Identification of mutations in the COL4A5 collagen gene in Alport syndrome.

X-linked Alport syndrome is a hereditary glomerulonephritis in which progressive loss of kidney function is often accompanied by progressive loss of hearing. Ultrastructural defects in glomerular basement membranes (GBM) of Alport syndrome patients implicate an altered structural protein as the cause of nephritis. The product of COL4A5, the alpha 5(IV) collagen chain, is a specific component of GBM within the kidney, and the gene maps to the same X chromosomal region as does Alport syndrome. Three structural aberrations were found in COL4A5, in intragenic deletion, a Pst I site variant, and an uncharacterized abnormality, which appear to cause nephritis and deafness, with allele-specific severity, in three Alport syndrome kindreds in Utah.

X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis.

In X-linked nephrogenic diabetes insipidus (NDI) the urine of male patients is not concentrated after the administration of the antidiuretic hormone arginine-vasopressin. This disease is due to mutations in the V2 receptor gene that maps to chromosome region Xq28. In 1969, Bode and Crawford suggested that most NDI patients in North America shared common ancestors of Ulster Scot immigrants who arrived in Halifax in 1761 on the ship Hopewell. A link between this family and a large Utah kindred was also suggested. DNA was obtained from 17 affected male patients from the "Hopewell" kindred and from four additional families from Nova Scotia and New Brunswick who shared the same Xq28 NDI haplotype. The Utah kindred and two families (Q2, Q3) from Quebec were also studied. The "Hopewell" mutation, W71X, is a single base substitution (G-->A) that changes codon 71 from TGG (tryptophan) to TGA (stop). The W71X mutation was found in affected members of the Hopewell and of the four satellite families. The W71X mutation is the cause of X-linked NDI for the largest number of related male patients living in North America. Other families (Utah, Q2 and Q3) that are historically and ethnically unrelated bear other mutations in the V2 receptor gene.

Acute renal failure after percutaneous cholangiography.

A patient had acute renal insufficiency following repeated injections of water-soluble radiologic contrast material for transhepatic cholangiography .

Expression of mRNA for type IV collagen alpha1, alpha5 and alpha6 chains by cultured dermal fibroblasts from patients with X-linked Alport syndrome.

COL4A5 mutations causing X-linked Alport syndrome (XLAS) are frequently associated with absence of the alpha3, alpha4,alpha5 and alpha6 chains of type IV collagen from basement membranes and increased amounts of the alpha1(IV) and alpha2(IV) chains in glomerular basement membrane. Although many COL4A5 mutations have been described in XLAS, the mechanisms by which these mutations influence the basement membrane appearance of chains other than alpha5(IV) remain poorly understood. In this study, we used dermal fibroblasts from eight normal individuals and nine males with XLAS to test the hypotheses that COL4A5 mutations increase transcription of COL4A1 and suppress transcription of COL4A6. Ribonuclease protection assays revealed that alpha1(IV), alpha5(IV) and alpha6(IV) transcripts were expressed in cultures of dermal fibroblasts. The mRNA levels for alpha1(IV) in eight of nine patients with XLAS were not increased compared to controls; one patient with a large COL4A5 deletion showed significant elevation of alpha1(IV) mRNA levels. No differences in steady-state mRNA levels for alpha6(IV) were found when XLAS fibroblasts were compared with controls, even though little or no alpha6(IV) protein was detectable at the dermal-epidermal junction by immunofluorescence study. This finding suggests that post-transcriptional events account for the absence of alpha6(IV) in the Alport dermal-epidermal junction.

Failure to visualize acutely injured kidneys with technetium-99m DMSA does not preclude recoverable function.

A 35-yr-old patient developed severe acute tubular necrosis requiring hemodialysis. A [99mTc]dimercaptosuccinic acid scan of the kidneys showed no renal uptake at 4 or 24 hr, but the patient subsequently recovered normal renal function as judged by a normal serum creatinine. Based on this case report and a review of the literature, one cannot assume irreversible loss of function in patients with acute renal failure, based on the absence of radiopharmaceutical uptake by the kidneys.

Efficient detection of Alport syndrome COL4A5 mutations with multiplex genomic PCR-SSCP.

We have performed effective mutation screening of COL4A5 with a new method of direct, multiplex genomic amplification that employs a single buffer condition and PCR profile. Application of the method to a consecutive series of 46 United States patients with diverse indications of Alport syndrome resulted in detection of mutations in 31 cases and of five previously unreported polymorphisms. With a correction for the presence of cases that are not likely to be due to changes at the COL4A5 locus, the mutation detection sensitivity is greater than 79%. The test examines 52 segments, including the COL4A6/COL4A5 intergenic promoter region, all 51 of the previously recognized exons and two newly detected exons between exons 41 and 42 that encode an alternatively spliced mRNA segment. New genomic sequence information was generated and used to design primer pairs that span substantial intron sequences on each side of all 53 exons. For SSCP screening, 16 multiplex PCR combinations (15 4-plex and 1 3-plex) were used to provide complete, partially redundant coverage of the gene. The selected combinations allow clear resolution of products from each segment using various SSCP gel formulations. One of the 29 different mutations detected initially seemed to be a missense change in exon 32 but was found to cause exon skipping. Another missense variant may mark a novel functional site located in the collagenous domain.

Evaluation of labetalol in elderly patients with essential hypertension.

Labetalol was evaluated in a multicenter, placebo-controlled study of elderly patients (greater than or equal to 60 years) with mild to moderate essential hypertension. After a placebo-washout period, doses were titrated from 100 mg BID to a maximum of 400 mg BID over a 6-week period. Once blood pressure control (standing diastolic blood pressure [SDBP] less than 90 mm Hg and greater than or equal to 10 mm Hg reduction from baseline) was achieved or the maximum allowable dosage had been given, the dosage remained the same until the end of the study. The titration phase was followed by a 4-week maintenance period. Blood pressure control was achieved in 37/54 (69%) of the patients who were treated with labetalol compared with 21/58 (36%) of the patients who received placebo (P less than .001). Twenty-nine (78%) of those controlled on labetalol responded to doses of 200 mg or less BID, and there was no significant difference between groups with respect to orthostatic blood pressure changes. Adverse experiences were generally mild and occurred with similar frequency in the labetalol and placebo groups; six patients who received labetalol and five who received placebo withdrew from the study due to adverse experiences, but in only one case (labetalol) was the adverse experience considered drug-related. In summary, labetalol effectively and safely lowered diastolic blood pressure in the elderly without producing significant orthostatic changes.

Type of hemodialysis and preference for behavioral involvement: interactive effects on adherence in end-stage renal disease.

Examined the effects of hemodialysis type (i.e., staff controlled, in center vs. patient controlled, home) and patient preference for behavioral involvement on adherence and emotional adjustment in a sample of 53 patients with end-stage renal disease. Consistent with person x treatment interaction models, higher levels of preference for behavioral involvement were associated with better dietary adherence (i.e., lower serum potassium) for patients receiving dialysis at home but worse dietary adherence for patients receiving treatment in a dialysis center. A similar though weaker patient x treatment type matching pattern was observed for fluid-intake adherence (i.e., interdialytic weight gain). No effects were observed for patients' self-reported depression levels. Possible mechanisms for the interactional effect on adherence are discussed.

Health locus of control and depression in end-stage renal disease.

Research on the association between health locus of control and depression in chronic illness has produced contradictory findings, perhaps because of a failure to consider contextual variables. In this study of 96 hemodialysis patients, the belief that one's health is controllable was associated with less depression among Ss who had not previously experienced a failed renal transplant. This belief was associated with greater depression for Ss who had returned to dialysis following an unsuccessful transplant. This interactive effect occurred among severely ill Ss, but health locus of control was unrelated to depression among Ss with less severe disease. This pattern occurred both when control perceptions reflected a belief in the Ss' own or powerful others' (i.e., health care providers) ability to influence health outcomes. Results underscore the adaptive value of congruence between control beliefs and objective circumstances in chronic illness.

Hemodialysis does not affect erythrocyte sodium-lithium countertransport.

Sodium-lithium countertransport measurements on erythrocytes are currently of interest because some hypertensive subjects and their relatives have abnormally high values. Woods et al [1] reported that red cells taken from dialysis patients after hemodialysis had significantly lower sodium-lithium countertransport than before dialysis. They suggested that sodium-lithium countertransport is influenced by 'a dialyzable plasma factor'. We conducted experiments to further evaluate their observations relating to the 'dialyzable plasma factor'. However, we have been unable to confirm their findings. Neither an effect of hemodialysis on sodium-lithium countertransport in erythrocytes from maintenance dialysis patients nor any effect of dialysis on normal erythrocytes in vitro was evident. Our results do not support the existence of a dialyzable plasma factor affecting sodium-lithium countertransport.

Toxic shock following staphylococcal peritonitis.

A case of toxic shock syndrome (TSS) in a male continuous ambulatory peritoneal dialysis (CAPD) patient is described. The prodromal phase started with staphylococcal peritonitis and deteriorated to the malignant phase of TSS approximately 48 hours from the time he presented to the local emergency room. Desquamation first affected the extremities and likely involved his gastrointestinal tract. His course of peritonitis involved unusual pain, with progression into toxic shock in spite of appropriate antibiotic coverage.

Alport syndrome: clinical update.

This review of the literature on Alport syndrome (AS) places emphasis on genetic and clinical issues related to the sensorineural hearing loss in type III and type IV X-linked AS. The review covers prevalence, medical issues, genetic issues, audiologic findings, vestibular findings, the pathophysiology of hearing loss in type III AS, age- and phenotype-specific normative data and concludes with a discussion regarding future auditory-genetic research with AS.

Experience with the Astra dental implant system.

The Astra Dental Implant System appears to be a relatively successful and economical method of osseointegration. This article lists its clinical components, explains how the system is fitted and discusses the preliminary results.

A two year review of the treatment and complications of mandibular angle fractures.

A review of all patients with treated mandibular angle fractures at a district general hospital, over a two year period, was undertaken. Forty one consecutive patients with 43 mandibular angle fractures were identified. Thirty eight fractures were treated by open reduction and internal fixation with miniplates and 5 by intermaxillary fixation (IMF). Fractures treated with miniplates were reduced under direct vision to give an anatomical reduction without using temporary intermaxillary fixation. The shortened operative time together with the prompt administration of intravenous antibiotics following injury and rapid treatment of fractures after admission resulted in a low complication rate of 7.3% of patients requiring a subsequent surgical procedure. Although IMF has an important role to play in the general treatment of facial fractures, we suggest that there is a place for single miniplate fracture fixation without the use of temporary IMF when treating simple angle fractures. As this technique is quick and has a low complication rate its use in military situations should be considered.

Pregnancy and cystinuria.

46 pregnancies in patients with cystinuria treated with a high fluid intake alone or in combination with D-penicillamine resulted in 41 normal births. New stones formed in 18 pregnancies, with stone passage early in 4 of them. No patient required stone removal during pregnancy. Other pregnancy-related problems included hypertension and urinary-tract infection, which responded to conventional management. Assiduous maintenance of a sustained high fluid intake is even more important than usual during pregnancy and the puerperium. D-penicillamine appears relatively safe for severe cases, although most patients can be managed without it. With careful medical management stone-forming cystinurics can be safely conducted through pregnancy without increased risks to the mother or fetus.

Cost of hypertension treatment.

A retrospective analysis was conducted of the cost of hypertension care at one internal medicine clinic, looking at the cost of office visits, laboratory tests, and medications. Cost of hypertension care was $947 the first year of treatment, $575 the second year, and $420 per year thereafter. Drug costs were the major determinant of cost of care, comprising 80% of the total cost of treatment after the first year of therapy.