Prevalence of Helicobacter pylori infection in children in the Bahamas.

OBJECTIVE: Helicobacter pylori (H pylori) is a common bacterial infection that is associated with significant morbidity and mortality worldwide. This bacterium causes a chronic infection that is causally related to illnesses ranging from gastritis, peptic ulcer disease to gastric cancer. It is generally considered that it is acquired in childhood but the prevalence varies considerably between countries and communities. There are few data on the prevalence of H pylori in the Caribbean and none on the prevalence of H pylori in children in the Bahamas. The aim of this pilot study was to determine the prevalence of H pylori infection in a cohort of school children in the Bahamas. METHODS: One hundred and sixty-one children attending a public primary school in the Bahamas were invited to participate in this study. Consent was obtained for 107 children and each participant completed a brief questionnaire. Valid data were available for 96 of these children. Active H pylori infection was determined using the 13C urea breath test (UBT). RESULTS: Fifty-two children tested positive for H pylori, yielding a prevalence of 54.2%. The median age in the study was nine years with 46.9% male and 53.1% female. No significant relationship was found between gender breastfeeding, pets and H pylori status. CONCLUSION: The prevalence reported in this study is the highest reported in asymptomatic children in the Caribbean. Further studies are required to determine risk factors for acquisition of H pylori infection in this population.

Systemic antifungal therapy for tinea capitis in children.

BACKGROUND: Tinea capitis is a common contagious fungal infection of the scalp in children. Systemic therapy is required for treatment and to prevent spread. OBJECTIVES: To assess the effects of systemic anti-fungal drugs for tinea capitis in children. SEARCH STRATEGY: We searched the Cochrane Skin Group Specialised Register (June 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2005), MEDLINE (2003 to June 2005), EMBASE ( 2003 to June 2005), LILACS (1982 to July 2005), CINAHL (1982 to July 2005), the ACP journal club (1991 to July 2005) and Healthstar (1975 to July 2005). SELECTION CRITERIA: Randomised controlled trials (RCTs) that evaluated systemic antifungal therapy in people with normal immunity under the age of 18 who had tinea capitis confirmed by microscopy or growth of dermatophytes in culture or both. DATA COLLECTION AND ANALYSIS: At least two authors independently examined each retrieved trial for eligibility and quality. MAIN RESULTS: We included 21 studies (1812 participants). Infections involving Trichophyton species: Terbinafine for four weeks and griseofulvin for eight weeks showed similar efficacy in 3 studies involving 382 participants (RR 1.09; 95% CI 0.95 to 1.26). Cure rates following treatment with itraconazole and griseofulvin for 6 weeks were similar in 1 study of 35 children (RR 1.06; 95% CI 0.81 to 1.39). Another study of 100 children did not show any significant difference in cure between itraconazole for 2 weeks compared with griseofulvin for 6 weeks (RR 0.89; 95% CI 0.76 to 1.04). There was no difference between itraconazole and terbinafine for treatment periods lasting 2 to 3 weeks in 2 studies involving 160 children (RR 0.93; 95% CI 0.72 to 1.19). Two studies that included 140 children found similar cure rates between 2 to 4 weeks of fluconazole with 6 weeks of griseofulvin (RR 0.92; 95% CI 0.80 to 1.05). Microsporum infections: There was no significant difference in cure between terbinafine and griseofulvin in children with Microsporum infections in 1 small study of 29 children (RR 0.64; 95% CI 0.19 to 2.20). AUTHORS' CONCLUSIONS: The best evidence suggests that newer treatments including terbinafine, itraconazole and fluconazole may be similar to griseofulvin in children with tinea capitis caused by Trichophyton species. Newer treatments may be preferred because shorter treatment durations may improve treatment adherence, although they may be more expensive. There is not enough evidence on the use of systemic treatments in children with Microsporum infections. Not all treatments for tinea capitis are available in paediatric formulations but all have reasonable safety profiles.

Long-term efficacy and safety of acarbose in the treatment of obese subjects with non-insulin-dependent diabetes mellitus.

BACKGROUND: Acarbose delays the release of glucose from complex carbohydrates and disaccharides by inhibiting intestinal alpha-glucosidases, attenuating postprandial increments in blood glucose and insulin. This multicenter double-blind study compared the efficacy and safety of acarbose with placebo in the treatment of obese subjects with non-insulin-dependent diabetes mellitus (NIDDM) managed by diet. METHODS: Two hundred twelve obese subjects with NIDDM who had not received any diabetic medication for at least 12 weeks were randomized to receive acarbose or placebo. The subjects were stratified by fasting glucose level above or below 11.1 mmol/L (200 mg/dL). Based on the subject's therapeutic response and tolerance, the acarbose dosage was titrated from 50 to 300 mg three times per day. This 36-week study consisted of a 6-week pretreatment period, a 24-week double-blind treatment period, and a 6-week posttreatment period. RESULTS: Ninety-one subjects given acarbose and 98 subjects who received placebo were evaluable for efficacy. During a standard meal tolerance test at the double-blind end point, the differences between treatment groups in mean change from baseline were as follows: 0.9 mmol/L (16 mg/dL) for fasting plasma glucose level, approximately 2.8 mmol/L (50 mg/dL) for postprandial plasma glucose level, and 0.59% (P < .0001) for hemoglobin A1c concentration (for all three measurements, values decreased in the acarbose group and increased in the placebo group). CONCLUSIONS: Acarbose improved both fasting and postprandial hyperglycemia and improved overall glycemic control as measured by the hemoglobin A1c level. These findings suggest a beneficial role for acarbose in combination with diet in the treatment of obese subjects with NIDDM.

A double-blind placebo-controlled trial evaluating the safety and efficacy of acarbose for the treatment of patients with insulin-requiring type II diabetes.

OBJECTIVE: To determine whether a forced titration of acarbose (from 50 to 300 mg three times daily) administered over a 24-week period, in conjunction with diet and insulin therapy, improves glycemic control and reduces daily insulin requirements in insulin-requiring type II diabetes. RESEARCH DESIGN AND METHODS: This multicenter, randomized, double-blind, placebo-controlled trial was 36 weeks in duration. The trial consisted of a 6-week pretreatment period, a 24-week double-blind treatment period, and a 6-week post-treatment follow-up period. The primary efficacy variables were the mean change from baseline in HbA1c levels and the mean percentage change from baseline in total daily insulin dose. RESULTS: Treatment with acarbose was associated with significant reductions in HbA1c levels of 0.40% (P = 0.0001) and in total daily insulin dose of 8.3% (P = 0.0015). There were also significant reductions in all plasma glucose variables measured, including a 0.9 mmol/l reduction in fasting glucose (P = 0.0440), a 2.6 mmol/l reduction in glucose Cmax (P = 0.0001) and a 270 mmol.min-1.l-1 reduction in glucose area under the curve (P = 0.0002). Although acarbose treatment was associated with a greater incidence of adverse events than was placebo treatment, primarily flatulence and diarrhea, these events did not generally prevent patients from completing the study. CONCLUSIONS: The results of this study suggest that acarbose is a safe and effective adjunct to diet and insulin therapy for the management of insulin-requiring type II diabetes.

Reduction of glycosylated hemoglobin and postprandial hyperglycemia by acarbose in patients with NIDDM. A placebo-controlled dose-comparison study.

OBJECTIVE: To compare the safety and efficacy of three doses of acarbose (100, 200, and 300 mg three times daily) with placebo for the treatment of non-insulin-dependent diabetes mellitus (NIDDM) in patients maintained on dietary therapy alone. RESEARCH DESIGN AND METHODS: This multicenter double-blind placebo-controlled trial was 22 weeks in duration. The trial consisted of a 2-week screening period, a 4-week placebo run-in period, and a 16-week double-blind treatment period. The primary measure of drug efficacy was the mean change from baseline in HbA1c levels. Additional efficacy variables included the mean change from baseline in fasting and postprandial plasma glucose and serum insulin levels. RESULTS: After 16 weeks of treatment, acarbose-treated patients had statistically significant reductions in mean HbA1c levels of 0.78, 0.73, and 1.10% (relative to placebo) in the 100-, 200-, and 300-mg t.i.d. groups, respectively. Significant reductions in fasting and postprandial plasma glucose levels, glucose area under the time-concentration curve, and maximum glucose concentration were also observed in acarbose-treated patients. Although there were no statistically significant differences among the 100-, 200-, and 300-mg treatment groups, there was a trend toward a dose-response relationship for most plasma glucose variables that were measured. Gastrointestinal side effects (e.g., abdominal pain, flatulence, and diarrhea) and serum transaminase elevations (e.g., aspartate aminotransferase [AST] and alanine aminotransferase [ALT] were more frequently reported in the acarbose-treated patients than in the placebo-treated control patients. Transaminase elevations occurred only at the 200-, and 300-mg dosages and were readily reversible on discontinuation of treatment. CONCLUSIONS: Acarbose at doses of 100, 200, and 300 mg administered three times daily for 16 weeks significantly reduced HbA1c levels and postprandial hyperglycemia. Treatment with acarbose is a safe and effective adjunct to dietary therapy for the treatment of NIDDM.

Some metabolic effects of overeating in man.

Metabolic responses to 20 days of overeating were examined in five healthy volunteers. Overfeeding caused a variable increase (1-18%) in basal metabolic rate but no change in metabolic rate during light exercise. Postprandial resting metabolic rate was 8-40% higher (mean 18%) during overeating. The increase in oxygen consumption during a norepinephrine infusion was the same before (20 +/- 2%) and after (17 +/- 3%) overfeeding. Overfeeding elevated basal insulin concentrations in all subjects and increased the insulin response to intravenous glucose in four of five subjects. Overfeeding did not significantly alter mean serum T3 concentrations or erythrocyte 86Rb uptake (an index of Na+,K+-ATPase activity). These data do not confirm reports that overfeeding increases metabolic rate more during exercise than during rest. They also suggest that the increase in resting metabolic rate during overfeeding is not caused by increased responsiveness to norepinephrine or increased serum T3 concentrations.

Thermic effect of medium-chain and long-chain triglycerides in man.

The thermic effects of 400 kcal meals of medium-chain triglycerides (MCT) and long-chain triglycerides (LCT) were compared in seven healthy men. Metabolic rate was measured before the meals and for 6 h after the meals by indirect calorimetry. Mean postprandial oxygen consumption was 12% higher than basal oxygen consumption after the MCT meal but was only 4% higher than the basal oxygen consumption after the LCT meal. There was a 25-fold increase in plasma beta-hydroxybutyrate concentration and a slight increase in serum insulin concentration after MCT ingestion but not after LCT ingestion. Plasma triglyceride concentrations increased 68% after the LCT meal and did not change after the MCT meal. These data raise the possibility that long-term substitution of MCT for LCT would produce weight loss if energy intake remained constant.

Multicenter, placebo-controlled trial comparing acarbose (BAY g 5421) with placebo, tolbutamide, and tolbutamide-plus-acarbose in non-insulin-dependent diabetes mellitus.

BACKGROUND: Acarbose delays release of glucose from complex carbohydrates and disaccharides by inhibiting intestinal alpha-glucosidases, thereby attenuating postprandial increments in blood glucose and insulin. This multicenter, double-blind, placebo-controlled study compared the efficacy and safety of diet alone, acarbose, tolbutamide, and acarbose-plus-tolbutamide in non-insulin-dependent diabetes mellitus (NIDDM) patients. PATIENTS AND METHODS: A total of 290 patients with NIDDM and fasting plasma glucose levels of at least 140 mg/dL were randomized to receive treatment TID with acarbose 200 mg, tolbutamide 250 to 1,000 mg, a combination of both drugs, or placebo. A 6-week run-in period was followed by double-blind treatment for 24 weeks, then a 6-week follow-up period. RESULTS: All active treatments were superior (P < 0.05) to placebo in reducing postprandial hyperglycemia and HbA1c levels. The ranking in order of efficacy was: acarbose-plus-tolbutamide, tolbutamide, acarbose, and placebo. The postprandial reductions in glucose were approximately 85 mg/dL for acarbose-plus-tolbutamide, 71 mg/dL for tolbutamide, 56 mg/dL for acarbose, and 13 mg/dL for placebo. Tolbutamide was associated with increases in body weight and postprandial insulin levels when taken alone, but these were ameliorated when tolbutamide was taken in combination with acarbose. Acarbose alone or in combination with tolbutamide caused significantly more gastrointestinal adverse events (mainly flatulence and soft stools or diarrhea) than tolbutamide or placebo, but these were generally well tolerated. Clinically significant elevations in hepatic transaminase levels occurred in 3 patients in the acarbose group and 2 in the acarbose-plus-tolbutamide group. Transaminase levels returned to normal when therapy was discontinued. CONCLUSIONS: Acarbose was effective and well tolerated in the treatment of NIDDM. Control of glycemia was significantly better with acarbose compared with diet alone. Acarbose-plus-tolbutamide was superior to tolbutamide alone.

Structural features and biochemical properties of TNF-alpha converting enzyme (TACE).

Tumor necrosis factor-alpha is a potent cytokine, secreted primarily by activated monocytes and macrophages, that possesses a broad range of immunomodulating properties. Involvement of this cytokine has been validated in disease states such as arthritis and Crohn's disease and implicated in diverse neuroimmunological pathologies such as multiple sclerosis, Alzheimers and stroke. TNF-alpha is initially synthesized as a 26 kDa precursor molecule that is subsequently processed to the mature form by cleavage of the Ala76 Val77 bond. The 17 kDa carboxy-terminal protein is then secreted to function in a paracrine manner. The enzyme that processes precursor TNF-alpha has previously been identified as a microsomal metalloprotease called TNF-alpha converting enzyme (TACE). We have now purified and partially cloned the enzyme. TACE represents a novel target for therapeutic intervention in a variety of inflammatory and neuroimmunological diseases.

Mitochondrial respiratory enzyme function and superoxide dismutase activity following brain glutathione depletion in the rat.

In substantia nigra from patients with Parkinson's disease, there are decreased levels of reduced glutathione (GSH) and diminished activities of mitochondrial complex I and alpha-ketoglutarate dehydrogenase (alpha-KGDH), along with increased activity of superoxide dismutase (SOD). However, the interrelationship among these events is uncertain. We now report the effect of decreased brain GSH levels on SOD and mitochondrial respiratory enzyme activity in rat brain. In addition, we have investigated the ability of thioctic acid, an endogenous antioxidant, to alter these parameters. Unilateral or bilateral intracerebroventricular (ICV) administration of buthionine sulphoximine (BSO; 1 x 3.2 mg or 2 x 1.6 mg) over a 48-hr period reduced cortical GSH by 55-70%. There was no change in the activity of complex I, II/III, or IV or of citrate synthase in cortex. Similarly, there was no alteration of mitochondrial or cytosolic SOD activity. Thioctic acid (50 or 100 mg/kg IP) alone had no effect on cortical GSH levels in control animals and did not reverse the decrease in GSH levels produced by unilateral or bilateral ICV BSO administration. Thioctic acid (50 or 100 mg/kg IP) had no overall effect on complex I, II/III, or IV or on citrate synthase activity in control animals. Thioctic acid also did not alter cortical mitochondrial respiratory enzyme activity in BSO-treated rats. At the lower dose, thioctic acid tended to increase mitochondrial and cytosolic SOD activity in control animals and in BSO-treated rats. However, at the higher dose, thioctic acid tended to decrease mitochondrial SOD activity. Overall, there was no consistent effect of thioctic acid (50 or 100 mg/kg IP) on SOD activity in control or BSO-treated animals. This study shows that BSO-induced glutathione deficiency does not lead to alterations in mitochondrial respiratory enzyme activity or to changes in SOD activity. GSH depletion in Parkinson's disease therefore may not account for the alterations occurring in complex I and mitochondrial SOD in substantia nigra. Thioctic acid did not alter brain GSH levels or mitochondrial function. Interestingly, however, it did produce some alterations in SOD activity, which may reflect either its antioxidant activity or its ability to act as a thiol-disulphide redox couple.

The isomers of thioctic acid alter C-deoxyglucose incorporation in rat basal ganglia.

Nigral cell death in Parkinson's disease is associated with decreased reduced glutathione (GSH) levels, impaired complex I activity and inhibition of alpha-ketoglutarate dehydrogenase (alpha-KGDH) in substantia nigra. Thioctic acid exerts antioxidant activity through a thiol-disulphide redox couple and is an essential cofactor for alpha-KGDH. However, it is not known whether or not thioctic acid enters basal ganglia or exerts beneficial effects in Parkinson's disease. As a global measure of altered cerebral function, the effect of R- and S-thioctic acid on 14C-2-deoxyglucose (14C-2DG) incorporation was investigated in rats. Rats were treated with either R- or S-thioctic acid (50 mg/kg IP) or 0.9% saline acutely or for 5 days and 14C-2DG incorporation in basal ganglia was assessed. Following acute administration, R- but not S-thioctic acid caused an overall increase in 14C-2DG incorporation that was significant in both substantia nigra zona compacta and zona reticulata. R-thioctic acid also increased the incorporation of 14C-2DG in the medial forebrain bundle, thalamus, and red nucleus. S-thioctic acid decreased 14C-2DG incorporation in the subthalamic nucleus, but increased it in the red nucleus. Following repeated administration, R-thioctic acid no longer increased 14C-2DG incorporation in either zona compacta or zona reticulata of substantia nigra. However, both R- and S-thioctic acid now decreased 14C-2DG incorporation in the subthalamic nucleus. The data suggest that thioctic acid does enter the brain can alter neuronal activity in areas of the basal ganglia intimately associated with the motor deficits exhibited in Parkinson's disease.

The effect of adrenergic blockade on glucose-induced thermogenesis.

The effect of alpha, beta, or combined sympathetic blockade on the increase in energy expenditure and concentrations of norepinephrine, glucose, and insulin following oral intake of 100 g of glucose was studied in lean subjects. Alpha blockade with intravenous (IV) phentolamine (n = 5) infusion increased oxygen consumption after glucose ingestion but no more than it increased the oxygen consumption when no glucose was given. Beta blockade with IV propranolol (n = 13) and combined alpha and beta blockade (n = 6) did not affect basal metabolic rate or the increase in metabolic rate after glucose ingestion. Phentolamine or combined propranolol plus phentolamine administration markedly increased plasma norepinephrine concentrations. Basal glucose and insulin concentrations were not affected by any of the infused drugs. Glucose-stimulated insulin concentrations were unchanged by propranolol and combined blockade, whereas there was a trend (P = 0.07) toward an increased response to glucose during phentolamine administration. These data do not support a role for the sympathetic nervous system in the increase in metabolic rate following glucose ingestion. The increase in metabolic rate during phentolamine administration can be attributed to beta adrenergic stimulation.

Pyrazinoylguanidine downregulates the glucose fatty-acid cycle in hypertensive, hyperinsulinemic diabetic patients.

Eight hypertensive patients with noninsulin dependent diabetes mellitus (NIDDM) were administered the experimental drug pyrazinoylguanidine (PZG) either alone or in combination with calcium-channel or beta-blockers. This treatment appeared to "downregulate" the glucose fatty acid cycle and reduced both systolic and diastolic blood pressures and mean body weight. Patients served as their own controls in this dose-escalation study, which included placebo treatment (baseline) 3 weeks, 300 mg PZG for 3 weeks and 600 mg for 3 weeks. PZG reduced increased serum concentrations of free fatty acids (FFA), glucose, and triglycerides (TG). TG concentrations correlated inversely with serum HDL-cholesterol concentrations. The beta-blockers used by several patients increased their FFA, glucose, insulin and TG concentrations, as well as blunting their response to PZG. The calcium-channel blockers exerted these effects to a much lesser extent. PZG reduced or abolished glycosuria, related to PZG's capacity to decrease hyperglycemia. Withdrawal of PZG restored glycosuria, as blood sugar increased. PZG was well tolerated. No patient reported any adverse effect or missed a weekly clinic visit (12 weeks). PZG deserves further study as supplementary and/or replacement therapy in NIDDM patients who are hypertensive and hyperlipidemic.

Cyclosporin inhibition of apoptosis induced by mitochondrial complex I toxins.

The cause of dopaminergic cell death in Parkinson's disease (PD) remains unknown, but may involve oxidative stress and mitochondrial complex I deficiency. Opening of the permeability transition pore and disruption of the mitochondrial transmembrane potential are known to be common events in the apoptotic pathway. Cyclosporin A and its non-immunosuppressant analogue, N-methyl-4-valine cyclosporin inhibit the opening of the mitochondrial megachannel. Complex I inhibitors, including MPP+, are known to induce both apoptosis in cell culture and parkinsonism in man and other primates. The present study using propidium iodide and FITC-TUNEL staining to identify apoptotic cells, demonstrates that rotenone, MPP+ and tetrahydroisoquinoline induce apoptosis in PC12 cells. Apoptosis induced by these agents was decreased by cyclosporin A and N-methyl-4-valine cyclosporin. Thus, apoptosis induced by inhibitors of mitochondrial complex I is probably mediated by permeability pore opening and collapse of the mitochondrial membrane potential. This observation may allow the development of novel neuroprotective strategies in disorders that may involve mitochondrial dysfunction and apoptotic cell death.

Free radical scavengers protect dopaminergic cell lines from apoptosis induced by complex I inhibitors.

The cause of dopaminergic neurodegeneration in Parkinson's disease remains unclear, but may involve both oxidative stress and mitochondrial complex I inhibition. We have demonstrated that complex I inhibitors, including rotenone, MPP+, isoquinoline and tetrahydroisoquinoline, induce apoptosis in PC12 and SK-N-MC dopaminergic cell lines which was decreased by pretreatment with N-acetylcysteine, TEMPO, dihydrolipoic acid or pyrrolidine dithiocarbamate. These results indicate that the pathway leading to apoptosis following complex I inhibition involves free radical generation. The free radical generation may result directly from inhibition of the mitochondrial respiratory chain or indirectly during the apoptotic process itself. This has important implications for our understanding of the relationship between complex I deficiency and oxidative stress and neurodegeneration in Parkinson's disease.

Troglitazone in type II diabetes mellitus.

Troglitazone, a new antihyperglycemic agent, is approved for use alone, with oral sulfonylureas, or with insulin in the treatment of type II diabetes mellitus. Rather than stimulating insulin secretion, it enhances insulin sensitivity. Potential advantages of troglitazone over oral sulfonylureas include decreased endogenous insulin concentrations, decreased exogenous insulin requirements, reduced hypoglycemic risk, and convenient once/day administration. The effect on morbidity and mortality from lowering endogenous and exogenous insulin concentrations remains to be determined. Troglitazone also has potential disadvantages. It induces cytochrome P450 isoenzyme 3A4, although few drug interactions have been identified to date. Serum transaminases must be monitored routinely because of rarely reported cases of idiosyncratic hepatocellular injury. In addition, the cost of troglitazone is much higher than that of other oral antihyperglycemic agents or insulin. Given the available information, troglitazone has limited benefit over oral sulfonylureas or metformin as monotherapy or in combination with oral sulfonylureas. Until additional combination and comparative studies have been done, the agent should be reserved for patients with poor glycemic control receiving high daily doses of insulin.

Dietary intake in patients with acquired immunodeficiency syndrome (AIDS), patients with AIDS-related complex, and serologically positive human immunodeficiency virus patients: correlations with nutritional status.

One of the major clinical manifestations of the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC) is the development of cachexia. This most likely results from a multifactorial interplay of poor diet, malabsorption, and altered metabolism. To assess the potential role of nutrient intake in the development or persistence of malnutrition, a detailed analysis was performed of a 72-hr diet record in clinically stable patients with AIDS (N = 18), ARC (N = 12) and in human immunodeficiency virus (HIV) seropositive controls without significant manifestations of disease (N = 13). Total calorie intake was 39.1 +/- 13.2 kcal/kg/day in AIDS patients vs 34.6 +/- 7.8 kcal/kg/day in ARC patients or 31.9 +/- 17.7 kcal/kg/day in HIV seropositive cases (all p = NS). Likewise, mean protein intakes were similar among the groups and exceeded recommended daily dietary allowance (RDA) guidelines. The mean body weight changes from the inception of illness were -11 +/- 1% in AIDS, -6 +/- 7% in ARC, vs +3 +/- 2% in HIV-seropositive-only cases (p less than 0.05 vs AIDS and ARC). Dietary vitamin and mineral analysis revealed that 88% of AIDS, 88% of HIV seropositive, and 89% of ARC patients were ingesting less than 50% RDA for at least one nutrient. The mean number of deficiencies per patient was 1.8 +/- 1.3 in AIDS, 3.8 +/- 3.5 in ARC, and 2.9 +/- 2.5 in HIV-seropositive-only cases (p less than 0.05 AIDS vs ARC). There were no significant correlations between specific anthropometric measurements and dietary intakes of protein or fat.(ABSTRACT TRUNCATED AT 250 WORDS)