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C Wittenberg

Publications and source records attributed to C Wittenberg.

At least 37 records · Page 2Linked to original sources
PubMed1995

CLN3, not positive feedback, determines the timing of CLN2 transcription in cycling cells.

Transcriptional activation of the budding yeast CLN1 and CLN2 genes during the late G1 phase of the cell cycle has been attributed to a positive feedback loop, wherein the transcription of both genes is stimulated by the accumulation of their protein products. We demonstrate that in cycling cells CLN2 does not play a role in determining the timing of its own transcriptional activation. First, we show that CLN3 alone is sufficient to maximally activate CLN2 transcription. Cells that lack functional CLN1 and CLN2 genes activate the CLN2 promoter with the same kinetics and at the same size as cells in which all three CLN genes are functional. In addition, CLN2 transcription is activated with similar kinetics in cells that have CLN2 as their only functional CLN gene and in CLN-deficient cells. Promoter analysis shows that CLN3-dependent activation of CLN2 transcription is directed primarily through the previously identified UAS1 region although another cis-acting region, UAS2, also can contribute to CLN2 activation under some conditions. The ability to activate transcription of CLN2 is not a unique property of CLN3 because ectopically expressed CLN2 can both activate the endogenous CLN2 promoter and induce Start. We propose that failure of the endogenous CLN2 gene to contribute significantly to activation of its own transcription results from its relative effectiveness at inducing Start, cell cycle progression and, subsequently, inactivation of CLN2 expression.

Base Sequence↗
PubMed1995

A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure.

BACKGROUND: Congestive heart failure is the most common indication for admission to the hospital among older adults. Behavioral factors, such as poor compliance with treatment, frequently contribute to exacerbations of heart failure, a fact suggesting that many admissions could be prevented. METHODS: We conducted a prospective, randomized trial of the effect of a nurse-directed, multidisciplinary intervention on rates of readmission within 90 days of hospital discharge, quality of life, and costs of care for high-risk patients 70 years of age or older who were hospitalized with congestive heart failure. The intervention consisted of comprehensive education of the patient and family, a prescribed diet, social-service consultation and planning for an early discharge, a review of medications, and intensive follow-up. RESULTS: Survival for 90 days without readmission, the primary outcome measure, was achieved in 91 of the 142 patients in the treatment group, as compared with 75 of the 140 patients in the control group, who received conventional care (P = 0.09). There were 94 readmissions in the control group and 53 in the treatment group (risk ratio, 0.56; P = 0.02). The number of readmissions for heart failure was reduced by 56.2 percent in the treatment group (54 vs. 24, P = 0.04), whereas the number of readmissions for other causes was reduced by 28.5 percent (40 vs. 29, P not significant). In the control group, 23 patients (16.4 percent) had more than one readmission, as compared with 9 patients (6.3 percent) in the treatment group (risk ratio, 0.39; P = 0.01). In a subgroup of 126 patients, quality-of-life scores at 90 days improved more from base line for patients in the treatment group (P = 0.001). Because of the reduction in hospital admissions, the overall cost of care was $460 less per patient in the treatment group. CONCLUSIONS: A nurse-directed, multidisciplinary intervention can improve quality of life and reduce hospital use and medical costs for elderly patients with congestive heart failure.

Aged↗
PubMed1995

Dosage suppressors of the dominant G1 cyclin mutant CLN3-2: identification of a yeast gene encoding a putative RNA/ssDNA binding protein.

Three G1 cyclins, CLN1, CLN2, and CLN3, have been identified in the budding yeast Saccharomyces cerevisiae. G1 cyclins are essential, albeit functionally redundant, rate-limiting activators of cell cycle initiation. We have isolated dosage-dependent suppressor genes (designated HMD genes) of the mating defect caused by CLN3-2, a dominant mutation in CLN3, HMD2 and HMD3 are identical to STE4 and STE5, respectively, HMD1 is an essential gene that encodes a protein containing a putative RNA binding domain. Overproduction of HMD1 results in a relatively specific reduction in the level of the CLN3 or CLN3-2 transcript. This reduction occurs subsequent to transcription initiation of CLN3 since overexpression of HMD1 did not affect expression of a heterologous transcript from the CLN3 promoter but did result in a reduction of CLN3 transcript expressed from a heterologous promoter. HMD1 has at least one essential role independent of its effect on CLN3 since HMD1 remains essential for viability in the absence of a functional CLN3 gene.

Amino Acid Sequence↗
PubMed1994

Cell cycle-dependent transcription of CLN2 is conferred by multiple distinct cis-acting regulatory elements.

The budding yeast Saccharomyces cerevisiae CLN1, CLN2, and CLN3 genes encode functionally redundant G1 cyclins required for cell cycle initiation. CLN1 and CLN2 mRNAs accumulate periodically throughout the cell cycle, peaking in late G1. We show that cell cycle-dependent fluctuation in CLN2 mRNA is regulated at the level of transcriptional initiation. Mutational analysis of the CLN2 promoter revealed that the major cell cycle-dependent upstream activating sequence (UAS) resides within a 100-bp fragment. This UAS contains three putative SWI4-dependent cell cycle boxes (SCBs) and two putative MluI cell cycle boxes (MCBs). Mutational inactivation of these elements substantially decreased CLN2 promoter activity but failed to eliminate periodic transcription. Similarly, inactivation of SWI4 decreased CLN2 transcription without affecting its periodicity. We have identified a second UAS in the CLN2 upstream region that can promote cell cycle-dependent transcription with kinetics similar to that of the intact CLN2 promoter. Unlike the major CLN2 UAS, this newly identified UAS promotes transcription in cells arrested in G1 by inactivation of cdc28. This novel UAS is both necessary and sufficient for regulated transcription driven by a CLN2 promoter lacking functional SCBs and MCBs. Although this UAS itself contains no SCBs or MCBs, its activity is dependent upon SWI4 function. The characteristics of this novel UAS suggest that it might have a role in initiating CLN2 expression early in G1 to activate the positive feedback loop that drives maximal Cln accumulation.

Base Sequence↗
PubMed1994

Which cuff size is preferable for blood pressure monitoring in most hypertensive patients?

The accuracy of blood pressure (BP) measurements in obese hypertensives is still controversial. We investigated whether a large sized cuff could be appropriate for BP measurements in patients with different arm circumferences. Fifty hypertensive patients (23 males and 27 females, mean age 54 +/- 12 years, mean weight 75 +/- 12 kg) underwent BP measurements under standardised conditions using both a standard cuff (23 x 12 cm) and a large cuff (34 x 15 cm). Ambulatory blood pressure monitoring (ABPM) was subsequently performed in each subject using a large cuff. The average of two measurements performed in the clinic was compared with the mean daytime measurements. Thirty-one subjects had an arm circumference of < 30 cm (group 1) and weighted 68 +/- 10 kg, while 19 (group 2) had a larger arm circumference (> or = 30 cm) and were overweight (86 +/- 8 kg). BP in group 1 was 149 +/- 23/91 +/- 12 mmHg with the standard cuff and 143 +/- 24/88 +/- 13 mmHg with the large cuff (P < 0.003). In group 2, the respective readings were 153 +/- 22/100 +/- 16 mmHg (standard cuff) and 144 +/- 19/93 +/- 16 mmHg (large cuff; P < 0.0004). These findings suggest that in overweight hypertensives, the use of the standard cuff results in overestimation of BP and that large cuffs should be used exclusively in this population. The use of a large cuff in lean patients has yet to be clarified.

Adult↗
PubMed1994

Concomitant administration of isradipine and spirapril prevents reduction of renal function induced by acute administration of spirapril in patients with reduced renal function.

Angiotensin-converting enzyme (ACE) inhibitors may cause a further decrease in renal function in patients who already have renal failure. The acute effects of the ACE inhibitor spirapril on renal function were investigated in 10 patients with mild-to-moderate renal failure (serum creatinine of 1.5-2.5 mg/dl). Acute oral administration of spirapril at 6 mg resulted in decreases in inulin clearance (from 53.7 +/- 12.8 to 44.6 +/- 8.8 ml/min; p < 0.02; n = 5) and in PAH clearances (from 215 +/- 141.9 to 184 +/- 37.8 ml/min; p < 0.006; n = 5). However, when the acute administration of 6 mg of spirapril was given concomitantly with isradipine at 5 mg, there were no changes in these renal function parameters.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

FAR1 is required for posttranscriptional regulation of CLN2 gene expression in response to mating pheromone.

Yeast cells arrest during the G1 interval of the cell cycle in response to peptide mating pheromones. The FAR1 gene is required for cell cycle arrest but not for a number of other aspects of the pheromone response. Genetic evidence suggests that FAR1 is required specifically for inactivation of the G1 cyclin CLN2. From these observations, the FAR1 gene has been proposed to encode an element of the interface between the mating pheromone signal transduction pathway and the cell cycle regulatory apparatus. We show here that FAR1 is necessary for the decrease in CLN1 and CLN2 transcript accumulation observed in response to mating pheromone but is unnecessary for regulation of the same transcripts during vegetative growth. However, the defect in regulation of CLN1 expression is dependent upon CLN2. We show that pheromone regulates the abundance of Cln2 at a posttranscriptional level and that FAR1 is required for that regulation. From these observations, we suggest that FAR1 function is limited to posttranscriptional regulation of CLN2 expression by mating pheromone. The failure of mating pheromone to repress CLN2 transcript levels in far1 mutants can be explained by the stimulatory effect of the persistent Cln2 protein on CLN2 transcription via the CLN/CDC28-dependent feedback pathway.

Cell Cycle↗
PubMed1993

Bacteremia complicating peritonitis in peritoneal dialysis patients.

Bacteremia is a rare complication of peritonitis in end-stage renal failure (ESRF) patients treated by peritoneal dialysis. Three of our ESRF patients on peritoneal dialysis developed bacteremia during a peritonitis episode (1/19 peritonitis episodes). In 2 cases, the responsible organism was Escherichia coli and peritonitis was most likely associated with infection of the biliary tract. The 3rd patient had a perforation of the colon and Klebsiella spp. was the infective organism. Only the last patient survived but had to be transferred to hemodialysis. Bacteremia during peritonitis is infrequent in peritoneal dialysis patients and it appears to be related to other intra-abdominal events.

Aged↗
PubMed1992

G1 control in yeast and animal cells.

In budding yeast, Saccharomyces cerevisiae, the cell cycle is controlled at the G1/S phase transition by regulating the activity of the CDC28 protein kinase. This is the budding yeast homologue of the cdc2 protein kinase associated in most organisms with control of mitosis. In budding yeast CDC28 controls both the G1/S phase transition and the G2/M phase transition by being differentially activated by two distinct classes of positive regulatory subunits known as G1 cyclins or CLNs and B-type cyclins or CLBs, respectively. To establish whether a similar dual role for Cdc2-related kinases exists in animal cells, we and others have sought human homologues of yeast G1 cyclins. Of several candidates, cyclin E is the most promising in that it accumulates prior to S phase and is associated with a pre-S phase protein kinase activity. The kinetics of accumulation of cyclin E-associated protein kinase activity is consistent with a role at the mammalian cell cycle restriction point.

Animals↗
PubMed1992

Long-term antihypertensive and renal effects of isradipine in hypertensive patients with normal and reduced renal function.

The long-term hemodynamic and antihypertensive effects of isradipine were investigated in 11 patients who had normal renal function and 9 who had reduced renal function. The dose regimen was 1.25-5 mg twice daily, depending on blood pressure response. After 24 weeks of active treatment, systolic/diastolic blood pressure decreased from 172/106 to 155/94 mm Hg (p less than 0.05) in the patients with normal renal function, and from 176/105 to 169/93 mm Hg (p less than 0.01) in those with impaired renal function. Contrary to the results of short-term treatment, no changes in inulin and p-aminohippuric acid (PAH) clearances were observed in either study group. There were no significant changes in plasma renin, aldosterone, glucose, or lipids, nor were these changes in protein excretion in either group; however, sodium excretion increased significantly in both groups. On the basis of our results, we conclude that isradipine has a place in the treatment of hypertensive patients with mild renal insufficiency.

Administration, Oral↗
PubMed1992

Overdiagnosis of hypertension in the elderly.

Seventeen untreated and 36 treated hypertensives aged 65 years or more were referred to our clinic because of repeated values of systolic blood pressure > or = 160 mmHg and diastolic blood pressure > or = 95 mmHg. All 53 patients underwent 24h blood pressure monitoring during their customary daily activities. Eleven (65%) untreated and 23 (64%) treated patients were normotensive during their daily activities. Thus, ambulatory BP monitoring appears to be useful in the elderly hypertensive patients in detecting those whose BP is elevated only in the clinic. Ambulatory BP obtained outside the clinic may be useful in diagnostic and therapeutic decision-making in the elderly population.

Aged↗
PubMed1992

Causes of death in patients with end-stage renal disease treated by dialysis in a center in Israel.

The causes of death in 84 end-stage renal failure patients, treated with dialysis, who died during a 66-month period were reviewed retrospectively. Cardiac and infectious diseases were the main cause of death (27% each). These two constituted 44% of causes of death in hemodialysis and 75% in continuous ambulatory peritoneal dialysis patients. Malignant disease (7%) and hyperkalemia (5%) were responsible for death only in hemodialysis patients. Patients who died following hyperkalemia were younger than 50 years old. Patients who died from malignant disease were dialyzed for more than 3 years. In summary, the mode of dialysis therapy, age at start of therapy, time on dialysis, and previous cardiac disease may play a role in determining the causes of death in dialysis patients.

Adolescent↗
PubMed1991

A cyclin B homolog in S. cerevisiae: chronic activation of the Cdc28 protein kinase by cyclin prevents exit from mitosis.

A cyclin B homolog was identified in Saccharomyces cerevisiae using degenerate oligonucleotides and the polymerase chain reaction. The protein, designated Scb1, has a high degree of similarity with B-type cyclins from organisms ranging from fission yeast to human. Levels of SCB1 mRNA and protein were found to be periodic through the cell cycle, with maximum accumulation late, most likely in the G2 interval. Deletion of the gene was found not to be lethal, and subsequently other B-type cyclins have been found in yeast functionally redundant with Scb1. A mutant allele of SCB1 that removes an amino-terminal fragment of the encoded protein thought to be required for efficient degradation during mitosis confers a mitotic arrest phenotype. This arrest can be reversed by inactivation of the Cdc28 protein kinase, suggesting that cyclin-mediated arrest results from persistent protein kinase activation.

Alleles↗