Intermittent systemic exposure to lipopolysaccharide-induced inflammation disrupts hippocampal long-term potentiation and impairs cognition in aging male mice.

Age-related cognitive decline, a common component of the brain aging process, is associated with significant impairment in daily functioning and quality of life among geriatric adults. While the complexity of mechanisms underlying cognitive aging are still being elucidated, microbial exposure and the multifactorial inflammatory cascades associated with systemic infections are emerging as potential drivers of neurological senescence. The negative cognitive and neurobiological consequences of a single pathogen-associated inflammatory experience, such as that modeled through treatment with lipopolysaccharide (LPS), are well documented. Yet, the brain aging impacts of repeated, intermittent inflammatory challenges are less well studied. To extend the emerging literature assessing the impact of infection burden on cognitive function among normally aging mice, here, we repeatedly exposed adult mice to intermittent LPS challenges during the aging period. Male 10-month-old C57BL6 mice were systemically administered escalating doses of LPS once every two weeks for 2.5 months. We evaluated cognitive consequences using the non-spatial step-through inhibitory avoidance task, and both spatial working and reference memory versions of the Morris water maze. We also probed several potential mechanisms, including cortical and hippocampal cytokine/chemokine gene expression, as well as hippocampal neuronal function via extracellular field potential recordings. Though there was limited evidence for an ongoing inflammatory state in cortex and hippocampus, we observed impaired learning and memory and a disruption of hippocampal long-term potentiation. These data suggest that a history of intermittent exposure to LPS-induced inflammation is associated with subtle but significantly impaired cognition among normally aging mice. The broader impact of these findings may have important implications for standard of care involving infections in aging individuals or populations at-risk for dementia.

Tocotrienol supplementation suppressed bone resorption and oxidative stress in postmenopausal osteopenic women: a 12-week randomized double-blinded placebo-controlled trial.

Tocotrienols have shown bone-protective effect in animals. This study showed that a 12-week tocotrienol supplementation decreased concentrations of bone resorption biomarker and bone remodeling regulators via suppressing oxidative stress in postmenopausal osteopenic women. INTRODUCTION: Tocotrienols (TT) have been shown to benefit bone health in ovariectomized animals, a model of postmenopausal women. The purpose of this study was to evaluate the effect of 12-week TT supplementation on bone markers (serum bone-specific alkaline phosphatase (BALP), urine N-terminal telopeptide (NTX), serum soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), and serum osteoprotegerin (OPG)), urine calcium, and an oxidative stress biomarker (8-hydroxy-2'-deoxyguanosine (8-OHdG)) in postmenopausal women with osteopenia. METHODS: Eighty-nine postmenopausal osteopenic women (59.7 ± 6.8 year, BMI 28.7 ± 5.7 kg/m2) were randomly assigned to three groups: (1) placebo (430 mg olive oil/day), (2) low TT (430 mg TT/day, 70% purity), and (3) high TT (860 mg TT/day, 70% purity). TT, an extract from annatto seed with 70% purity, consisted of 90% delta-TT and 10% gamma-TT. Overnight fasting blood and urine samples were collected at baseline, 6, and 12 weeks for biomarker analyses. Eighty-seven subjects completed the 12-week study. RESULTS: Relative to the placebo group, there were marginal decreases in serum BALP level in the TT-supplemented groups over the 12-week study period. Significant decreases in urine NTX levels, serum sRANKL, sRANKL/OPG ratio, and urine 8-OHdG concentrations and a significant increase in BALP/NTX ratio due to TT supplementation were observed. TT supplementation did not affect serum OPG concentrations or urine calcium levels throughout the study period. There were no significant differences in NTX level, BALP/NTX ratio, sRANKL level, and sRANKL/OPG ratio between low TT and high TT groups. CONCLUSIONS: Twelve-week annatto-extracted TT supplementation decreased bone resorption and improved bone turnover rate via suppressing bone remodeling regulators in postmenopausal women with osteopenia. Such osteoprotective TT's effects may be, in part, mediated by an inhibition of oxidative stress. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02058420. TITLE: Tocotrienols and bone health of postmenopausal women.

[Nonsurgical and surgical treatment of an urachal fistula in an alpaca cria. A case report]. / Konservative und chirurgische Therapie der Urachusfistel bei einem Alpaka-Cria. Ein Fallbericht.

Urachal fistula is a neonatal condition. There are two reported forms: a congenital and an acquired form. We describe the case of a 6-hour-old female alpaca cria that was presented with a damp umbilicus and a meconium impaction. Conservative treatment of the urachal fistula with local and systemic medication was unsuccessful after 6 days; therefore, a resection of the umbilicus under general anaesthesia was performed. Reconvalescence was uneventful.

Effect of green tea and Tai Chi on bone health in postmenopausal osteopenic women: a 6-month randomized placebo-controlled trial.

UNLABELLED: Postmenopausal women with osteopenia received green tea polyphenols (GTP) supplement and/or Tai Chi exercise for 6 months. Bone turnover biomarkers, calcium metabolism, and muscle strength were measured. This study showed that GTP supplementation and Tai Chi exercise increased bone formation biomarkers and improved bone turnover rate. Tai Chi exercise increased serum parathyroid hormone. GTP supplementation, Tai Chi exercise, and the combination of the two all improved muscle strength in postmenopausal women with osteopenia. INTRODUCTION: This study evaluated the effect of GTP supplementation and Tai Chi (TC) exercise on serum markers of bone turnover (bone-specific alkaline phosphatase, BAP, and tartrate-resistant acid phosphatase, TRAP), calcium metabolism, and muscle strength in postmenopausal osteopenic women. METHODS: One hundred and seventy-one postmenopausal osteopenic women were randomly assigned to four groups: (1) placebo (500 mg starch/day), (2) GTP (500 mg GTP/day), (3) placebo + TC (placebo plus TC training at 60 min/session, three sessions/week), and (4) GTP + TC (GTP plus TC training). Overnight fasting blood and urine samples were collected at baseline, 1, 3, and 6 months for biomarker analyses. Muscle strength was evaluated at baseline, 3, and 6 months. One hundred and fifty subjects completed the 6-month study. RESULTS: Significant increases in BAP level due to GTP intake (at 1 month) and TC (at 3 months) were observed. Significant increases in the change of BAP/TRAP ratio due to GTP (at 3 months) and TC (at 6 months) were also observed. Significant main effect of TC on the elevation in serum parathyroid hormone level was observed at 1 and 3 months. At 6 months, muscle strength significantly improved due to GTP, TC, and GTP + TC interventions. Neither GTP nor TC affected serum TRAP, serum and urinary calcium, and inorganic phosphate. CONCLUSION: In summary, GTP supplementation and TC exercise increased BAP and improved BAP/TRAP ratio. TC exercise increased serum parathyroid hormone. GTP supplementation, TC exercise, and the combination of the two all improved muscle strength in postmenopausal women with osteopenia.

Effect of water addition to a total mixed ration on feed temperature, feed intake, sorting behavior, and milk production of dairy cows.

The objective of this study was to determine the effects of water addition to a high-moisture total mixed ration (TMR) on feed temperature, feed intake, feed sorting behavior, and milk production of dairy cows. Twelve lactating Holstein cows (155.8+/-60.1 DIM), individually fed once daily at 1000 h, were exposed to 3 diets in a Latin square design with 28-d treatment periods. Diets had the same ingredient composition [30.9% corn silage, 30.3% alfalfa haylage, 21.2% high-moisture corn, and 17.6% protein supplement; dry matter (DM) basis] and differed only in DM concentration, which was reduced by the addition of water. Treatment diets averaged 56.3, 50.8, and 44.1% DM. The study was conducted between May and August when environmental temperature was 18.2+/-3.6 degrees C and ambient temperature in the barn was 24.4+/-3.3 degrees C. Dry matter intake (DMI) was monitored for each animal for the last 14 d of each treatment period. For the final 7 d of each period, milk production was monitored, feed temperature and ambient temperature and humidity were recorded (daily at 1000, 1300, and 1600 h), and fresh feed and orts were sampled for determination of sorting. For the final 4 d of each period, milk samples were taken for composition analysis. Samples taken for determining sorting were separated using a Penn State Particle Separator that had 3 screens (19, 8, and 1.18 mm) and a bottom pan, resulting in 4 fractions (long, medium, short, and fine). Sorting was calculated as the actual intake of each particle size fraction expressed as a percentage of the predicted intake of that fraction. Greater amounts of water added to the TMR resulted in greater increases in feed temperature in the hours after feed delivery, greater sorting against long particles, and decreased DMI, reducing the overall intake of starch and neutral detergent fiber. Milk production and composition were not affected by the addition of water to the TMR. Efficiency of production of milk was, however, increased with greater amounts of water added to the TMR. The increases in feed temperature in the hours after feed delivery were enhanced by higher ambient temperatures; this may be indicative of feed spoilage and thus may have contributed to the reduced DMI observed. Overall, these results suggest that the addition of water to high-moisture TMR (less than 60% DM) containing primarily haylage and silage forage sources will not always discourage cows from sorting, but rather may increase this behavior and limit the nutrient consumption of cows, particularly when ambient temperature is high.

Erythrocyte-derived measures of membrane lipid composition in healthy men: associations with arachidonic acid at low to moderate but not high insulin sensitivity.

The lipid composition of erythrocyte membranes was explored as a surrogate for that of skeletal muscle in investigations into the influence of membrane fatty acid composition on insulin sensitivity. In a preliminary study (study 1), erythrocyte and monocyte/platelet membrane fatty acid percentages were compared with those of muscle membrane in 10 otherwise healthy men undergoing orthopedic surgery. In a further study (study 2), relationships between erythrocyte membrane fatty acid concentrations and insulin sensitivity, S(I), measured using the intravenous glucose tolerance test (IVGTT), were evaluated in 30 asymptomatic men. In study 1, significant positive correlations were found between muscle and erythrocyte membrane fatty acid percentages for 16:0 saturated fatty acid (r = 0.92, P <.001), and for the 18:2n-6, 20:4n-6, 20:5n-3, and 22:5n-3 polyunsaturated fatty acids (PUFAs) (r = 0.67 to 0.83, P <.05 to.01). There were fewer and weaker associations between muscle and monocyte/platelet membrane fatty acid compositions. In study 2, highly insulin-sensitive individuals (n = 8) had significantly lower erythrocyte membrane fatty acid concentrations than those with low/normal S(I). Among those with low/normal S(I) (n = 22), S(I) correlated positively with erythrocyte membrane arachidonic acid concentration (r = 0.57, P <.01) and with total PUFAs (r = 0.46, P <.05). Indices of delta 6 and delta 5 desaturase activities were significantly higher and lower, respectively, in high compared with low/normal S(I) individuals. For a range of fatty acids, erythrocyte membrane fatty acid composition shows close associations with that of muscle membranes. Measurements in erythrocyte membranes support a role for membrane arachidonic acid content in the modulation of insulin sensitivity, specifically at low/normal insulin sensitivities.

Drug use and sexual risk behaviours among female Russian IDUs who exchange sex for money or drugs.

Countries of the former Soviet Union are experiencing the steepest increases in annual HIV incidence in the world. Over 80% of registered HIV cases in Russia have occurred among intravenous drug users (IDUs), but current conditions set the stage for a heterosexually-transmitted epidemic. IDUs who also trade sex for money or drugs may serve as a conduit, or 'bridge' group, through which HIV could make inroads into the general Russian population. The present study examined the prevalence of sex trading among female Russian IDUs, and further examined drug use, sexual behaviour, and perceived vulnerability in this group. Female IDUs (n=100) in St Petersburg, Russia participated; 37% reported a history of sex trading. This group reported a mean of 49.5 male sexual partners in the previous month and an average of 15.4 unprotected vaginal intercourse acts in the previous 30 days. A significant minority (44%) also reported sharing injection equipment with others. Mathematical models to calculate risk estimates for HIV seroconversion indicated that participants were at significant risk of contracting HIV and infecting sexual partners. Despite significant rates of risk behaviours, most participants perceived themselves to be at little risk of contracting HIV. Effective HIV prevention programmes targeted at this group are urgently needed and are likely to be a cost-effective step in curtailing the spread of HIV in the region.

Effects of low and high dose oestradiol and dydrogesterone therapy on insulin and lipoprotein metabolism in healthy postmenopausal women.

OBJECTIVE: Menopause diminishes insulin secretion and elimination, increases risk of diabetes and adversely affects lipoprotein metabolism. This study was undertaken to establish whether oral oestradiol plus dydrogesterone postmenopausal hormone therapy can modify these changes. DESIGN: Randomized prospective trial of postmenopausal women taking low dose therapy (1 mg/day oestradiol-17 beta with 5 or 10 mg/day dydrogesterone for days 17-28 of each cycle, n = 15) or high dose therapy (2 mg/day oestradiol-17 beta with 10 or 20 mg/day orally administered dydrogesterone, n = 9). MEASUREMENTS: Patients underwent measurement of glucose, insulin and C-peptide in the fasting state and during an intravenous glucose tolerance test (IVGTT) at baseline and after 12 and 24 cycles of treatment. Modelling analysis was used to derive measures of insulin secretion, elimination and sensitivity. Fasting serum lipids, lipoproteins and apolipoproteins were also measured. RESULTS: In both groups there were significant reductions in fasting glucose, insulin and C-peptide. Pancreatic insulin secretion during the IVGTT was increased by treatment (ranging from 45% to 92%, P < 0.01). Insulin elimination was increased at both the peripheral (16% to 43%, P < 0.05) and hepatic (18% to 31%, P < 0.05) levels. Insulin sensitivity was unaffected. Low density lipoprotein (LDL) cholesterol was reduced and high density lipoprotein (HDL) cholesterol increased with treatment. CONCLUSIONS: Postmenopausal hormone therapy with oestradiol plus dydrogesterone can favourably affect lipoprotein concentrations and can reverse menopause-associated changes in insulin secretion and elimination.

SARS Surveillance Project--Internet-enabled multiregion surveillance for rapidly emerging disease.

INTRODUCTION: On March 15, 2003, CDC requested health-care and public health agencies to conduct surveillance for severe acute respiratory syndrome (SARS). The SARS Surveillance Project (SARS-SP) was established to rapidly implement multiregional SARS surveillance in emergency departments (EDs) by using existing Internet-based tools. OBJECTIVES: The objectives of SARS-SP were to 1) disseminate and update SARS screening forms for ED triage, 2) establish surveillance for SARS syndrome elements by using Regional Emergency Medicine Internet (REMI), 3) expand surveillance to multiple regions, and 4) evaluate the usefulness of Internet tools for agile surveillance during a rapidly emerging global epidemic. METHODS: SARS-SP developed, distributed, and updated an Internet-based triage form to identify patients for infection control and public health reporting. EDs then were invited to report visit frequencies with various SARS syndrome elements to local public health authorities by using the REMI Internet application (first in one metropolitan area, and later in four). After pilot-testing in one metropolitan area, the surveillance system was implemented in three others. RESULTS: Active syndromic surveillance was established by health departments in Milwaukee, Wisconsin; Denver, Colorado; Akron, Ohio; and Fort Worth, Texas. A total of 27 EDs reported syndrome frequencies from >146,000 patient encounters. CONCLUSIONS: ED and public health partners reported being satisfied with the system, confirming the usefulness of Internet tools in the rapid establishment of multiregion syndromic surveillance during an emerging global epidemic.

Sociodemographic characteristics associated with medical appointment adherence among HIV-seropositive patients seeking treatment in a county outpatient facility.

BACKGROUND: Adherence is a major problem facing HIV-seropositive patients. Low adherence has been associated with faster disease progression as well as development of drug-resistant strains of HIV. Thus it is critical to understand factors associated with treatment compliance. This study examined the independent contributions of disease severity, age, gender, household income, homelessness, ethnicity, and sexual orientation on appointment adherence. METHODS: Participants (n = 671) scheduled for appointments in an outpatient county treatment facility for HIV-related medical care completed demographic questionnaires and clinic staff collected appointment attendance data. RESULTS: Multiple regression analyses indicated that patients diagnosed with AIDS, older in age, and receiving a higher income were more likely to keep medical appointments. Additionally, African American ethnicity and identifying as heterosexual were associated with missing scheduled medical appointments. CONCLUSIONS: These data suggest that cultural and sociodemographic characteristics influence patients' adherence to outpatient services. Implications for interventions aimed at increasing medical adherence are discussed.

Relationships of sexual, physical, and emotional abuse to emotional and behavioral problems among incarcerated adolescents.

This study examined the relationships of sexual, physical and emotional abuse to emotional (internalizing) and behavioral (externalizing) problems among incarcerated girls and boys. Participants were youth who were remanded to the correctional facilities within a statewide juvenile correctional system in a southern state in the United States of America. Each participant completed a structured interview regarding abuse history, emotional and behavioral difficulties, and demographic characteristics. Multiple regression analyses indicated that girls were more likely than boys to internalize their problems. The only abuse variable that was positively and significantly associated with emotional problems was emotional abuse. Greater behavioral problems were significantly related to youths being younger in age, white ethnicity, history of sexual abuse, and history of physical abuse. There were overall gender differences for internalizing problems, but not for externalizing problems among incarcerated adolescents. Furthermore, physical and sexual abuses were related to externalizing problems but not to internalizing problems. Thus, different types of abuse appear to have different effects on adolescent behavior. Implications for future research and practice are discussed.

Acute stress reactions to everyday stressful life events among sexual abuse survivors with PTSD.

This study examined symptoms of Acute Stress Disorder (ASD), which is often thought of as a precursor to PTSD, among 54 women who already had PTSD for childhood sexual abuse for which they were seeking treatment. We examined the prevalence of ASD symptoms as well as their relationships to trauma symptoms measured by the Trauma Symptom Checklist-40. The ASD diagnosis requires the occurrence of a traumatic life event as well as meeting specific symptoms criteria. We found that fourty-four percent of participants met all symptom criteria for ASD, but only three of these 24 participants described a traumatic life event. Moreover, ASD symptoms were significantly related to trauma symptom scores. These findings suggest that a significant proportion of women with PTSD for childhood sexual abuse may be highly symptomatic for everyday stressful events that would not be experienced as traumatizing to others. Thus, these individuals need assistance in coping with everyday life stressors that do not involve a serious threat or injury in addition to needing help to alleviate their trauma symptoms.

Serving street-dwelling individuals with psychiatric disabilities: outcomes of a psychiatric rehabilitation clinical trial.

OBJECTIVES: This study tested a psychiatric rehabilitation approach for organizing and delivering services to street-dwelling persons with severe mental illness. METHODS: Street-dwelling persons with severe mental illness were randomly assigned to the experimental program (called Choices) or to standard treatment in New York City. We assessed study participants at baseline and at 6-month intervals over 24 months, using measures of service use, quality of life, health, mental health, and social psychological status. The average deviation from baseline summary statistic was employed to assess change. RESULTS: Compared with persons in standard treatment (n = 77), members of the experimental group (n = 91) were more likely to attend a day program (53% vs 27%), had less difficulty in meeting their basic needs, spent less time on the streets (55% vs 28% reduction), and spent more time in community housing (21% vs 9% increase). They showed greater improvement in life satisfaction and experienced a greater reduction in psychiatric symptoms. CONCLUSIONS: With an appropriate service model, it is possible to engage disaffiliated populations, expand their use of human services, and improve their housing conditions, quality of life, and mental health status.

Relationships of perceived stress to coping, attachment and social support among HIV-positive persons.

The purpose of this study was to examine the relationships of coping, attachment style and perceived social support to perceived stress within a sample of HIV-positive persons. Participants were 147 HIV-positive persons (80 men and 67 women). Multiple regression analysis was used to examine the relationships of the demographic variables, AIDS status, three coping styles, three attachment styles and perceived quality of general social support with total score on the Perceived Stress Scale (PSS). PSS score was significantly associated with less income, greater use of behavioural and emotional disengagement in coping with HIV/AIDS, and less secure and more anxious attachment styles. These results indicate that HIV-positive persons who experience the greatest stress in their daily lives are those with lower incomes, those who disengage behaviourally/emotionally in coping with their illness, and those who approach their interpersonal relationships in a less secure or more anxious style.

Psychologists' beliefs about the prevalence of childhood sexual abuse: the influence of sexual abuse history, gender, and theoretical orientation.

OBJECTIVE: This study examined the influence of sexual abuse history, gender, theoretical orientation, and age on beliefs about the prevalence of childhood sexual abuse among clinical and counseling psychologists. METHOD: A mail survey design was used in this study. Participants were randomly selected from the American Psychological Association membership database. There were 615 psychologists who completed self-report measures on beliefs about the prevalence of childhood sexual abuse and demographic characteristics. RESULTS: Overall, clinicians' scores on the prevalence of childhood sexual abuse were moderate. There were significant gender differences on beliefs, suggesting that women were more likely believe that childhood sexual abuse is a common occurrence compared to men. Multiple regression analysis indicated that clinician characteristics (history of sexual abuse, gender, and theoretical orientation) were significantly related to beliefs about the prevalence of childhood sexual abuse. However, these characteristics only accounted for a small amount of the overall variance predicting beliefs. CONCLUSIONS: These results suggest that clinicians do not hold extreme beliefs regarding the prevalence of childhood sexual abuse. Moreover, certain clinician characteristics are associated with their beliefs, which in turn, may impact their clinical judgment and treatment decisions. Furthermore, much of the variance was unaccounted for in the model indicating that psychologists' beliefs are complex and are not unduly influenced by their personal characteristics. Implications for clinical practice and future research are discussed.

Improving the quality and quantity of life among patients with cancer: a review of the effectiveness of group psychotherapy.

Cancer patients suffer from a number of psychosocial problems related to the progression of their disease as well as standard medical interventions. Fortunately, there is empirical evidence suggesting that group psychotherapy is effective at ameliorating psychological distress and in some cases improving survival. For this literature review we examined the psychological morbidity, particularly anxiety and depression, among cancer patients. Further, we conducted a critical examination of the current evidence regarding the effectiveness of group psychotherapy for improving the quality as well as the quantity of life in cancer patients. Finally, we explored the specific components of effective group psychotherapy, which has been associated with enhanced survival. We conclude that there is compelling evidence indicating that group psychotherapy improves the quality of life of cancer patients. Furthermore, there is a growing body of evidence suggesting that group psychotherapy improves survival of cancer patients.

Renal cortical Na+-K+-ATPase activity and abundance is decreased in normal pregnant rats.

During late pregnancy, the rat undergoes massive plasma volume expansion due to cumulative renal sodium retention. In the present study, conducted in virgin, mid- (days 11-13), and late-pregnant (days 18-20) rats, we measured both Na+-K+-ATPase activity (by coupled enzyme assay) and abundance of the alpha-subunits of the Na+-K+-ATPase (by Western and slot blot analyses) in renal cortex, medulla, and brain stem. Unexpectedly, Na+-K+-ATPase in renal cortex, in both stages of pregnancy, is reduced versus the virgin, consistent with our finding of a reduced quantity of the alpha1-subunit. In renal medulla, there is a small rise in activity at midterm, but there is no difference in either activity or abundance of the alpha1-subunit in late pregnancy, when renal Na retention is maximal. In brain stem, where only alpha2- and alpha3-subunits are evident, pregnancy has no impact on enzyme activity or abundance of either isoform. In conclusion, the outcome of these experiments was unexpected in that we did not observe increased renal Na+-K+-ATPase activity in late pregnancy in the rat. In fact, in renal cortex, Na+-K+-ATPase activity and abundance are reduced. Whatever promotes net sodium retention in pregnancy must be capable of overwhelming this and several other strong natriuretic signals.

Designing a system for managing the performance of mental health managed care: an example from New York State's prepaid mental health plan.

The organization, financing, and delivery of publicly funded behavioral health services are undergoing massive changes nationwide. Managed care principles and practices are being implemented widely and are being relied on increasingly to meet the challenges of containing costs and improving service effectiveness. To meet these goals, comprehensive systems are under development for measuring and reporting outcomes experienced by individuals who received services and for assessing the impact of managed care strategies on the service delivery system. This article presents an example from the Prepaid Mental Health Program in New York State. It highlights the development, implementation, and early experiences with the plan's performance management system for public sector managed behavioral health, a basis for continuous quality improvement activities and information reporting products such as report cards. Policy, administrative, and financial implications are illuminated.

Tumour necrosis factor alpha as a predictor of impaired peak leg blood flow in patients with chronic heart failure.

Tumour necrosis factor alpha (TNF alpha) is increased in patients with cardiac cachexia, a condition associated with reduced peripheral blood flow both at rest and after interventions causing vasodilation. By contrast, in patients with chronic heart failure (CHF), higher TNF levels are associated with a greater capacity for vasodilation in the arm. To clarify the relationship between peripheral blood flow and TNF in CHF, we studied the relation between TNF alpha and blood flow in the leg (plethysmography, post maximal exercise and 5 min ischaemia) in 34 patients (age 63 +/- 2 years, ejection fraction 29 +/- 3%, peak VO2 16.6 +/- 1.1 ml/kg/min, mean +/- SEM). Peak leg blood flow correlated significantly with total TNF alpha (r = 0.68, p < 0.0001, peak VO2 (r = 0.54), and soluble TNF receptors 1 (r = 0.56) and 2 (r = 0.52, all p < 0.002). TNF alpha, soluble TNF receptors 1 and 2 and aldosterone correlated with peak blood flow independently of age, ejection fraction, peak VO2 and functional NYHA class. TNF alpha was the only parameter that showed strong correlations for peak blood flow in all clinically relevant subgroups (severe vs. mild, ischaemic vs. dilated, cachectic vs. non-cachectic patients). This study shows a close and inverse relationship between peak leg blood flow and the plasma concentration of TNF alpha, suggesting a pathophysiological role for TNF alpha in reducing peak peripheral blood flow in CHF.