Biomedical subjects

Melanie Peters

Publications and source records attributed to Melanie Peters.

9 recordsLinked to original sources

PubMed2005

Perinatal management of a preterm neonate affected by hyperprostaglandin E2 syndrome (HPS).

BACKGROUND: Neonates affected by hyperprostaglandin E(2) syndrome (HPS) present with severe polyuria. Both urinary losses as well as prostaglandin synthesis inhibitors may precipitate acute renal failure (ARF). AIM: Our goal was to maintain euvolaemia by replacement of urinary losses. PATIENT: Our patient was born prematurely with a family history typical of HPS. Urinary salt and water losses and PGE(2) excretion were determined in 2- to 4-h intervals. Salt and water were replaced accordingly. RESULTS: Within the first 48 h, urinary losses and PGE(2) increased continuously to 50 ml/kg/h and 374 ng/h/1.73 m(2), respectively. Following exposure to 0.05-0.5 mg/kg/d indomethacin, urinary output decreased steadily to 10-15/ml/kg/h. CONCLUSION: In euvolaemic preterm neonates with HPS and the need for excessive replacement of salt and water, inhibition of renal PGE(2) excretion with indomethacin effectively reduces polyuria and natriuresis without acutely compromising renal function.

Bartter Syndrome↗

PubMed2005

Impact of tele-advice on community nurses' knowledge of venous leg ulcer care.

AIM: This paper reports a study assessing the impact of the provision of expert tele-advice to community nurses in enhancing their knowledge of leg ulcer care. BACKGROUND: Community nurses have traditionally been responsible for the care of patients with leg ulcers. However, access to expert medical and nursing advice has been restricted to the local hospital environment. The introduction of e-health and telemedicine have created opportunities to provide online and immediate access to wound care expertise from centres of excellence to primary health care staff in managing patients' wounds in their own home. METHOD: A stratified randomized controlled trial was used to examine community nurses' knowledge before and after the provision of expert tele-advice. A knowledge measurement tool comprised of 40 multiple-choice questions was adopted, with correct responses identified by a panel of wound care experts. The questions covered the three themes of dressings, management and physiology, with different levels of difficulty categorized as easy, medium or difficult. The tool was administered before and after the intervention (12 weeks) to both the experimental and control groups. RESULTS: Statistically significant improvements were observed only for the experimental group in the areas of dressings and management, as well as in the medium level questions. No statistically significant improvement was seen for the easy questions, as there was little room for improvement because of preintervention high scores. For the difficult questions, it was thought that more time would be needed for a more positive outcome. CONCLUSIONS: The results suggest that tele-advice can be of great benefit to community nurses in enhancing their knowledge in the practice of leg ulcer care. This will have significant implications for more efficient use of human resources and cost effectiveness in wound care.

Clinical Competence↗

PubMed2005

Salt handling in the distal nephron: lessons learned from inherited human disorders.

The molecular basis of inherited salt-losing tubular disorders with secondary hypokalemia has become much clearer in the past two decades. Two distinct segments along the nephron turned out to be affected, the thick ascending limb of Henle's loop and the distal convoluted tubule, accounting for two major clinical phenotypes, hyperprostaglandin E syndrome and Bartter-Gitelman syndrome. To date, inactivating mutations have been detected in six different genes encoding for proteins involved in renal transepithelial salt transport. Careful examination of genetically defined patients ("human knockouts") allowed us to determine the individual role of a specific protein and its contribution to the overall process of renal salt reabsorption. The recent generation of several genetically engineered mouse models that are deficient in orthologous genes further enabled us to compare the human phenotype with the animal models, revealing some unexpected interspecies differences. As the first line treatment in hyperprostaglandin E syndrome includes cyclooxygenase inhibitors, we propose some hypotheses about the mysterious role of PGE(2) in the etiology of renal salt-losing disorders.

Diuretics↗

PubMed2003

Classification and rescue of ROMK mutations underlying hyperprostaglandin E syndrome/antenatal Bartter syndrome.

BACKGROUND: Mutations in the renal K+ channel ROMK (Kir 1.1) cause hyperprostaglandin E syndrome/antenatal Bartter syndrome (HPS/aBS), a severe tubular disorder leading to renal salt and water wasting. Several studies confirmed the predominance of alterations of current properties in ROMK mutants. However, in most of these studies, analysis was restricted to nonmammalian cells and electrophysiologic methods. Therefore, for the majority of ROMK mutations, disturbances in protein trafficking remained unclear. The aim of the present study was the evaluation of different pathogenic mechanisms of 20 naturally occurring ROMK mutations with consecutive classification into mutational classes and identification of distinct rescue mechanisms according to the underlying defect. METHODS: Mutated ROMK potassium channels were expressed in Xenopus oocytes and a human kidney cell line and analyzed by two electrode voltage clamp analysis, immunofluorescence, and Western blot analysis. RESULTS: We identified 14 out of 20 ROMK mutations that did not reach the cell surface, indicating defective membrane trafficking. High expression levels rescued six out of 14 ROMK mutants, leading to significant K+ currents. In addition, two early inframe stop mutations could be rescued by aminoglycosides, resulting in full-length ROMK and correct trafficking to the plasma membrane in a subset of transfected cells. CONCLUSION: In contrast to previous reports, most of the investigated ROMK mutations displayed a trafficking defect that might be rescued by pharmacologic agents acting as molecular chaperones. The evaluation of different disease-causing mechanisms will be essential for establishing new and more specific therapeutic strategies for HPS/aBS patients.

Animals↗

PubMed2002

Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family.

Magnesium is an essential ion involved in many biochemical and physiological processes. Homeostasis of magnesium levels is tightly regulated and depends on the balance between intestinal absorption and renal excretion. However, little is known about specific proteins mediating transepithelial magnesium transport. Using a positional candidate gene approach, we identified mutations in TRPM6 (also known as CHAK2), encoding TRPM6, in autosomal-recessive hypomagnesemia with secondary hypocalcemia (HSH, OMIM 602014), previously mapped to chromosome 9q22 (ref. 3). The TRPM6 protein is a new member of the long transient receptor potential channel (TRPM) family and is highly similar to TRPM7 (also known as TRP-PLIK), a bifunctional protein that combines calcium- and magnesium-permeable cation channel properties with protein kinase activity. TRPM6 is expressed in intestinal epithelia and kidney tubules. These findings indicate that TRPM6 is crucial for magnesium homeostasis and implicate a TRPM family member in human disease.

Adult↗

PubMed2002

Barttin increases surface expression and changes current properties of ClC-K channels.

The term Bartter syndrome encompasses a heterogeneous group of autosomal recessive salt-losing nephropathies that are caused by disturbed transepithelial sodium chloride reabsorption in the distal nephron. Mutations have been identified in the NKCC2 (Na(+)-K(+)-2Cl(-)) cotransporter and ROMK potassium channel, which cooperate in the process of apical sodium chloride uptake, and ClC-Kb chloride channels, which mediate basolateral chloride release. Recently, mutations in barttin, a protein not related to any known ion transporter or channel, were described in BSND, a variant of Bartter syndrome associated with sensorineural deafness. Here we show that barttin functions as an activator of ClC-K chloride channels. Expression of barttin together with ClC-K in Xenopus oocytes increased ClC-K current amplitude, changed ClC-K biophysical properties, and enhanced ClC-K abundance in the cell membrane. Co-immunoprecipitation revealed a direct interaction of barttin with ClC-K. We performed in situ hybridization on rat kidney slices and RT-PCR analysis on microdissected nephron segments to prove co-expression of barttin, ClC-K1 and ClC-K2 along the distal nephron. Functional analysis of BSND-associated point mutations revealed impaired ClC-K activation by barttin. The results demonstrate regulation of a CLC chloride channel by an accessory protein and indicate that ClC-K activation by barttin is required for adequate tubular salt reabsorption.

Animals↗

PubMed2002

Clinical presentation of genetically defined patients with hypokalemic salt-losing tubulopathies.

PURPOSE: Hypokalemic salt-losing tubulopathies (Bartter-like syndromes) comprise a set of clinically and genetically distinct inherited renal disorders. Mutations in four renal membrane proteins involved in electrolyte reabsorption have been identified in these disorders: the furosemide-sensitive sodium-potassium-chloride cotransporter NKCC2, the potassium channel ROMK, the chloride channel ClC-Kb, and the thiazide-sensitive sodium-chloride cotransporter NCCT. The aim of this study was to characterize the clinical features associated with each mutation in a large cohort of genetically defined patients. PATIENTS AND METHODS: The phenotypic characteristics of 65 patients with molecular defects in NKCC2, ROMK, ClC-Kb, or NCCT were collected retrospectively. RESULTS: ROMK and NKCC2 patients presented with polyhydramnios, nephrocalcinosis, and hypo- or isosthenuria. Hypokalemia was less severe in the ROMK patients compared with the NKCC2 patients. In contrast, NCCT patients had hypocalciuria, hypomagnesemia, and marked hypokalemia. While this dissociation of renal calcium and magnesium handling was also observed in some ClC-Kb patients, a few ClC-Kb patients presented with hypercalciuria and hypo- or isosthenuria. CONCLUSIONS: ROMK, NKCC2, and NCCT mutations usually have uniform clinical presentations, whereas mutations in ClC-Kb occasionally lead to phenotypic overlaps with the NCCT or, less commonly, with the ROMK/NKCC2 cohort. Based on these results, we propose an algorithm for the molecular diagnosis of hypokalemic salt-losing tubulopathies.

Algorithms↗

PubMed2001

Primary gene structure and expression studies of rodent paracellin-1.

The novel member of the claudin multigene family, paracellin-1/claudin-16, encoded by the gene PCLN1, is a renal tight junction protein that is involved in the paracellular transport of magnesium and calcium in the thick ascending limb of Henle's loop. Mutations in human PCLN1 are associated with familial hypomagnesemia with hypercalciuria and nephrocalcinosis, an autosomal recessive disease that is characterized by severe renal magnesium and calcium loss. The complete coding sequences of mouse and rat Pcln1 and the murine genomic structure are here presented. Full-length cDNAs are 939 and 1514 bp in length in mouse and rat, respectively, encoding a putative open-reading frame of 235 amino acids in both species with 99% identity. Exon-intron analysis of the human and mouse genes revealed a 100% homology of coding exon lengths and splice-site loci. By radiation hybrid mapping, the murine Pcln1 gene was assigned directly to marker D16Mit133 on mouse chromosome 16 (syntenic to a locus on human chromosome 3q27, which harbors the human PCLN1 gene). Mouse multiple-tissue Northern blot showed Pcln1 expression exclusively in the kidney. The expression profile along the nephron was analyzed by reverse transcriptase-PCR on microdissected nephron segments and immunohistochemistry of rat kidney. Paracellin-1 expression was restricted to distal tubular segments including the thick ascending limb of Henle's loop, the distal tubule, and the collecting duct. The identification and characterization of the rodent Pcln1 genes provide the basis for further studies of paracellin-1 function in suitable animal models.

Amino Acid Sequence↗

PubMed2001

Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive tubular disorder that is frequently associated with progressive renal failure. The primary defect is related to impaired tubular reabsorption of magnesium and calcium in the thick ascending limb of Henle's loop. Mutations in PCLN-1, which encodes the renal tight junction protein paracellin-1 (claudin-16), were identified as the underlying genetic defects. Comprehensive clinical data and the results of PCLN-1 mutation analysis of 25 FHHNC families with 33 affected individuals are presented. Patients presented mainly with urinary tract infections, polyuria, and hematuria at a median age of 3.5 yr. At the time of diagnosis, the GFR was already decreased to <60 ml/min per 1.73 m(2) for 11 patients. Twelve patients exhibited progression to end-stage renal disease, at a median age of 14.5 yr. Treatment with magnesium salts and thiazides seemed to have no effect on the progression of the disease. Genotype analysis revealed PCLN-1 mutations in all except three mutant alleles (94%). Fifteen different mutations were observed, including eight novel mutations. The accumulation of mutations affecting the first extracellular loop was striking, with 48% of all mutant alleles exhibiting a Leu151Phe exchange. Haplotype analysis strongly suggested a founder effect among patients with FHHNC who originated from Germany or eastern European countries. In 13 of 23 families, hypercalciuria and/or nephrolithiasis were observed in otherwise unaffected family members, indicating a possible role of heterozygous PCLN-1 mutations in yielding hypercalciuric stone-forming conditions.

Adolescent↗