Sub-acute herpes simplex virus myelitis in a patient with esophageal cancer on chemo-radiation with 5-fluorouracil: a case report.

No reported cases to date describe herpes simplex virus (HSV) myelitis in association with cancer and chemo-radiation. We report a case of sub-acute HSV myelitis in a 54-year-old man receiving chemo-radiation with 5-flourouracil for esophageal cancer who presented to the emergency department with increasing numbness in both lower limbs that gradually spread to waist level. Magnetic resonance imaging with gadobutrol contrast 1 week later showed transverse myelitis involving the dorsal columns. Radiation-induced myelitis was suspected, and the patient was initially treated with dexamethasone; however, CSF analysis revealed HSV myelitis. Treatment with antivirals resolved much of the numbness. HSV myelitis can be confused with complications of radiation or malignancy in patients presenting with focal neurological deficits.

Are elevated circulating intercellular adhesion molecule 1 levels more strongly predictive of diabetes than vascular risk? Outcome of a prospective study in the elderly.

AIMS/HYPOTHESIS: The aim of this prospective study was to determine whether circulating intercellular adhesion molecule (ICAM) 1, as a potential surrogate of 'endothelial activation', is more strongly associated with risk of vascular events than with incident diabetes. METHODS: We related baseline ICAM-1 levels to vascular events (866 CHD and stroke events in 5,685 participants) and incident diabetes (292 in 4,945 without baseline diabetes) in the elderly over 3.2 years of follow-up. RESULTS: ICAM-1 levels correlated positively with triacylglycerol but negatively with LDL- and HDL-cholesterol. ICAM-1 levels were higher in those who developed diabetes (388.6 +/- 1.42 vs 369.4 +/- 1.39 ng/ml [mean+/-SD], p = 0.011) and remained independently associated with new-onset diabetes (HR 1.84, 95% CI 1.26-2.69, p = 0.0015 per unit increase in log[ICAM-1] after adjusting for classical risk factors and C-reactive protein). By contrast, ICAM-1 levels were not significantly (p = 0.40) elevated in those who had an incident vascular event compared with those who remained event-free, and corresponding adjusted risk associations were null (HR 0.98, 95% CI 0.80-1.22, p = 0.89) in analyses adjusted for other risk factors. CONCLUSIONS/INTERPRETATION: We show that elevated ICAM-1 levels are associated with risk of incident diabetes in the elderly at risk, despite no association with incident cardiovascular disease risk. We suggest that perturbations in circulating ICAM-1 levels are aligned more towards diabetes risk.

Genetic variation in the interleukin-1 beta-converting enzyme associates with cognitive function. The PROSPER study.

Inflammation is thought to play an important role in the development of cognitive decline and dementia in old age. The interleukin-1 signalling pathway may play a prominent role in this process. The gene encoding for interleukin-1 beta-converting enzyme (ICE) is likely to influence IL-1 beta levels. Inhibition of ICE decreases the age-related increase in IL-1 beta levels and may therefore improve memory function. We assessed whether genetic variation in the ICE gene associates with cognitive function in an elderly population. All 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) were genotyped for the 10643GC, 9323GA, 8996AG and 5352GA polymorphisms in the ICE gene. Cross-sectional associations between the polymorphisms and cognitive function were assessed with linear regression. Longitudinal associations between polymorphisms, haplotypes and cognitive function were assessed with linear mixed models. All associations were adjusted for sex, age, education, country, treatment with pravastatin and version of test where appropriate. Subjects carrying the variants 10643C and 5352A allele had significantly lower IL-1 beta production levels (P < 0.01). Furthermore, we demonstrated that homozygous carriers of the 10643C and the 5352A allele performed better on all executive function tests at baseline and during follow-up compared to homozygous carriers of the wild-type allele (all P < 0.02). The haplotype with two variants present (10643C and 5352A) was associated with better executive function (all P < 0.02) compared to the reference haplotype without variants. For memory function the same trend was observed, although not significant. Genetic variation in the ICE gene is associated with better performance on cognitive function and lower IL-1 beta production levels. This suggests that low levels of IL-1 beta are protective for memory and learning deficits. Inhibition of ICE may therefore be an important therapeutic target for maintaining cognitive function in old age.

Lymphotoxin-alpha C804A polymorphism is a risk factor for stroke. The PROSPER study.

Inflammation plays a prominent role in the development of atherosclerosis, which is the most important risk factor for vascular events. Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine and is found to be expressed in atherosclerotic lesions. We investigated the association between the C804A polymorphism within the LTA gene and coronary and cerebrovascular events in 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). The primary endpoint was the combined endpoint of death from coronary heart disease, non-fatal myocardial infarction, and clinical stroke. Secondary endpoints were the coronary and cerebrovascular components separately. All associations were assessed with a Cox-proportional hazards model adjusted for sex, age, pravastatin use, and country. Our overall analysis showed a significant association between the C804A polymorphism and the primary endpoint (p = 0.03). After stratification for gender, this association was found only in males. Furthermore, we found that the association between the C804A polymorphism and the primary endpoint was mainly attributable to clinical strokes (p = 0.02). The C804A polymorphism in the LTA gene associates with clinical stroke, especially in men. But further research is warranted to confirm our results.

Synthetic polycyclic musks in Hong Kong sewage sludge.

Synthetic polycyclic musks [Cashmeran (DPMI), Celestolide (ADBI), Phantolide (AHMI), Traseolide (ATII), Tonalide (AHTN), and Galaxolide (HHCB)] were determined in dewatered sludge samples from 10 major sewage treatment plants in Hong Kong using primary treatment (PT), secondary treatment (SecT) or chemical-enhanced primary treatment (CEPT) methods. The concentrations of HHCB, AHTN, AHMI and ADBI ranged from below detection limits to 78.6mg/kg dry weight. HHCB and AHTN were the two predominant polycyclic musks in sludge samples, suggesting the extensive use of these two polycyclic musks in Hong Kong. Polycyclic musk levels in CEPT sludge were significantly higher than those in SecT and PT sludge, suggesting that CEPT sludge has a higher ability to retain polycyclic musks. Comparisons to global concentrations revealed that HHCB and AHTN concentrations detected in Hong Kong sludge ranked first and second respectively. However, the estimated levels of HHCB and AHTN in the discharged effluent from sewage treatment plants may pose low potential risks to aquatic organisms according to the threshold effect levels derived for fish. Nevertheless, the polycyclic musks released in sewage treatment plant effluents may bioconcentrate and bioaccumulate in the marine environment in Hong Kong. Therefore, monitoring studies in marine ecosystems, particularly on the two prevailing polycyclic musks, are necessary.

Polycyclic musks in green-lipped mussels (Perna viridis) from Hong Kong.

Six polycyclic musk compounds [Cashmeran (DPMI), Celestolide (ADBI), Phantolide (AHMI), Traseolide (ATII), Tonalide (AHTN), and Galaxolide (HHCB)] were analysed in marine green-lipped mussels (Perna viridis) from Hong Kong. ADBI, HHCB and AHTN were detected in almost all samples, while AHMI, ATII and DPMI were not detected. Concentrations of ADBI, HHCB and AHTN in mussels ranged from below detection limit-0.0743 (mean: 0.0246), 0.247-6.08 (mean: 1.15) and 0.0591-0.738 (mean: 0.190)mg/kg lipid weight, respectively. Mussels from two sampling sites in central Victoria Harbour contained the highest total polycyclic musk levels, suggesting that these waters are heavily influenced by domestic sewage. Concentrations of HHCB and AHTN detected in the mussel samples were the second highest and the highest levels, respectively, compared to global concentrations. A preliminary risk assessment indicated that HHCB and AHTN in mussels pose little or no threat to the health of shellfish consumers. Nevertheless, more comprehensive studies are required to further assess the ecological and human health risks associated with polycyclic musks.

Genetic variation in the interleukin-10 gene promoter and risk of coronary and cerebrovascular events: the PROSPER study.

Proinflammatory cytokines, like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), are implicated in the development of atherosclerosis. The role of anti-inflammatory cytokines, like IL-10, is largely unknown. We investigated the association of four single nucleotide polymorphisms (SNPs) in the promoter region of the IL-10 gene (4259AG, -1082GA, -592CA, and -2849GA), with coronary and cerebrovascular disease in participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial. All associations were assessed with Cox proportional hazards models adjusted for sex, age, pravastatin use, and country. Haplotype analysis of the four SNPs showed a significant association between haplotype 4 (containing the -592A variant allele) and risk of coronary events (P = 0.019). Moreover, analysis of separate SNPs found a significant association between -2849AA carriers with incident stroke (HR (95%CI) 1.50 (1.04-2.17), P value = 0.02). Our study suggests that not only proinflammatory processes contribute to atherosclerosis, but that also anti-inflammatory cytokines may play an important role.

The dual-specificity CLK kinase induces neuronal differentiation of PC12 cells.

CLK is a dual-specificity protein kinase capable of phosphorylating serine, threonine, and tyrosine residues. We have investigated the action of CLK by establishing stable PC12 cell lines capable of inducibly expressing CLK. Expression of CLK in stably transfected PC12 cells mimicked a number of nerve growth factor (NGF)-dependent events, including the morphological differentiation of these cells and the elaboration of neurites. Moreover, CLK expression enhanced the rate of NGF-mediated neurite outgrowth of these cells, indicating that CLK expression and NGF treatment activate similar signal transduction pathways. CLK expression, unlike NGF, was not able to promote PC12 cell survival in serum-free media, demonstrating that CLK only partially recapitulated the actions of NGF on these cells and that the biochemical pathways necessary for morphological differentiation can be stimulated without also stimulating those necessary for survival. Induction of CLK expression also resulted in the selective activation of protein kinases that are components of growth factor-stimulated signal transduction cascades, including ERK1, ERK2, pp90RSK, and S6PKII. Induction of CLK expression, however, did not stimulate pp70S6K or Fos kinase, two NGF-sensitive protein kinases. These data indicate that CLK action mediates the morphological differentiation of these cells through its capacity to independently stimulate signal transduction pathways normally employed by NGF.

Atrazine concentrations, gonadal gross morphology and histology in ranid frogs collected in Michigan agricultural areas.

The triazine herbicide atrazine has been suggested to be a potential disruptor of normal sexual development in male frogs. The goals of this study were to collect native ranid frogs from sites in agricultural and non-agricultural areas and determine whether hypothesised atrazine effects on the gonads could be observed at the gross morphological and histological levels. Juvenile and adult green frogs (Rana clamitans), bullfrogs (R. catesbeiana) and leopard frogs (R. pipiens) were collected in the summers of 2002 and 2003. Atrazine concentrations were below the limit of quantification at non-agricultural sites, and concentrations did not exceed 2 microg/L at most agricultural sites. One concentration greater than 200 microg atrazine/L was measured once at one site in 2002. Hermaphroditic individuals with both male and female gonad tissue in either one or both gonads, were found at a low incidence at both non-agricultural and agricultural sites, and in both adults and juveniles. Testicular oocytes (TO) were found in male frogs at most of the sites, with the greatest incidence occurring in juvenile leopard frogs. TO incidence was not significantly different between agricultural and non-agricultural sites with the exception of juveniles collected in 2003. Atrazine concentrations were not significantly correlated with the incidence of hermaphroditism, but maximum atrazine concentrations were correlated with TO incidence in juvenile frogs in 2003. However, given the lack of a consistent relationship between atrazine concentrations and TO incidence, it is more likely the TOs observed in this study result from natural processes in development rather than atrazine exposure.

Plasma steroid hormone concentrations, aromatase activities and GSI in ranid frogs collected from agricultural and non-agricultural sites in Michigan (USA).

The triazine herbicide atrazine has been hypothesized to disrupt sexual development in frogs by up-regulating aromatase activity, resulting in greater estradiol (E2) concentrations and causing feminization in males. The goal of this study was to collect native ranid frogs from atrazine-exposed ponds and determine whether relationships exist between measured atrazine concentrations and the gonadosomatic index (GSI), plasma concentrations of testosterone (T), E2 or 11-ketotestosterone (KT), or with aromatase activity. In the summer of 2002 and 2003, adult and juvenile green frogs (Rana clamitans), bullfrogs (R. catesbeiana) and Northern leopard frogs (R. pipiens) were collected from areas with extensive corn cultivation and areas where there was little agricultural activity in south-central Michigan. Atrazine concentrations were below the limit of quantification at non-agricultural sites. Atrazine concentrations did not exceed 2 microg/L at most agricultural sites, but a concentration of 250 microg atrazine/L was measured in one sample from one site in 2002. Plasma steroid concentrations varied among locations. Aromatase activity was measurable in less than 11% of testes in adult males, and in less than 4% of testes in juvenile males. Median aromatase activities in ovaries of adult females ranged from 3 to 245 pmol/h/mg protein, and maximum activities were 2.5-fold greater in juveniles than in adults. Atrazine concentrations were not significantly correlated with any of the parameters measured in this study. These results indicate that atrazine does not up-regulate aromatase in green frogs in the wild, and does not appear to affect plasma steroid hormone concentrations.

Comparison of two noninvasive screening tests for renovascular hypertension.

OBJECTIVE: To compare and contrast the diagnostic accuracy rates of two newer noninvasive screening tests for renovascular hypertension, the most common curable cause of secondary hypertension. PATIENTS AND METHODS: One hundred fifty patients, thought to have a high probability of renovascular hypertension by established clinical criteria, underwent both the captopril challenge test and the renal scintigram with angiotensin-converting enzyme inhibitor, while on their usual antihypertensive regimen except angiotensin-converting enzyme inhibitors. If the result of either test was abnormal, angiography was undertaken, followed immediately by angioplasty (if a stenosis was found) or by renal vein renin determinations. Patients whose blood pressures were lower 6 to 12 weeks after a revascularization procedure (surgery or angioplasty) were diagnosed as having renovascular hypertension. RESULTS: Of the 150 patients, 100 underwent angiography, and 59 had renal artery stenosis. Of 53 patients who had surgery (n = 21) or angioplasty (n = 32), 51 had lowered blood pressures compared with before the procedure. Sensitivity and specificity of the tests were as follows: renal scintigram with angiotensin-converting enzyme inhibitor: 92% and 91% (all patients) and 92% and 80% (only patients with angiograms); captopril challenge test: 76% and 82% (all patients) and 76% and 58% (only patients with angiograms). Little difference in accuracy rates was observed in subgroup analyses in patients with chronic renal impairment, previous diuretic or beta-blocker therapy, or bilateral renal artery stenosis. CONCLUSIONS: In selected, treated patients with a high probability of renovascular hypertension, the renal scintigram with angiotensin-converting enzyme inhibitor was a more accurate noninvasive screening test than the captopril challenge test. Noninvasive screening tests for renovascular hypertension can help to identify patients who should undergo angiography and often predict success after revascularization.

Improved safety of glucagon testing for pheochromocytoma by prior alpha-receptor blockade. A controlled trial in a patient with a mixed ganglioneuroma/pheochromocytoma.

The glucagon stimulation test has been superseded in recent years by the clonidine suppression test because it can provoke dangerous increases in blood pressure in patients with pheochromocytomas. We describe the first patient in whom a pheochromocytoma was diagnosed by a glucagon test, after which the blood pressure (but not the plasma catecholamine) response to a second injection of glucagon was blocked by pretreatment with phenoxybenzamine. After the tumor (which contained both pheochromocytoma and ganglioneuroma tissue) was removed, a third glucagon test result was negative. This experience suggests that patients with normal plasma catecholamine levels who are suspected of harboring a pheochromocytoma may be accurately diagnosed, but potentially dangerous increases in blood pressure may be minimized, by performing the glucagon test after alpha-adrenergic blockade.

Electrocardiographic changes during acute treatment of hypertensive emergencies with sodium nitroprusside or fenoldopam.

BACKGROUND: Electrocardiograms are routinely obtained before and during the acute treatment of hypertensive emergencies, usually to rule out "ischemic changes." Despite a few anecdotal reports of electrocardiographic changes, little is known about the incidence and significance of such changes, or their relationship to the treatment used. METHODS: We prospectively analyzed 12-lead electrocardiograms from 21 patients admitted for hypertensive emergencies (average blood pressure, 222 +/- 4/140 +/- 3 mm Hg). Patients were randomly assigned to treatment with sodium nitroprusside (n = 11) or the dopamine receptor agonist fenoldopam mesylate (n = 10). Electrocardiograms were obtained at baseline and within 30 minutes of reaching goal blood pressure (diastolic blood pressure, 100 to 110 mm Hg). RESULTS: There was no significant effect of either drug treatment on PR interval, QRS duration, QT interval, or R-wave amplitude, and no major ST-segment changes were noted. During treatment with either drug, the average T-wave amplitude decreased in all leads except aVR. New T-wave inversions in lead V4 occurred in two and four patients after fenoldopam and nitroprusside treatment, respectively. There were no clinically apparent episodes of myocardial ischemia in any patient. CONCLUSIONS: Even in the absence of obvious myocardial ischemia, a decrease in T-wave amplitude, including T-wave inversion, occurs commonly during acute blood pressure reduction in hypertensive emergencies, an observation that may be explained by the accompanying acute changes in cardiac chamber volumes.

Dopamine receptor agonists in cardiovascular medicine.

The cardiovascular and renal effects of dopamine are mediated through peripheral catecholamine receptors. Knowledge of the receptor type responsible for each of the actions of dopamine leads to its rational use clinically and to understanding the hemodynamic actions of the newer dopamine receptor agonists recently introduced into clinical trials. Several of the newer agonists have profiles of receptor activities that differ from dopamine, and early clinical studies indicate that they will have different therapeutic indications and applications.

Optimal insulin delivery in diabetic ketoacidosis (DKA) and hyperglycemic, hyperosmolar nonketotic coma (HHNC).

Both diabetic ketoacidosis (DKA) and hyperglycemic, hyperosmolar nonketotic coma (HHNC) are stressful metabolic occurrences brought about by the orchestration of numerous events. Adequate hydration and replacement of electrolytes, along with physiologic doses of insulin, are treatment objectives for both of these conditions. Additionally, the physician must search for the factors precipitating these events and frequently evaluate the patient's overall condition.

Efficacy of nifedipine as a step 3 antihypertensive drug.

The efficacy of nifedipine (N) as a "step 3" antihypertensive drug was assessed in 15 patients who remained hypertensive in spite of atenolol 100 mg and bendrofluazide 5 mg daily. Nifedipine was added in doses of 10, 20, and 30 mg three times daily in a placebo-controlled double-blind trial. Supine mean blood pressure was reduced by 11.9% +/- 6.2% by N 10 mg three times daily, by 13.9% +/- 7.6% by N 20 mg three times daily and by 20.3% +/- 6.2% by N 30 mg three times daily. Plasma potassium was reduced from 3.9 +/- 0.5 mEq/liter on placebo to 3.6 +/- 0.5 mEq/liter on N 10 mg three times daily, 3.6 +/- 0.4 mEq/liter on N 20 mg three times daily (p less than 0.05), and 3.5 +/- 0.5 mEq/liter on N 30 mg three times daily (p less than 0.05). Heart rate, body weight, renal function, and plasma glucose were not altered. Nifedipine is thus a useful third-line hypotensive agent that should be used in combination with a potassium-sparing diuretic.

Effect of centrally acting alpha-adrenergic agonists on sympathetic nervous system function in humans.

Three studies were undertaken to reevaluate whether there is a peripheral component in the reduction of sympathetic activity caused by centrally acting drugs; and whether the antihypertensive effect of these drugs is due entirely to this reduction. Plasma growth hormone and norepinephrine concentrations were used as respective markers of central alpha-adrenoceptor stimulation and peripheral sympathetic activity. In six normal volunteers, intravenous infusion of 0.2 mg clonidine and 2 mg guanfacine was compared. The falls in systolic blood pressure and plasma norepinephrine concentration were slightly greater after clonidine (18 mm Hg and 0.22 ng/ml) than after guanfacine (12 mm Hg and 0.13 ng/ml) administration. These falls occurred earlier than the rise in growth hormone, which rose to a maximum of 23 and 20 IU/ml respectively at 45 minutes after dosing. In six patients with essential hypertension clonidine and alpha-methyldopa caused similar falls in blood pressure and plasma norepinephrine concentration although these changes occurred later with alpha-methyldopa. Plasma growth hormone levels remained undetectable in most patients. In Wistar rats the effect of central and peripheral alpha 2-blockade on clonidine-induced changes was compared. Two groups of six rats received intravenous RX 781094, 0.3 mg/kg, or vehicle 10 minutes before receiving clonidine, 5 micrograms/kg i.v. In the latter, control group, clonidine reduced mean blood pressure by 30.7 +/- 1.9 mm Hg and heart rate by 46 +/- 6.7 beats/min. Plasma norepinephrine fell from 0.22 +/- 0.023 ng/ml to 0.116 +/- 0.013 ng/ml. After pretreatment with RX 781094, blood pressure did not change and heart rate fell by 18 +/- 2.7 beats/min.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucose tolerance during antihypertensive therapy in patients with diabetes mellitus.

Many antihypertensive drugs have adverse effects on glycemic control when they are used in diabetic patients. This was noted for thiazide diuretics in 1960, and the mechanism of the effects remains uncertain. Indirect evidence suggests that changes in the serum potassium are at least contributory, although the principal mechanism of thiazide-induced hyperglycemia is probably a reduction in the insulin response to glucose. Beta blockers also adversely affect blood sugar control but only by a small margin. The main cause for concern with beta blockers, however, is their effect during hypoglycemia in which nonselective agents delay blood sugar recovery. In diabetic patients, the institution of antihypertensive therapy should be followed by a reassessment to note any changes in sugar, potassium, and lipids, or side effects.

The role of alpha-adrenoceptor blockade in the antihypertensive effects of fenoldopam in humans.

Fenoldopam, a dopamine-1 receptor agonist, has been reported to exhibit alpha-adrenoceptor-blocking actions in intact and isolated animal preparations. To determine whether alpha-adrenoceptor blockade contributes to its antihypertensive properties in humans, the effects of fenoldopam on the pressor responses to norepinephrine and angiotensin II were compared in eight normal volunteers. Fenoldopam (0.5 micrograms/kg/min) shifted the dose-response curves for both agonists to the right (p less than 0.05). Dose ratios for an increase in mean blood pressure of 10 mm Hg were 3.3 +/- 0.9 for norepinephrine and 3.2 +/- 0.6 for angiotensin II (p not significant). Consequently, fenoldopam is not a selective alpha-adrenoceptor antagonist at therapeutic concentrations in humans.

Blood pressure and plasma norepinephrine concentrations after endogenous norepinephrine release by tyramine.

To determine whether small changes in sympathetic activity would cause detectable changes in plasma norepinephrine (NE) levels, and whether the effects of endogenously released and exogenous NE differ, we injected tyramine infusions and l-norepinephrine (l-NE), into six healthy subjects, and the changes in blood pressure (BP) and plasma NE were related. The mean increase in systolic BP was approximately 17 mm Hg with both infusions; diastolic BP increased with l-NE but did not rise significantly with tyramine. Heart rate fell more with l-NE than with tyramine infusions. The maximum increase in plasma NE levels was more than 500% during l-NE infusions but less than 200% with tyramine. There was no correlation between plasma NE and absolute levels of systolic BP when individual data were plotted for tyramine infusions, whereas mean group changes in systolic BP correlated strongly with mean group plasma NE, both during tyramine and l-NE infusions. The slope of the relationship was much steeper for tyramine than for l-NE. We conclude that the use of plasma NE to measure small differences in sympathetic activity among individuals is limited by interindividual variability, whereas changes in sympathetic activity within groups are more likely to be detected.