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The genetics of atopy.

Since the original introduction by Coca and Coombs in 1923, the concept of atopy has always been linked to the relevance of an inherited predisposition in causing immediate-type hypersensitivity reactions to common allergens. However, the mechanisms underlying this predisposition have long been vague and controversial. Only recently, the better knowledge of the basic pathophysiological abnormalities of atopy as well as the availability of molecular biology techniques for gene mapping, have renewed the interest of several research groups for the genetics of atopy and have produced substantial progress in its understanding.

Asthma↗

Recurrent rhabdomyolysis associated with influenza-like illness in a weight-lifter.

OBJECTIVE: This report describes a unique case of recurring rhabdomyolysis associated with influenza-like illness. PATIENT: A 16-year-old black male, a physically fit weight-lifter, presented complaining of a brief history of upper respiratory infection. He had experienced muscular aches and observed his urine was a brown "Coca Cola" color. He was diagnosed with an influenza-like illness and associated rhabdomyolysis. He had been previously treated for a similar episode of flu-like symptoms and brown urine two years before. The patient was treated with IV fluids and discharged on day seven. He has remained asymptomatic. Post-discharge muscle biopsy results indicated a partial deficiency of carnitine palmitoyltransferase II, a rare defect in mitochondrial metabolism. DISCUSSION: Although traumatic rhabdomyolysis cases have been reported, few case reports have been documented associating an influenza-like illness and rhabdomyolysis. Deficiency of carnitine palmitoyltransferase often causes nonexercise-induced rhabdomyolysis. CONCLUSION: Prevention should consist and a yearly influenza vaccination education on nutrition and exercise.

Adolescent↗

Acute effects of soft drink intake on calcium and phosphate metabolism in immature and adult rats.

OBJECTIVE: To test the acute effects of the intake of a phosphoric acid containing soft drink on acid-base balance and on calcium and phosphate metabolism. MATERIAL AND METHODS: We studied 14 young adult male Sprague-Dawley rats aged 90 days, and 14 immature animals aged 30 days. Half of the animals in each group were randomly assigned to receive either tap water (controls), or Coca-Cola ad libitum for seven days. After this period, the rats were individually placed in metabolic cages to collect 24 hours urine, and they were exsanguinated by aortic puncture. Immediately, pH and ionized calcium were measured in whole blood. Creatinine, phosphate and total calcium were determined in the urine and plasma. Plasma levels of PTH, 1 alpha, 25 (OH)2 D3 and 25 OH D3 were measured by IRMA and RIA commercial kits. RESULTS: The animals receiving the soft drink, both adults and immature, developed significant hypercalciuria and hyperphosphaturia. In immature animals, the plasma pH dropped from 7.45 +/- 0.04 to 7.33 +/- 0.02 (p < 0.05) but did not change in adult animals. Ionized calcium dropped significantly from 1.06 +/- 0.04 to 0.80 +/- 0.06 meq/L (p < 0.05) in immature animals but not in the adult animals. Only immature rats developed significant reduction of 1 alpha, 25 (OH)2 D3 and 25 OH D3, whereas only the adult rats developed significant hyperparathyroidism. Immature animals showed more severe derangement of calcium and phosphate metabolism related to soft drink intake.

Acid-Base Equilibrium↗

[Comparative study of clinical effectiveness of antibiotic prophylaxis in aseptic mouth-jaw- and facial surgery].

METHODS: This study evaluates the clinical efficiency of four regimens of antibiotic prophylaxis against wound infection in aseptic oral and maxillofacial surgery that does not involve implantation of foreign material and included 140 adult patients randomly distributed into four groups. Patients from two groups received prophylactic amoxicillin/clavulanate in a single-dose regimen or a 5-day regimen, respectively. Subjects from the other two groups received cefazolin in a single-dose regimen or a 5-day regimen, respectively. RESULTS: Clinical prophylactic efficiency proved to be equal for the four types of antibiotic regimens. DISCUSSION: Single-dose regimens are more economical, easier to administer, and carry a lower risk of inducing bacterial resistance. Amoxicillin/clavulanate is more expensive than cefazolin. For aseptic maxillofacial surgery that does not involve implantation of foreign material, we recommend preoperative single-dose antibiotic prophylaxis with cefazolin 2 g i.v. (in adult patients).

Adult↗

Impact of chronic kidney disease on health-related quality-of-life improvement after coronary artery bypass surgery.

BACKGROUND: Little is known about the impact of chronic kidney disease (CKD) on health-related quality-of-life outcomes after coronary artery bypass grafting (CABG). METHODS: Our objective was to examine the changes in physical function (PF) and mental health (MH) 6 months after CABG in 1055 patients with and without CKD. The primary end points were mean change in score and status of "improved" or "worsened" in both PF and MH subscales of the Medical Outcomes Trust Short Form 36-Item Health Survey from baseline to 6 months after CABG, stratified by CKD stage (0-5). RESULTS: Absolute PF and MH scores at baseline and at 6 months varied by renal impairment level. Patients with severe CKD (stages 4-5) had a mean (SD) decrease in PF score at 6 months of 3 (3) compared with increases in the rest of the cohort (P<.001). After adjustment for baseline score, 21% of patients with advanced CKD experienced worsened PF scores, compared with 0% of patients with stages 0 to 2 and stage 3 CKD (P<.001). In contrast to PF scores, patients with and without CKD had similar improvements in mean MH scores at 6 months, and patients with stages 4 to 5 CKD had the highest frequency of those with improved MH scores (77%). After adjustment, no patients experienced worsened MH scores. CONCLUSIONS: After 6 months, patients with severe CKD who underwent CABG had improvement in MH but not improvement in PF and may have had worsened PF compared with those without severe CKD. Comparable evidence regarding quality-of-life outcomes in the absence of CABG is needed to more fully inform decision making regarding patients with severe CKD and coronary artery disease.

Activities of Daily Living↗

Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease.

CONTEXT: Patients with renal disease are at high risk for cardiovascular mortality. Determining which interventions best offset this risk remains a health priority. OBJECTIVE: To quantify the representation of patients with renal disease in randomized controlled trials for interventions proven efficacious for cardiovascular disease. DATA SOURCES: We searched MEDLINE for trials published from 1985 through 2005 in 11 major medical and subspecialty journals. STUDY SELECTION: Randomized controlled trials for chronic congestive heart failure and acute myocardial infarction of treatments that are currently listed as class I or II recommendations in the current American College of Cardiology/American Heart Association guidelines were included. DATA EXTRACTION: Two reviewers independently abstracted data on study and patient characteristics, renal measurements, outcomes, and prognostic features. DATA SYNTHESIS: A total of 153 trials were reviewed. Patients with renal disease were reported as excluded in 86 (56%) trials. Patients with renal disease were more likely to be excluded from trials that were multicenter; of moderate enrollment size; North American; that tested renin-angiotensin-aldosterone system antagonists and anticoagulants; and that tested chronic congestive heart failure. Only 8 (5%) original articles reported the proportion of enrolled patients with renal disease, and only 15 (10%) reported mean baseline renal function. While 81 (53%) trials performed subgroup analyses of some baseline characteristic in the original article, only 4 (3%) subgroup analyses of treatment stratified by renal disease were performed. CONCLUSION: Major cardiovascular disease trials frequently exclude patients with renal disease and do not provide adequate information on the renal function of enrollees or the effect of interventions on patients with renal disease.

Cardiovascular Diseases↗

Potential contribution of epithelial Na+ channel to net secretion of aqueous humor.

The aqueous humor of the eye is secreted by the bilayered ciliary epithelium, consisting of the pigmented (PE) cell layer facing the stroma and the nonpigmented (NPE) cell layer facing the aqueous humor. Cells within each layer and between the two layers are linked by gap junctions, forming a ciliary epithelial syncytium. Unidirectional secretion from the stroma to the aqueous proceeds both through the cells (the transcellular pathway) and between the cells (the paracellular pathway). Net formation of aqueous humor must, however, be the algebraic sum of unidirectional secretion and unidirectional reabsorption from the aqueous humor back into the stoma. The mechanisms potentially underlying reabsorption of aqueous humor by the NPE cells have recently been addressed by studying the regulatory response (RVI) of anisosmotically shrunken NPE cells. The results indicated that epithelial Na+ channels with a high affinity to amiloride likely contribute to reabsorption of solute from the aqueous humor. We have substantiated this possibility by using Northern analysis to identify in human ciliary body RNA a 3.7-kb transcript corresponding to the alpha-subunit of the amiloride-sensitive, alpha beta gamma-ENaC epithelial sodium channel. We have also found that the Na(+)-channel inhibitor benzamil inhibits the RVI without affecting the cell volume of isotonic cell suspensions. This observation supports the hypothesis that the low conductance, highly selective epithelial Na+ channel is activated by shrinkage and contributes to unidirectional reabsorption as aqueous humor. Examples are provided of how the integrative regulation of aqueous humor formation can involve conjugate actions on both unidirectional secretion and reabsorption.

Amiloride↗

The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma.

BACKGROUND: Natural killer (NK) cells have a spontaneous cytotoxic capacity-against tumor cells. These cells represent a small proportion of human colon carcinoma-infiltrating lymphocytes. Their prognostic significance in these tumors has yet to be determined. METHODS: One hundred and fifty-seven patients who each had a colectomy for large bowel adenocarcinoma were studied. No patient received adjuvant therapy. Immunohistochemical stains were performed for NK cells using the monoclonal antibody CD57. The number of NK cells was counted using a MICRON image analyzer. The total area studied for each tumor was 1 cm2. In this area, 50 intratumoral fields of 0.173 mm2 were selected. The degree of NK infiltration was classified as little (< 50 NK cells), moderate (50-150 NK cells), and extensive (> 150 NK cells). The Kaplan-Meier method was used to obtain survival figures. Multivariate analyses were performed using the Cox regression model. RESULTS: At 5 years, patients with little and moderate NK infiltration showed significantly shorter survival rates (overall and disease free survival) than those with extensive infiltration (P < 0.01). Three significant factors affecting survival were selected in a stepwise fashion in increasing order as follows: TNM stage, NK infiltration, and lymphocytic infiltration. Patients with TNM Stage III disease and extensive NK infiltration showed significantly longer survival rates than those with little or moderate infiltration (P < 0.001). In these patients, multivariate analysis using the Cox regression model identified two significant variables: number of involved lymph nodes and NK cells infiltration. CONCLUSIONS: In patients with colorectal carcinoma, an extensive intratumoral infiltration of NK cells is associated with a favorable tumor outcome. Intratumoral infiltration of NK cells can be used as a variable with prognostic value, especially in patients with TNM Stage III disease.

Adenocarcinoma↗

Hepatic injury in the toxic epidemic syndrome caused by ingestion of adulterated cooking oil (Spain, 1981).

We describe the clinico-pathological characteristics of hepatic injury associated with the toxic-epidemic syndrome caused by the consumption of adulterated rapeseed oil. Of 842 toxic-epidemic syndrome patients admitted to our hospital between May, 1981, and January, 1982, 24.1% showed signs of liver involvement which was more frequent in women and in the fourth decade of life. No statistical significance was found in relation to alcohol consumption, treatment with potentially hepatotoxic antibiotics, or adult respiratory distress syndrome. Most (91.6%) patients with hepatic injury were asymptomatic; jaundice or abdominal pain was rarely noted. One patient died of acute liver failure following Budd-Chiari syndrome. Serum gamma-glutamyl transpeptidase activity was raised in all cases, alkaline phosphatase in 94.6%, and less frequently lactate dehydrogenase (80%), SGPT (84.7%), and SGOT (76%). Serum total bilirubin was usually normal (89.2%). The histologic lesion was similar to drug-induced cholestatic hepatitis. Lamellar inclusions, canalicular injury, giant mitochondria, and hyperplasia of the smooth endoplasmic reticulum were seen by electron microscopy. Ultrastructural signs of cholestasis were common (78.9%). The pathogenesis of this lesion is unknown; however, because of similarities with chlorpromazine-induced cholestatic hepatitis, we suggest that a combination of hypersensitivity and intrinsic hepatoxicity is a possible mechanism.

Adult↗

Na+/H+ exchange regulates intracellular pH in a cell clone derived from bovine pigmented ciliary epithelium.

The regulation of intracellular pH (pHi) was monitored in a virus-transformed cell clone derived from bovine ciliary body exhibiting characteristics of pigmented ciliary epithelium. Data were obtained from confluent monolayers grown on plastic coverslips in nominally bicarbonate-free media using the pH-sensitive absorbance of 5- (and 6-) carboxy-4',5'-dimethylfluorescein. Under resting conditions, pHi averaged 6.98 +/- 0.01 (SEM; n = 57). When cells were acid loaded by briefly exposing them to Ringer containing NH4+ and then withdrawing the NH4+, pHi spontaneously regained its initial value. In the presence of 1 mM amiloride or in the absence of Na+, this process was blocked, indicating the involvement of an Na+/H+ exchanger in the regulation of pHi after an acid load. Removing Na+ during resting conditions decreased cytoplasmatic pH. This acidification could be slowed by amiloride, which is evidence for reversal of the Na+/H+ countertransport exchanging intracellular Na+ for extracellular protons. Application of 1 mM amiloride during steady state led to a slow acidification. Thus the Na+/H+ exchanger is operative during resting conditions extruding protons, derived from cellular metabolism, or from downhill leakage into the cell. Addition of Na+ to Na+ -depleted cells led to an alkalinization, which was sensitive to amiloride, with an IC50 of about 20 microM. This alkalinization was attributed to the Na+/H+ exchanger and exhibited saturation kinetics with increasing Na+ concentrations, with an apparent KM of 29.6 mM Na+. It is concluded that Na+/H+ exchange regulates pHi during steady state and after an acid load.

Amiloride↗

Expression of Na,K-ATPase alpha subunit isoforms in the human ciliary body and cultured ciliary epithelial cells.

We have analyzed the expression of Na,K-ATPase alpha subunit isoforms in the transporting ciliary processes of the human eye and in cultured cells derived from non-pigmented (NPE) and pigmented (PE) ciliary epithelium. Northern hybridization analysis shows that the mRNAs encoding all the three distinct forms of Na,K-ATPase alpha subunit [alpha 1, alpha 2, and alpha 3] are expressed in the human ciliary processes in vivo. Immunohistochemical analysis using antibodies specific for each of the three alpha subunit isoforms confirms that these polypeptides are present in the microsomal fraction from the human ciliary processes. The monoclonal antibody McB2, which is specific to the Na,K-ATPase alpha 2 subunit isoform, has been found to decorate specifically the basolateral membrane domains of NPE cells but not of the PE cells, suggesting its expression in vivo only in the ocular NPE ciliary epithelium. However, cultured cells derived from the NPE and PE layers exhibit a different pattern of expression of mRNA and protein for the Na,K-ATPase alpha subunit isoforms when compared to the tissue. Both the NPE and PE cells express alpha 1 and alpha 3 mRNA and polypeptide, whereas alpha 2 mRNA and polypeptide are undetectable in these cells. The established cell lines derived from the NPE layer express comparable levels of the alpha 1 and alpha 3 isoforms of Na,K-ATPase as detected in the primary culture. However, the established NPE cell lines are also distinguishable from the normal PE cells when analyzed by Western blot analysis with A x 2 antibodies. The results presented here clearly show that the NPE and PE cells in the ciliary body have a distinct expression of Na,K-ATPase alpha subunit isoforms as compared to cultured cells.

Blotting, Western↗