Managing malaria in tuberculosis patients on fluoroquinolone-containing regimens: assessing the risk of QT prolongation.

The role of fluoroquinolones (FQs) in the management of drug-susceptible and drug-resistant tuberculosis (TB) is under investigation. They are currently being used off-licence to treat TB patients who develop hepatotoxicity on standard therapy, and in patients with drug-resistant disease. Prolongation of ventricular repolarisation, recorded as lengthening of the QT interval on an electrocardiogram, is a recognised adverse effect associated with FQs. Significant prolongation of the QT interval may precipitate torsades de pointe, a potentially fatal tachyarrhythmia. Currently licensed FQs are considered safe, and there are very few reports of associated arrhythmias, but most labels contraindicate concomitant administration of other agents that prolong QT. In many high TB burden countries, malaria is also endemic. Many antimalarials, and possibly malaria infection itself, may prolong QT; under current licence, co-administration of FQs with these antimalarials is contraindicated due to potential risk of additive QT prolongation. This poses significant challenges in planning future policy on FQ use for first-line anti-tuberculosis treatment; the duration of TB treatment makes concomitant malaria treatment inevitable, and options without FQ contraindications are limited. Furthermore, malaria diagnosis is often poor and access to treatment uncontrolled, with many patients buying 'over-the-counter' and/or 'traditional' remedies; concomitant use with anti-tuberculosis treatment is thus likely to be unregulated. Drug interaction studies are urgently required to assess the safety of managing patients with TB and malaria within endemic, resource-poor settings where programmatic management and low-cost monitoring are essential for effective implementation of public health strategies.

The role of HDL cholesterol in metabolic syndrome predicting cardiovascular events. The Gubbio population study.

BACKGROUND AND AIMS: Metabolic syndrome (MS) has recently been claimed to be an important new risk factor for the occurrence of coronary heart disease (CHD) and cardiovascular disease (CVD) events, although it is simply a combination of known risk factors used in a dichotomized fashion. The aims of this analysis were to explore the predictive role of MS for CHD and CVD events in a population study, in comparison with using the same factors in a continuous fashion, with special emphasis on HDL cholesterol. METHODS AND RESULTS: In the second examination of the Gubbio population study from central Italy, 2650 cardiovascular disease-free men and women, aged 35-74 years around 1990, were examined and followed-up for 12 years. The classic risk factors (sex, age, systolic blood pressure, serum cholesterol and smoking habits) were studied as predictors of CHD and CVD events, alone and with the contribution of other factors (HDL cholesterol, blood glucose, serum triglycerides and waist circumference) included in the so-called MS, based on several multivariate models. MS was also tested after adjustment for other risk factors. MS produced a predictive significant relative risk of 1.67 for CHD events and 1.82 for CVD events, but considering its single risk factors, the only ones contributing to prediction were HDL cholesterol and systolic blood pressure. Dedicated analyses showed that MS does not add anything to the power of prediction beyond the role of the single risk factors treated in a continuous fashion, while the best predictive power is obtained using classic risk factors (sex, age, smoking habits, total cholesterol, systolic blood pressure) with the addition of HDL cholesterol. CONCLUSIONS: The predictive power of MS is bound only to the presence of HDL cholesterol and blood pressure and does not add anything to using the same risk factor treated in a continuous fashion.

Challenges associated with current and future TB treatment.

Current tuberculosis (TB) treatment is based on a combination of drugs that were developed mostly in the central decades of the last century. Cure rates are high for drug sensitive strains of Mycobacterium tuberculosis (M. tb) when the recommended complex and lengthy treatment protocols are adhered to. However the difficulty in correctly prescribing and adhering to these protocols, the emergence of M tb strains resistant to multiple drugs, and drug-drug interactions that interfere with optimal treatment of HIV and TB coinfected patients have generated a pressing need for improved TB therapies. Together with the ominous global burden of TB, these shortcomings of current treatment have contributed to a renewed interest in the development of improved drugs and protocols for the treatment of tuberculosis. This article highlights hurdles related to the optimized use of existing drugs and challenges related to the development of novel, improved products, focusing in particular on aspects inherent in TB drug clinical development. Concluding comments propose processes for more efficient development of new TB therapies.

Modulation of BDNF and TrkB expression in rat hippocampus in response to acute neurotoxicity by diethyldithiocarbamate.

In this study, we examined the expression profile of brain-derived neurotrophic factor (BDNF) and its receptor TrkB in adult rat hippocampus following acute administration of diethyldithiocarbamate (DDTC), a neurotoxic compound which was previously shown to induce microglia activation and cell death. Semiquantitative RT-PCR analysis detected significant variations of BDNF mRNA levels in whole hippocampus homogenates, with a peak at 24h after DDTC injection. Increased BDNF protein expression was demonstrated by immunohistochemistry in various hippocampal subfields. The most relevant increase was observed in the hilus of the dentate gyrus where BDNF levels at 120h were found to be almost four times those of basal levels. Full-length TrkB (TrkB.FL) encoding mRNA was also shown to undergo an earlier increase in the hippocampus of DDTC-treated rats. TrkB immunostaining with an antibody binding both full-length and truncated (TrkB.T) isoforms was found to increase at 120h in the hippocampal CA2 and CA3 regions. These results demonstrate that DDTC modulates the expression of BDNF and its receptor in the adult rat hippocampus and suggest a possible involvement of this neurotrophin in the protective response to DDTC-induced neuronal damage.

Low glomerular filtration in the population: prevalence, associated disorders, and awareness.

Estimated glomerular filtration rate (eGFR) was used for analysis of kidney disease prevalence in the United States. The study investigated on prevalence, associated disorders, and kidney disease awareness in an Italian population sample. Data were collected on serum creatinine, other laboratory indices, blood pressure, and medical history in the Gubbio Population Study (n=4574, both sexes, ages 18-95 years). Analyses were carried out on eGFR (equation of Modification Diet in Renal Disease study), disorders potentially secondary to kidney dysfunction (hypertension, high serum uric acid, high serum phosphorus/low serum calcium, high serum potassium, cardiovascular disease, anemia), and kidney disease awareness. The prevalence of eGFR <60 ml/min x 1.73 m(2) increased with age in both sexes (from <1% for ages 18-24 years to >30% for ages > or =75 years, P<0.001). In the group with eGFR <60 ml/min x 1.73 m(2), number of disorders secondary to kidney dysfunction was > or =2 in the majority of persons, was higher than in persons with eGFR > or =60 ml/min x 1.73 m(2) (P<0.001), and was inversely related to eGFR (P<0.001). The prevalence of reported kidney disease was 3.3% in the group with eGFR <60 ml/min x 1.73 m(2) and directly related to serum creatinine and number of disorders secondary to kidney dysfunction (P<0.001). Low kidney function is frequent in the older population and is associated with disorders typical of kidney disease. Persons with low kidney function are rarely aware of kidney disease unless of very high serum creatinine or presence of many disorders typical of kidney disease.

Is there a relationship between left ventricular mass and plasma glucose and lipids independent of body mass index? Results of the Gubbio Study.

BACKGROUND AND AIMS: The association between left ventricular (LV) mass (M) and variables described as features of the insulin resistance syndrome, such as obesity and measures o lipid and carbohydrate metabolisms, has been reported in hypertensives. The aim of the present study was to investigate in a large, population based group of non hypertensive people, the prevalence of LV hypertrophy (H) and the relationship of LVM with some of the variables described in the insulin resistance syndrome, independently of obesity. For this reason we investigated the normotensive subjects in the age range 45-54 yrs (n = 435) of the total population of participants in the Gubbio Population Study. METHODS AND RESULTS: Serum lipids, cholesterol (Chol), triglyceride (Tg), HDL cholesterol, fasting blood glucose (FBG), blood pressure (BP), body weight and height were measured and body mass index (BMI) was calculated; LVM was assessed by M-mode echocardiography. Using a normalization criterion not related to body weight (g/m2.7) and the cut-off of 49.2 g/m2.7 for men and 46.7 g/m2.7 for women, LVH was found in 25% of the sample whilst, when LVM was corrected by body surface area (cut-off 116 g/m2 for men and 104 g/m2 for women), the prevalence of LVH was quite lower (10.3%). In the univariate analyses LVMi was closely related to BP, BMI and metabolic variables whilst in the multivariate analysis only BP, BMI, and age were detected as independent predictors of LVMi. When the sample was divided into obese and non-obese subjects on the basis of BMI (cut-off 30 kg/m2), no difference in metabolic variables was seen between subjects with and without LVH within each BMI class. Regarding left ventricular geometry, RWT was positively related to triglycerides and blood glucose and inversely to HDL-chol. CONCLUSIONS: The present study in the middle age normotensive sample of the general population of Gubbio extends to normotensives the relationship between left ventricular mass and metabolic parameters already seen in hypertensives. BMI seems to account for most of the increases in LVM since the prevalence of LVH, which was definitely high when LVM was not normalized to body weight, fell to approximately 4% when the influence of body weight was excluded. Moreover differences in metabolic values between subjects with and without LVH disappeared when the subjects were stratified by BMI. Left ventricular geometry, on the other hand, seems to be related to some metabolic variables.

Comparison of low-dose rofecoxib versus 1000 mg naproxen in patients with osteoarthritis. Results of two randomized treatment trials of six weeks duration.

OBJECTIVE: To compare the efficacy and safety of rofecoxib 12.5 mg once daily to naproxen 500 mg twice daily in patients > or = 40 years of age with knee or hip osteoarthritis (OA). METHOD: Two identical 6-week, randomized, double-blind studies were conducted (1 in Africa, Australia, Europe, Canada, Mexico, & South America; 1 in Asia). Primary endpoints were pain walking on a flat surface, patient global assessment of response to therapy, and investigator global assessment of disease status. RESULTS: Overall, 944 patients participated. For all efficacy endpoints, treatment effects for rofecoxib and naproxen were comparable and seen at the first measures of efficacy. Both compounds were generally well-tolerated, with an improved gastrointestinal safety profile for rofecoxib versus naproxen. CONCLUSIONS In these studies, rofecoxib 12.5 mg once daily (the lowest indicated dose) and naproxen 500 mg twice daily showed similar treatment effects in OA patients. Rofecoxib and naproxen were generally well tolerated.

Comparison of rofecoxib, celecoxib, and naproxen on renal function in elderly subjects receiving a normal-salt diet.

BACKGROUND: This study compared directly the renal effects of two selective cyclooxygenase (COX)-2 inhibitors (rofecoxib and celecoxib) with naproxen (dual COX-1/COX-2 inhibitor) and placebo in healthy elderly subjects on a sodium-replete diet. METHODS: A total of 67 elderly subjects stabilized in the clinic for weight and urinary sodium on a controlled 200-mEq sodium diet were randomized in a double-blind fashion to receive rofecoxib, 25 mg daily (n = 17); celecoxib, 200 mg twice daily (n = 17); naproxen, 500 mg twice daily (n = 17); or matching placebo (n = 16) for 28 days. Subjects were sequestered in the clinic for the first 14 treatment days on the controlled diet. RESULTS: Daily urinary sodium excretion during the first 72 hours of treatment (primary endpoint) significantly decreased in rofecoxib, celecoxib, and naproxen groups compared with baseline (P < or =.05). Rofecoxib and celecoxib decreases in urinary sodium excretion rates that were comparable with each other, on the basis of predefined boundaries (-39.5 versus -27.1 mEq/d, respectively) and to naproxen (-40.6, mEq/d). Rofecoxib, celecoxib, and naproxen increased mean systolic blood pressure to a similar degree (3.4, 4.3, and 3.1 mm Hg, respectively, versus -1.3 mm Hg for placebo) after 14 days of treatment; small changes also occurred in diastolic blood pressure (0.3, 0.8, and -0.4 mm Hg, respectively, versus -1.4 mm Hg for placebo). Changes from baseline in creatinine clearance, body weight, and urinary potassium excretion among active treatments were similar. After 28 days of treatment, findings were generally consistent with those at 14 days. No subject reported edema or discontinued treatment as the result of an adverse experience. CONCLUSION: In healthy elderly subjects on a sodium-replete diet, the COX-2 inhibitors rofecoxib and celecoxib did not differ from a nonselective nonsteroidal anti-inflammatory drug (naproxen), in influencing renal function as measured by urinary sodium excretion, systolic and diastolic blood pressure, creatinine clearance, or weight change.

Relation of urinary urea to blood pressure: interaction with urinary sodium.

A previous study reported that urinary markers of protein intake are inversely related to blood pressure via unknown mechanisms. In man and rats, protein intake affects renal function and increases renal sodium excretion. The present study investigates the relation between markers of protein intake and blood pressure and the possible role of sodium in this relation. Blood pressure status, overnight urinary urea as index of protein intake, urinary and plasma sodium, and other variables were measured in a population sample of 3705 men and women, aged 25-74 years, without high plasma creatinine. Urinary urea was inversely related to blood pressure and hypertension: in multivariate analyses, 6.5 mmol/h higher urinary urea (about one s.d. in men and women) was related to 4.25 mm Hg lower systolic blood pressure (95% confidence interval = 1.34-8.49), and to 0.65 lower risk of hypertension (95% CI 0.34-0.87). An interaction was found between overnight urinary sodium and the relation of urinary urea to blood pressure: the relation was significant only in persons with overnight urinary sodium above the median. Urinary urea was significantly and inversely also related to plasma sodium. Data confirm an inverse relation to blood pressure of protein intake as measured by urinary urea. The possibility of sodium-related mechanisms is supported by the interaction of urinary sodium with the relation and by the inverse association of urinary urea with plasma sodium. The hypothesis is made that high protein intake could counteract sodium-dependent blood pressure rise via stimulation of renal sodium excretion.

Tolerability profiles of rofecoxib (Vioxx) and Arthrotec. A comparison of six weeks treatment in patients with osteoarthritis.

OBJECTIVE: To compare the incidence of selected spontaneously reported adverse events (AEs) in patients with osteoarthritis (OA) treated with rofecoxib (VIOXX, 12.5 mg qd) or Arthrotec (diclofenac 50 mg/misoprostol 200 mcg bid). METHODS: Double-blind, parallel-group, 6-week study of patients aged > or = 40 years with a clinical diagnosis of OA treated with rofecoxib or Arthrotec. Primary endpoint: self-reported diarrhea; secondary endpoints: abdominal pain, discontinuations due to AEs, GI AEs and NSAID-type GI AEs (ie., acid reflux, dyspepsia, epigastric discomfort, heartburn, nausea, vomiting). RESULTS: Among 483 patients (80.3% females, mean age 62.1), the rofecoxib group vs the Arthrotec group respectively reported diarrhea 6.2% vs 16.2% (p<0.001); drug-related diarrhea 3.7% vs 16.2% (p<0.001); one or more clinical AEs 52.9% vs 73.0% (p<0.001); GI AEs 28.9% vs 48.5% (p<0.001); NSAID-type GI AEs 18.6% vs 29.9% (p=0.004); discontinuations due to abdominal pain 0.4% vs 3.7% (p<0.05); and discontinuations due to any AE 4.1% vs 9.1% (p=0.029). No significant differences were observed in efficacy. CONCLUSION: Rofecoxib 12.5 mg qd has improved GI tolerability and similar efficacy compared to Arthrotec (diclofenac 50 mg/misoprostol 200 mcg bid).

Effects of microenvironment on morphology and function of the microglial cell line BV-2.

Effects of microenvironmental changes were examined in the microglial cell line BV-2. In serum supplemented medium cells were ameboid shaped and exhibited thin cytoplasmatic processes at lower concentration or in absence of serum. High levels of acetylated low-density lipoprotein (LDL) receptor and of phagocytic and proliferative activity were detected. Lipopolysaccharide (LPS) and the neuropeptide substance P (SP) induced secretion of interleukin-6. Low interleukin-3 secretion was detected only occasionally and was not influenced by LPS and SP. In defined medium, "process-bearing" cells were evident. Compared to cultures in serum supplemented medium, the cells expressed lower acetylated LDL-binding and phagocytic activity while actively proliferated, the response to LPS was reduced and to SP absent. Granulocyte/macrophage colony-stimulating factor increased the number of process-bearing cells, of acetylated LDL-binding and of IL-6 secretion induced by LPS. Cell morphology was not influenced by neurotrophins like nerve growth factor and brain-derived neurotrophic factor. The described phenotypical and functional plasticity makes the BV-2 cell line a useful model to investigate mechanisms of microglial activation.

Analysis of the distribution of copper amine oxidase in cell walls of legume seedlings.

Copper-containing amine oxidase (CuAO) has been proposed to play a role in H2O2 production in plant cell walls during cell development and in response to pathogen attack. We have compared the localisation of CuAO in pea (Pisum sativum L.), lentil (Lens culinaris M.) and chick pea (Cicer arietinum L.) grown under different light conditions, using both immuno- and histochemical techniques. The enzyme was detected by indirect immunofluorescence in the cell walls of parenchyma tissues of etiolated pea and lentil plants and was particularly abundant at intercellular spaces. Upon de-etiolation, CuAO largely disappeared from cortical cell walls except in the region of intercellular spaces. In the apical internode of light-grown seedlings, CuAO occurred mainly in cortical cell walls and, to some extent, in cell walls of xylem vessels. In both the elongation zone and mature regions of roots, CuAO was restricted to cortical cell walls and some cell junctions close to the meristem. Extensin epitopes co-localised to intercellular spaces of the cortex in de-etiolated pea, indicating that CuAO may have a role in cell wall strengthening at intercellular spaces. In chick pea, the localisation of the enzyme varied between different cultivars that have differing susceptibility to the fungus Ascochyta rabiei. In a susceptible cultivar Calia, immunogold labelling localised CuAO to cell walls of the cortex, as in lentil and pea, while in a resistant cultivar Sultano, it was most abundant in xylem vessels and, in light-grown plants, in the epidermis. These expression patterns are discussed with regard to the possible functions of amine oxidase in cell growth, cell differentiation and pathogen resistance.

Pulse pressure and isolated systolic hypertension: association with microalbuminuria. The GUBBIO Study Collaborative Research Group.

BACKGROUND: The long-term risk of end-stage renal disease is high in persons with isolated systolic hypertension, that is, those with an elevation of pulse pressure and not of diastolic pressure. Other data suggest that pulse pressure is a predictor of the hypertension-induced organ damage. Microalbuminuria is considered an early sign of glomerular damage caused by hypertension. The study shows the relationship of pulse pressure and isolated systolic hypertension to microalbuminuria in nondiabetic subjects. METHODS: This is a cross sectional analysis for a population sample of 677 men and 890 women, aged 45 to 64 years, who were without diabetes mellitus and macroalbuminuria. Data collection included: overnight urinary albumin and creatinine excretion; fasting plasma glucose, cholesterol, and creatinine; creatinine clearance; and blood pressure, weight, height, medical history, and smoking habit. Pulse pressure was calculated as systolic minus diastolic pressure. Isolated systolic hypertension was defined as systolic pressure > or =140 mm Hg in persons not on antihypertensive drugs and with diastolic pressure <90 mm Hg. Microalbuminuria was defined as urinary albumin excretion > or =20 microg/min. RESULTS: Pulse pressure and isolated systolic hypertension were significantly related to urinary albumin excretion and the prevalence of microalbuminuria in univariate and multivariate analyses. Controlling for gender and other variables, the risk of microalbuminuria was 1.71 with a 15 mm Hg higher pulse pressure (95% CI, 1.31 to 2.22) and 4.95 in the presence of isolated systolic hypertension (95% CI, 3.15 to 7.76). CONCLUSIONS: In nondiabetic, middle-aged adults, pulse pressure and isolated systolic hypertension are directly related to microalbuminuria, independent of diastolic pressure and other correlates.

Montelukast versus salmeterol in patients with asthma and exercise-induced bronchoconstriction. Montelukast/Salmeterol Exercise Study Group.

BACKGROUND: Montelukast, a leukotriene receptor antagonist, and salmeterol, a long-acting beta(2)-receptor agonist, each have demonstrated benefits in the treatment of exercise-induced bronchoconstriction (EIB) in short-term studies. Direct comparisons between these agents in long-term studies are limited. OBJECTIVE: We sought to compare montelukast and salmeterol in the long-term treatment of EIB. METHODS: One hundred ninety-seven patients with mild asthma and a postexercise fall in FEV(1) of at least 18% were randomized (double-blind) to receive montelukast 10 mg once daily or salmeterol 50 microg twice daily for 8 weeks. Exercise challenge was repeated at day 3, week 4, and week 8 after randomization near the end of the dosing interval for both drugs. The primary efficacy endpoint was the maximal percent fall in postexercise FEV(1) at week 8. RESULTS: Montelukast was effective in treating EIB without inducing tolerance and provided superior (P

Prospective analysis of traits related to 6-year change in sodium-lithium countertransport. Gubbio Population Study Research Group.

Sodium-lithium countertransport (Na-Li CT) activity in red blood cells relates cross-sectionally and longitudinally to blood pressure and hypertension. Lifestyle and metabolic factors relate cross-sectionally to this sodium transporter. The aim of this study was to conduct a prospective analysis of 6-year Na-Li CT change and of traits related to Na-Li CT change. In 2183 participants in the Gubbio Population Study (972 men and 1211 women; baseline ages, 18 to 74 years), the following data collected at baseline and 6-year follow-up were analyzed: Na-Li CT; gender; age; body mass index (BMI); blood pressure; antihypertensive treatment; alcohol intake; smoking habits; urinary sodium-to-potassium ratio; and plasma cholesterol, glucose, uric acid, sodium, potassium, and triglycerides (measured only at follow-up). Six-year changes were defined as follow-up minus baseline values. Na-Li CT was higher at follow-up than at baseline in both genders (P<0.001). Baseline Na-Li CT; baseline and change values of BMI; and change values of alcohol intake, plasma potassium, and plasma glucose related to Na-Li CT change significantly and independently with control for other variables. Follow-up plasma triglyceride levels also related independently to Na-Li CT change. Coefficients were positive for BMI, alcohol intake, and plasma glucose and triglyceride levels and were negative for baseline Na-Li CT and plasma potassium levels. Baseline and change values of other variables did not relate significantly to Na-Li CT change. In conclusion, in prospective analyses, BMI, alcohol intake, plasma glucose, and lipids were directly related to Na-Li CT change; baseline Na-Li CT and plasma potassium levels were inversely related. The data support the concept that lifestyle and related metabolic factors influence Na-Li CT.

Developmentally and wound-regulated expression of the gene encoding a cell wall copper amine oxidase in chickpea seedlings.

A chickpea cDNA encoding a cell wall copper amine oxidase (CuAO) was cloned and characterised. The 2010 bp open reading frame encodes a protein of 76.5 kDa which shares significant primary structure homology with other known CuAOs. Southern blot analysis indicates that in chickpea CuAO is encoded by a single gene or a small gene family. This cDNA was essential for studying the role of CuAO during seedling development and wound healing in chickpea seedlings. CuAO transcript level and activity were modulated during seedling development in parallel with cell maturation. Moreover, mechanical wounding induced a rapid increase of CuAO mRNA accumulation and enzyme activity which remained high during the wound-healing process. Aminoguanidine, a specific CuAO inhibitor, decreased the deposition of lignin-suberin barrier along the lesion. CuAO may be a limiting factor in H2O2 production in the cell wall of chickpea seedlings and its expression seems to integrate with the remodelling of plant cell wall occurring during ontogenesis and wound healing.

Microalbuminuria in nondiabetic adults: relation of blood pressure, body mass index, plasma cholesterol levels, and smoking: The Gubbio Population Study.

BACKGROUND: Evidence exists that cardiovascular risk factors influence progression toward end-stage renal failure. We tested the hypothesis that in nondiabetic middle-aged adults without macroalbuminuria, cardiovascular risk factors are related to urinary albumin excretion and prevalence of microalbuminuria, a sign of early nephropathy. METHODS: Cross-sectional analysis of data for 1567 participants in The Gubbio Population Study (677 men and 890 women), aged 45 to 64 years, without macroalbuminuria, without diabetes mellitus, and with fasting plasma glucose levels of less than 7.8 mmol/L (140 mg/ dL). Data collection included albumin and creatinine excretion in timed overnight urine collection; levels of fasting plasma cholesterol, glucose, triglycerides, creatinine, and uric acid; creatinine clearance; red blood cell sodium-lithium countertransport; blood pressure; weight; height; medical history; smoking status; and alcohol intake. Urinary albumin excretion and prevalence of microalbuminuria were the dependent variables. RESULTS: Blood pressure, plasma cholesterol levels, smoking, and body mass index significantly related to urinary albumin excretion and prevalence of microalbuminuria. In analyses with control for multiple variables, relative risk for microalbuminuria (urinary albumin excretion, 20-199 microg/min) in men and women was 2.51 and 1.62, respectively, with 18 mm Hg higher (1 SD) systolic blood pressure; 2.25 and 2.10, respectively, with 1.0-mmol/L (40 mg/dL) higher plasma cholesterol level; 1.99 and 1.91, respectively, for smokers vs nonsmokers; and 1.83 and 1.33, respectively, with 4 kg/m2 higher body mass index. Findings were similar for microalbuminuria defined as urinary albumin excretion of at least 25 microg/dL glomerular filtration rate. CONCLUSION: Major cardiovascular risk factors are independent correlates of microalbuminuria in nondiabetic middle-aged adults.

Expression of mRNA encoding neurotrophins and neurotrophin receptors in human granulocytes and bone marrow cells--enhanced neurotrophin-4 expression induced by LTB4.

The expression of neurotrophin and neurotrophin receptor mRNAs in human granulocytes and bone marrow cells was examined using ribonuclease protection assay and reverse transcription-polymerase chain reaction. The granulocytes expressed mRNA coding for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-4 (NT-4), but not neurotrophin-3 (NT-3). Moreover, the inflammatory mediator leukotriene B4 (LTB4) up-regulated the expression of NT-4 mRNA in granulocytes, but did not affect the expression of other neurotrophin mRNAs. Granulocytes generally lacked expression of mRNA coding for neurotrophin receptors. In contrast, human bone marrow cells consistently expressed mRNA for trkB (the BDNF and NT-4 receptor) and displayed variable expression of mRNA coding for trkA (the tyrosine kinase NGF receptor) and LNGFR (the low-affinity NGF receptor), whereas mRNA for trkC (the NT-3 receptor) was not expressed. Contrary to granulocytes, normal bone marrow cells generally expressed only low levels of mRNA encoding BDNF and NT-4. Expression of mRNA encoding NGF and NT-3 was not detected. However, significantly increased expression of BDNF mRNA was observed when bone marrow cells from patients with chronic myeloproliferative disorders (MPD) were analyzed. The results suggest that neurotrophins may act as granulocyte-derived effector molecules and that human bone marrow cells may be targets for these compounds, in particular BDNF and NT-4.

Baseline sodium-lithium countertransport and 6-year incidence of hypertension. The Gubbio Population Study.

BACKGROUND: Sodium-lithium countertransport (Na-Li CT) activity is high in persons with hypertension. This study investigated whether high Na-Li CT relates to development of hypertension. METHODS AND RESULTS: At the baseline visit of the Gubbio Population Study, 4210 people of the 5376 surveyed were 18 to 74 years old; of these, 1599 were hypertensive (systolic pressure > or = 140 mm Hg, or diastolic pressure > or = 90 mm Hg, or on antihypertensive drug therapy). Of the 2611 nonhypertensives, 302 did not have Na-Li CT measured and 580 did not participate in 6-year follow-up. This analysis, therefore, deals with data collected on 1729 men 18 to 74 years old and women 18 to 74 years old who at baseline were nonhypertensive and had Na-Li CT measurement. Compared with individuals who were nonhypertensive at baseline and follow-up, individuals with incident hypertension at follow-up (systolic pressure > or = 140 mm Hg, or diastolic pressure > or = 90 mm Hg, or on antihypertensive drug therapy) had higher baseline values of Na-Li CT, blood pressure, age, body mass index, plasma cholesterol, and alcohol intake (P < .05). Baseline Na-Li CT was positively associated (P < .05) with development of hypertension in quartile analysis, with highest incidence of hypertension among men and women with Na-Li CT in the highest quartile (for men, > or = 376 and for women, > or = 311 mumol Li-L red blood cells-1.h-1). In univariate logistic regression, incidence of hypertension was related to baseline value of Na-Li CT, blood pressure, age, body mass index, plasma cholesterol, and alcohol intake (P < .05). In multiple logistic regression analysis, individuals with baseline Na-Li CT higher by 127 mumol (pooled SD for men and women) had 1.23 times greater risk of incident hypertension with control for sex and baseline age, body mass index, systolic pressure, and other confounders (P < .001). CONCLUSIONS: Na-Li CT is a predictor of hypertension risk in adults.