Potential role of coenzyme Q10 in facilitating recovery from statin-induced rhabdomyolysis.

Rhabdomyolysis is a rare, but serious complication of statin therapy, and represents the most severe end of the spectrum of statin-induced myotoxicity. We report a case where coenzyme Q10 facilitated recovery from statin-induced rhabdomyolysis and acute renal failure, which had initially persisted despite statin cessation and haemodialysis. This observation is biologically plausible due to the recognised importance of coenzyme Q10 in mitochondrial bioenergetics within myocytes, and the fact that statins inhibit farnesyl pyrophosphate production, a biochemical step crucial for coenzyme Q10 synthesis. Coenzyme Q10 is generally well tolerated, and may potentially benefit patients with statin-induced rhabdomyolysis.

Acute tubulointerstitial nephritis following treatment with exenatide.

BACKGROUND: Acute tubulointerstitial nephritis, a cause of acute kidney injury, is seen occasionally following treatment with medications such as antibiotics and non-steroidal anti-inflammatory drugs. To date, the development of biopsy-proven acute tubulointerstitial nephritis after treatment with exenatide has not been reported. CASE REPORT: A 58-year-old man was prescribed exenatide for poorly controlled Type 2 diabetes mellitus. He subsequently developed deterioration in kidney function, with the estimated glomerular filtration rate declining from 59 to 39 ml min(-1) 1.73 m(-2) over 2 months. Despite cessation of exenatide, there was continued deterioration in estimated glomerular filtration rate to 16 ml min(-1) 1.73 m(-2). He underwent renal biopsy and the sections showed active diffuse tubulointerstitial nephritis with infiltration of eosinophils. He was treated with prednisolone over several months with incomplete recovery in kidney function. CONCLUSION: Acute tubulointerstitial nephritis should be suspected if there is deterioration in kidney function in a patient treated with exenatide in the absence of other causes of acute kidney injury such as dehydration or hypotension.

Metformin therapy in patients with chronic kidney disease.

Metformin therapy is limited in patients with chronic kidney disease (CKD) due to the potential risk of lactic acidosis. This open-label observational study investigated metformin and lactate concentrations in patients with CKD (n = 22; creatinine clearances 15-40 ml/min) and in two dialysed patients. Patients were prescribed a range of metformin doses (250-2000 mg daily) and metformin concentrations were compared with data from healthy subjects (scaled to 1500 mg twice daily). A subset of patients (n = 7) was controlled on low doses of metformin (250 or 500 mg daily). No correlation between metformin and lactate concentrations was observed. Three patients had high lactate concentrations (>2.7 mmol/l) and two had high metformin concentrations (3-5 mg/l), but none had any symptoms of lactic acidosis. Reducing metformin dosage and monitoring metformin concentrations will allow the safe use of metformin in CKD, provided that renal function is stable.

Online version of the food allergy quality of life questionnaire-adult form: validity, feasibility and cross-cultural comparison.

BACKGROUND: Food-allergic reactions occur in 3-4% of the adult population in Western countries. It has been shown that food allergy may impair health-related quality of life (HRQL). Food allergy quality of life questionnaires (FAQLQs) have been developed and validated, including an adult form (FAQLQ-AF). These questionnaires may be particularly useful for cross-cultural comparisons. OBJECTIVES: The aims of this study were to translate the FAQLQ-AF from Dutch into English and validate an online version in the United States. Additionally, HRQL of American and Dutch food-allergic adults was compared. METHODS: The Dutch FAQLQ-AF was translated into English as set out by the World Health Organization and converted to an electronic online format. Participants (food allergic American adults) were recruited through the 'Food Allergy and Anaphylaxis Network' website and completed the questionnaire online. Construct validity, internal consistency, discriminative ability and feasibility were analysed. A cross-cultural comparison was made using the Dutch FAQLQ-AF scores. RESULTS: Data from 180 American participants were analysed. The online FAQLQ-AF had a good construct validity (correlation with FAIM: ρ=0.72; P<0.001), internal consistency (Cronbach's α=0.95) and was discriminative for 'anaphylaxis' vs. 'no anaphylaxis' and 'number of food allergies'. The most striking finding was a significantly greater impairment in HRQL in the American participants, as compared with their Dutch counterparts (the total FAQLQ-AF scores were 4.3 vs. 3.5, respectively; P<0.001, where 1 signifies no impairment and 7 signifies extreme impairment in HRQL). CONCLUSIONS AND CLINICAL RELEVANCE: The online American FAQLQ-AF is a valid instrument to measure HRQL in food-allergic patients in the United States. Additionally, HRQL of American food-allergic adults may be more impaired than Dutch food-allergic adults. The FAQLQ-AF can now be used to determine the HRQL in American food-allergic adults and can assist clinicians in optimizing management strategies for food-allergic patients.

The clinical spectrum of necrotizing glomerulonephritis.

Twenty patients with necrotizing glomerulonephritis were seen at a general teaching hospital over a 6-year period. These patients represented 5.2% of the histologically verified glomerulonephritis population. Twelve patients had an associated systemic illness (vasculitis in 6, Wegener's granulomatosis in 2, Goodpasture syndrome in 2, infective endocarditis in 1, pulmonary renal syndrome in 1). The clinical course was variable, with equal numbers of patients having rapidly progressive and indolent courses. Four patients (20%) had less than 10% normal glomeruli on renal biopsy and developed end-stage renal failure. Although immunosuppressive and anticoagulant therapy was associated with an improvement in renal function, 6 patients (30%) had died after a mean follow-up period of 25 months.

Dialysis osteodystrophy. A study involving 94 patients.

Dynamic skeletal histomorphometry was performed in 94 unselected patients receiving maintenance dialysis for chronic renal failure. An attempt was made to correlate the results with the clinical, biochemical and radiological findings. Skeletal histology was abnormal in each case. Hyperparathyroidism was present as the only abnormality in 18 patients and osteomalacia in 26; 50 patients showed both abnormalities. Osteomalacia, in contrast to hyperparathyroidism, increased in prevalence and severity with the duration of dialysis and with bone aluminum content. The majority of patients had histological osteosclerosis. It was impossible to predict either the nature or the severity of the histological lesions on the basis of symptoms and physical signs or on the basis of most biochemical parameters (including serum concentrations of three vitamin D metabolites). Serum alkaline phosphatase values and serum immunoreactive parathyroid hormone (iPTH) concentrations were positively correlated with the severity of histological hyperparathyroidism. Subperiosteal erosions of the phalanges were associated with severe histological hyperparathyroidism in each case but this radiological sign was absent in 66% of patients with histological hyperparathyroidism. Radiological osteosclerosis was associated with severe histological osteomalacia in each case, but this radiological sign was absent in 87% of patients with histological osteomalacia. No other radiological sign proved a reliable guide to the underlying skeletal histology. In the majority of dialysis patients, a skeletal biopsy is required for an accurate diagnosis of the nature and severity of azotemic osteodystrophy.

Molecular characterization of a human brain adenosine A2 receptor.

A cDNA encoding a G protein-coupled receptor of unknown ligand specificity was isolated from a human hippocampal cDNA library by virtue of the high degree of structural homology between members of this receptor family. The cloned receptor DNA was transfected into human embryonic kidney 293 cells. Stably transfected cell lines bound a variety of adenosine agonists and antagonists with affinities characteristic of a brain adenosine A2a receptor. The A2a specific agonist CGS21680 stimulated cAMP production but did not alter intracellular calcium concentrations in transfected 293 cells.

Decreased uptake of L-cystine by duodenal brush border membrane vesicles from patients with cystinuria.

BACKGROUND: The pathophysiology of cystinuria remains unclear. Decreased absorption of L-cystine across brush border membranes of small intestinal and renal proximal tubular epithelial cells is likely but has not been directly demonstrated. AIMS: To compare the rates of L-cystine transport by isolated duodenal brush border membranes of normal individuals and patients with cystinuria. METHODS: Distal duodenal biopsies were taken from normal individuals and patients with cystinuria. Brush border membrane vesicles (BBMV) were prepared using magnesium aggregation and differential centrifugation and the rates of L-cystine transport into the vesicles measured using a rapid filtration technique. RESULTS: Rates of L-cystine transport by BBMV from patients with cystinuria were reduced at 5 minute (p = 0.003) and 30 minute (p = 0.053). Time points, indicating that L-cystine absorption across brush border membranes is abnormal in cystinuria.

D-penicillamine and the transport of L-cystine by rat and human renal cortical brush-border membrane vesicles.

Brush-border membrane vesicles (BBMV) were prepared from rat and human renal cortical tissue by magnesium aggregation and differential centrifugation, and the uptake of L-cystine, L-cysteine, and L-cysteine-D-penicillamine were assessed by a rapid-filtration technique. L-Cystine uptake was relatively sodium independent and associated with membrane binding. Sodium-stimulated uptake was sensitive to a cation but not anion diffusion potential. Both sodium-independent and sodium-stimulated uptake rates were inhibited by the cationic L-amino acids and by some neutral L-amino acids. The uptake rates of L-cysteine and L-cysteine-D-penicillamine were more sodium dependent, and sodium-stimulated uptake rates were more sensitive to cation and anion diffusion potentials. Neither the sodium-independent nor the sodium-stimulated uptake rates of L-cysteine or L-cysteine-D-penicillamine were inhibited by the cationic L-amino acids. L-Cysteine-D-penicillamine showed relatively little membrane binding. It is concluded that L-cystine is transported into renal cortical BBMV by pathways distinct from those concerned with the transport of L-cysteine and L-cysteine-D-penicillamine, and it is postulated that these differences may account for some of the effects of D-penicillamine in cystinuria.

Mechanisms underlying volume regulatory decrease by Necturus gallbladder epithelium.

Volume regulatory decrease (VRD) by Necturus gallbladder epithelial cells in Cl Ringer was unaffected by the addition of 5 mM BaCl2 to apical perfusates but was inhibited by the addition of 5 mM BaCl2 and 50 or 3 microM phencyclidine (PCP) to serosal perfusates, suggesting that K channels in the basolateral membrane were activated during VRD. VRD was unaffected by replacement of Cl with NO3 or SCN, suggesting that Cl-dependent Na-K-Cl and K-Cl cotransport were not involved. In SCN Ringer, VRD was inhibited by the addition of 0.1 mM bumetanide to serosal perfusates, suggesting that bumetanide-sensitive anion channels in the basolateral membrane were also activated. A transient 10-mV hyperpolarization of the membrane potential was associated with VRD. The channel blockers that inhibited VRD had little or no effect on the hyperpolarization, suggesting that the changes in membrane potential were unrelated to the changes in cell volume. Perfusion of the apical surface of the epithelium with isotonic solutions containing 10 mM D-glucose resulted in a variable increase in cell volume followed by a variable shrinkage to normal, suggesting that VRD was also activated during organic solute absorption. The increase in cell volume was blocked by the addition of 0.01 or 1 mM phlorizin to mucosal perfusates. The reduction in cell volume was inhibited by the addition of 0.1 mM bumetanide, but not BaCl2 or PCP, to serosal perfusates, indicating the the shrinkage mechanism secondary to glucose addition differed from that seen after exposure to hypotonic perfusates.

Activation of osmolyte efflux from cultured renal papillary epithelial cells.

The rabbit renal papillary epithelial cell line PAP-HT25 accumulates sorbitol and other organic osmolytes when cultured in hypertonic media. When returned to isotonic media, PAP-HT25 cells swell because of water influx and then shrink to their normal volume because of rapid osmolyte and water efflux (volume regulatory decrease, VRD). Sorbitol efflux from PAP-HT25 cells during VRD was reduced to 18% of control by incubation of the cells with 100 microM eicosatetraynoic acid (ETYA), indicating that an enzyme that metabolizes arachidonic acid (AA) is a key component of the efflux process. Sorbitol efflux was unaffected by incubation with cyclooxygenase and lipoxygenase inhibitors but was reduced to 9% by incubation with 100 microM ketoconazole and to 37% by incubation with 100 microM SKF-525A, indicating that the cytochrome P-450 limb of the AA cascade is involved in the efflux process. The efflux of other organic osmolytes betaine and myoinositol, but not glycerolphosphorylcholine, was also inhibited by incubation with ETYA and ketoconazole.

Peanut and tree nut allergic reactions in restaurants and other food establishments.

BACKGROUND: The clinical features of food-allergic reactions in restaurants and other food establishments have not been studied. Of the registrants in the United States Peanut and Tree Nut Allergy Registry (PAR), 13.7% have reported reactions associated with such establishments. OBJECTIVE: The purpose of this study was to determine the features of allergic reactions to peanut and tree nut in restaurant foods and foods purchased at other private establishments (eg, ice cream shops and bakeries). METHODS: Telephone interviews were conducted through use of a structured questionnaire. Subjects/parental surrogates were randomly selected from among the 706 PAR registrants who reported a reaction in a restaurant or other food establishment. RESULTS: Details were obtained for 156 episodes (29 first-time reactions) from 129 subjects/parental surrogates. Most reactions were caused by peanut (67%) or tree nut (24%); for some reactions (9%), the cause was a combination of peanut and another nut or was unknown. Symptoms began at a median of 5 minutes after exposure and were severe in 27% of reactions. Overall, 86% of reactions were treated (antihistamines, 86%; epinephrine, 40%). Establishments commonly cited were Asian food restaurants (19%), ice cream shops (14%), and bakeries/doughnut shops (13%). Among meal courses, desserts were a common cause (43%). Of 106 registrants with previously diagnosed allergy who ordered food specifically for ingestion by the allergic individual, only 45% gave prior notification about the allergy to the establishment. For 83 (78%) of these 106 reactions, someone in the establishment knew that the food contained peanut or tree nut as an ingredient; in 50% of these incidents, the food item was "hidden" (in sauces, dressings, egg rolls, etc), visual identification being prevented. In 23 (22%) of the 106 cases, exposures were reported from contamination caused primarily by shared cooking/serving supplies. In the remaining 21 subjects with previously diagnosed allergy, reactions resulted from ingestion of food not intended for them, ingestion of food selected from buffet/food bars, or skin contact/inhalation (residual food on tables, 2; peanut shells covering floors, 2; being within 2 feet of the cooking of the food, 1). CONCLUSIONS: Restaurants and other food establishments pose a number of dangers for peanut- and tree nut-allergic individuals, particularly with respect to cross-contamination and unexpected ingredients in desserts and Asian food. Failure to establish a clear line of communication between patron and establishment is a frequent cause of errors.

Sorbitol permease: an apical membrane transporter in cultured renal papillary epithelial cells.

The efflux of sorbitol from the rabbit papillary epithelial cell line PAP-HT25 occurs through a specific transport pathway, which we denote the "sorbitol permease." The permease was studied by measuring cell volume changes that accompanied osmotic swelling and by determination of the sorbitol efflux from plasma membrane vesicles. The cell volume studies showed that sorbitol efflux in response to hypotonicity occurred only across the apical membrane of the cells and that loss of sorbitol was the primary mechanism for regulatory volume decrease (RVD) by these cells. Quinidine, a permeant inhibitor of the sorbitol permease, was shown to prevent RVD when added to either apical or basolateral bathing solution. Cell volume experiments also showed that the permease was present only on the apical membrane of cells that had been grown in isotonic medium and did not accumulate sorbitol. The permease could be demonstrated in membrane vesicles obtained from cells exposed to a hypotonic environment before being homogenized. Quinidine blocked the sorbitol efflux from vesicles indicating that it either directly inhibited the permease or a membrane-associated activation step.

Molecular cloning and expression of an adenosine A2b receptor from human brain.

A novel receptor cDNA was isolated from a human hippocampal cDNA library. The encoded polypeptide contains structural features consistent with its classification as a G protein-coupled receptor and shares 45% homology with the human A1 and A2a adenosine receptors. Chinese hamster ovary K1 cells expressing this receptor showed marked stimulation of adenylate cyclase when treated with 1mM adenosine. There was no response to ligands selective for A1 and A2a receptors but the general adenosine agonist N-ethylcarboxyamidoadenosine (NECA) caused a 10 fold increase in cyclic AMP accumulation with an EC50 of approximately 0.9 microM. This effect was inhibited by the adenosine receptor antagonist theophylline. Specific binding of A1 and A2a selective agonists and NECA was not detected. It is proposed that the novel receptor is a human brain adenosine A2b receptor subtype.

Self-reported allergic reactions to peanut on commercial airliners.

BACKGROUND: Allergic reactions to food occurring on commercial airlines have not been systematically characterized. OBJECTIVE: We sought to describe the clinical characteristics of allergic reactions to peanuts on airplanes. METHODS: Participants in the National Registry of Peanut and Tree Nut Allergy who indicated an allergic reaction while on a commercial airliner were interviewed by telephone. RESULTS: Sixty-two of 3704 National Registry of Peanut and Tree Nut Allergy participants indicated a reaction on an airplane; 42 of 48 patients or parental surrogates contacted confirmed the reaction began on the airplane (median age of affected subject, 2 years; range, 6 months to 50 years). Of these, 35 reacted to peanuts (4 were uncertain of exposure) and 7 to tree nuts, although 3 of these 7 reacted to substances that may have also contained peanut. Exposures occurred by ingestion (20 subjects), skin contact (8 subjects), and inhalation (14 subjects). Reactions generally occurred within 10 minutes of exposure (32 of 42 subjects), and reaction severity correlated with exposure route (ingestion > inhalation > skin). The causal food was generally served by the airline (37 of 42 subjects). Medications were given in flight to 19 patients (epinephrine to 5) and to an additional 14 at landing/gate return (including epinephrine to 1 and intravenous medication to 2), totaling 79% treated. Flight crews were notified in 33% of reactions. During inhalation reactions as a result of peanut allergy, greater than 25 passengers were estimated to be eating peanuts at the time of the reaction. Initial symptoms generally involved the upper airway, with progression to the skin or further lower respiratory reactions (no gastrointestinal symptoms). CONCLUSIONS: Allergic reactions to peanuts and tree nuts caused by accidental ingestion, skin contact, or inhalation occur during commercial flights, but airline personnel are usually not notified. Reactions can be severe, requiring medications, including epinephrine.

The US Peanut and Tree Nut Allergy Registry: characteristics of reactions in schools and day care.

OBJECTIVE: Severe food-allergic reactions occur in schools, but the features have not been described. STUDY DESIGN: Participants in the US Peanut and Tree Nut Allergy Registry (PAR) who indicated that their child experienced an allergic reaction in school or day care were randomly selected for a telephone interview conducted with a structured questionnaire. RESULTS: Of 4586 participants in the PAR, 750 (16%) indicated a reaction in school or day care, and 100 subjects or parental surrogates described 124 reactions to peanut (115) or tree nuts (9); 64% of the reactions occurred in day care or preschool, and the remainder in elementary school or higher grades. Reactions were reported from ingestion (60%), skin contact/possible ingestion (24%), and inhalation/possible skin contact or ingestion (16%). In the majority of reactions caused by inhalation, concomitant ingestion/skin contact could not be ruled out. Various foods caused reactions by ingestion, but peanut butter craft projects were commonly responsible for the skin contact (44%) or inhalation (41%) reactions. For 90% of reactions, medications were given (86% antihistamines, 28% epinephrine). Epinephrine was given in school by teachers in 4 cases, nurses in 7, and parents or others in the remainder. Treatment delays were attributed to delayed recognition of reactions, calling parents, not following emergency plans, and an unsuccessful attempt to administer epinephrine. CONCLUSIONS: School personnel must be educated to recognize and treat food-allergic reactions. Awareness must be increased to avoid accidental exposures, including exposure from peanut butter craft projects.

Genetics of peanut allergy: a twin study.

BACKGROUND: The role of genetics in the etiology of peanut allergy is unknown. For complex genetic traits, twin studies can provide information on the relative contribution of genetic factors to a disease, as the relative confounding effects of environmental factors are markedly decreased. OBJECTIVE: This study was performed to search for evidence that genetic factors influence peanut allergy by comparing the concordance rate for this allergy among monozygotic and dizygotic twins. METHODS: Twin pairs with at least one member with peanut allergy were ascertained through the Food Allergy Network by advertisements in the organization's newsletters and Web site. Individuals with peanut allergy or parental surrogates were interviewed by telephone. A full atopic history was obtained, and peanut allergy and zygosity were determined using previously validated questionnaires. Heritability of peanut allergy was determined using univariate genetic model fitting by maximum likelihood with the Mx statistical modeling software package. RESULTS: Seventy-five twin pairs were recruited. Seventeen pairs were excluded because of unconvincing peanut allergy histories (9 pairs, including 4 of uncertain zygosity) or because one twin had reportedly never ingested peanut (8 pairs). The median age of the 58 remaining twin pairs was 5 years (range 1 to 58 years). Seventy individuals had peanut allergy. In addition to convincing histories of peanut allergy, 52 (74%) had been tested (skin prick testing with or without radioallergosorbent assay) and all had positive reactions to peanut. Twenty-nine of the 70 had experienced >1 reaction to peanut; 29 of 70 had multisystem reactions. Among the monozygotic pairs (n = 14), 9 were concordant for peanut allergy (pairwise concordance, 64.3%) and among dizygotic pairs (n = 44), 3 were concordant for peanut allergy (pairwise concordance, 6.8%; chi(2) = 21.38, P <.0001). Heritability of peanut allergy was estimated at 81. 6% (95% confidence interval 41.6% to 99.7%) with model fitting using a population prevalence of peanut allergy of 0.4%. CONCLUSIONS: The significantly higher concordance rate of peanut allergy among monozygotic twins suggests strongly that there is a significant genetic influence on peanut allergy.

A voluntary registry for peanut and tree nut allergy: characteristics of the first 5149 registrants.

BACKGROUND: A voluntary registry of individuals with peanut and/or tree nut allergy was established in 1997 to learn more about these food allergies. OBJECTIVE: The purpose of this study was to elucidate a variety of features of peanut and tree nut allergy among the first 5149 registry participants. METHODS: The registry was established through use of a structured questionnaire distributed to all members of the Food Allergy and Anaphylaxis Network and to patients by allergists. Parental surrogates completed the forms for children under the age of 18 years. RESULTS: Registrants were primarily children (89% of registrants were younger than 18 years of age; the median age was 5 years), reflecting the membership of the Network. Isolated peanut allergy was reported by 3482 registrants (68%), isolated tree nut allergy by 464 (9%), and allergy to both foods by 1203 (23%). Registrants were more likely to have been born in October, November, or December (odds ratio, 1.2; 95% CI, 1.18-1.23; P <.0001). The median age of reaction to peanut was 14 months, and the median age of reaction to tree nuts was 36 months; these represented the first known exposure for 74% and 68% of registrants, respectively. One half of the reactions involved more than 1 organ system, and more than 75% required treatment, frequently from medical personnel. Registrants with asthma were more likely than those without asthma to have severe reactions (33% vs 21%; P <.0001). In comparison with initial reactions, subsequent reactions due to accidental ingestion were more severe, more common outside the home, and more likely to be treated with epinephrine. CONCLUSIONS: Allergic reactions to peanut and tree nut are frequently severe, often occur on the first known exposure, and can become more severe over time.

Clinical experiences with human parathyroid hormone 1-34.

Human parathyroid hormone (PTH) 1-34 was given to nine normal subjects and to 10 patients with hypoparathyroidism. There were no side effects associated with the protocol employed. In normal subjects, five statistically significant changes occurred during the period of observation: plasma cyclic adenosine monophosphate (cAMP) rose by a factor of 3 (at 30 min), nephrogenous cyclic AMP rose approximately 40-fold (at 60 min), urinary phosphate rose by a factor of 2 (at 120 min), urine calcium levels fell by 50% between 60 and 120 min, and plasma prolactin rose by a factor of 1.4 (at 60 min). The cAMP responses were significantly blunted in five patients with chronic hypocalcemia, chronic hyperphosphatemia, and detectable serum immunoreactive PTH levels. On the basis of this test these patients were designated as suffering from pseudohypoparathyroidism. The acute phosphaturic and hypocalciuric responses were apparently intact in these five individuals. Human PTH 1-34 is likely to replace bovine material in the delineation of syndromes associated with PTH resistance.