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Biomedical subjects

J H Bauer

Publications and source records attributed to J H Bauer.

At least 19 recordsLinked to original sources
PubMed2001

Characterization of a p75(NTR) apoptotic signaling pathway using a novel cellular model.

The p75 neurotrophin receptor (p75(NTR)) belongs to the tumor necrosis factor receptor/nerve growth factor receptor superfamily. In some cells derived from neuronal tissues it causes cell death through a poorly characterized pathway. We developed a neuronal system using conditionally immortalized striatal neurons, in which the expression of p75(NTR) is inducibly controlled by the ecdysone receptor. In these cells p75(NTR) induces apoptosis through its death domain in a nerve growth factor-independent manner. Caspases 9, 6, and 3 are activated by receptor expression indicating the activation of the common effector pathway of apoptosis. Cell death is blocked by a dominant negative form of caspase 9 and Bcl-X(L) consistent with a pathway that involves mitochondria. Significantly, the viral flice inhibitory protein E8 protects from p75(NTR)-induced cell death indicating that death effector domains are involved. A p75(NTR) construct with a deleted death domain dominantly interferes with p75(NTR) signaling, implying that receptor multimerization is required. However, in contrast to the other receptors of the family, p75(NTR)-mediated apoptosis does not involve the adaptor proteins Fas-associated death domain protein or tumor necrosis factor-associated death domain protein, and the apical caspase 8 is not activated. We conclude that p75(NTR) signals apoptosis by similar mechanisms as other death receptors but uses different adaptors and apical caspases.

Apoptosis↗
PubMed2001

The bladder angiotensin system in female rats: response to infusions of angiotensin I and the angiotensin converting enzyme inhibitor enalaprilat.

PURPOSE: A local renin angiotensin (ANG) system has been identified in the bladder. To our knowledge little is known about this system. To define further the physiology of this system we performed this study. MATERIALS AND METHODS: The circulating and bladder tissue concentrations of ANG I and ANG II were examined in anesthetized Sprague-Dawley female rats in estrus, diestrus or pregnancy. Each was given an intravenous bolus infusion of ANG I, the ANG converting enzyme inhibitor enalaprilat or saline. RESULTS: The mean concentrations of ANG I and ANG II were markedly higher in bladder tissue than in whole blood at the highest levels in pregnancy. The concentration of ANG I and ANG II increased significantly in the bladder tissue and circulation after the ANG I infusion in estrus and diestrus. In pregnancy only circulatory ANG I increased, while circulatory ANG II, tissue ANG I and ANG II remained unchanged. Enalaprilat infusion was associated with an increased concentration of whole blood ANG I in all groups and decreased plasma ANG II in estrus and diestrus but not in pregnancy. The bladder tissue ANG I response was unchanged in all groups. Bladder tissue ANG II was decreased in estrus and diestrus but unchanged in pregnancy. CONCLUSIONS: These data support the hypothesis that ANG converting enzyme is deactivated and an alternate pathway is activated in pregnancy. The data also demonstrate that tissue absorption of ANG peptide is diminished in pregnancy. Compared with responses in similarly studied male rats the circulating conversion of ANG I to ANG II is delayed in female rats and responses to ANG converting enzyme inhibition are enhanced, thus, suggesting subtle differences in the sexes in the renin ANG system. Enalapril appears to have more effect at the tissue level in nonpregnant females than in pregnant females and male rats.

Angiotensin I↗
PubMed2000

Wild-type huntingtin protects from apoptosis upstream of caspase-3.

Expansion of a polyglutamine sequence in the N terminus of huntingtin is the gain-of-function event that causes Huntington's disease. This mutation affects primarily the medium-size spiny neurons of the striatum. Huntingtin is expressed in many neuronal and non-neuronal cell types, implying a more general function for the wild-type protein. Here we report that wild-type huntingtin acts by protecting CNS cells from a variety of apoptotic stimuli, including serum withdrawal, death receptors, and pro-apoptotic Bcl-2 homologs. This protection may take place at the level of caspase-9 activation. The full-length protein also modulates the toxicity of the poly-Q expansion. Cells expressing full-length mutant protein are susceptible to fewer death stimuli than cells expressing truncated mutant huntingtin.

Animals↗
PubMed1998

Identification and functional characterization of DR6, a novel death domain-containing TNF receptor.

Tumor nectosis factor (TNF) receptors are key players in inflammation and immune regulation. A new member of this family, termed death receptor-6 (DR6), has been identified. Like other death receptors, DR6 is a type I transmembrane receptor, possesses four extracellular cysteine-rich motifs and a cytoplasmic death domain. DR6 is expressed in most human tissues and abundant transcript was detected in heart, brain, placenta, pancreas, thymus, lymph node and several non-lymphoid cancer cell lines. DR6 interacts with TRADD, which has previously been shown to associate with TNFR1. Furthermore, ectopic expression of DR6 in mammalian cells induces apoptosis and activation of both NF-kappaB and JNK.

Amino Acid Sequence↗
PubMed1998

Heteromerization of the gammac chain with the interleukin-9 receptor alpha subunit leads to STAT activation and prevention of apoptosis.

Interleukin-9 (IL-9) is a cytokine with pleiotropic effects on mast cell and T cell lines. It exerts its effects through the IL-9R complex consisting of IL-9Ralpha and the common gammac subunit. Here we report functional evidence for receptor heteromerization for efficient signal transduction, and we define minimal requirements in the two receptor subunits for IL-9R function. Tyrosine 336 of the IL-9Ralpha and the membrane-proximal segment of gammac are both crucial for signaling. The activated IL-9R complex employs the Janus kinases JAK1 and JAK3 for subsequent activation of the signal transducer and activator transcription (STAT) factors STAT-1, STAT-3, and STAT-5. This process is independent of Tyk2. We demonstrate further that the activated STAT complexes consist of STAT-1 and STAT-5 homodimers and STAT-1-STAT-3 heterodimers. Finally, we show that IL-9R signaling in a T cell line does not result in detectable mitogen-activated protein kinase activation and leads to unsustained proliferation. Nonetheless, these T cells are efficiently protected from dexamethasone-induced apoptosis. These results further define the molecular architecture of the IL-9R and its specific connections to various biologic responses.

Animals↗
PubMed1998

Modern antihypertensive treatment and the progression of renal disease.

BACKGROUND: In animal models of hypertension, the resistance state of the preglomerular (afferent) and postglomerular (efferent) capillary arterioles may determine whether a particular form of antihypertensive therapy will spare the kidney from hemodynamic-mediated glomerular injury. In experimental models of renal disease with impaired autoregulation, control of systemic blood pressure is a prerequisite for normalizing glomerular capillary hydraulic pressure. CLINICAL STUDIES: In humans, effective blood pressure control reverses renal hemodynamic abnormalities in hypertensive patients, reduces microalbuminuria in essential hypertensive, nondiabetic, and diabetic renal diseases, and attenuates but does not prevent the progression of nondiabetic and diabetic renal disease. Although some researchers have concluded that angiotensin converting enzyme inhibitors are the renal protective drugs of choice, these pronouncements are not based on clinical trials correlating specific drug-mediated changes in albumin or protein excretion with the longitudinal assessment of glomerular filtration rate (GFR), permitting derivation of a slope-defining change in GFR, and/or the longitudinal assessment of renal structure (i.e. renal biopsy). Definitive clinical trials have not been reported. It is important to recognize that an elevated serum creatinine is a powerful predictor of mortality and that, in most patients, death is caused by a cardiovascular or cerebrovascular event, rather than by renal failure. CONCLUSION: Because morbidity and mortality of essential hypertension and nondiabetic or diabetic renal disease is related primarily to cardiovascular or cerebrovascular events, the antihypertensive 'drugs of choice' should be those that reduce these risks, prevent or regress target-organ damage, and optimize treatment of concomitant diseases.

Animals↗
PubMed1996

The urinary bladder angiotensin system: response to infusions of angiotensin I and angiotensin-converting enzyme inhibitors.

The circulating and urinary bladder tissue concentrations of angiotensin I (ANG I) and angiotensin II [ANG-(1-8)] were examined in anesthetized Sprague-Dawley male rats given an intravenous bolus infusion of either ANG I, the angiotensin-converting enzyme (ACE) inhibitors enalaprilat or ramiprilat, or saline. The mean concentrations of ANG I and ANG-(1-8) were markedly higher in the urinary bladder tissue than in whole blood. There was a significant increase in the concentration of ANG I and ANG-(1-8), both in the urinary bladder tissue and the circulation, after the ANG I infusion. Both ACE inhibitors were associated with an increase in the concentration of whole blood ANG I; however, tissue ANG I levels were significantly increased only following ACE inhibition with ramiprilat but not with enalaprilat. Both plasma and urinary bladder tissue ANG-(1-8) levels decreased significantly following ACE inhibition, but only with ramiprilat. The elevated urinary bladder tissue levels of ANG I and ANG-(1-8) at baseline, compared with circulating levels, and the maintenance of ANG-(1-8) in bladder tissue in the face of inhibition of the circulatory renin-angiotensin system with enalaprilat support the presence of an autocrine/paracrine renin-angiotensin system in the urinary bladder. Under the current experimental conditions, ramiprilat appears to have enhanced bladder activity compared with enalaprilat.

Anesthesia↗
PubMed1995

The angiotensin II type 1 receptor antagonists. A new class of antihypertensive drugs.

The angiotensin II (AII) type 1 receptor antagonists represent a new pharmacologic class of drugs that are specifically designed to displace AII from its type 1 receptor subtype. These drugs antagonize AII-induced biologic actions, including smooth-muscle contraction, sympathetic pressor mechanisms, and aldosterone release. Initial clinical trials suggest that these drugs are effective in the treatment of essential hypertension and hypertensive patients with intrinsic renal disease. Thus, they are the newest addition to the therapeutic armamentarium for the treatment of hypertensive diseases. We review the developmental history and pharmacology of the AII type 1 receptor antagonists. We specifically discuss the following factors: mechanism(s) of action; members under clinical investigation; effects on renal function, salt and water excretion, and plasma renin activity, plasma AII type 1, and plasma aldosterone concentrations; and efficacy and safety. Given the demonstrable benefits of AII type 1 receptor blockade, these drugs should achieve broad utility in the treatment of hypertensive diseases.

Acrylates↗
PubMed1995

Accuracy of disposable blood pressure transducers used in the critical care setting.

OBJECTIVES: To assess the initial accuracy, drift in calibration over several hours, and decline in accuracy over daily use of blood pressure transducers used in the critical care setting. DESIGN: Prospective, criterion standard. SETTING: Three critical care units in a university hospital. SUBJECTS: Twenty-seven consecutively available high-pressure transducers were used to measure intra-arterial blood pressures, and 11 consecutively available low-pressure transducers were used to measure central venous and pulmonary arterial blood pressures. INTERVENTIONS: High-pressure transducers were compared with a mercury column manometer, and low-pressure transducers were compared with a water column manometer at three pressure levels. Data were collected initially after installation of the pressure transducer, at 3 hrs, and at 6 hrs. Data collections were repeated on subsequent days. MEASUREMENTS AND MAIN RESULTS: a) The majority of pressure transducers are accurate; b) there is no drift in the accuracy of pressure transducers over several hours; c) the accuracy of pressure transducers does not decline over subsequent days. Some transducers over-estimated standard pressures by 10 mm Hg and/or underestimated standard pressure by 17 mm Hg. CONCLUSIONS: The majority of pressure transducers used in the critical care setting are accurate, although there are some transducers that may compromise patient care. Blood pressure transducers should be checked against a standard manometer upon installation, and daily during use.

Blood Pressure Determination↗
PubMed1994

Diabetic nephropathy: can it be prevented? Are there renal protective antihypertensive drugs of choice?

Diabetic nephropathy is the most common cause of end-stage renal disease in the United States. This review focuses on (1) the problem of diabetic nephropathy, (2) hypertension in patients with diabetes mellitus, (3) the pathophysiology of diabetic nephropathy, and (4) therapeutic methods designed to provide renal protection to patients with diabetes mellitus. The treatments discussed are (1) strict metabolic control, (2) strict control of systemic hypertension, (3) control of glomerular hypertension, and (4) dietary protein restriction. Diabetic nephropathy can be retarded; renal protection depends primarily on strict metabolic control and strict control of systemic hypertension. With respect to the kidney, there are no unique renal protective antihypertensive drugs of choice.

Antihypertensive Agents↗
PubMed1994

Urinary angiotensin II: a marker of renal tissue activity?

The methodology for the collection, extraction, separation and measurement of urinary angiotensin II [the octapeptide, ANG(1-8)] is described. To determine the origin of urinary ANG(1-8), mean arterial pressure, renal hemodynamics and the arterial, renal venous and urinary concentrations of ANG(1-8) were examined prior to and following the constant intra-arterial infusion of tritiated angiotensin II [3H-ANG(1-8)] in graded doses of 0.5, 2.0 and 2.5 ng/kg/min in 5 uninephrectomized, anesthetized female dogs. The infusion of 3H-ANG-(1-8) had no significant effect on mean arterial pressure, glomerular filtration rate, renal blood flow or urine flow rate. The mean concentration of ANG(1-8) in the urine was 3.7 fmol/ml. None or only trace amounts of 3H-ANG(1-8) were detected in the urine in spite of marked increases in renal arterial 3H-ANG(1-8) concentrations. These observations suggest that urinary ANG(1-8) was derived de novo from the intrarenal generation of angiotensin II. In addition, plasma and urinary concentrations of ANG(1-8) were assessed in patients with essential hypertension undergoing treatment with either a diuretic (n = 14) or an angiotensin-converting enzyme inhibitor (n = 14). Although the concentrations of plasma ANG(1-8) responded appropriately to the respective therapies, the urinary excretion of ANG(1-8) was not different following either therapy. These data suggest that ANG(1-8) collected from the urinary bladder may not occur in adequate concentrations to accurately assess the activity of the intrarenal renin-angiotensin system.

Angiotensin II↗
PubMed1993

A review of common errors in the indirect measurement of blood pressure. Sphygmomanometry.

There are three sources of error in the indirect measurement of blood pressure: (1) observer bias, (2) faulty equipment, and (3) failure to standardize the techniques of measurement. This article examines each area extensively, discusses the cumulative effect of these errors on the accuracy of indirect blood pressure measurement, and reviews the recommendations for proper indirect measurement of blood pressure.

Blood Pressure Determination↗
PubMed1993

The effects of olfactory experience on nest odor preferences and pup retrieval in rats.

Previous studies have shown that maternal rats are attracted to their own bedding and that of other dams but not to that of virgins. The present studies were designed to test two hypotheses: First, that the addition of a novel botanical odor to the bedding of maternal animals would result in subsequent preferences for such an odor. Second, such a preference should enable dams to discriminate between pups odorized with familiar and unfamiliar odors as measured by differential retrieval of the pups. Both hypotheses were confirmed. In addition, we found that preferences established during a first pregnancy and lactation affected the retrieval of pups during a second lactational period, but could be overturned by new olfactory experience during that second lactational period.

Animals↗
PubMed1993

Short- and long-term effects of spirapril on renal hemodynamics in patients with essential hypertension.

Sixteen essential hypertensive patients were entered into a protocol assessing the effect of Spirapril, an angiotensin-converting enzyme (ACE) inhibitor, on blood pressure, the renin-aldosterone system, and renal function. Specifically monitored before, during 6 weeks, and 6 months of Spirapril therapy were plasma renin activity, plasma aldosterone, serum ACE, the renal clearances of creatinine, inulin, and para-aminohippurate, and urinary albumin excretion. Blood pressure was well controlled. Spirapril stimulated plasma renin activity and suppressed ACE throughout the entire protocol. Renal clearances were unchanged. Renal vascular resistance was decreased. Urinary albumin excretion was decreased. The authors conclude that the ACE inhibitor, Spirapril, when used as an effective antihypertensive agent, preserves renal function, lowers renal vascular resistance, and decreases urinary albumin excretion.

Adult↗
PubMed1993

An evaluation of the renal protective effect of manidipine in the uninephrectomized spontaneously hypertensive rat.

The effects of calcium antagonism on the development and progression of renal disease are controversial. To address this problem, studies were performed on young, uninephrectomized spontaneously hypertensive rats (SHRs) with the dihydropyridine calcium antagonist, manidipine, to assess its effect on the early pathogenesis of focal glomerulosclerosis. Male SHRs underwent uninephrectomy at age 10 to 11 weeks and were subsequently assigned to no treatment (control), a predetermined subvasodepressor (low) dose of manidipine (2.5 mg/kg body weight), or a predetermined antihypertensive (high) dose of manidipine (20 mg/kg body weight). All animals received a diet containing 0.4% sodium and 23% protein. Serial determinations of body weight, systolic tail cuff pressure, and 24-hour urinary excretion of creatinine, sodium, and protein (UprotV) were made at 1- to 6-week intervals, for a total treatment period of 12 weeks. In final experiments plasma was obtained for creatinine, angiotensin I, and angiotensin II determinations, and renal tissue was harvested for histologic and morphometric analysis. Compared with the untreated control, low-dose manidipine therapy had no effect on body weight, systolic blood pressure, creatinine clearance, UprotV, renal histologic findings, glomerular volume, or plasma angiotensin I or II concentrations. In contrast, high-dose manidipine therapy decreased systolic blood pressure from 194 +/- 3 to 160 +/- 4 mm Hg (p < 0.01). Creatinine clearance and UprotV were unchanged. Although body weight was not different, kidney weight was higher. However, mean glomerular volume was lower. More importantly, the prevalence of mesangial expansion with proliferation was lower: 6.7% (control) versus 2.8% (high-dose manidipine) (p < 0.01). Finally, plasma angiotensin I and angiotensin II concentrations did not differ.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1993

Renal tissue angiotensin II: response to infusions of angiotensin I and an angiotensin-converting enzyme inhibitor.

A procedure for the collection, processing, extraction, separation, and measurement of renal tissue angiotensin II [ANG-(1-8)] is described. The arterial plasma and renal tissue concentrations of ANG-(1-8) were examined in anesthetized Sprague-Dawley male rats (10 to 12 weeks of age) given an intravenous saline infusion (group 1; n = 6), an intravenous bolus infusion of 0.5 microgram angiotensin I (group 2; n = 6), or an intravenous bolus of an angiotensin-converting enzyme inhibitor (group 3; n = 6). Plasma and renal tissue were collected at the peak mean arterial pressure (MAP) response. The mean (+/- SEM) concentration of ANG-(1-8) in the group given the saline vehicle was 12 +/- 2 fmol/mL in the plasma and 2.4 +/- 0.3 pmol/g in the renal tissue. The angiotensin I bolus significantly increased MAP by 40%. Following the angiotensin I infusion, at the time of peak MAP response, the concentration of the circulating and renal tissue ANG-(1-8) were 12-fold and twofold higher, respectively, compared with the saline vehicle. The angiotensin-converting enzyme inhibitor significantly decreased MAP by 10% and decreased the circulating and renal tissue ANG-(1-8) levels by 75% and 62.5%, respectively, compared with the saline vehicle. The rapid conversion of exogenous angiotensin I to ANG-(1-8) in renal tissue provides direct evidence that renal tissue can generate de novo ANG-(1-8) from a circulating precursor. Furthermore, plasma and renal tissue respond similarly to acute angiotensin-converting enzyme inhibition.

Angiotensin I↗
PubMed1992

A randomized, double-blind, placebo-controlled trial to evaluate the effect of enalapril in patients with clinical diabetic nephropathy.

It is unknown if the antiproteinuric effect of angiotensin-converting enzyme (ACE) inhibitors reflects attenuation in the rate of progression of diabetic nephropathy. We report the results of a randomized, double-blind clinical trial designed to evaluate the longitudinal (18-month) effect of the ACE inhibitor, enalapril (5 to 40 mg/d), versus a placebo on 24-hour urinary protein excretion and on the rate of progression of renal disease in 33 patients with clinical diabetic nephropathy. Systemic blood pressure was controlled throughout the trial with conventional antihypertensive drugs. Glomerular filtration rate (GFR), determined by Tc99mDTPA renal clearance, and urinary protein excretion were monitored at 3-month intervals. Enalapril, in contrast to placebo therapy, was associated with an initial (40%) and sustained (33%) decrease in urinary protein excretion. Patients randomized to both enalapril or placebo experienced mean decreases in GFR, from 1.01 mL/s/1.73 m2 (61 mL/min/1.73 m2) to 0.85 mL/s/1.73 m2 (51 mL/min/1.73 m2), and from 1.06 mL/s/1.73 m2 (64 mL/min/1.73 m2) to 0.97 mL/s/1.73 m2 (58 mL/min/1.73 m2), respectively. Eleven of 18 patients (61%) randomized to enalapril, and 10 of 15 (66%) patients randomized to placebo, had a decrease in GFR; their rates of progression were -1.18 mL/min/1.73 m2/mo and -1.00 mL/min/1.73 m2/mo, respectively. In the absence of changes in blood pressure, the addition of an ACE inhibitor to patients with clinical diabetic nephropathy could not be shown to confer a unique renal protective effect. A prolonged decrease in 24-hour protein excretion could not be shown to predict attenuation in the progression of established clinical diabetic nephropathy.

Adult↗