An unusual patient with hypercalciuria, recurrent nephrolithiasis, hypomagnesemia and G227R mutation of Paracellin-1. An unusual patient with hypercalciuria and hypomagnesemia unresponsive to thiazide diuretics

A 19-year-old female patient with hypercalciuria and recurrent nephrolithiasis/urinary tract infection unresponsive to thiazide type diuretics is presented. The patient first experienced nephrolithiasis at the age of 4 years. Afterwards, recurrent passages of stones and urinary tract infection occurred. On diagnostic evaluation at the age of 19 years, she also had hypocitraturia and hypomagnesemia. Her serum calcium concentrations were near the lower limit of normal (8.5-8.8 mg/dl; normal range: 8.5-10.5), her serum magnesium concentrations were 1.15-1.24 mg/dl (normal range: 1.4-2.5) and urinary calcium excretion was 900 mg/24 h. PTH concentrations were increased (110-156 pg/ml; normal range: 10-65). We tried to treat the patient with hydrochlorothiazide at a dose of 50 mg/day. During treatment with thiazide diuretics, PTH concentration remained high and the patient had recurrent urinary tract infections and passages of stones. Serum magnesium concentration did not normalize even under the parenteral magnesium infusion. Her mother had a history of nephrolithiasis 20 years ago. Severe hypomagnesemia in association with hypercalciuria/urinary stones is reported as a rare autosomal recessive disorder caused by impaired reabsorption of magnesium and calcium in the thick assending limp of Henle's loop. Recent studies showed that mutations in the CLDN16 gene encoding paracellin-1 cause the disorder. In exon 4, a homozygous nucleotide exchange (G679C) was identified for the patient. This results in a point mutation at position Glycine227, which is replaced by an Arginine residue (G227R). The mother was heterozygous for this mutation. G227 is located in the fourth transmembrane domain and is highly conserved in the claudin gene family. This case indicates the pathogenetic role of paracellin-1 mutation in familial hypomagnesemia with hypercalciuria and nephrocalcinosis and further underlines the risk of stone formation in heterozygous mutation carriers.

Early recurrent ischemic stroke in stroke patients undergoing intravenous thrombolysis

BACKGROUND: We assessed the incidence of early recurrent ischemic stroke in stroke patients treated with intravenous tissue-type plasminogen activator (tPA) and the temporal pattern of its occurrence compared with symptomatic intracranial hemorrhage (ICH). METHODS AND RESULTS: Prospectively collected, population-based data for 341 consecutive acute stroke patients (62% men; mean age, 66 years) treated with tPA according to the National Institute of Neurological Disorders and Stroke study protocol at 8 medical centers in Switzerland (3 academic and 5 community) between January 2001 and November 2004 were retrospectively analyzed. The primary outcome measure was neurological deterioration > or = 4 points on the National Institutes of Health Stroke Scale occurring within 24 hours of tPA treatment and caused either by recurrent ischemic stroke (defined as the occurrence of new neurological symptoms suggesting involvement of initially unaffected vascular territories and evidence of corresponding ischemic lesions on cranial computed tomography scans, in the absence of ICH) or by ICH. Early recurrent ischemic stroke was diagnosed in 2 patients (0.59%; 95% confidence interval, 0.07% to 2.10%) and symptomatic ICH in 15 patients (4.40%; 95% confidence interval, 2.48% to 7.15%). Both recurrent ischemic strokes occurred during thrombolysis, whereas symptomatic ICHs occurred 2 to 22 hours after termination of tPA infusion. CONCLUSIONS: Recurrent ischemic stroke is a rare cause of early neurological deterioration in acute stroke patients undergoing intravenous thrombolysis, with a different temporal pattern compared with that of symptomatic ICH.

Kernel Estimation of Rate Function for Recurrent Event Data

Recurrent event data are largely characterized by the rate function but smoothing techniques for estimating the rate function have never been rigorously developed or studied in statistical literature. This paper considers the moment and least squares methods for estimating the rate function from recurrent event data. With an independent censoring assumption on the recurrent event process, we study statistical properties of the proposed estimators and propose bootstrap procedures for the bandwidth selection and for the approximation of confidence intervals in the estimation of the occurrence rate function. It is identified that the moment method without resmoothing via a smaller bandwidth will produce curve with nicks occurring at the censoring times, whereas there is no such problem with the least squares method. Furthermore, the asymptotic variance of the least squares estimator is shown to be smaller under regularity conditions. However, in the implementation of the bootstrap procedures, the moment method is computationally more efficient than the least squares method because the former approach uses condensed bootstrap data. The performance of the proposed procedures is studied through Monte Carlo simulations and an epidemiological example on intravenous drug users.

A region on equine chromosome 13 is linked to recurrent airway obstruction in horses

REASONS FOR STUDY: Equine recurrent airway obstruction (RAO) is probably dependent on a complex interaction of genetic and environmental factors and shares many characteristic features with human asthma. Interleukin 4 receptor a chain (IL4RA) is a candidate gene because of its role in the development of human asthma, confirmation of this association is therefore required. METHODS: The equine BAC clone containing the IL4RA gene was localised to ECA13q13 by the FISH method. Microsatellite markers in this region were investigated for possible association and linkage with RAO in 2 large Warmblood halfsib families. Based on a history of clinical signs (coughing, nasal discharge, abnormal breathing and poor performance), horses were classified in a horse owner assessed respiratory signs index (HOARSI 1-4: from healthy, mild, moderate to severe signs). Four microsatellite markers (AHT133, LEX041, VHL47, ASB037) were analysed in the offspring of Sire 1 (48 unaffected HOARSI 1 vs. 59 affected HOARSI 2-4) and Sire 2 (35 HOARSI 1 vs. 50 HOARSI 2-4), age 07 years. RESULTS: For both sires haplotypes could be established in the order AHT133-LEXO47-VHL47-ASB37. The distances in this order were estimated to be 2.9, 0.9 and 2.3 centiMorgans, respectively. Haplotype association with mild to severe clinical signs of chronic lower airway disease (HOARSI 2-4) was significant in the offspring of Sire 1 (P = 0.026) but not significant for the offspring of Sire 2 (P = 0.32). Linkage analysis showed the ECA13q13 region containing IL4RA to be linked to equine chronic lower airway disease in one family (P<0.01), but not in the second family. CONCLUSIONS: This supports a genetic background for equine RAO and indicates that IL4RA is a candidate gene with possible locus heterogeneity for this disease. POTENTIAL RELEVANCE: Identification of major genes for RAO may provide a basis for breeding and individual prevention for this important disease.

[Metaphylaxis of recurrent renal calcium stones]

Calcium containing renal stones represent a common medical problem and show a high rate of recurrence. Therefore, besides the treatment of acute stone episodes, also the prevention of new stone episodes is of crucial importance in the medical care of stone formers. To avoid stone recurrences, medical as well as dietary measures should be established based on the results of a thorough evaluation and the elaboration of an individual risk profile. This review article describes and discusses the currently established treatment options for the prophylaxis of calcium-containing renal stones.

Pretherapeutic staging of recurrent laryngeal carcinoma: clinical findings and imaging studies compared with histopathology

OBJECTIVE: To assess the accuracy of preoperative imaging studies and clinical and endoscopic examinations for recurrent laryngeal carcinoma evaluation. STUDY DESIGN AND SETTING: A retrospective comparative study was performed at a university department on 42 recurrent laryngeal carcinomas. Surgical specimens were cut into whole-organ slices. Histologic findings were compared with the findings of the different preoperative diagnostic modalities. RESULTS: The craniocaudal tumor spread was correctly evaluated by endoscopy and imaging studies in 52% and 24%, respectively, and the contralateral tumor spread in 50% and 52%, respectively. The sensitivity, specificity, and accuracy for detection of tumor infiltration of the thyroid was 48%, 88%, and 64% and of the cricoid 47%, 80%, and 67%. The accuracy of recurrent tumor classification (crT) was 50%; most tumors were underclassified. CONCLUSION: The inadequately evaluated tumor spread and the inadequately classified recurrent tumors were underestimated and underclassified in most cases, respectively.

Is alcohol ablation of the septum associated with recurrent tachyarrhythmias?

QUESTIONS UNDER STUDY: Alcohol ablation (AA) of the septum has been introduced as new therapy in hypertrophic cardiomyopathy (HCM). It was feared that iatrogenic myocardial infarction due to AA may induce re-entry tachyarrhythmias and increase sudden cardiac death. METHODS AND RESULTS: Twenty-four patients (mean age 52 years) underwent successful AA. Clinical follow-up (FU) ranged from 0.3 to 0.7 years (mean 2.8). One patient died (suicide) 4 years after AA. Left ventricular (LV) outflow gradient (peak-to-peak) decreased (median) after AA from 43 (IQR 25 to 4) mmHg to 1 (IQR 0 to 12) mmHg (rest) (p <0.001) and from 130 (IQR 75 to 165) mmHg to 13 (IQR 0 to 31) mmHg (postextrasystolic) (p <0.001). Transient AV block occurred in 22% (5/24) necessitating temporary pacing. A permanent pacemaker was implanted in 4% (1/24). NYHA-class was 2.5 (IQR 2.0 to 3.0) before and 1.5 (IQR 1.3 to 2.0) (p <0.001) after AA. During FU, 2 pacemakers were implanted due to bradycardia (no AV block). A right bundle branch block was found in 13% (2/24) before and 46 % (11/24) after AA (p = 0.003). Non-sustained ventricular tachycardia (NSVT) was observed in 13% (2/16) before and 22% (5/23) (p = 0.46) after AA. Two patients required ICD implantation. CONCLUSIONS: Long-term FU is excellent in HCM after AA. The pressure gradient drops below 25 mm Hg in 95% (23/24) of all patients. Transient AV block occurs in 22% (5/24), but permanent pacemaker implantation is rarely needed (13%, 2/24). Severe NSVT occurs in 13% (2/16) before and 22% (5/23) after AA but ICD implantation is only occasionally required.

Histologic characteristics and tumor spread of recurrent glottic carcinoma: analysis on whole-organ sections and comparison with tumor spread of primary glottic carcinomas

BACKGROUND: The assessment of the precise tumor extent of recurrent glottic carcinomas is a challenge. METHODS: The histologic characteristics of 29 recurrent glottic carcinomas after radiation failures, initially classified as T1 and T2, were analyzed on whole-organ slices. The growth patterns of 21 recurrent prT3 and prT4 and 52 primary pT3 and pT4 carcinomas were compared. RESULTS: Fifteen of 29 (52%) recurrent carcinomas were under-staged by imaging studies and endoscopy. Most recurrent carcinomas presented with multicentric tumor foci, whereas most primary carcinomas with a concentric tumor growth pattern (p < .05). Undifferentiated dissociated tumor cells were observed more often in the vicinity of recurrent tumor foci than of the primary tumor mass (p < .05). CONCLUSION: Recurrent glottic carcinomas are often under-staged and present with multiple tumor foci dispersed in different regions of the larynx. If voice-preserving salvage surgery is considered as a treatment option, these facts should be kept in mind.

Recurrent ischemic colitis in a patient with leiden factor V mutation and systemic lupus erythematous with antiphospholipid syndrome

Ischemic colitis results from insufficient blood supply to the large intestine and is often associated with hypercoagulable states. The condition comprises a wide range presenting with mild to fulminant forms. Diagnosis remains difficult because these patients may present with non-specific abdominal symptoms. We report a 51- year-old female patient with known Leiden factor V mutation as well as systemic lupus erythematous along with antiphospholipid syndrome suffering from recurrent ischemic colitis. At admission, the patient complained about abdominal pain, diarrhea and rectal bleeding lasting for 24 hours. Laboratory tests showed an increased C-reactive protein (29.5 mg/dl), while the performed abdominal CT-scan revealed only a dilatation of the descending colon along with a thickening of the bowel wall. Laparotomy was performed showing an ischemic colon and massive peritonitis. Histological examination proved the suspected ischemic colitis. Consecutively, an anti-coagulation therapy with coumarin and aspirin 100 was initiated. Up to the time point of a follow up examination no further ischemic events had occurred. This case illustrates well the non-specific clinical presentation of ischemic colitis. A high index of suspicion, recognition of risk factors and a history of non-specific abdominal symptoms should alert the clinicians to the possibility of ischemic disease. Early diagnosis and initiation of anticoagulation therapy or surgical intervention in case of peritonitis are the major goals of therapy.

Oral sirolimus for prevention of recurrent infrainguinal arterial obstructions after surgical and endovascular revascularizations

No data are currently available on the role of oral sirolimus in the prevention of recurrent stenosis in the periphery. We report the effects of oral sirolimus in the prevention of recurrent infrainguinal obstructions in patients with complex peripheral arterial disease. Three patients with ischemic rest pain of the lower limbs and repeated short-term need for surgical and/or endovascular revascularization: 9 times within 12 months, 7 times within 15 months, 11 times within 26 months, respectively. Oral sirolimus on a case by case basis, resulted in less frequent restenosis and longer intervention-free intervals: three re-interventions within 37 months in the first patient, one balloon angioplasty within 17 months in the second, and three re-interventions within 21 months in the third patient, respectively. Side effects, in particular dyspepsia and diarrhoea, were mild and tolerable. To our knowledge, this is the first report to show that oral sirolimus was successfully administered in patients with recurrent excessive neointimal proliferation after revascularization of peripheral arterial lesions lowering the necessity of re-intervention and hence prolonging intervention-free intervals.