Mutational analysis of the RPGRIP1L gene in patients with Joubert syndrome and nephronophthisis.

Joubert syndrome (JS) is an autosomal recessive disorder, consisting of mental retardation, cerebellar vermis aplasia, an irregular breathing pattern, and retinal degeneration. Nephronophthisis (NPHP) is found in 17-27% of these patients, which was designated JS type B. Mutations in four separate genes (AHI1, NPHP1, CEP290/NPHP6, and MKS3) are linked to JS. However, missense mutations in a new ciliary gene (RPGRIP1L) were found in type B patients. We analyzed a cohort of 56 patients with JS type B who were negative for mutations in three (AHI1, NPHP1, and CEP290/NPHP6) of the four genes previously linked to the syndrome. The 26 exons encoding RPGRIP1L were analyzed by means of PCR amplification, CEL I endonuclease digestion, and subsequent sequencing. Using this approach, four different mutations in the RPGRIP1L gene in five different families were identified and three were found to be novel mutations. Additionally, we verified that missense mutations are responsible for JS type B and cluster in exon 15 of the RPGRIP1L gene. Our studies confirm that a T615P mutation represents the most common mutation in the RPGRIP1L gene causing disease in about 8-10% of JS type B patients negative for NPHP1, NPHP6, or AHI1 mutations.

Initial experience with isradipine for the treatment of hypertension in children.

BACKGROUND: Isradipine is a calcium channel blocker of the dihydropyridine class. It has limited effects on myocardial contractility; is available in a powder-filled capsule and has a half-life of 6 to 8 hours. METHODS: Pharmacy records were reviewed to identify pediatric patients who had received isradipine. The following demographic data were obtained: age, weight, sex, underlying medical problems, and initial blood pressure values. Information concerning isradipine included the initial dose and its interval, subsequent dose escalations, blood pressure response to the medication, and duration of therapy. RESULTS: The study population comprised 12 patients, ranging in age from 10 days to 11 years. The etiology of the hypertension was renal in 9 cases and nonrenal in 3. Initial dosing with isradipine was 0.1 mg/kg/dose. Six patients had emergent hypertension, and their blood pressure had been controlled with intravenous nicardipine before oral isradipine. Six patients received initial therapy with oral isradipine. Isradipine was monotherapy in 7 patients and in combination with other agents in 5 patients. The dose of isradipine required for blood pressure control was 0.6 +/- 0.3 mg/kg/day (range, 0.3 to 1.2 mg/kg/day). Isradipine failed to provide effective blood pressure control in 2 patients. In 1 of these patients, isradipine was effective after peritoneal dialysis. CONCLUSIONS: Isradipine is an effective, orally administered agent for control of hypertension in children.

Acute interstitial nephritis following amoxicillin overdose.

Antibiotics are commonly prescribed medications for pediatric infections. Acute interstitial nephritis has been reported with B-lactam antibiotics. We report the case of a 4-year-old boy who ingested 240 mg/kg of amoxicillin and developed acute oliguric renal failure with hematuria and crystalluria. The patient was hospitalized for serial renal function and electrolyte evaluation. Although he developed hyperkalemia, full recovery was obtained with conservative management. This case emphasizes that medications considered to be non-toxic even with overdose can have serious adverse effects which may require therapeutic intervention.

Relationship between conditional early acceptance into medical school and medical school leadership and academic performance: the Conley Scholar experience at the University of Missouri-Columbia.

UNLABELLED: The Conley Scholars Program at the University of Missouri-Columbia was created in 1987 to guarantee top flight students entrance to medical school without the frantic competition well known in undergraduate pre-med programs. The program provides greater freedom as undergraduates than most combined baccalaureate-MD programs. It is not known how this freedom and avoidance of the "pre-med syndrome" affects medical school performance and relative leadership qualities compared to traditional medical students. The goals of this study are to: a) compare relative composition and performance of Conley medical students to traditional medical students; b) assess the role of Conleys in leadership positions within medical school organizations. METHODS: Using the medical school computer data files and AMCAS application files, composition, academic, and leadership data were collected regarding all medical school classes containing Conleys. Statistical analysis was performed on all data. RESULTS: The results suggest that: a) Conley Scholars averaged significantly higher undergraduate GPAs than other medical students; b) Conley Scholars averaged higher GPAs throughout medical school; c) Conley Scholars are more likely to hold medical school leadership roles than traditional medical students. CONCLUSIONS: The results confirm the value of the Conley Scholar Program. Benefits extend beyond academic achievement to encompass the development of leadership skills recognized by faculty and peers.

Nicardipine for hypertensive emergencies in children with renal disease.

Hypertensive emergencies secondary to renal diseases were treated with nicardipine in three children. Nicardipine is the first intravenously administered dihydropyridine calcium channel blocker. Its physiological actions include vasodilation, with limited effects on the chronotropic and inotropic function of the myocardium. Nicardipine, starting at 5 microg/kg per min and then continued at a maintenance infusion of 1-3 microg/kg per min, effectively controlled the mean arterial pressure in the three patients. Apart from occasional superficial thrombophlebitis in a fourth patient, no adverse effects were noted.

Hypertensive crisis in children.

Children presenting with hypertension should be considered for emergency treatment when there is evidence of end-organ toxicity. Complications of extreme hypertension may be very serious, even life threatening, with the potential for life-long sequelae. Of greatest significance is damage to the central nervous system. Treatment of hypertensive emergencies should be directed toward the lowering of blood pressure enough to reduce toxicity, but not at a rate likely to cause hypoperfusion of vital organs. This blood pressure reduction should, in general, be carefully controlled in an intensive care unit, with attention to central nervous system, cardiac, and renal function. Intravenous agents are preferable under these circumstances, due to greater ease in modulating blood pressure. In the absence of specific contraindications, a continuous infusion of nicardipine or sodium nitroprusside is preferable. Intravenous labetalol by bolus injection, followed by continuous infusion, also may be used. Oral agents should be reserved for circumstances in which symptoms of end-organ toxicity are mild or absent. Since general pediatricians have limited experience with the treatment of hypertensive emergencies, consultation with physicians experienced in treating hypertensive emergencies is suggested when possible.

Lithium carbonate decreases ultrafiltration rates in an experimental model of PD.

Animal studies have shown increased fluid absorption from the peritoneal cavity following intraperitoneal (ip) vasopressin. Lithium is known to antagonize vasopressin effects on fluid absorption in kidney distal nephrons. The aim of the present study was to see whether lithium-containing exchanges increase the ultrafiltration rates (UF) during peritoneal dialysis (PD) in rats. PD was carried out in 6 Sprague-Dawley rats with 1.5% dextrose-containing PD solution using 15-ml volumes. Each exchange (ex) took 1 min for inflow, 4 mins for outflow and 25 mins for dwell. All rats underwent 9 consecutive half-hourly exs. During exs 4-6 lithium carbonate 2.5 mM was added to the PD solution. During lithium-containing exs significant increases in the glucose absorption rates (3.9 +/- 7.8 vs 37.5 +/- 8.1 mg/ex; p = 0.025) were associated with significant reductions in the UF (3.03 +/- 0.25 vs 1.78 +/- 0.12 ml/ex; p = 0.005). In conclusion, the isolated increase in glucose absorption without increases in the dialysate protein concentration with ip lithium, may suggest either a selective increase in size of the pores with a mean dimater near that of the glucose molecule or enhanced lymphatic absorption. ip lithium did not increase the UF in a rat model of PD.

Scorpion envenomation in eastern Saudi Arabia.

STUDY OBJECTIVE: To prospectively collect data on the initial presentation of victims of scorpion envenomation during the deployment of US forces to Saudi Arabia in support of Operation Desert Shield. DESIGN: A four-month prospective analysis of the circumstances, initial clinical signs and symptoms, treatment rendered, and subsequent clinical course of patients suffering scorpion envenomation. Data were analyzed using descriptive statistics. Scorpions were identified from physical remains. SETTING: Open desert in eastern Saudi Arabia 250 miles northeast of Riyadh. Ten battalion aid stations supporting a US armored cavalry division provided first-echelon medical care to 7,000 soldiers. TYPE OF PARTICIPANTS: The 40 male and three female patients were American military personnel between 19 and 33 years old. INTERVENTION: The constraints of military action precluded an interventional protocol. Each medical officer rendered appropriate medical care according to experience. MEASUREMENT AND MAIN RESULTS: During 118 days of encampment, 57 cases were reported, with 43 containing sufficient data for inclusion in the study. Thirty-six (63%) cases occurred during six weeks of initial fortification activity in open desert. Thirty-five victims (79%) presented for medical care within one hour after envenomation. The most common local symptoms and signs were pain (100%) and erythema (63%). The prevalent systemic symptom was apprehension (44%), with tachycardia (72%) and hypertension (58%) the prevalent systemic signs. With one exception, neurologic and cardiorespiratory complications were transient and responded well to fluid support and low doses of beta-sympathomimetics, parasympathetic antagonists, H1 blockers, and analgesics. CONCLUSION: The local and systemic response by victims in this study are consistent with previously documented cases of scorpion envenomation. In adult patients without serious prior adverse medical conditions, intervention is best limited to supportive measures.

Kinetics of peritoneal dialysis in children: role of lymphatics.

Intraperitoneal fluid is absorbed continuously by convective flow into the peritoneal cavity lymphatics. We evaluated the role of lymphatic absorption in the kinetics of peritoneal dialysis during standardized four hour exchanges in six children using 40 ml/kg of 2.5% dextrose dialysis solution. Cumulative lymphatic absorption averaged 10.4 +/- 1.6 ml/kg and reduced the total net transcapillary ultrafiltration during the dwell time by 73 +/- 10%. Due to the considerable lymphatic absorption rate, maximum intraperitoneal volume was observed before osmolar equilibrium. Extrapolated to four study exchanges per day, lymphatic absorption decreased the potential daily drain volumes in the children by 27 +/- 5% and daily peritoneal urea and creatinine clearances by 24 +/- 4% and 22 +/- 5%, respectively. Compared with four hour exchanges using two liters of 2.5% dextrose dialysis solution in 10 adult CAPD patients with average peritoneal transport, the children had more rapid equilibration of urea, greater absorption of dialysate glucose, higher lymphatic absorption and lower net ultrafiltration (P less than 0.01 to P less than 0.05). Lymphatic absorption therefore causes a relatively greater reduction in net ultrafiltration and solute clearances in children than in adults.

Neonatal renal failure: usefulness of diagnostic indices.

Forty-two oliguric neonates were prospectively studied to evaluate the usefulness and reliability of various diagnostic indices in differentiating renal failure from functional (prerenal) oliguria. Twenty-two infants had functional oliguria, 16 had renal failure, and four infants had probable early renal failure. Statistically significant differences between functional oliguria and renal failure were found with regard to the urine sodium, urine to serum ratios of sodium, urea, and creatinine, renal failure index, and fractional excretion of sodium. However, sharp demarcation of the two groups was possible only when the renal failure index or fractional excretion of sodium was used. Fractional excretion of sodium values of 2.5 or greater seem to differentiate renal failure from functional oliguria in this study.

Abnormal pyruvate and alpha-ketoglutarate dehydrogenase complexes in a patient with lactic acidemia.

Activities of pyruvate decarboxylase (PDC), alpha-ketoglutarate decarboxylase (KGDC) and both the pyruvate and alpha-ketoglutarate dehydrogenase complexes (PDH complex and KGDH complex) were measured, and kinetic properties of PDC were studied in fibroblasts derived from normal individuals and from a 2-yr-old girl with congenital lactic acidemia and severe retardation of growth and development. The activities of PDC, KGDC, PDH complex, and KGDH complex in the patient were 1.12 +/- 0.12, 2.33 +/- 0.42, 9.00 +/- 0.50, and 16.46 +/- 1.57 and in controls 3.10 +/- 0.16, 5.36 +/- 0.56, 24.13 +/- 1.61 and 44.95 +/- 3.72 nmole/mg protein/hr. The optimum pH (6.0) and Michaelis constants (Km) for pyruvate of PDC (1.0-1.6 X 10(-5) M) were similar in fibroblasts of the patient and controls. PDC activity was more sensitive to denaturation by heat in the fibroblasts of the patient than those from controls, while heat denaturation curves of KGDC were similar in the patient and control. Higher concentrations of thiamine pyrophosphate (TPP) were required to protect PDC from heat denaturation in the patient. TPP was more easily removed from PDC in the patient than in the control by washing the fibroblasts with alkaline buffer. These results suggest that the PDC enzyme of the patient is in an altered molecular form, to which TPP is loosely bound. This particular constellation of abnormalities has not previously been reported in patients with lactic acidemia.

Propranolol in human plasma and breast milk.

To assess the problem of continuing propranolol therapy in a breast-feeding mother, studies were performed to determine simultaneously plasma and breast milk concentrations of propranolol after single dose (40 mg) and continuous dose (40 mg 4 times daily) treatment with this drug. Breast milk and plasma concentrations of propranolol peaked between 2 and 3 hours after dosing. Propranolol concentrations in breast milk were less than 40 and 64 percent, respectively, of peak plasma propranolol concentrations after single dose and continuous dose administration. It was estimated that the maximal cumulative propranolol load to this breast-feeding infant, consuming 500 ml of whole milk, when the mother received 40 mg of propranolol 4 times daily would be 21 microgram/24 hours. This dose is considerably less than the usual therapeutic dose of propranolol for infants.