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David S Geller

Publications and source records attributed to David S Geller.

13 recordsLinked to original sources
PubMed2006

Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule.

The mechanisms that govern homeostasis of complex systems have been elusive but can be illuminated by mutations that disrupt system behavior. Mutations in the gene encoding the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and hyperkalemia. We show that physiology in mice transgenic for genomic segments harboring wild-type (TgWnk4(WT)) or PHAII mutant (TgWnk4(PHAII)) Wnk4 is changed in opposite directions: TgWnk4(PHAII) mice have higher blood pressure, hyperkalemia, hypercalciuria and marked hyperplasia of the distal convoluted tubule (DCT), whereas the opposite is true in TgWnk4(WT) mice. Genetic deficiency for the Na-Cl cotransporter of the DCT (NCC) reverses phenotypes seen in TgWnk4(PHAII) mice, demonstrating that the effects of the PHAII mutation are due to altered NCC activity. These findings establish that Wnk4 is a molecular switch that regulates the balance between NaCl reabsorption and K+ secretion by altering the mass and function of the DCT through its effect on NCC.

Animals↗
PubMed2006

Autosomal dominant pseudohypoaldosteronism type 1: mechanisms, evidence for neonatal lethality, and phenotypic expression in adults.

Autosomal dominant pseudohypoaldosteronism type 1 (adPHA1) is a rare condition that is characterized by renal resistance to aldosterone, with salt wasting, hyperkalemia, and metabolic acidosis. It is thought of as a mild disorder; affected children's symptoms respond promptly to salt therapy, and treatment is not required after childhood. Mutations in the mineralocorticoid receptor gene (MR) cause adPHA1, but the long-term consequences of MR deficiency in humans are not known. Herein are described six novel adPHA1-causing MR mutations (four de novo) and evidence that haploinsufficiency of MR is sufficient to cause adPHA1. Furthermore, genotype-phenotype correlation is reported in a large adPHA1 kindred. A number of cases of neonatal mortality in infants who were at risk for adPHA1 were identified; coupled with the frequent identification of de novo mutations in affected individuals, this suggests that the seemingly benign adPHA1 may have been a fatal neonatal disorder in previous eras, preventing propagation of disease alleles. In contrast, it is shown that adult patients with adPHA1 are clinically indistinguishable from their wild-type relatives except for presumably lifelong elevation of renin, angiotensin II, and aldosterone levels. These data highlight the critical role of MR in the maintenance of salt homeostasis early in life and illuminate the sodium dependence of pathologic effects of renin and angiotensin II. They furthermore argue that nongenomic effects of aldosterone play no significant role in the long-term development of cardiovascular disease.

Adult↗
PubMed2006

Intramedullary fixation of tibial shaft fractures using an expandable nail: early results of 54 acute tibial shaft fractures.

OBJECTIVE: To evaluate and present our experience using the expandable nail system for the treatment of acute tibial shaft fractures. DESIGN: Retrospective study. SETTING: Two level-1 trauma centers-University teaching hospitals. METHODS: Fifty-four consecutive patients were treated by this nail system for acute tibial shaft fracture. Two nail diameters were used, 8.5 mm and 10 mm. Operation, hospitalization and healing times, reaming versus nonreaming, isolated versus multiple injuries, and reoperations were recorded and analyzed statistically. RESULTS: Follow-up was obtained either until fracture healing or for a minimum of 1 year with an average of 14 months (12 to 24). All fractures healed in an average time of 72 days (21 to 204). The average healing times for patients treated with 8.5-mm and 10-mm nails were 77.2 days (27 to 204) and 63.4 days (21 to 121), respectively. Average operative time was 103 minutes (40 to 185) if reamed and 56 minutes (30 to 80) if unreamed. Average healing times were 65.4 days (21 to 190) if reamed and 79.5 days (42 to 204) if unreamed. There were 11 complications (20.4%) related to the nailing: 3 deep infections, 2 superficial infections, 2 bone shortenings of 1 cm secondary to nail protrusion in the knee, 1 compartment syndrome, 1 fracture propagation, 1 distal malalignment, and 1 delayed union. Hardware was removed in 6 patients (3 infections, 2 patients' request and 1 protrusion into the knee), and 1 additional patient underwent exchange nailing due to a delayed union. CONCLUSIONS: The expandable nail offers the theoretical advantages of improved load sharing and rotational control without the need for interlocking screws. This study demonstrates satisfactory healing and alignment for the treatment of tibial shaft fractures using this device. However, caution must be exercised when using this nail in cases of significant comminution and in cases where the fracture pattern involves the more proximal or distal aspect of the tibial shaft.

Adult↗
PubMed2006

Differential interaction of RU486 with the progesterone and glucocorticoid receptors.

Steroid hormone receptor antagonists are widely used in clinical medicine, but their use is often complicated by the lack of receptor specificity to presently available drugs. We previously demonstrated an important role of a widely conserved helix 3 (H3)-helix 5 (H5) interaction in determining the sensitivity and specificity of steroid hormone receptors to receptor agonists. Intriguingly, the same H3 residues also play a crucial role in receptor antagonism; mutation of these residues alters the response of these receptors to antagonists. Given the close interaction of H3 and H5 residues at this site, we asked whether H5 residues might also play a role in the sensitivity of these receptors to antagonists. We demonstrate here that modification of H5 residues produces marked changes in the sensitivities of the glucocorticoid and progesterone receptor (PR) to RU486 antagonism. Moreover, while we confirm previous reports that alteration of the H3 residue, Gly 722 prevents RU486-mediated inhibition of the PR, we show that the corresponding substitution in the glucocorticoid receptor does not inhibit RU486-mediated receptor antagonism. Taken together, our data support the notion that RU486 binds differently to these two receptors, providing a potential target for the design of more specific antiglucocorticoid and antiprogestin drugs.

Animals↗
PubMed2005

A critical role of helix 3-helix 5 interaction in steroid hormone receptor function.

The ligand-binding domains of steroid hormone receptors possess a conserved structure with 12 alpha-helices surrounding a central hydrophobic core. On agonist binding, a repositioned helix 12 forms a pocket with helix 3 (H3) and helix 5 (H5), where transcriptional coactivators bind. The precise molecular interactions responsible for activation of these receptors remain to be elucidated. We previously identified a H3-H5 interaction that permits progesterone-mediated activation of a mutant mineralocorticoid receptor. We were intrigued to note that the potential for such interaction is widely conserved in the nuclear receptor family, indicating a possible functional significance. Here, we demonstrate via transcriptional activation studies in cell culture that alteration of residues involved in H3-H5 interaction consistently produces a gain of function in steroid hormone receptors. These data suggest that H3-H5 interaction may function as a molecular switch regulating the activity of nuclear receptors and suggest this site as a general target for pharmacologic intervention. Furthermore, they reveal a general mechanism for the creation of nuclear receptors bearing increased activity, providing a potentially powerful tool for the study of physiologic pathways in vivo.

Animals↗
PubMed2005

Monogenic low renin hypertension.

Monogenic forms of low renin hypertension can now be identified in a large and heterogeneous family of hypertensive patients with highly specific etiologies and similar clinical manifestations. These include the following well-characterized disorders: apparent mineralocorticoid excess, Liddle's Syndrome, steroid 11beta-hydroxylase (11beta-OHD) and steroid 17-hydroxylase (17-OHD) deficiencies, glucocorticoid-remediable hyperaldosteronism (familial hyperaldosteronism type I), familial hyperaldosteronism type II, hypertension exacerbated by pregnancy and primary hyperaldosteronism (Conn's syndrome). The successful elucidation of specific DNA mutations in most of these conditions has emphasized the role of molecular genetics in hypertension, a field in which diagnosis can now be made on proven genetic evidence. The current knowledge of these genetic markers enables practitioners to make precise diagnoses, and to initiate specific therapy, in patients with these relatively uncommon but interesting and often treatable forms of hypertension.

Humans↗
PubMed2005

Mineralocorticoid resistance.

The mineralocorticoid aldosterone plays a crucial role in regulation of volume and electrolyte homeostasis. In recent years there has been considerable progress in deciphering the role of aldosterone in human physiology by the study of monogenic disorders exhibiting mineralocorticoid resistance. Although these disorders are rare, the elucidation of their molecular basis has yielded many insights into aldosterone biology that are proving relevant to the care of patients with a wide variety of cardiovascular diseases. Recent advances in understanding the molecular basis of syndromes of mineralocorticoid resistance are reviewed with a view towards an improved understanding of the role of aldosterone in renal sodium transport and its relationship to cardiovascular disease.

Aldosterone↗
PubMed2005

A content analysis of e-mail communication between primary care providers and parents.

BACKGROUND: E-mail exchange between parents of patients and providers has been cited by the Institute of Medicine as an important aspect of contemporary medicine; however, we are unaware of any data describing actual exchanges. OBJECTIVE: The purpose of this study was to evaluate the content of e-mails between providers and parents of patients in pediatric primary care, as well as parent attitudes about e-mail. DESIGN/METHODS: Over a 6-week period, all e-mail exchanges between 2 primary care pediatricians and their patients' parents were evaluated and coded. An exchange was defined as the e-mails between parent and primary care provider about a single inquiry. Parents also completed a questionnaire regarding this service. RESULTS: Of 55 parents, 54 (98%) agreed to have their e-mails with their pediatrician reviewed. The 54 parents generated 81 e-mail exchanges; 86% required only 1 e-mail response from the pediatrician, and the other 14% required an average of 1.9 responses. E-mail inquiries were all for nonacute issues (as judged by S.G.A.) and included inquiries about a medical question (n = 43), medical update (n = 20), subspecialty evaluation (n = 9), and administrative issue (n = 9). The 81 exchanges resulted in 9 appointments, 21 phone calls, 4 subspecialty referrals, 34 prescriptions or recommendations for over-the-counter medications, 11 administrative tasks, and 1 radiograph. Of 91 pediatrician-generated e-mails, 39% were sent during the workday (9 am to 5 pm, Monday to Friday), 44% were sent on weeknights, and 17% were sent on weekends. During the study period, the 2 physicians estimated an average of 30 minutes/day spent responding to e-mail. Of the 54 parents, 45 (83%) returned the survey; 93% were mothers and 86% had completed college. Ninety-eight percent were very satisfied with their e-mail experience with their pediatrician. Although 80% felt that all pediatricians should use e-mail to communicate with parents and 65% stated they would be more likely to choose a pediatrician based on access by e-mail, 63% were unwilling to pay for access. CONCLUSIONS: This is the first study to describe actual e-mail exchange between parents and their providers. Exchanges seem to be different from those generated by the telephone, with more e-mails related to medical versus administrative issues and more resulting in office visits. Approximately 1 in 4 exchanges result in multiple e-mails back and forth between parent and provider. Parents who have actually exchanged e-mails with their providers overwhelmingly endorse it, although they are reluctant to pay for it.

Attitude to Computers↗
PubMed2004

Osteoporotic pertrochanteric hip fractures: management and current controversies.

The treatment of intertrochanteric hip fractures has evolved over the past 80 years because of a better understanding of fracture anatomy, application of biomechanical principles, and novel technologic advances. Surgical treatment of intertrochanteric hip fractures is the current standard of care, with short-term goals of fracture stabilization and early patient mobilization and the long-term objective of restoring patients to their previous level of independence and function. Treatment for stable intertrochanteric hip fractures includes use of percutaneous intramedullary devices and open reduction and internal fixation using a sliding hip screw. To date, none of these devices has shown any clear clinical advantage over the dynamic hip screw. Intramedullary fixation has multiple theoretical advantages for the treatment of unstable fracture patterns; however, it remains unclear if ultimate functional outcome warrants the added expense of such treatment. For patients with a reverse obliquity fracture pattern, the advantage of the intramedullary construct has been shown.

Aged↗