GCKR and PPP1R3B identified as genome-wide significant loci for plasma lactate: the Atherosclerosis Risk in Communities (ARIC) study.

AIM: To investigate the genetic influence of circulating lactate level, a marker of oxidative capacity associated with diabetes. METHODS: We conducted a genome-wide association study of log-transformed plasma lactate levels in 6901 European-American participants in the Atherosclerosis Risk in Communities study. For regions that achieved genome-wide significance in European-American participants, we conducted candidate region analysis in African-American subjects and tested for interaction between metformin use and the index single nucleotide polymorphisms for plasma lactate in European-American subjects. RESULTS: The genome-wide association study in European-American subjects identified two genome-wide significant loci, GCKR (rs1260326, T allele ß=0.08; P=1.8×10(-47) ) and PPP1R3B/LOC157273 (rs9987289, A allele ß=0.06; P=1.6×10(-9) ). The index single nucleotide polymorphisms in these two loci explain 3.3% of the variance in log-transformed plasma lactate levels among the European-American subjects. In the African-American subjects, based on a region-significant threshold, the index single nucleotide polymorphism at GCKR was associated with plasma lactate but that at PPP1R3B/LOC157273 was not. Metformin use appeared to strengthen the association between the index single nucleotide polymorphism at PPP1R3B/LOC157273 and plasma lactate in European-American subjects (P for interaction=0.01). CONCLUSIONS: We identified GCKR and PPP1R3B/LOC157273 as two genome-wide significant loci of plasma lactate. Both loci are associated with other diabetes-related phenotypes. These findings increase our understanding of the genetic control of lactate metabolism.

Combined admixture mapping and association analysis identifies a novel blood pressure genetic locus on 5p13: contributions from the CARe consortium.

Admixture mapping based on recently admixed populations is a powerful method to detect disease variants with substantial allele frequency differences in ancestral populations. We performed admixture mapping analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP), followed by trait-marker association analysis, in 6303 unrelated African-American participants of the Candidate Gene Association Resource (CARe) consortium. We identified five genomic regions (P< 0.001) harboring genetic variants contributing to inter-individual BP variation. In follow-up association analyses, correcting for all tests performed in this study, three loci were significantly associated with SBP and one significantly associated with DBP (P< 10(-5)). Further analyses suggested that six independent single-nucleotide polymorphisms (SNPs) contributed to the phenotypic variation observed in the admixture mapping analysis. These six SNPs were examined for replication in multiple, large, independent studies of African-Americans [Women's Health Initiative (WHI), Maywood, Genetic Epidemiology Network of Arteriopathy (GENOA) and Howard University Family Study (HUFS)] as well as one native African sample (Nigerian study), with a total replication sample size of 11 882. Meta-analysis of the replication set identified a novel variant (rs7726475) on chromosome 5 between the SUB1 and NPR3 genes, as being associated with SBP and DBP (P< 0.0015 for both); in meta-analyses combining the CARe samples with the replication data, we observed P-values of 4.45 × 10(-7) for SBP and 7.52 × 10(-7) for DBP for rs7726475 that were significant after accounting for all the tests performed. Our study highlights that admixture mapping analysis can help identify genetic variants missed by genome-wide association studies because of drastically reduced number of tests in the whole genome.

2-methyltetrahydrofuran--lithium hexafluoroarsenate: a superior electrolyte for the secondary lithium electrode.

Rechargeable, high energy density lithium batteries require an efficient lithium electrode. Earlier work with electrolytes based on propylene carbonate, methyl acetate, and tetrahydrofuran yielded poor lithium electrode cycling efficiencies because of electrolyte reduction by lithium. Solutions of lithium hexafluoroarsenate in 2-methyltetrahydrofuran are found to be remarkably stable toward lithium, resulting in cycling efficiencies that approach 98 percent. The ability of 2-methyltetrahydrofuran to resist reduction by lithium is thought to be based on the position of its lowest unfilled molecular orbital relative to that of tetrahydrofuran.

Genitourinary Tract Infection Due to Mycobacterium avium intracellulare Complex Infection in Pretransplant Setting With Recurrence Following Transplant: A Case Report.

Genitourinary (GU) tract infection with Mycobacterium avium intracellulare complex (MAI) is very rare and, to our knowledge, has never been reported in the solid organ transplant literature. CASE DESCRIPTION: A 61-year-old Somali-born woman had a history of liver cirrhosis due to chronic hepatitis C infection. She was diagnosed as having and treated for latent tuberculosis infection and GU tract infection due to MAI. She received a total of 17 months antimycobacterial therapy consisting of azithromycin, ethambutol, and moxifloxacin. Within 5 months of the initiation of antimicrobial therapy, there was documented sterilization of urine mycobacterial cultures. Liver and kidney transplant was performed 3 months after finishing the treatment course. One year following transplant, GU tract infection due to MAI recurred. She declined further diagnostic testing as well as mycobacterial therapy. She died 15 months following transplant for reasons not related to infections. CONCLUSION: The treatment of MAI infection in solid organ transplant candidates and recipients is challenging, and the duration of therapy in this population is not known. The recurrence of infection following transplant in this case may argue in favor of a duration that extends beyond the date of transplant. The combination of a fluoroquinolone and ethambutol may successfully prevent reactivation of tuberculosis in patients with history of latent tuberculosis infection and deserves further evaluation.

The coming epidemic: hypertension in rural Kyrgyzstan, Central Asia.

Eastern Europe is experiencing an epidemic of cardiovascular disease far outpacing rates in Western Europe. This epidemic was heralded by a precipitous rise in hypertension prevalence. The former Soviet states of Central Asia may be facing a similar epidemic. In order to access this threat, we performed a retrospective analysis of data generated during humanitarian medical visits to two villages in Kyrgyzstan, Central Asia. The age-adjusted prevalence of hypertension was 39%. Hypertension was much more common among men than women (46 vs 33%, respectively). In addition, the rise in blood pressure with age was striking, surpassing the experience in Western countries. This epidemic of hypertension may herald a coming epidemic of cardiovascular disease in Central Asia.

Chronic intestinal pseudo-obstruction. A report of 27 cases and review of the literature.

Twenty-seven cases of chronic intestinal pseudo-obstruction are reported. The causes of pseudo-obstruction were progressive systemic sclerosis in 14, hollow visceral myopathy in 4, visceral neuropathy in 2, sclerosing mesenteritis in 1, and jejunal diverticulosis in 1. No identifiable cause was found in five. Chronic pseudo-obstruction is a long-term illness characterized by vomiting, abdominal distention, abdominal pain and weight loss. Involvement is often present throughout the intestine so that patients may present with a variety of symptoms deriving from the esophagus, stomach, small intestine, and colon. Hollow visceral myopathy and visceral neuropathy are usually familial and urologic involvement is sometimes present in the former. Abnormalities of smooth muscle function can be discerned by radiography and esophageal manometry. The pattern and distribution of the abnormalities are helpful in differentiating pseudo-obstruction from true mechanical obstruction. They may also be helpful in differentiating one form of pseudo-obstruction from another. The majority of cases have identifiable pathology within either the smooth muscle or myenteric plexus of the bowel wall. The natural history of pseudo-obstruction is variable. Remissions and exacerbations occur and may be unrelated to anything that is done therapeutically. The illness is unresponsive to any drug known to have an effect on intestinal motility. Antibiotic treatment of small intestinal bacterial overgrowth and selected surgical procedures may occasionally be palliative. Many patients develop malnutrition and require home parenteral nutrition in order to survive.

Penetration of intravenously administered cefoxitin into the aqueous humor of inflamed human eyes.

Intravenous injections of cefoxitin (2-g doses for adults and 40 mg/kg of body weight doses for children) were administered 90 minutes to two hours before surgery. All nine eyes had anterior segment inflammation. Samples of aqueous humor removed during surgery showed a mean cefoxitin concentration of 6.22 micrograms/ml, almost three times the concentration reported in uninflamed eyes. The greater penetration may have been the result of a breakdown in the blood-aqueous barrier. There were no complications.

'Osmosin' in general practice: preliminary report of a double-blind study in the treatment of osteoarthritis.

'Osmosin' (105 mg sodium indomethacin trihydrate) has been studied in a double-blind general practice trial of patients with osteoarthritis of the hip at a dose of 1 tablet in the morning and matching placebo at night versus 1 tablet twice daily. To date, 223 patients have completed the study, 113 in the lower dose and 110 in the higher dose group. In the preliminary analysis, the overall trend at 4 weeks favoured the higher dose in effectiveness and this group appeared to respond more rapidly. The incidence of side-effects was similar in both groups, but there were fewer drop-outs due to side-effects in the group receiving 'Osmosin' once daily. The preliminary results indicate that the response to 'Osmosin' is time-dependent as well as dose-dependent and, therefore, rather than increasing the dose early, it is probably preferable to initiate therapy with 1 'Osmosin' daily and review at 1 month the need to increase the dose to 1 'Osmosin' twice daily.

Efficacy and tolerance of a fixed ratio combination of hydrochlorothiazide, amiloride and timolol, taken before or after food, in the treatment of hypertension.

An open study was carried out in general practice to assess the efficacy and tolerance of a fixed ratio combination of hydrochlorothiazide (25 mg), amiloride (2.5 mg) and timolol (10 mg) in the treatment of patients with mild to moderate hypertension, and to determine if there were any differences in response when medication was taken before or after food. A total of 663 patients was studied and received 1 to 2 tablets once daily for a period of 12 weeks; 322 patients took their medication before and 341 after food. The results showed that there were similar significant reductions in systolic and diastolic blood pressure and in heart rate in both groups, over half of the patients being controlled (less than 90 mmHg diastolic) after 2 weeks and 80% by the end of the study period. Relatively few adverse effects were reported and the incidence during treatment was less than that recorded on entry to the study. There was no evidence to suggest that the timing of drug intake in relation to food had any effect on the efficacy or tolerance of the combination.

Hyperthermia with implanted electrodes.

A general solution is given for the steady state form of the heat conduction equation applied to a simple tumor model which is imagined as being heated by means of electrical currents flowing between metallic electrodes. The model assumes a homogeneous tumor with no bloodflow. The solution for the special case of constant temperature and potential at the surface of the heated volume is examined in detail. The solution shows that there exists, independent of the particular tumor and electrode geometry, a close relationship between the steady state temperature distribution and the electrical potential. Among the more important implications of this relationship are that equipotential surfaces within the heated volume are also isothermal surfaces and that no areas of excessive heat at or near any sharp edges or corners of the electrodes should develop, despite the high electric field intensity. Based on the theory, a procedure is outlined which might greatly facilitate the determination of temperature distributions in phantoms. Finally, the usefulness and the limitations of the theoretical models in clinical hyperthermia are discussed.

Temperature distributions in hyperthermia by electromagnetic induction: a theoretical model for the thorax.

Steady-state temperature solutions to the bioheat equation are presented for magnetic induction heating of a thoracic model consisting of a spherical tumor embedded in lung tissue which is layered by muscle and fatty tissue. Analytical solutions are presented for each of the tissue regions along with their numerical evaluations over a range of physical characteristics, including surface cooling effects. A strong dependence of tumor temperature on size and blood perfusion rate is shown to exist and can be used to optimize treatment parameters. Tendencies of the chest muscles and overlaying fatty tissue to overheat, particularly in the case of an obese patient, are discussed along with the alleviating influence of surface cooling. Healthy lung tissue, on the other hand, is shown to be safe from any significant damage in such a heating situation. Transient times required for tumors to achieve thermal equilibrium are computed and shown to depend strongly on tumor size and, to a lesser extent, on blood perfusion rate. Finally, the overall results obtained from the model are compared with available clinical data and are found to be in line with those observations.

Prediction of whole blood selenium levels in patients on long-term parenteral nutrition.

In an attempt to define clinical variables which might predict the whole blood selenium level prior to supplementation, whole blood selenium levels were determined in 21 home parenteral nutrition patients who were not receiving selenium supplementation. These levels were examined for possible correlations by single and multivariant analysis with the following clinical parameters: age at initiation of home parenteral nutrition, months of home parenteral nutrition received, hematocrit, albumin, estimated length of remaining small bowel, kilocalories per kilogram actual body weight infused per day, grams protein per kilogram actual body weight infused per day, and multiple of ideal body weight. Of all the combinations of variables examined, the best correlation obtained was between whole blood selenium levels and the total kilocalories per kilogram body weight per day delivered intravenously (r = -0.89, p less than 0.001). A statistically significant correlation (r = -0.67, p less than 0.01) was also observed between selenium levels and the grams protein per kilogram actual body weight infused per day. However, inclusion of this or additional variables did not increase the predictive value of the equation describing whole blood selenium levels as a function of the calories delivered. The implication of this study is that patients requiring more intensive nutritional support develop lower selenium levels during the course of treatment. Despite these correlations, no single clinical parameter or combination of parameters, however, was of sufficient predictive value to preclude laboratory determination of whole blood selenium values in deciding which patients might benefit from selenium supplementation.

Supplementation of total parenteral nutrition solutions with ferrous citrate.

Daily infusion of a total parenteral nutrition (TPN) formulation containing 1 liter of 5.5% Travasol provides less than 0.1 milligrams of iron. By comparison, a formulation which includes a liter of 10% Travamin provides 2 milligrams of iron per day. To meet iron requirements in patients infusing formulations containing Travasol, iron was added as ferrous citrate. In in virto experiments, 74% of this iron was available to transferrin. In seven patients in whom in vivo availability was tested by red cell incorporation, the mean availability was 81%. Ferrous citrate is recommended as a safe, effective additive to TPN solutions for adult patients requiring iron supplements.

DAE (daunorubicin, Ara-C, and etoposide) and intermediate dose Ara-C for remission induction and consolidation treatment of adult patients with acute myeloid leukemia.

Fifty-one patients (age 18-73 years) with acute myeloid leukemia were treated with daunorubicin, cytarabine, and etoposide in an age-adjusted protocol, with patients older than 50 receiving fewer days of therapy. Complete remission (CR) occurred in 66% of the patients (34 of 51 patients). Patients 50 years of age and younger achieved a 74% CR rate (23 of 31 patients) compared to a 55% CR rate (11 of 20 patients) in older patients. Of the 34 complete responders, 11 (32%) refused consolidation therapy and received traditional Chinese herbal medicine. All of these 11 patients relapsed after a short remission duration (median, 3.8 months) and died. The median remission duration and median overall survival of 23 complete responders receiving at least two courses of consolidation therapy were 10.1 and 19.8 months, respectively. The actuarial 3-year disease-free survival for these 23 complete responders was 21 +/- 9%. Myelosuppression was the major toxicity, and nonhematological side effects were acceptable. The regimen appeared to have acceptable toxicity, and its efficacy was comparable with that of standard regimens with long-term maintenance therapy.

Pharmaceutical services in the United States Air Force.

The status of pharmaceutical services in the United States Air Force medical service is described. Air Force pharmacy is adopting new programs, staffing standards, inventory methods, and roles for pharmacists and technicians. One of the most visible changes is TRICARE, an interservice program that provides improved access to care. Many Air Force medical treatment facilities have been closed; prescription mail-out programs and networks of community pharmacies are filling the gap. The Air Force pharmacy team consists of more than 1300 pharmacists and technicians. Air Force pharmacists are military officers first. Great emphasis is placed on medical readiness training and continuing education. Some Air Force pharmacies are very small outpatient operations filling fewer than 300 prescriptions per day; others fill well over 4000. Many hospitals are being considered for more outpatient-focused operations. Because of anticipated minor reductions in pharmacist staffing, Air Force pharmacists will have to maximize efficiencies to maintain or improve current levels of service. More and better patient information will be provided and distributive processes streamlined. A greater role for technicians is anticipated. The future includes pharmacists serving in a wide variety of leadership and staff positions, improving the use of computers, and incorporating new technologies. Air Force pharmacy is changing to ensure uninterrupted fulfillment of its responsibilities.

Implications of elbow arthrodesis for individuals with paraplegia.

A 38-year-old woman who had a recent injury resulting in T-3 Frankel Class C paraplegia and a comminuted fracture of the right elbow is described in this case report. The elbow required an arthrodesis, but the position in which the elbow should be fused was not initially known. To illustrate to the rehabilitation team and the patient the advantages and disadvantages of each of two elbow positions under consideration for the arthrodesis, the author recruited an individual with paraplegia to demonstrate some activities of daily living with two elbow splints that stimulated the two positions of fusion being considered. The patient and the rehabilitation team concluded that the 30-degree flexion fusion offered more functional mobility than the 90-degree flexion fusion. At the completion of her initial rehabilitation, the patient was a full-time manual wheelchair user. She was independent in all self-care and transfers, including uneven transfers to heights of 22.9 cm (9 in) over and 45.7 (18 in) lower than the wheelchair seat. She drives a four-wheel-drive vehicle and is independent in stowing her wheelchair.

Testing shelled corn for aflatoxin, Part II: modeling the observed distribution of aflatoxin test results.

The suitability of several theoretical distributions to predict the observed distribution of aflatoxin test results in shelled corn was investigated. Fifteen positively skewed theoretical distributions were each fitted to 18 empirical distributions of aflatoxin test results for shelled corn. The compound gamma distribution was selected to model aflatoxin test results for shelled corn. The method of moments technique was chosen to estimate the parameters of the compound gamma distribution. Mathematical expressions were developed to calculate the parameters of the compound gamma distribution for any lot aflatoxin concentration and test procedure. Observed acceptance probabilities were compared to operating characteristic curves predicted from the compound gamma distribution, and all 18 observed acceptance probabilities were found to lie within a 95% confidence band. The parameters of compound gamma were used to calculate the fraction of aflatoxin-contaminated kernels in contaminated lots. At 20 ppb, it was estimated that about 6 in 10,000 kernels are contaminated.