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David S Goldfarb

Publications and source records attributed to David S Goldfarb.

At least 19 recordsLinked to original sources
PubMed2007

Nucleus-vacuole junctions and piecemeal microautophagy of the nucleus in S. cerevisiae.

Various modes of autophagy conspire to degrade virtually every compartment of the eukaryotic cell. In Saccharomyces cerevisiae, a process called "piecemeal microautophagy of the nucleus" (PMN) even pinches off and degrades nonessential portions of the nucleus. PMN is a constitutive process induced to high levels by starvation or rapamycin, an inhibitor of TOR kinase. PMN occurs at nucleus-vacuole (NV) junctions, which are Velcro-like patches formed by interactions between the vacuole membrane protein Vac8p and the outer-nuclear-membrane protein Nvj1p. In response to nutrient depletion, Nvj1p increasingly binds and sequesters two proteins with roles in lipid metabolism, Osh1p and Tsc13p. Tsc13p is required for the normal biogenesis of PMN vesicles. The sequestration of Osh1p by Nvj1p likely serves to negatively regulate the trafficking of tryptophan permease(s) to the plasma membrane. Thus, NV junctions and PMN orchestrate novel and sophisticated responses to nutrient limitation.

Autophagy↗
PubMed2006

Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness.

Acetazolamide, a potent carbonic anhydrase (CA) inhibitor, is the most commonly used and best-studied agent for the amelioration of acute mountain sickness (AMS). The actual mechanisms by which acetazolamide reduces symptoms of AMS, however, remain unclear. Traditionally, acetazolamide's efficacy has been attributed to inhibition of CA in the kidneys, resulting in bicarbonaturia and metabolic acidosis. The result is offsetting hyperventilation-induced respiratory alkalosis and allowance of chemoreceptors to respond more fully to hypoxic stimuli at altitude. Studies performed on both animals and humans, however, have shown that this explanation is unsatisfactory and that the efficacy of acetazolamide in the context of AMS is likely due to a multitude of effects. This review summarizes the known systemic effects of acetazolamide and incorporates them into a model encompassing several factors that are likely to play a key role in the drug's efficacy. Such factors include not only metabolic acidosis resulting from renal CA inhibition but also improvements in ventilation from tissue respiratory acidosis, improvements in sleep quality from carotid body CA inhibition, and effects of diuresis.

Acetazolamide↗
PubMed2006

Structure and function of nucleus-vacuole junctions: outer-nuclear-membrane targeting of Nvj1p and a role in tryptophan uptake.

Nvj1p resides in the outer nuclear membrane (ONM) and binds the vacuole membrane protein Vac8p to form nucleus-vacuole (NV) junctions in Saccharomyces cerevisiae. The induction of NVJ1 expression during starvation results in the sequestration of two additional binding partners, Tsc13p and Osh1p. Here, we map the domains of Nvj1p responsible for ONM targeting and partner binding. ONM targeting requires both the N-terminal signal anchor-like sequence and the topogenic membrane-spanning domain of Nvj1p. The N-terminal signal anchor-like sequence may anchor Nvj1p in the ONM by bridging to the inner nuclear membrane. A region encompassing the membrane-spanning domain is sufficient to bind Tsc13p. Osh1p and Vac8p bind to distinct regions in the cytoplasmic tail of Nvj1p. Overexpression of Nvj1p in trp1 cells causes a growth defect in low tryptophan that is rescued by additional copies of TAT1 or TAT2 tryptophan permeases. Conversely, nvj1-Delta trp1 cells grow faster than NVJ1+ trp1 cells in limiting tryptophan. Importantly, deleting the Osh1p-binding domain of Nvj1p abrogates the tryptophan transport-related growth defect of Nvj1p-overexpressing cells. Therefore, the Nvj1p-dependent sequestration of Osh1p negatively regulates tryptophan uptake from the medium, possible by affecting the trafficking of tryptophan permeases to the plasma membrane.

Amino Acid Sequence↗
PubMed2006

Chitosan does not reduce post-prandial urinary oxalate excretion.

Chitosan is a positively charged non-absorbable cellulose-like fibrillar biopolymer derived from shellfish which forms films with negatively charged surfaces. We hypothesized that negatively charged oxalate in the intestinal lumen could attach to the positively charged tertiary amino group of chitosan. We studied the effects of chitosan on intestinal oxalate absorption by measuring urinary oxalate excretion following an oral oxalate load with and without accompanying oral chitosan. The subjects consumed a fixed diet and collected urine for 24 h, in divided periods, during control and experimental protocols. Urine was collected with HCl and thymol as a preservative. For the control period, the subjects consumed an oxalate load, 50 g of cooked spinach, with water for lunch; the post-prandial urine collection was divided into three periods of 2 h. For the experimental period, 1 week later, the subjects consumed the same diet as that during the control period, but added 2 g of chitosan to the oxalate load. Post-prandial urinary oxalate excretion was expressed as mg oxalate/g creatinine. The spinach load was associated with a significant post-prandial increase in urinary oxalate during the control period of 25.7+/-12.8 mg/g creatinine. Accompanying the oxalate load with chitosan was well tolerated. There was no decrease in post-prandial urinary oxalate excretion during the experimental period: oxalate excretion rose by 31.3+/-16.9 mg/g creatinine (P=0.57, NS). We conclude that chitosan does not reduce acute intestinal oxalate absorption and therefore does not affect post-prandial urinary oxalate excretion.

Chelating Agents↗
PubMed2006

The availability and use of charcoal hemoperfusion in the treatment of poisoned patients.

BACKGROUND: Charcoal hemoperfusion (CHP) has been one of the preferred methods to enhance the elimination of certain toxins in selected poisoned patients. However, the availability of CHP may be limited because of the expense of cartridges, their narrow indications, and their limited shelf life. Improvements in hemodialysis (HD) technology may contribute to making CHP obsolete. We investigated the availability of CHP in in-hospital HD units at hospitals receiving ambulances dispatched through New York City's emergency response system, hereafter referred to as 911-receiving hospitals, and their recent history of CHP use in poisoned patients. METHODS: The medical directors or managers of all in-hospital HD units in the 911-receiving hospitals of New York City were contacted by E-mail and/or telephone. Participants were administered a standard survey that included questions regarding the availability of CHP cartridges and the date and indication for last CHP use. Participants at institutions that did not stock CHP cartridges were questioned about their opinions on the utility of CHP. RESULTS: Forty-two in-hospital HD units were surveyed, of which 34 (81%) completed the survey. Ten units (29%) had CHP cartridges available for immediate use. Each of these 10 units stocked between 1 and 4 adult-size CHP cartridges, and 1 unit stocked 2 pediatric-size CHP cartridges. Nine units had in-date CHP cartridges, and 1 unit had only expired CHP cartridges. Only 3 units performed CHP in the past 5 years (2 units, theophylline poisonings; 1 unit, aluminum overload). In the 24 units without CHP cartridges, 21 directors believed that most common toxins could be removed effectively through HD and thus CHP rarely was indicated. Only 1 director cited expense as a factor in not stocking CHP cartridges. Two directors reported no specific reason for not stocking the cartridges. CONCLUSION: CHP cartridges are available in only approximately one third of 911-receiving hospitals in New York City. CHP is infrequently performed to enhance toxin elimination in poisoned patients.

Charcoal↗
PubMed2006

Predictive value of a positive fecal occult blood test increases as the severity of CKD worsens.

BACKGROUND: Because chronic kidney disease (CKD) may be associated with gastrointestinal bleeding from trivial mucosal lesions, we hypothesized that the predictive value of a positive fecal occult blood test (FOBT) result for clinically important colonic lesions would decrease as the stage of CKD worsened. METHODS: We prospectively identified 1,225 consecutive asymptomatic average-risk patients who were referred for colonoscopy to evaluate a positive FOBT result. Using the Modification of Diet in Renal Disease equation, we estimated glomerular filtration rate (GFR) and staged the severity of CKD by using standard criteria as follows: normal/stage 1 (GFR > or = 90 mL/min/1.73 m2 [> or = 1.50 mL/s]), stage 2/3 (GFR 30 to 89 mL/min/1.73 m2 [0.50 to 1.48 mL/s]), and stage 4/5 (GFR < 30 mL/min/1.73 m2 [< 0.50 mL/s] or dialysis). RESULTS: Clinically important lesions were identified in 23.9% of 531 individuals with none/stage 1 CKD, 32.8% of 497 subjects with stage 2/3 CKD, and 42.6% of 197 patients with stage 4/5 CKD (P < 0.001). Compared with patients with none/stage 1 CKD, adjusted odds of identifying a clinically important lesion were 1.61 (95% confidence interval, 1.21 to 2.15) in subjects with stage 2/3 CKD and 2.33 (95% confidence interval, 1.62 to 3.36) in patients with stage 4/5 CKD. Prevalences of adenomas of 1 cm or greater (15.1% versus 20.1% versus 22.8%; P = 0.007), carcinomas (5.1% versus 10.1% versus 13.2%; P < 0.001), and vascular ectasias (1.7% versus 2.4% versus 6.1%; P = 0.003) increased with the severity of CKD. CONCLUSION: Contrary to our initial hypothesis, we found that the predictive value of a positive FOBT result for clinically important colonic lesions increased as the severity of CKD worsened.

Aged↗
PubMed2005

Atg19p ubiquitination and the cytoplasm to vacuole trafficking pathway in yeast.

The cytoplasm to vacuole (Cvt) trafficking pathway in S. cerevisiae is a constitutive biosynthetic pathway required for the transport of two vacuolar enzymes, aminopeptidase I (Ape1p) and alpha-mannosidase (Ams1p), to the vacuole. Ape1p and Ams1p bind to their receptor, Atg19p, in the cytosol to form a Cvt complex, which then associates with a membrane structure that envelops the complex before fusing with the vacuolar membrane. Ubiquitin-like modifications are required for both Cvt and macroautophagy, but no role for ubiquitin itself has been described. Here, we show that the deubiquitinating enzyme Ubp3p interacts with Atg19p. Moreover, Atg19p is ubiquitinated in vivo, and Atg19p-ubiquitin conjugates accumulate in cells lacking either Ubp3p or its cofactor, Bre5p. Deletion of UBP3 also leads to decreased targeting of Ape1p to the vacuole. Atg19p is ubiquitinated on two lysine residues, Lys(213) and Lys(216), which, when mutated, reduce the interaction of Atg19p with Ape1p. These results suggest that both ubiquitination and deubiquitination of Atg19p are required for its full function.

Amino Acid Sequence↗
PubMed2005

Increased nuclear envelope permeability and Pep4p-dependent degradation of nucleoporins during hydrogen peroxide-induced cell death.

The death of yeast treated with hydrogen peroxide (H(2)O(2)) shares a number of morphological and biochemical features with mammalian apoptosis. In this study, we report that the permeability of yeast nuclear envelopes (NE) increased during H(2)O(2)-induced cell death. Similar phenomena have been observed during apoptosis in mammalian tissue culture cells. Increased NE permeability in yeast was temporally correlated with an increase in the production of reactive-oxygen species (ROS). Later, after ROS levels began to decline and viability was lost, specific nuclear pore complex (NPC) proteins (nucleoporins) were degraded. Although caspases are responsible for the degradation of mammalian nucleoporins during apoptosis, the deletion of the metacaspase gene YCA1 had no effect on the stability of yeast nucleoporins. Instead, Pep4p, a vacuolar cathepsin D homolog, was responsible for the proteolysis of nucleoporins. Coincident with nucleoporin degradation, a Pep4p-EGFP reporter migrated out of the vacuole in H(2)O(2)-treated cells. We conclude that increases in ROS and NPC permeability occur relatively early during H(2)O(2)-induced cell death. Later, Pep4p migrates out of vacuoles and degrades nucleoporins after the cells are effectively dead.

Apoptosis↗
PubMed2005

Targeting of Tsc13p to nucleus-vacuole junctions: a role for very-long-chain fatty acids in the biogenesis of microautophagic vesicles.

TSC13 is required for the biosynthesis of very-long-chain fatty acids (VLCFAs) in yeast. Tsc13p is a polytopic endoplasmic reticulum (ER) membrane protein that accumulates at nucleus-vacuole (NV) junctions, which are formed through Velcro-like interactions between Nvj1p in the perinuclear ER and Vac8p on the vacuole membrane. NV junctions mediate piecemeal microautophagy of the nucleus (PMN), during which bleb-like portions of the nucleus are extruded into invaginations of the vacuole membrane and degraded in the vacuole lumen. We report that Tsc13p is sequestered into NV junctions from the peripheral ER through Vac8p-independent interactions with Nvj1p. During nutrient limitation, Tsc13p is incorporated into PMN vesicles in an Nvj1p-dependent manner. The lumenal diameters of PMN blebs and vesicles are significantly reduced in tsc13-1 and tsc13-1 elo3-Delta mutant cells. PMN structures are also smaller in cells treated with cerulenin, an inhibitor of de novo fatty acid synthesis and elongation. The targeting of Tsc13p-GFP into NV junctions is perturbed by cerulenin, suggesting that its binding to Nvj1p depends on the availability of fatty acid substrates. These results indicate that Nvj1p retains and compartmentalizes Tsc13p at NV junctions and that VLCFAs contribute to the normal biogenesis of trilaminar PMN structures in yeast.

Acylation↗
PubMed2005

Nephrolithiasis complicating treatment of diabetes insipidus.

A decrease in urine volume is considered the therapeutic goal of the treatment of central diabetes insipidus (DI) with desmopressin (dDAVP). A low urine volume is a risk factor for kidney stone formation. This is the first report of nephrolithiasis in association with DI. It is likely that successful therapy with dDAVP and the patient's own purposeful decreased fluid intake contributed to calcium oxalate stone formation. Prevention of stone recurrence requires an increase in urine volume. The patient's compliance with this recommendation led to an episode of acute hyponatremia, a well-known complication of dDAVP therapy. The challenge of the management of stones in the setting of DI requires balancing the conflicting goals of both decreasing and increasing urine volume.

Adult↗
PubMed2005

Effect of cystine-binding thiol drugs on urinary cystine capacity in patients with cystinuria.

PURPOSE: To determine the effect of cystine-binding thiol drugs (CBTD) on urinary cystine capacity in patients with cystinuria. PATIENTS AND METHODS: Seven cystinuric patients performed two sets of urine collections while on and off CBTD while controlling for all other variables: diet and fluid and alkali intake. They monitored and recorded their diet for 3 days and performed urine collections on days 2 and 3. They then stopped the CBTD for 7 days. On days 8, 9, and 10, they replicated their diets of days 1 through 3 and performed two more urine collections on days 9 and 10. Two patients took D-penicillamine, four took tiopronin, and one took tiopronin and captopril. The cystine capacity was determined, and the values obtained when the patient was on and off the CBTD were compared to determine whether CBTDs affect urinary cystine capacity. To measure the cystine capacity, we used a solid-phase assay in which cystine crystals are added to the urine and incubated for 48 hours. The crystals are spun down and resolubilized in high-pH buffer, and the amount of cystine in the crystals is calculated. The solid phase will take up cystine from urine (negative cystine capacity) that is supersaturated and give up cystine to an undersaturated urine (positive cystine capacity). RESULTS: All seven patients had significant improvement in urinary cystine capacity on CBTDs. The mean cystine capacity off CBTD was -130.6 +/- 280.8, while the value during CBTD use was 43.1 +/- 131.2 (P < 0.05). On CBTDs, two patients still had negative values, but both had important improvements. The mean urinary volumes were similar on and off CBTD, indicating adequate and similar fluid intake. Urine pH values and urinary excretion of sodium and urea also were comparable, indicating consistency of citrate intake and diet. CONCLUSIONS: Our results demonstrate that CBTDs lower the urinary supersaturation of cystine, as shown by a less-negative or more-positive cystine capacity. Cystine capacity can be measured directly, even in the presence of CBTDs. The value of this measurement lies in the potential to monitor the response to the drug, prescribe the minimum effective dose, and potentially decrease the adverse effects often associated with CBTDs.

Administration, Oral↗
PubMed2005

A twin study of genetic and dietary influences on nephrolithiasis: a report from the Vietnam Era Twin (VET) Registry.

BACKGROUND: Nephrolithiasis is a complex phenotype that is influenced by both genetic and environmental factors. We conducted a large twin study to examine genetic and nongenetic factors associated with stones. METHODS: The VET Registry includes approximately 7500 male-male twin pairs born between 1939 to 1955 with both twins having served in the military from 1965 to 1975. In 1990, a mail and telephone health survey was sent to 11,959 VET Registry members; 8870 (74.2%) provided responses. The survey included a question asking if the individual had ever been told of having a kidney stone by a physician. Detailed dietary habits were elicited. In a classic twin study analysis, we compared concordance rates in monozygotic (MZ) and dizygotic (DZ) twins. We also conducted a cotwin control study of dietary risk factors in twins discordant for stones. RESULTS: Among dizygotic twins, there were 17 concordant pairs and 162 discordant pairs for kidney stones. Among monozygotic twins, there were 39 concordant pairs and 163 discordant pairs. The proband concordance rate in MZ twins (32.4%) was significantly greater than the rate in DZ twins (17.3%) (chi(2)= 12.8; P < 0.001), consistent with a genetic influence. The heritability of the risk for stones was 56%. In the multivariate analysis of twin pairs discordant for kidney stones, we found a protective dose-response pattern of coffee drinking (P= 0.03); those who drank 5 or more cups of coffee were half as likely to develop kidney stones as those who did not drink coffee (OR = 0.4, 95% CI 0.2, 0.9). Those who drank at least 1 cup of milk per day were half as likely to report kidney stones (OR = 0.5, 95% CI 0.3, 0.8). There were also marginally significant protective effects of increasing numbers of cups of tea per day and frequent consumption of fruits and vegetables. Other factors such as the use of calcium supplements, alcohol drinking, consumption of solid dairy products, and the amount of animal protein consumed were not significantly related to kidney stones in the multivariate model. CONCLUSION: These results confirm that nephrolithiasis is at least in part a heritable disease. Coffee, and perhaps tea, fruits, and vegetables were found to be protective for stone disease. This is the first twin study of kidney stones, and represents a new approach to elucidating the relative roles of genetic and environmental factors associated with stone formation.

Diet↗
PubMed2005

Use of a probiotic to decrease enteric hyperoxaluria.

BACKGROUND: Patients with inflammatory bowel disease have a 10- to 100-fold increased risk of nephrolithiasis, with enteric hyperoxaluria being the major risk factor for these and other patients with fat malabsorptive states. Endogenous components of the intestinal microflora can potentially limit dietary oxalate absorption. METHODS: Ten patients were studied with chronic fat malabsorption, calcium oxalate stones, and hyperoxaluria thought to be caused by jejunoileal bypass (1) and Roux-en-Y gastric bypass surgery for obesity (4), dumping syndrome secondary to gastrectomy (2), celiac sprue (1), chronic pancreatitis (1), and ulcerative colitis in remission (1). For 3 months, patients received increasing doses of a lactic acid bacteria mixture (Oxadrop), VSL Pharmaceuticals), followed by a washout month. Twenty-four-hour urine collections were performed at baseline and after each month. RESULTS: Mean urinary oxalate excretion fell by 19% after 1 month (1 dose per day, P < 0.05), and oxalate excretion remained reduced by 24% during the second month (2 doses per day, P < 0.05). During the third month on 3 doses per day oxalate excretion increased slightly, so that the mean was close to the baseline established off treatment. Urinary oxalate again fell 20% from baseline during the washout period. Calcium oxalate supersaturation was reduced while on Oxadrop, largely due to the decrease in oxalate excretion, although mean changes did not reach statistical significance. CONCLUSION: Manipulation of gastrointestinal (GI) flora can influence urinary oxalate excretion to reduce urinary supersaturation levels. These changes could have a salutary effect on stone formation rates. Further studies will be needed to establish the optimal dosing regimen.

Aged↗
PubMed2004

Uric acid stones following hepatic transplantation.

We report the case of a 52 year old man with a history of insulin-requiring diabetes and hepatitis B with cirrhosis who received an orthotopic liver transplant. One year later he developed renal colic and was found to have a 3 mm stone at the left ureterovesical junction. Numerous other stones formed and infrared spectroscopy analysis demonstrated all to be composed of 100% uric acid. Urine collections demonstrated a low urine pH of 5.1 without hyperuricosuria. His stones were effectively prevented with potassium citrate therapy. Few incidence data are available for uric acid stone occurrence in solid organ recipients. Calcineurin inhibitors are thought to often cause hyperuricemia on the basis of decreased urate excretion. However, this effect would not be expected to cause hyperuricosuria nor uric acid stones. This class of drugs may also be associated with low urine pH, perhaps on the basis of hypoaldosteronism, but the contribution of such a syndrome to uric acid stone formation is not established.

Calcineurin Inhibitors↗