László Kovács

The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection

The urinary tract functions in close proximity to the outside environment, yet must remain free of microbial colonization to avoid disease. The mechanisms for establishing an antimicrobial barrier in this area are not completely understood. Here, we describe the production and function of the cathelicidin antimicrobial peptides LL-37, its precursor hCAP-18 and its ortholog CRAMP in epithelial cells of human and mouse urinary tract, respectively. Bacterial contact with epithelial cells resulted in rapid production and secretion of the respective peptides, and in humans LL-37/hCAP-18 was released into urine. Epithelium-derived cathelicidin substantially contributed to the protection of the urinary tract against infection, as shown using CRAMP-deficient and neutrophil-depleted mice. In addition, clinical E. coli strains that were more resistant to LL-37 caused more severe urinary tract infections than did susceptible strains. Thus, cathelicidin seems to be a key factor in mucosal immunity of the urinary tract.

Six novel mutations in the arginine vasopressin gene in 15 kindreds with autosomal dominant familial neurohypophyseal diabetes insipidus give further insight into the pathogenesis.

Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is caused by postnatal arginine vasopressin (AVP) deficiency resulting from mutations in the AVP gene encoding the AVP pre-prohormone. To advance the understanding of adFNDI further, we have searched for mutations in the AVP gene in 15 unrelated kindreds in which diabetes insipidus appeared to be segregating. In nine kindreds, seven different previously described mutations were identified. In each of the other six kindreds, unique novel mutations were identified. Two of these (225A>G and 227G>A) change a nucleotide in the translation initiation codon of the signal peptide, whereas the other four (1797T>C, 1884G>A, 1907T>G, and 2112C>G) predict amino-acid substitutions in the neurophysin II moiety of the AVP prohormone, namely V67A (NP36), G96D (NP65), C104G (NP73), and C116W (NP85). Among these, the mutation predicting the V67A (NP36) substitution is remarkable. It affects a region of the neurophysin II not affected by any other mutations, produces only a minor change, and its inheritance suggests an incomplete penetrance. Our findings both confirm and further extend the mutation pattern that has emerged in adFNDI, suggesting that the mutations affect amino-acid residues known or reasonably presumed to be important for the proper folding and/or dimerization of the neurophysin II moiety of the AVP prohormone.

The role of bladder capacity in antidiuretic and anticholinergic treatment for nocturnal enuresis

PURPOSEnWe evaluated combination treatment with desmopressin and oxybutynin in patients with enuresis who did not respond to desmopressin monotherapy. Furthermore, we compared 2 methods of estimating bladder capacity and evaluated the ability of these methods to predict the response to desmopressin and oxybutynin.nnnMATERIALS AND METHODSnA total of 60 children with a mean age +/- SD of 10.6 +/- 3.0 years who had monosymptomatic nocturnal enuresis completed the study. After a 2-week observation period maximal voided volume during free access to fluid intake was determined by a 2-day frequency-volume chart and maximal voided volume after water load was determined on a separate day. Patients then received 20 mug desmopressin intranasally at bedtime during 2 weeks. In nonresponders to desmopressin with less than a 50% decrease in wet nights 5 mg oxybutynin twice daily was added for another 2 weeks.nnnRESULTSnOf the patients 41 (68%) showed more than 50% decrease in wet nights during the 2-week desmopressin treatment period (4.6 +/- 1.6 to 0.7 +/- 0.8, p <0.001). In desmopressin nonresponders combined treatment with desmopressin and oxybutynin resulted in a further decrease in wet nights (4.0 +/- 1.2 to 1.7 +/- 1.4, p <0.001). Maximal voided volume during free access to fluid intake was significantly higher in desmopressin responders than in nonresponders (244 +/- 111 vs 160 +/- 65 ml, p <0.001). In contrast, maximal voided volume after water load was not significantly different between desmopressin responders and nonresponders.nnnCONCLUSIONSnThe study indicates a role for oxybutynin in combination with desmopressin in children who are not responding to desmopressin monotherapy. Maximal voided volume during free access to fluid intake is a clinically useful predictor of the response to desmopressin but not to oxybutynin.

Effect of Laser Acupuncture for Monosymptomatic Nocturnal Enuresis on Bladder Reservoir Function and Nocturnal Urine Output

PURPOSEnThe alternative treatments for enuresis have been reported with high efficacy but in noncontrolled studies. Therefore, using a prospective, single-blind, randomized, placebo controlled design we evaluated the effect of laser acupuncture on bladder reservoir function and enuresis frequency in cases of monosymptomatic nocturnal enuresis with reduced maximal voided volume.nnnMATERIALS AND METHODSnA total of 31 patients with monosymptomatic nocturnal enuresis, with at least 3 enuretic nights per week and less than 70% of normal age related maximal voided volume without first morning void (Koffs formula), no constipation, urinary tract abnormalities, or daytime incontinence were randomized into group 1--active laser acupuncture, group 2--placebo treatment with red light and skin contact and group 3--placebo treatment with red light without skin contact. After a 2-week run-in period (when patients made home recordings of nocturnal urinary production and during 2 weekends frequency-volume charts), the patients started a 5-week treatment. During the last 2 weeks of treatment patients performed the same recordings as during the run-in period.nnnRESULTSnWe found no significant effect of active laser acupuncture on maximal voided volume (first morning void excluded), maximal morning voided volume, voiding frequency, enuresis frequency before and after treatment or nocturnal urine production among the patient groups. However, we found that laser acupuncture resulted in a significant increase in average daytime voided volume. We found no effect of skin contact during placebo laser acupuncture.nnnCONCLUSIONSnLaser acupuncture is a safe but inefficient treatment for monosymptomatic nocturnal enuresis with reduced maximal voided volume. However, we found subtle effects on bladder reservoir function.

Pachydermodactyly: A Review

Synovitis is the characteristic feature of inflammatory joint disease. If synovitis is localized to interphalangeal joints, rheumatoid arthritis, psoriatic arthritis, and juvenile idiopathic arthritis are among the most common differential diagnoses. The absence of pain, tenderness, and limitation of function despite progressive swelling of proximal interphalangeal joints suggests an alternative diagnosis, for example pachydermodactyly (PDD). This is a benign disease, associated with asymptomatic, progressive swelling of periarticular soft tissue, which usually occurs in young males. PDD is probably the result of repetitive mechanical stimulation. One hundred and twenty-one cases have been reported in the literature. Some of these were initially misdiagnosed and treated for inflammatory arthritis. We provide a comprehensive review of the literature on pachydermodactyly to promote awareness of this rare but important differential diagnosis of arthritis.

Genetic defects in ciliary genes in autosomal dominant polycystic kidney disease

AIM To evaluate the genetic defects of ciliary genes causing the loss of primary cilium in autosomal dominant polycystic kidney disease (ADPKD). METHODS We analyzed 191 structural and functional genes of the primary cilium using next-generation sequencing analysis. We analyzed the kidney samples, which were obtained from 7 patients with ADPKD who underwent nephrectomy. Each sample contained polycystic kidney tissue and matched normal kidney tissue. RESULTS In our study, we identified genetic defects in the 5 to 15 genes in each ADPKD sample. The most frequently identified defects were found in genes encoding centrosomal proteins (PCM1, ODF2, HTT and CEP89) and kinesin family member 19 (KIF19), which are important for ciliogenesis. In addition, pathogenic mutations in the PCM1 and KIF19 genes were found in all ADPKD samples. Interestingly, mutations in the genes encoding the intraflagellar transport proteins, which are the basis of animal models of ADPKD, were only rarely detected. CONCLUSION The results of our study revealed the actual state of structural ciliary genes in human ADPKD tissues and provided valuable indications for further research.

Two novel mutations in seven Czech and Slovak kindreds with familial neurohypophyseal diabetes insipidus—benefit of genetic testing

AbstractFamilial neurohypophyseal diabetes insipidus (FNDI) is a rare hereditary disorder with unknown prevalence characterized by arginine-vasopressin hormone (AVP) deficiency resulting in polyuria and polydipsia from early childhood. We report the clinical manifestation and genetic test results in seven unrelated kindreds of Czech or Slovak origin with FNDI phenotype. The age of the sign outset ranged from 2 to 17xa0years with remarkable interfamilial and intrafamilial variability. Inconclusive result of the fluid deprivation test in three children aged 7 and 17xa0years old might cause misdiagnosis; however, the AVP gene analysis confirmed the FNDI. The seven families segregated together five different mutations, two of them were novel (c.164Cxa0>xa0A, c.298Gxa0>xa0C). In addition, DNA analysis proved mutation carrier status in one asymptomatic 1-year-old infant.n Conclusions: The present study together with previously published data identified 38 individuals with FNDI in the studied population of 16 million which predicts a disease prevalence of 1:450,000 for the Central European region. The paper underscores that diagnostic water deprivation test may be inconclusive in polyuric children with partial diabetes insipidus and points to the clinical importance and feasibility of molecular genetic testing for AVP gene mutations in the proband and her/his first degree relatives.What is Known:• At least 70 different mutations were reported to date in about 100 families with neurohypophyseal diabetes insipidus (FNDI), and new mutations appear sporadically.Whatis New:• Two novel mutations of the AVP gene are reported• The importance of molecular testing in children with polyuria and inconclusive water deprivation test is emphasized.

Changes of physico-chemical characteristics of red blood cells in children with nephrotic syndrome

Changes of milieu interieur in nephrotic syndrome (NS) have many consequences in various organs. We have measured the electrical charge of erythrocytes (Ery) with binding of alcian blue (AB) in 18 children with relapse of NS (12 minimal changes, 3 membranous and 3 mesangioproliferative glomerulonephritis) and 15 healthy children. The most important finding was that the binding of AB to Ery in patients with minimal change nephrotic syndrome (MCNS) and other aetiologies of NS was significantly less than that in the control group (p<0.05). In addition, we have studied the thermal denaturation of the Ery membranes by differential scanning microcalorimetry. In some children with NS we have seen the splitting of B transition. We suppose that these phenomena occur as the result of structural change, which may involve lipoprotein components of the cytoskeletal network.

Endogenous digoxin-like substance in the urine of preterm infants with late hyponatremia

On addmission their mean serum calcium and magnesium levels were 2.6 + 0.45 and 0.81 _+ 0.12 mmol/1, respectively. These data suggest that serum calcium and magnesium levels are not appropriate parameters for controlling juvenile diabetes. This is not very surprising, since serum values of magnesium represent only about 0.5%-1% of the total magnesium content of the body and calcium also is an ion with mostly intracellular actions.