Impact of cardio-renal syndrome on adverse outcomes in patients with Fabry disease in a long-term follow-up.

AIMS: Fabry disease (FD) is a rare X-linked lysosomal storage disease with a deficiency of α-galactosidase A leading to progressive sphingolipid accumulation in different organs, among them heart and kidney. We evaluated the impact of cardio-renal syndrome (CRS) on the incidence of major cardiovascular complications and death in a prospective FD cohort. METHODS AND RESULTS: A total of 104 genetically proven FD patients were annually followed at the University Hospitals Zurich and Bern. The main outcome was a composite of incident renal replacement therapy (RRT), hospitalisation due to decompensated Heart Failure, new onset atrial fibrillation, pacemaker/ICD implantation, stroke/TIA and death. Estimated glomerular filtration rate (eGFR) and left ventricular myocardial mass index (LVMMI) where explored as the primary exposure variables. During the median follow-up of 103 [59-155] months, events occurred in 27 patients. In a Cox regression analysis, both higher LVMMI and lower eGFR were independently associated with a greater risk of developing adverse events after adjustment for multiple confounders (HR 1.67 [1.04-2.73] P=0.03 per SD increase in LVMMI, HR 0.45 [0.25-0.83], P=0.01 per SD decrease in eGFR). In patients with CRS, the risk to develop events was significantly increased if adjusted for demographics and RRT (HR 4.46 [1.07-18.62], P=0.04), approaching significance if additionally adjusted for hypertension (HR 4.05 [0.95-17.29], P=0.06). In Kaplan-Meier-Analysis, the poorest event-free survival was observed among patients with CRS. CONCLUSIONS: CRS was associated with a high risk to develop cardiovascular complications and death, emphasizing the importance of its prevention and early recognition. A focus on cardio-reno-protective therapies is crucial.

P2Y2 receptor activation inhibits the expression of the sodium-chloride cotransporter NCC in distal convoluted tubule cells.

Luminal nucleotide stimulation is known to reduce Na(+) transport in the distal nephron. Previous studies suggest that this mechanism may involve the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC), which plays an essential role in NaCl reabsorption in the cells lining the distal convoluted tubule (DCT). Here we show that stimulation of mouse DCT (mDCT) cells with ATP or UTP promoted Ca(2+) transients and decreased the expression of NCC at both mRNA and protein levels. Specific siRNA-mediated silencing of P2Y2 receptors almost completely abolished ATP/UTP-induced Ca(2+) transients and significantly reduced ATP/UTP-induced decrease of NCC expression. To test whether local variations in the intracellular Ca(2+) concentration ([Ca(2+)]i) may control NCC transcription, we overexpressed the Ca(2+)-binding protein parvalbumin selectively in the cytosol or in the nucleus of mDCT cells. The decrease in NCC mRNA upon nucleotide stimulation was abolished in cells overexpressing cytosolic PV but not in cells overexpressing either a nuclear-targeted PV or a mutated PV unable to bind Ca(2+). Using a firefly luciferase reporter gene strategy, we observed that the activity of NCC promoter region from -1 to -2,200 bp was not regulated by changes in [Ca(2+)]i. In contrast, high cytosolic calcium level induced instability of NCC mRNA. We conclude that in mDCT cells: (1) P2Y2 receptor is essential for the intracellular Ca(2+) signaling induced by ATP/UTP stimulation; (2) P2Y2-mediated increase of cytoplasmic Ca(2+) concentration down-regulates the expression of NCC; (3) the decrease of NCC expression occurs, at least in part, via destabilization of its mRNA.

Radiation-induced esophageal injury: a spectrum from esophagitis to cancer.

Radiation esophagitis is a common but frequently unrecognized complication of therapeutic radiation to the neck, chest, or mediastinum. The spectrum of injury ranges from acute self-limited esophagitis to life-threatening esophageal perforation. Complications such as stricture or primary esophageal cancer may occur many years after irradiation, and their linkage to radiation may not be considered. Five cases of radiation-induced injury are described, and the spectrum of radiation-induced esophageal injury is reviewed.

The use of functional analyses to test causes of self-injurious behaviour: rationale, current status and future directions.

Self-injurious behaviour (SIB) is a relatively common phenomenon among severely retarded persons and involves various repetitious behaviours resulting in tissue damage. Perhaps because of the damage it does, the behaviour has generated a considerable amount of applied research and discussion, and much of this research has involved attempts to reduce SIB through the manipulation of antecedents or consequences. The purpose of this paper was to determine the extent to which those conducting this research used a functional analysis of SIB to determine why the behaviour was occurring and subsequently matched treatment to one of these reasons. Results showed that only a small proportion of the studies reported analyses that would allow the experimenter to determine reasons for the self-injurious behaviour. The discussion centres on why functional analyses are not conducted in ways that would lend treatment to be based on hypotheses of why SIB occurs.

Clostridium difficile colitis secondary to intravenous vancomycin.

Nearly every known antibiotic has been implicated as a cause of Clostridium difficile colitis. We report the first case resulting from monotherapy with intravenous vancomycin. The patient was on chronic hemodialysis and was treated with intravenous vancomycin for presumed cervical osteomyelitis. After 29 days of therapy he developed abdominal pain and diarrhea and his stool was found to contain both C. difficile and cytotoxin. The patient responded with symptomatic and microbiological recovery to withdrawal of the drug and treatment with oral metronidazole. The prolonged elevation of serum vancomycin levels in patients with renal failure may predispose them to the development of C. difficile colitis.

The advantages of the 30-cm flexible sigmoidoscope over the 60-cm flexible sigmoidoscope.

To determine the optimal length of the flexible fiberoptic sigmoidoscope we performed a randomized, blinded comparison study of the standard 60-cm instrument with a prototype 30-cm instrument with identical design features. Ninety-six male patients referred for symptom evaluation underwent examination with both instruments in random order by different examiners; positive examinations were followed by colonoscopy or surgery. Performance of the 30-cm sigmoidoscope compared with the 60-cm instrument revealed that the former was significantly more likely to yield a complete examination (74 vs. 32 examinations, p less than 0.002), took less time to perform (6.4 vs. 9.8 min, p less than 0.0001), and was more acceptable to patients and physicians. The 30-cm instrument was not significantly less effective than the 60-cm instrument in detecting polyps (21 vs. 25), adenocarcinoma (six for each), and inflammatory lesions. For these reasons, we conclude that the 30-cm flexible sigmoidoscope has a role in the evaluation of colorectal complaints.

Failure of cimetidine in Zollinger-Ellison syndrome.

Both the pharmacokinetics and the pharmacodynamics of cimetidine were investigated in three patients with Zollinger-Ellison syndrome, who were unresponsive to conventional dosing regimens. Doses employed in these patients ranged from 2400 to 5400 mg daily. The poor response to oral cimetidine, as measured by acid secretion and gastric pH, was associated with subtherapeutic and unreliable cimetidine serum concentrations. The response to intravenous cimetidine was only a transient suppression of gastric secretion. The failure of cimetidine to control gastric hypersecretion in these patients was attributed to both a diminished oral bioavailability and a decreased pharmacologic response to the drug.

H2-Histamine receptor blocking agents in the Zollinger-Ellison syndrome. Experience in seven cases and implications for long-term therapy.

H2-Histamine receptor blocking agents metiamide and cimetidine were assessed in seven patients with Zollinger-Ellison syndrome (serum gastrin greater than 300 microgram/ml, basal acid output greater than 15 meq/h, ratio of basal acid output to maximal acid output greater than 0.5). Intravenous or oral administration of the drugs lowered acid secretion by at least 70% in all cases. Subsequent treatment of six patients for 3 to 15 months (oral therapy) and one patient for 1 month (intravenous therapy) showed that the drugs abolished symptoms in all seven, abolished diarrhea in five, allowed ulcer healing in six, and were well tolerated without adverse effects in seven. No patient failed to respond to the drug, although one died from tumor progression and two required total gastrectomy for complex reasons. The results indicate that patients with Zollinger-Ellison syndrome can be managed medically and, in light of current mortality trends, gain little from the extra risks attending total gastrectomy.

Hyperhistaminemia and hyperchlorhydria in basophilic granulocytic leukemia.

A patient with basophilic granulocytic leukemia had hyperhistaminemia, hyperchlorhydria and gastroduodenal ulceration. Because the patient's whole blood, plasma, and urinary histamine levels were increased and the serum gastrin was normal, it was concluded that endogenous hyperhistaminemia was responsible for an ulcerogenic diathesis clinically indistinguishable from that seen in the Zollinger-Ellison syndrome.

Intestinal folate absorption. II. Conversion and retention of pteroylmonoglutamate by jejunum.

These studies were designed to determine whether pteroylmonoglutamic acid (PGA) at physiologic concentrations is transported across the small intestine unaltered or is reduced and methylated to the circulating folate form (5-methyltetrahydrofolate [5-MeFH(4)]) during absorption. [(3)H]PGA was incubated in vitro on the mucosal side of rat jejunum. Of the folate transferred to the serosal side, the percent identified as 5-MeFH(4) by DEAE-Sephadex chromtography was inversely related to the initial mucosa PGA concentration: at 7, 20, and 2,000 nM, 44%, 34%, and 2%, respectively, was converted to 5-MeFH(4). In contrast, less than 4% of the folate transferred across ileal mucosa was 5-MeFH(4) when the initial mucosa concentration was 20 nM. Specific activity of dihydrofolate (DHF) reductase, the enzyme responsible for converting PGA to tetrahydrofolic acid, was measured in villus homogenates and was significantly greater in the jejunum than in the ileum. 1,000 nM methotrexate (MTX), a DHF reductase inhibitor, markedly inhibited PGA conversion to 5-MeFH(4) by the jejunum. Studies of transmural flux, initial rate of mucosal entry (influx) and mucosal accumulation (uptake) of folate were also performed. Although MTX did not alter the influx of PGA, MTX decreased jejunal mucosal uptake but increased transmural movement. Transmural folate movement across ileal mucosa was greater than across jejunal mucosa although mucosal uptake was greater in the jejunum than in the ileum. These results could explain previous studies which have failed to identify conversion of PGA to 5-MeFH(4) when intestinal preparations have been exposed to higher and less physiologic concentrations of PGA. Further, these studies suggest that 5-MeFH(4) may be retained by the jejunal mucosa.