the vitamin D receptor, are associated with separate features of radiographic osteoarthritis of the knee.
OBJECTIVE: To study the association of the COL2A1 genotype, in relation to the vitamin D receptor (VDR) genotype, with features of radiographic osteoarthritis (ROA) in a population of elderly men and women. METHODS: In this cross-sectional study, we analyzed a population-based sample of 851 men and women ages 55-80 years from a large cohort study, the Rotterdam Study. We determined the prevalence of ROA of the knee according to the Kellgren/Lawrence (K/L) score and features of ROA (presence of osteophytes and narrowing of the joint space [JSN]) without considering clinical parameters of the disease. Genotypes were determined at a variable-number tandem repeats marker 1 kb downstream of the COL2A1 gene using a newly developed heteroduplexing method. The VDR genotype was previously determined by a direct molecular haplotyping polymerase chain reaction method to establish the phase of alleles at 3 adjacent restriction fragment length polymorphisms for Bsm I, Apa I, and Taq I. RESULTS: We found the COL2A1 genotype to be associated with a 2-fold increased risk for JSN, but not with osteophytes or the K/L score. We had previously found the VDR genotype to be associated with osteophytes and the K/L score, but not with JSN. When the COL2A1 genotype was analyzed in combination with the VDR genotype, we found evidence suggesting that the presence of haplotypes of the 2 genes was associated with increased risk for ROA. CONCLUSION: Our findings demonstrate that both the COL2A1 gene and the VDR gene are involved in ROA, but in separate features. The COL2A1 genotype is associated with JSN, while the VDR genotype is associated with osteophytes.
Aged↗