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Biomedical subjects

D Rosen

Publications and source records attributed to D Rosen.

At least 19 recordsLinked to original sources
PubMed1996

Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group.

OBJECTIVES: To determine whether the administration of 1.5 million units of streptokinase intravenously within 4 hours of the onset of acute ischemic stroke would reduce morbidity and mortality at 3 months and whether outcomes may be better for those receiving therapy within 3 hours of stroke onset compared with those receiving it after 3 hours. DESIGN: Randomized, double-blind, placebo-controlled trial with 3-month follow-up. PARTICIPANTS: A total of 340 patients, aged 18 to 85 years, with moderate to severe strokes were randomized from 40 centers throughout Australia from June 1992 to November 1994. INTERVENTION: Administration of 1.5 million units of streptokinase or placebo intravenously in 100 mL of normal saline over 1 hour. MAIN OUTCOME MEASURE: Combined death and disability score (Barthel index <60) 3 months after the stroke. RESULTS: Using an intention-to-treat analysis with a combined death and disability score at 3 months after stroke as the primary end point, we found a nonsignificant overall trend toward unfavorable outcomes for streptokinase vs placebo (relative risk [RR] of unfavorable outcome, 1.08; 95% confidence interval [CI], 0.74-1.58) and an excess of hematomas (13.2%[12.6% symptomatic] in the treated group, 3% [2.4% symptomatic] for placebo [P<.01]). However, poor outcomes were confined to patients receiving therapy more than 3 hours after stroke onset (RR of unfavorable outcome, 1.22; 95% CI, 0.80-1.86). In contrast, among the 70 patients who were entered into the trial within 3 hours of stroke onset, there was a trend toward improved outcomes for those who received streptokinase (RR of unfavorable outcome, 0.66; 95% CI, 0.28-1.58), and this outcome pattern was significantly better than for those receiving therapy after 3 hours (P=.04). Streptokinase administration resulted in excess deaths in the group treated after 3 hours (RR, 1.98; 95% CI, 1.18-3.35), but not among those treated within 3 hours (RR, 1.11; 95% CI, 0.38-3.21). CONCLUSION: The administration of streptokinase within 4 hours of acute ischemic stroke increased morbidity and mortality at 3 months. While treatment within 3 hours of stroke was safer and associated with significantly better outcomes than later treatment, it showed no significant benefit over placebo. The timing of thrombolytic therapy for acute stroke is critical.

Acute Disease↗
PubMed1996

The effect of thigh-length support stockings on the hemodynamic response to ambulation in pregnancy.

OBJECTIVE: Our purpose was to determine the effect of thigh-length support stockings on hemodynamic response when pregnant subjects change from the sitting to the lateral recumbent position and then after standing with ambulation. STUDY DESIGN: Eighteen subjects in the late second and early third trimester of pregnancy acted as their own controls. The cardiovascular status of the subjects was assessed by a noninvasive technique--thoracic electrical bioimpedance before and after wearing support stockings for 1 week. Urine catecholamines were measured in 13 patients before and after wearing support stocking to assess the release of catecholamines. Samples were collected after the subjects had been in the lateral recumbent position 40 minutes and again 40 minutes later after standing with ambulation. RESULTS: Heart rate and mean arterial blood pressure decreased significantly when subjects changed from the sitting to the lateral recumbent position and then increased with ambulation. Wearing compression stockings significantly increased mean arterial pressure and afterload in all three positions. Position change from lateral recumbent to standing and ambulation marginally increased urinary dopamine levels (p = 0.097) and significantly increased norepinephrine levels (p = 0.006). CONCLUSIONS: There are significant hemodynamic changes in pregnant subjects when they change from the sitting position to the lateral recumbent position and then change to standing with ambulation. Support stocking have a significant mechanical effect: they significantly increase afterload and systemic vascular resistance by preventing pooling of blood in the lower extremities. There may also be a biochemical effect that results in less catecholamine release. These results suggest that compression stockings could play an important role in supporting the circulation during ambulation.

Adult↗
PubMed1996

Endoscopic sinus surgery in the developmentally delayed child.

Functional endoscopic sinus surgery (FESS) has gained widespread support as the treatment of choice for chronic sinusitis in children. Seven developmentally delayed children were evaluated for chronic sinusitis with symptoms of cough, chronic rhinorrhea, and head banging because of pain. All seven were nonresponsive to repeated courses of oral and sometimes intravenous antibiotics; computed tomography scans on all revealed sinus disease. FESS was performed on all of them. Three children had marked respiratory difficulty at the end of the procedure, with two requiring reintubation. Two children were not able to take oral feedings postoperatively. Because of the complicated postoperative course, a second-look procedure was performed in only two children. We believe that FESS for developmentally delayed children should be tailored accordingly and that a second-look procedure should not be a routine.

Adolescent↗
PubMed1995

Lytic reaction of in vivo primed peritoneal exudate CTL. Induction of high-conductance single channels in the target cell membrane.

CTL, primary effectors in immune responses, deliver a "lethal hit" signal to target cells, causing their destruction. The precise membrane events associated with the lethal hit remain elusive. We investigated the signal(s) mediating destruction of tumor target cells (EL4) by perforin-deficient peritoneal exudate CTL (PEL). We utilized patch clamp techniques to record electrophysiological events associated with the cytolytic interaction of PEL and EL4 in isolated conjugates. PEL-EL4 interaction resulted in induction in EL4 cells, of single channels (followed by EL4 destruction), with a mean conductance of 437 pS and a reversal potential of -1.0 mV, suggestive of nonselective pathways. Similar channels were induced in EL4 cells conjugated with perforin-rich PEL blasts (PEB), by perforin, postnuclear extract from PEL (pnPEL) and from other cytotoxic lymphocytes, but not from noncytolytic lymphocytes. As similar channels were induced by pnPEL in EL4 membrane patches, we propose that these channels result from a direct effect of PEL-derived channel-forming substance(s) on the target cell's membrane. Importantly, postnuclear extracts from perforin-devoid cytotoxic PEL-hybridomas induced similar channels, suggesting the presence of a nonperforin, channel-forming activity in PEL and PEL-hybridomas. Based on the present study, we conclude that the delivery of the lethal hit by cytolytic PEL and PEL-hybridoma is associated with induction in the target cell of high-conductance channels, which most likely mediate its destruction. We propose that these channels are related to the Fas pathway of lymphocytotoxicity.

Animals↗
PubMed1995

Phosphorylation of the Drosophila engrailed protein at a site outside its homeodomain enhances DNA binding.

The engrailed gene encodes a homeodomain-containing phosphoprotein that binds DNA. Here, we show that engrailed protein is posttranslationally modified in embryos and in embryo-derived cultured cells but is essentially unmodified when expressed in Escherichia coli. Engrailed protein produced by bacteria can be phosphorylated in nuclear extracts prepared from Drosophila embryos, and phosphotryptic peptides from this modified protein partly reproduce two-dimensional maps of phosphotryptic fragments obtained from metabolically labeled engrailed protein. The primary embryonic protein kinase modifying engrailed protein is casein kinase II (CK-II). Analysis of mutant proteins revealed that the in vitro phosphoacceptors are mainly clustered in a region outside the engrailed homeodomain and identified serines 394, 397, 401, and 402 as the targets for CK-II phosphorylation. CK-II-dependent phosphorylation of an N-truncated derivative of engrailed protein purified from bacteria increased its DNA binding 2-4-fold.

Amino Acid Sequence↗
PubMed1995

Treatment of ovariectomized rats with the complex of rhIGF-I/IGFBP-3 increases cortical and cancellous bone mass and improves structure in the femoral neck.

Sixteen-week-old Sprague-Dawley rats were ovariectomized (Ovx) or sham-operated and housed for 8 weeks to develop osteopenia prior to systemic administration of rhIGF-I (0.9 and 2.6 mg/kg) alone or the rhIGF-I/IGFBP-3 (0.9, 2.6 and 7.5 mg/kg) complex. After 8 weeks of treatment, proximal femurs were fixed, embedded, and cut through the midneck region. Structural and dynamic histomorphometric analyses were performed using standard techniques. Ovx increased endocortical resorption and modeling-dependent periosteal formation which resulted in decreased cortical bone area. Despite increased bone formation, trabecular number, thickness, and area were all reduced due to increased resorption. Structural changes following Ovx included fewer struts and nodes, a higher percentage of the simpler strut forms, and reduced endocortico-trabecular connectivity. Eight weeks of treatment with rhIGF-I or rhIGF-I/IGFBP-3 promoted periosteal and endocortical bone formation and reduced the endocortical resorption induced by Ovx. Both rhIGF-I formulations stimulated bone formation on existing trabecular surfaces which increased trabecular thickness and area but not trabecular number. These treatments prevented further deterioration of the trabecular network caused by Ovx and preserved endocortico-trabecular connectivity. In summary, changes in the femoral neck following Ovx appear to be similar in rats and humans. The highest dose of rhIGF-I/IGFBP-3 used in this study showed the best results in promoting cortical and cancellous bone formation, and appears to be promising therapy for human osteopenias.

Animals↗
PubMed1995

Systemic administration of rhIGF-I or rhIGF-I/IGFBP-3 increases cortical bone and lean body mass in ovariectomized rats.

The purpose of this study was to compare dose-related effects on cortical bone and lean body mass following subcutaneous administration of rhIGF-I alone, or bound to an equimolar amount of rhIGFBP-3 to adult Ovx rats. At the age of 16 weeks, rats were ovariectomized or sham-operated and were allowed 8 weeks to develop osteopenia. After being divided into control (saline treated) or treatment groups, rats were injected daily during an 8-week period with 0.9 and 2.6 mg/kg of rhIGF-I, or with 0.9, 2.6, and 7.5 mg/kg of rhIGF-I bound to rhIGFBP-3. Fluorescent bone markers were given 9 and 2 days prior to necropsy. Body weights and lean body mass were monitored throughout the experiment. Cortical bone histomorphometry was performed on tibial cross-sections at the tibiofibular junction, and endochondral bone growth was measured at the distal femoral metaphysis. All rats treated with rhIGF-I or the rhIGF-I/IGFBP-3 complex had increased body weights, corresponding to a dose-dependent increase in lean body mass. Endochondral growth was slightly increased in all experimental groups, but was not dose-dependent. A dramatic increase in periosteal, modeling-dependent formation, coupled with decreased or unchanged resorption on the endocortical envelope resulted in a dose-dependent increase in cortical thickness and cross-sectional area in groups treated with the complex of rhIGF-I/IGFBP-3. This complex appeared to be more effective in promoting positive musculoskeletal changes than rhIGF-I alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗
PubMed1995

The effect of systemically administered rhIGF-I/IGFBP-3 complex on cortical bone strength and structure in ovariectomized rats.

The action of systematically administered recombinant human insulinlike growth factor-I (rhIGF-I) complexed to its natural binding protein-3 (rhIGFBP-3) on cortical bone dynamic, structural, and mechanical properties was tested in previously ovariectomized (Ovx) rats. Bilateral ovariectomy or sham surgery was performed on 16-week-old female Sprague-Dawley rats. Eight weeks after surgery basal Sham and Ovx rats were killed to establish baseline cortical bone values before the initiation of treatment with rhIGF-I/IGFBP-3 complex. At that time, Ovx rats had increased body weight and body fat mass with reduced femoral BMC and BMD relative to basal Shams. Bone formation rates in Ovx rats were increased on both cortical envelopes relative to time-matched controls. The thickness of the inner lamellar bone layer and average cortical width were reduced due to increased endocortical erosion. A similar ratio between Sham and Ovx rats in body mass and composition and femoral BMC and BMD continued throughout the experiment. Sixteen weeks after surgery bone formation rates at both cortical envelopes in Ovx rats were reduced relative to Shams, but endocortical erosion remained high causing a further decrease in thickness of the inner lamellar layer. As a result of periosteal bone modeling. Ovx rats exhibited a larger femoral cross-sectional area and periosteal perimeter, as well as a thicker outer lamellar layer. Newly deposited periosteal bone increased ultimate torque values in the Ovx rats relative to Shams at 16 weeks. Treatment of Ovx rats with the rhIGF-I/IGFBP-3 complex increased body weight, lean body mass, and femoral BMC and BMD.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1995

Breast cancer among women exposed to polybrominated biphenyls.

We conducted a nested case-control study with 1,925 women enrolled in a polybrominated biphenyl (PBB) registry to examine the association between breast cancer and serum PBBs. Twenty women who developed breast cancer were matched to 290 control subjects on sex, race, and age. Women with serum PBB levels of 2.0-3.0 parts per billion (ppb) [odds ratio (OR) = 3.5; 95% confidence interval (CI) = 0.9-13] or 4.0 ppb or greater (OR = 3.1; 95% CI = 0.8-12) had a higher estimated risk for breast cancer than women with less than 2.0 ppb. The odds ratios were unchanged when available breast cancer risk factors were included in the analysis.

Breast Neoplasms↗
PubMed1995

Parthenogenesis-inducing microorganisms in Aphytis (Hymenoptera: Aphelinidae).

Production of males in uniparental lines of two species in the parasitic wasp genus Aphytis was induced by rifampicin, and male sexual functioning was determined. Wolbachia-specific 16S rDNA primers were used in a PCR in order to: (1) assess correlation between thelytokous reproduction and the presence of Wolbachia; (2) detect the loss of Wolbachia DNA in uniparental A. lingnanensis following antibiotic treatments, with or without the presence of a host; and (3) clone and sequence part of the Wolbachia 16S rDNA from the uniparental Aphytis species for phylogenetic studies. Males produced viable sperm that was transferred to the female spermatheca following mating. However, sperm failure to effect egg fertilization resulted in all-male progeny. Wolbachia were found in the two uniparental (A. lingnanensis and A. diaspidis) but not in the two biparental (A. lingnanensis and A. melinus) Aphytis lines tested. They can be detected in wasps up to 7 days following antibiotic treatments, regardless of the presence of host. The 16S rDNA for the symbionts in the two Aphytis species is virtually identical, and is most closely related to the Wolbachia found in Muscidifurax uniraptor (Pteromalidae).

Animals↗
PubMed1994

Benefit of systemically administered rhIGF-I and rhIGF-I/IGFBP-3 on cancellous bone in ovariectomized rats.

The dose-related effects of systemically administered rhIGF-I and rhIGF-I/IGFBP-3 were monitored in the osteopenic rat skeleton at three different sites with cancellous bone: distal femoral metaphysis, epiphysis, and lumbar vertebral bodies. At the age of 16 weeks, rats were bilaterally ovariectomized (OVX) or sham operated (sham) and 8 weeks later divided into the control groups (sham OVX), and OVX groups treated with different doses of rhIGF-I or rhIGF-I/IGFBP-3 for 8 weeks. Fluorescent bone markers were given 9 and 2 days before necropsy. In addition, changes in designated bone sites as a result of ovariectomy alone were evaluated 8 and 16 weeks after surgery. High bone resorption, which dominates the postovariectomy remodeling process, resulted in a loss of cancellous bone at all measured sites. The highest trabecular bone loss was measured in the metaphyses (40%), compared with 22% in the lumbar vertebrae and 16% in the epiphyses. After 8 weeks of treatment with 7.5 mg/kg of rhIGF-I/IGFBP-3, bone formation rates were increased at all sites measured. Increased trabecular thickness was observed at the epiphyses and in the lumbar vertebral bodies. Increased bone resorption was restricted to the metaphyses of the rats that received the highest dose of rhIGF-I or rhIGF-I/IGFBP-3. Both formulations of rhIGF-I increased longitudinal bone growth similarly. This experiment demonstrates site-specific differences in cancellous bone reactions following ovariectomy. Epyphyses showed some advantages for cancellous bone histomorphometry over metaphyses and lumbar vertebral bodies. The data presented confirm the potential of rhIGF-I/IGFBP-3 complex to promote the bone formation process at various bone sites in osteoporotic rat skeleton.

Animals↗
PubMed1994

Mechanisms whereby cytotoxic T lymphocytes damage guinea-pig ventricular myocytes in vitro.

We studied possible mechanisms whereby cytotoxic T lymphocytes (CTL) damage the myocardium during the immunological rejection of the transplanted heart, by investigating the in vitro interaction between CTL and cardiac myocytes. We utilized the patch-clamp technique to record membrane currents and action potentials from concanavalin A-treated guinea-pig ventricular myocytes conjugated to mouse peritoneal exudate CTL (PEL). PEL-myocyte interaction reduced action potential duration at 50% repolarization (APD50) from 731.7 +/- 57.8 to 195.3 +/- 58.0 ms, action potential amplitude from 134.9 +/- 1.9 to 104.2 +/- 6.2 mV and resting membrane potential (Vm) from -80.9 +/- 0.5 to 72.5 +/- 1.5 mV. These changes were accompanied by generation of delayed afterdepolarizations, indicative of intracellular [Ca2+] overload. The electrophysiological alterations were associated with myocyte shortening (within 28.9 +/- 2.8 min) followed by complete cell destruction (within 43.5 +/- 4.3 min). To determine whether intracellular Ca2+ stores were involved in PEL-induced myocyte damage, the protective effects of ryanodine and caffeine were investigated. While ryanodine (10 microM) delayed the electrophysiological and morphological alterations, caffeine (5 mM) provided significant protection, suggesting that Ca2+ release from intracellular stores contributes to PEL-induced damage to the myocytes. Based on our findings, we suggest that the functional derangements seen in myocyte-lymphocyte conjugates can contribute to the overall decline in cardiac function during heart transplant rejection.

Action Potentials↗
PubMed1994

Cu/Zn superoxide dismutase activity in familial and sporadic amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease that is inherited as an autosomal dominant trait in approximately 10% of cases. Recently we and others identified several single-base mutations in the Cu/Zn superoxide dismutase (SOD1) gene in patients with familial ALS (FALS). Using single-strand conformational polymorphism, we studied the C to G mutation in exon 2 of the SOD1 gene (resulting in a leucine to valine substitution in position 38) in affected and unaffected members of a large Belgian family with FALS. We measured the SOD1 activity in red blood cell lysates in 14 members of this family, including the only surviving clinically affected patient. SOD1 activity of the family members carrying the mutation was less than half that of members without the mutation. In addition, in 11 patients with sporadic ALS and 11 age- and sex-matched controls, red blood cell SOD1 activity was normal. These studies indicate that SOD1 activity is reduced in these FALS patients but not in sporadic ALS patients. Moreover, this SOD1 enzyme abnormality is detectable years before onset of clinical ALS in carriers of this FALS mutation.

Adult↗
PubMed1994

Effects of purified perforin and granzyme A from cytotoxic T lymphocytes on guinea pig ventricular myocytes.

OBJECTIVE: Involvement of cytotoxic T lymphocytes (CTL) in heart transplant rejection as well as in viral myocarditis is well established, but the precise mechanisms whereby infiltrating CTL damage the myocardium are unknown. The aim of the study was to investigate how CTL derived perforin, the serine protease granzyme A, and the combination of both, damage guinea pig ventricular myocytes. METHODS: Action potentials and membrane currents were recorded by means of the whole cell configuration from guinea pig ventricular myocytes. RESULTS: Resembling the effects of CTL derived lytic granules, perforin caused gradual myocyte shortening and contracture, leading to complete loss of the rod shaped morphology and to cell destruction. These changes were preceded by shortening of action potential duration and reduction of resting potential and action potential amplitude, followed by complete inexcitability. Granzyme A alone was ineffective, but accelerated the deleterious effects of perforin on the morphological and electrophysiological properties of myocytes. The effects of perforin were further evaluated by measuring membrane currents by means of the whole cell voltage clamp. Perforin induced discrete changes in membrane current, reminiscent of single ion channels, with large conductance and open time of up to several seconds. Linear regression analysis of the channel I-V relations resulted in a conductance of 890 pS and a reversal potential of -7.6 mV. These results suggest that perforin induces large non-selective channels, which can account for most of the observed adverse effects. CONCLUSIONS: As CTL participate in the immunological rejection of the transplanted heart, it is conceivable, but remains to be shown, that part of this damage is inflicted by perforin containing lytic granules.

Action Potentials↗