Pestiferous slugs and their associated nematodes in agricultural fields, greenhouses, and nurseries in Alberta, Canada.

Some slug species are considered a nuisance in agriculture and horticulture worldwide, causing economic losses to growers. Phasmarhabditis is a genus of bacteria-feeding nematodes that can parasitize slugs and snails and thus potentially serve as a biological control agent. Canada had no record of Phasmarhabditis until a survey conducted in 2019 reported a Canadian strain of Phasmarhabditis californica from a single Arion rufus slug. To build on this discovery, we surveyed three major agricultural sites, ten greenhouses, and nurseries in Alberta from June to September 2021 to collect pest slug species and investigate their associated nematodes, specifically P. californica. Slugs were collected from the field and returned to the laboratory to check for emerging nematodes on White traps. We collected 1331 slugs belonging to nine species, with Deroceras reticulatum being the most common. Only 45 (3.38%) slug samples were positive for nematodes, and the majority were identified to species level: Alloionema appendiculatum, Caenorhabditis briggsae, Caenorhabditis elegans, Panagrolaimus subelongatus, and Mesorhabditis spiculigera. We did not isolate P. californica from any of the slugs collected from these survey sites, which included the original site where P. californica was discovered. However, four D. reticulatum slugs retrieved from a residential garden sample were infected with P. californica. These findings suggest the possibility of a fragmented distribution of P. californica across Alberta. Future research should focus on extensively surveying agriculture and horticulture sites and residential gardens in different provinces across Canada.

Genomic diversity and signals of selection processes in wild and farm-reared red-legged partridges (Alectoris rufa).

The genetic dynamics of wild populations with releases of farm-reared reinforcements are very complex. These releases can endanger wild populations through genetic swamping or by displacing them. We assessed the genomic differences between wild and farm-reared red-legged partridges (Alectoris rufa) and described differential selection signals between both populations. We sequenced the whole genome of 30 wild and 30 farm-reared partridges. Both partridges had similar nucleotide diversity (π). Farm-reared partridges had a more negative Tajima's D and more and longer regions of extended haplotype homozygosity than wild partridges. We observed higher inbreeding coefficients (FIS and FROH) in wild partridges. Selective sweeps (Rsb) were enriched with genes that contribute to the reproductive, skin and feather colouring, and behavioural differences between wild and farm-reared partridges. The analysis of genomic diversity should inform future decisions for the preservation of wild populations.

White fish reduces cardiovascular risk factors in patients with metabolic syndrome: the WISH-CARE study, a multicenter randomized clinical trial.

BACKGROUND AND AIMS: Reduction of cardiovascular risk with high consumption of fish in diet is still a matter of debate, and concerns about heavy metal contamination have limited consumption of oily fish. We aimed to evaluate the effect of regular ingestion of white fish on cardiovascular risk factors in patients with metabolic syndrome. METHODS AND RESULTS: Multicenter randomized crossover clinical trial including 273 individuals with metabolic syndrome. An 8-week only-one dietary intervention: 100 g/d of white fish (Namibia hake) with advice on a healthy diet, compared with no fish or seafood with advice on a healthy diet. Outcomes were lipid profile, individual components of the metabolic syndrome, serum insulin concentrations, homeostasis model of insulin resistance, serum C-reactive protein and serum fatty acid levels. We found a significant lowering effect of the intervention with white fish on waist circumference (P < 0.001) and diastolic blood pressure (P = 0.014). A significant lowering effect was also shown after the dietary intervention with fish on serum LDL concentrations (P = 0.048), whereas no significant effects were found on serum HDL or triglyceride concentrations. A significant rise (P < 0.001) in serum EPA and DHA fatty acids was observed following white fish consumption. Overall adherence to the intervention was good and no adverse events were found. CONCLUSION: In individuals with metabolic syndrome, regular consumption of hake reduces LDL cholesterol concentrations, waist circumference and blood pressure components of the metabolic syndrome. CLINICAL TRIAL REGISTRY: White Fish for Cardiovascular Risk Factors in Patients with Metabolic Syndrome Study, Registered under ClinicalTrials.gov Identifier: NCT01758601.

Liver lipocalin 2 expression in severely obese women with non alcoholic fatty liver disease.

BACKGROUND: Lipocalin 2 (LCN2) has been related to obesity, insulin resistance and metabolic disturbance. However, its relation with non alcoholic fatty liver disease (NAFLD) has hardly been studied. METHODS: We examined LCN2 circulating levels and its protein and gene expression in liver from women with severe obesity and NAFLD. We analyzed the liver histology of 59 white severely obese women (BMI ≥40 Kg/m²): 15 subjects presented normal liver histology or non-significant liver disease (NL), 18 simple steatosis (SS) and 26 non alcoholic steatohepatitis (NASH). We determined the anthropometric and metabolic features of the women. LCN2 levels were determined by an ELISA and liver mRNA expression by real time RT-PCR. We also studied LCN2 expression in HepG2 liver cells under various inflammatory stimuli. RESULTS: Liver LCN2 protein and gene expression were higher in NAFLD than in obese with NL. Liver LCN2 gene expression correlated with SS (r=0.351, p=0.016), and its protein expression correlated with NASH (r=0.705, p=0.003). LCN2 expression was detected in HepG2 cells after the administration of TNFα, IL6, resistin or adiponectin. LCN2 expression was induced by TNFα, IL6 and resistin. CONCLUSIONS: Liver LCN2 is related to NAFLD in severely obese women. Up-regulation of LCN2 expression is detected in HepG2 cells after exposure to TNFα, IL6 and resistin. These results suggest that LCN2 expression is induced under liver harmful conditions.

Zinc alpha-2 glycoprotein is implicated in dyslipidaemia in HIV-1-infected patients treated with antiretroviral drugs.

OBJECTIVES: Treated HIV-1-infected patients with lipodystrophy often develop insulin resistance and proatherogenic dyslipidaemia. Zinc alpha-2 glycoprotein (ZAG) is a recently characterized adipokine which has been shown to be involved in the development of obesity and metabolic syndrome in uninfected subjects. We assessed the relationship between circulating ZAG levels and metabolic derangements in HIV-1-infected patients receiving antiretroviral drugs. METHODS: Plasma ZAG levels were assessed in 222 individuals: 166 HIV-1-infected patients treated with antiretroviral drugs (77 with lipodystrophy and 89 without lipodystrophy) and 56 uninfected controls. Plasma ZAG levels were assessed by enzyme-linked immunosorbent assay (ELISA) and were correlated with fat distribution abnormalities and metabolic parameters. RESULTS: HIV-1-infected patients had lower plasma ZAG levels compared with uninfected controls (P < 0.001). No differences were found in ZAG plasma levels according to the presence of lipodystrophy, components of the metabolic syndrome or type of antiretroviral treatment regimen. Circulating ZAG levels were strongly determined by high-density lipoprotein cholesterol (HDLc) in men (B = 0.644; P < 0.001) and showed a positive correlation with total cholesterol (r = 0.312; P < 0.001) and HDLc (r = 0.216; P = 0.005). CONCLUSIONS: HIV-1-infected patients have lower plasma ZAG levels than uninfected controls. In infected patients, plasma ZAG levels are in close relationship with total cholesterol and HDLc.

A study of fatty acid binding protein 4 in HIV-1 infection and in combination antiretroviral therapy-related metabolic disturbances and lipodystrophy.

OBJECTIVE: The aim of the study was to determine circulating levels of fatty acid binding protein 4 (FABP-4) in a cohort of HIV-1-infected patients treated with combination antiretroviral therapy (cART) and to investigate the relationships between FABP-4 levels and insulin resistance, dyslipidaemia, lipodystrophy and levels of proinflammatory adipocytokines in these patients. METHODS: A total of 282 HIV-1-infected patients treated with stable cART for at least 1 year (132 with lipodystrophy and 150 without) and 185 uninfected controls (UCs) were included in the study. Anthropometric parameters were determined. Plasma levels of FABP-4, soluble tumour necrosis factor receptors 1 and 2 (sTNF-R1 and sTNF-R2), interleukin-18 (IL-18), IL-6, adiponectin and leptin were also analysed. Insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR). Subcutaneous adipose tissue mRNA expression of proinflammatory cytokines was assessed in 38 patients (25 with lipodystrophy and 13 without) by real-time polymerase chain reaction (PCR). RESULTS: The plasma FABP-4 concentration was significantly higher in patients with lipodystrophy than in those without (P=0.012). FABP-4 concentration was positively correlated with body mass index (BMI), HOMA-IR, and the concentrations of insulin, total cholesterol, triglycerides, sTNF-R1, leptin and IL-18, but showed a negative correlation with high-density lipoprotein (HDL) cholesterol and adiponectin concentrations. After adjusting for age, sex and BMI, the odds ratio (OR) for risk of lipodystrophy was found to be significantly increased for those with the highest levels of FABP-4 [OR 0.838, 95% confidence interval (CI) 0.435-1.616 for medium FABP-4 vs. OR 2.281, 95% CI 1.163-4.475 for high FABP-4]. In a stepwise regression model, FABP-4 was independently associated with HOMA-IR after controlling for clinical and inflammatory parameters (P=0.004). Moreover, a positive relationship was observed in patients with lipodystrophy between subcutaneous adipose tissue CD68 expression and FABP-4 plasma levels (r=0.525; P=0.031). CONCLUSIONS: cART-treated HIV-1-infected patients with lipodystrophy have a systemic overproduction of FABP-4, which is closely linked to insulin resistance and inflammatory markers in subcutaneous adipose tissue.

Macrophages are novel sites of expression and regulation of retinol binding protein-4 (RBP4).

Obesity is linked to a low-level chronic inflammatory state that may contribute to the development of associated metabolic complications. Retinol-binding protein 4 (RBP4) is an adipokine associated with parameters of obesity including insulin resistance indices, body mass index, waist circumference, lipid profile, and recently, with circulating inflammatory factors. Due to the infiltration of adipose tissue in obesity by macrophages derived from circulating monocytes and, on the other hand, the existence of a close genetic relationship between adipocytes and macrophages, we decided to examine if RBP4 is expressed in monocytes and/or primary human macrophages. While we did not detect expression of RBP4 in undifferentiated monocytes, RBP4 expression became evident during the differentiation of monocytes into macrophages and was highest in differentiated macrophages. Once we demonstrated the expression of RBP4 in macrophages, we checked if RBP4 expression could be regulated by inflammatory stimuli such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), or the endotoxin lipopolysaccharide (LPS). We observed that while RBP4 expression was strongly inhibited by TNF-alpha and LPS, it was not affected by IL-6. Our results highlight the complexity behind the regulation of this adipokine and demonstrate that RBP4 expression in macrophages could be modulated by inflammatory stimuli.

Anaphylactic shock as the cause of myocardial infarction in a woman with normal coronary arteries

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Adult subjects with Prader-Willi syndrome show more low-grade systemic inflammation than matched obese subjects.

AIM: Adult subjects with Prader-Willi syndrome (PWS) may show several conditions that are associated with an activation of innate immunity such as obesity, deficient GH secretion or hypogonadism. Our aim was to study whether obese adult PWS subjects show an additional low-grade systemic inflammation (LGSI) in relation to obese adult non-PWS subjects and lean healthy control subjects before and after a standardized liquid meal. METHODS: Seven obese adult PWS subjects, 7 matched obese non-PWS subjects and 7 lean healthy control subjects were studied for 6 h from the administration of a standard liquid meal. RESULTS: Compared to non-PWS, PWS subjects showed higher plasma concentrations of C-reactive protein (CRP) (p=0.030), complement component C3 (p=0.018), interleukin(IL)-18 (p=0.048), and IL-6 (p=0.041) that persisted post-prandially elevated for CRP (p<0.0001), C3 (p=0.015), and IL-18 (p=0.003). Tumor necrosis factor(TNF)-alpha did not differ between the 3 groups. These results were independent from IGF-I levels, homeostasis model assessment index, and body mass index (BMI). In male subjects with PWS, testosterone levels correlated to IL-18 (r=-0,646, p=0.041). CONCLUSIONS: Compared to matched non-PWS subjects, the obese PWS subjects in this study showed an additional LGSI that persisted postprandially and was independent from BMI, insulin resistance, and deficient GH secretion. However, in PWS males, high IL-18 levels were related to low testosterone concentrations.

Lower heart rate variability is associated with higher plasma concentrations of IL-6 in type 1 diabetes.

OBJECTIVE: In type 1 diabetes, cardiovascular autonomic neuropathy (CAN) is associated with cardiovascular risk factors related to insulin resistance, which in turn are associated with low-grade systemic inflammation. Reduced heart rate variability (HRV) is considered one of the first indicators of CAN. Since the autonomic nervous system interacts with systemic inflammation, we evaluated CAN to study its possible association with low-grade systemic inflammation. DESIGN: Cross-sectional study of a group of 120 subjects diagnosed with type 1 diabetes mellitus 14 years before. METHODS: Information recorded: 1) clinical characteristics: sex, age, body mass index, waist-to-hip ratio (WHR), blood pressure (BP), smoking, alcohol intake, insulin dose, HbA1c, and lipid profile; 2) plasma levels of soluble fractions of tumour necrosis factor alpha receptors 1 and 2, IL-6, and C-reactive protein; 3) insulin resistance by estimation of the glucose disposal rate (eGDR); and 4) tests for CAN: HRV in response to deep breathing (E/I ratio), HRV in response to the Valsalva maneuver, and changes in systolic BP responding to standing. RESULTS: A significant negative correlation was found between E/I ratio and plasma concentrations of IL-6 (r=-0.244, P=0.032), which remained significant after adjusting for potential confounding factors (age, sex, HbA1c, WHR, diastolic BP, triglycerides, HDL-cholesterol, retinopathy, nephropathy, peripheral neuropathy, insulin dose, and smoking; r=-0.231, P=0.039). No other significant associations were found between inflammation-related proteins, tests for CAN, and eGDR. CONCLUSIONS: These findings suggest a link between low-grade inflammation and early alterations of CAN in type 1 diabetes and may be of importance in the pathogenesis of CAN and/or its clinical implications.

Cefalea con déficit neurológicos focales y pleocitosis linfocitaria. ¿Una entidad infradiagnosticada? / Headaches with focal neurological deficits and lymphocytic pleocytosis. An underdiagnosed entity?

Introducción. Desde que Bartlesson describiese el síndrome de seudomigraña, se han publicado pocos casos del hoy denominado síndrome de cafalea con déficit neurológicos transitorios y pleocitosis linfocitaria en el líquido cefalorraquídeo (LCR). Caso clínico. Describimos el caso de una chica de 20 años que sufre tres episodios en 3 semanas de cefalea hemicraneal con parestesias, lenguaje incoherente y pleocitosis linfocitaria en el LCR, permaneciendo asintomática entre los ataques. Las pruebas de neuroimagen fueron normales, los estudios bacteriológicos negativos y se descartaron otras causas posibles de meningitis linfocitaria. Se llegó por exclusión al diagnóstico de cefalea con déficit neurológicos y pleocitosis linfocitaria o seudomigraña. Conclusiones. La seudomigraña es una entidad poco conocida, con unos criterios diagnósticos establecidos y en la que se debería pensar en cualquier persona joven con esta sintomatología debido a que presenta un curso benigno y autolimitado

Introduction. Since Bartlesson first described the pseudomigraine syndrome, few cases have been published on the now so-called headache with transit neurologic deficits and lymphocytic pleocytosis in cerebrospinal fluid (CSF). Case report. We describe the case of a twenty-yearold girl who had three attacks of hemicranial headache, numbness, language disorders and lymphocytic pleocytosis in CSF without symptoms between the attacks in a period of three weeks. The neuroradiological test results were normal, bacteriologic tests were negative and other etiologies of lymphocytic meningitis were discarded. The diagnostic of headache with neurological deficits and lymphocytic pleocytosis or pseudomygraine was reached by a method of exclusion. Conclusions. Pseudomigraine, with established criteria, is not a well-known disorder. We must consider it as a possibility in the case of young patients with the above- mentioned symptoms because it has a benign and self-limited course

[Headaches with focal neurological deficits and lymphocytic pleocytosis. An underdiagnosed entity?]. / Cefalea con déficit neurológicos focales y pleocitosis linfocitaria. Una entidad infradiagnosticada?

INTRODUCTION: Since Bartlesson first described the pseudomigraine syndrome, few cases have been published on the now so-called headache with transit neurologic deficits and lymphocytic pleocytosis in cerebrospinal fluid (CSF). CASE REPORT: We describe the case of a twenty-year-old girl who had three attacks of hemicranial headache, numbness, language disorders and lymphocytic pleocytosis in CSF without symptoms between the attacks in a period of three weeks. The neuroradiological test results were normal, bacteriologic tests were negative and other etiologies of lymphocytic meningitis were discarded. The diagnostic of headache with neurological deficits and lymphocytic pleocytosis or pseudomigraine was reached by a method of exclusion. CONCLUSIONS: Pseudomigraine, with established criteria, is not a well-known disorder. We must consider it as a possibility in the case of young patients with the above-mentioned symptoms because it has a benign and self-limited course.

Different TNFalpha expression elicited by glucose in monocytes from type 2 diabetes mellitus patients.

Increased plasma concentrations of tumor necrosis factor alpha (TNFalpha) system components appear in type 2 diabetes patients with poor glycemic control. We have analyzed the expression of TNFalpha, TNFR1 and TNFR2 when monocytes and lymphocytes isolated from a group of recent onset type 2 diabetic patients, with fasting glucose levels below 7.0mM and glycated haemoglobin (Hb1Ac) in the normal range, were stimulated with high glucose or LPS endotoxin. We report, that cultured monocytes from these type 2 diabetic patients, in comparison to monocytes from non-diabetic individuals, had an enhanced response to LPS but did not respond to an acute glucose challenge (p<0.05). No differences were observed in the cultured lymphocyte fractions. These results indicate the existence of differences, elicited by LPS or high glucose related stimulus, between monocytes isolated from non-diabetic subjects or from type 2 diabetes patients.

Protection from inflammatory disease in insulin resistance: the role of mannan-binding lectin.

AIMS/HYPOTHESIS: Decreased sensing of the innate immune system may lead to chronic activation of the inflammatory cascade. We hypothesised that mannan-binding lectin (MBL) deficiency may confer risk of obesity and insulin resistance. MATERIALS AND METHODS: We performed a cross-sectional study of MBL protein concentration (n=434) and MBL2 gene mutations (exon 1) (n=759) in association with obesity, markers of inflammation and insulin action (euglycaemic clamp, n=113), and a longitudinal study of MBL protein before and after weight loss in obese patients (n=10). We also studied the effects of MBL in vitro in muscle cells and circulating MBL-A (mouse equivalent of human MBL) in a mouse model. RESULTS: Among 434 consecutive non-diabetic men, the age-adjusted serum MBL concentration was lower in obese subjects than in lean subjects (median: 959 microg/ml [interquartile range: 116.8-2,044 microg/ml] vs 1,365 [467-2,513] microg/ml; p=0.01) and was accompanied by increased serum inflammatory markers. Insulin action correlated significantly with serum MBL (r=0.49, p<0.0001). Serum MBL concentration increased by a median of 110.2% after weight loss. The change in serum concentration of MBL was positively associated with the increase in insulin sensitivity (r=0.713, p=0.021). At least one MBL2 gene mutation was present in 48.2% of obese vs 39.3% of non-obese subjects (p=0.037). The plasma concentration of MBL-A was lower in insulin-resistant obese ob/ob mice, as was the glucose/insulin ratio. Incubation of rat soleus muscle with human MBL markedly increased fatty acid oxidation. CONCLUSIONS/INTERPRETATION: These findings suggest that MBL, previously thought only to be involved in inflammation and immune system function, affects metabolic pathways.

IL-18: relationship with anthropometry, body composition parameters, leptin and arterial hypertension.

OBJECTIVE: Interleukin-18 (IL-18) is a potent pro-inflammatory cytokine with potential atherogenic properties whose role in human obesity has been recently suggested. The aim of our study was to analyze the physiologic distribution of IL-18 among sexes and all decades of the adult life in a healthy population randomly selected and to study its relationship with anthropometric, body composition measurements and leptin concentrations. We also studied the relationship of IL-18 with smoking and arterial hypertension, known risk factors implicated in atherogenesis. MATERIALS AND METHODS: One hundred and thirty four men and 127 healthy women were included in the study. Plasma concentrations of IL-18 and leptin were determined in all subjects. Body composition was evaluated by bioelectrical impedanciometry. RESULTS: IL-18 was distributed similarly in men and women and throughout decades. No significant differences were found in IL-18 between obese and normal-weight men and women according to their body mass index and body fat content. Higher IL-18 concentrations were found in subjects with arterial hypertension. In the bivariate correlation analysis only waist to hip ratio correlated weakly with IL-18 in the whole population (r=0.12, p=0.04). In the multiple regression analysis the relationship between IL-18 and waist to hip ratio lost significance after adjusting for age, sex and body mass index. However, IL-18 remained associated with arterial hypertension (adjusted r2=0.25, p=0.023). CONCLUSIONS: The lack of correlation between IL-18 with anthropometric, body composition variables and leptin in our healthy population argues against a role of this cytokine in obesity. Moreover, our findings suggest the implication of this interleukin in the atherogenic process induced by arterial hypertension.

Expression of TWEAK and its receptor Fn14 in human subcutaneous adipose tissue. Relationship with other inflammatory cytokines in obesity.

TWEAK, a cytokine of the TNF family, has been found to be expressed under different inflammatory conditions but no data is available concerning the expression of this cytokine and its receptor (Fn14) in human obesity. In the present work we have evaluated the expression of many pro-inflammatory TNF system cytokines (TNF-alpha, TWEAK and their respective receptors, TNFR1, TNFR2 and Fn14) in human adipose tissue of 84 subjects some with different degree of obesity and type 2 diabetes, and its relation with inflammation by also measuring the expression of macrophage marker CD68. We detected expression of TWEAK and Fn14 in isolated mature adipocytes and in the stromovascular fraction. Additionally, we found that LPS upregulates the expression of both genes on THP-1 human monocytic cell line. TWEAK was expressed in adipose tissue of all studied subjects with no differences between obesity group, and was associated with Fn14 expression in morbid obese, mainly in women with type 2 diabetes. The data obtained here also showed that TNF-alpha and TNFR2 mRNAs were significantly more expressed in subcutaneous adipose tissue of subjects with morbid obesity compared to obese and non-obese subjects. In contrast, TNFR1 gene expression was negatively associated with BMI. Our results suggest that the expression of TNF-derived pro-inflammatory cytokines are increased in severe obesity, where macrophage infiltrate could modulate the inflammatory environment through activation of its receptors.

Tumour necrosis factor alpha in fat redistribution syndromes associated with combination antiretroviral therapy in HIV-1-infected patients: potential role in subcutaneous adipocyte apoptosis.

BACKGROUND: The pathogenesis of fat redistribution syndromes (FRS) observed in the setting of highly active antiretroviral therapy (HAART) for the treatment of HIV-1-infection remains elusive. A dysregulation of the tumour necrosis factor alpha (TNF-alpha) system occurs in HIV-infected patients with FRS. MATERIALS AND METHODS: The study looked at both the in vivo and in vitro relationship between TNF-alpha and the degree of subcutaneous adipocyte apoptosis in 60 HIV-1-infected patients on HAART with FRS, another 60 HIV-1-infected patients on HAART without FRS and 60 uninfected control patients. Apoptosis was assessed by the terminal deoxynucleotidyl transferase dUTP (deoxyuridine 5'-triphosphate)-digoxigenin Nick End Labelling (TUNEL) method. Soluble receptors of TNF-alpha were determined by the sandwich enzyme immunoassay technique. The in vitro viability was assessed by staining with 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) and apoptosis by TUNEL. RESULTS: HIV-1-infected patients with FRS had significantly higher degrees of subcutaneous adipocyte apoptosis than those without FRS (P = 0.0001) and uninfected controls (P < 0.0001). There was a statistically significant association between serum levels of soluble TNF-alpha receptors #1 and #2 and the degree of subcutaneous adipocyte apoptosis in patients with and without FRS (P < 0.0001 for both receptors). In vitro, the addition of TNF-alpha (10 ng mL(-1)) to an adipocyte culture embedded with indinavir, either alone or in clinically relevant combinations with stavudine (d4T) and lamivudine (3TC), significantly decreased adipocyte viability (P = 0.0001) and increased adipocyte apoptosis (P < 0.0001) with respect to that observed with the addition of antiretrovirals alone. CONCLUSIONS: TNF-alpha plays a significant role in subcutaneous adipocyte apoptosis, which occurs in the setting of FRS in HIV-1-infected patients on highly active antiretroviral therapy.

Diabetic neuropathy is associated with activation of the TNF-alpha system in subjects with type 1 diabetes mellitus.

OBJECTIVE: The development of diabetic neuropathy (DN) is predicted by cardiovascular risk factors associated with insulin resistance. As inflammation seems to be implicated in the pathogenesis of insulin resistance, we investigated whether subjects with type 1 diabetes mellitus (T1DM) and DN have an increase in plasma concentrations of inflammatory proteins involved in insulin resistance. DESIGN: Cross-sectional. Patients One hundred twenty subjects, all diagnosed with T1DM 14 years before. MEASUREMENTS: (1) Sex, age, body mass index, waist-to-hip ratio (WHR), blood pressure, smoking, alcohol intake, insulin dose, HbA1c and lipid profile; (2) DN (peripheral and cardiac autonomic), retinopathy and nephropathy; (3) plasma concentrations of soluble fractions of tumour necrosis factor alpha receptors 1 and 2 (sTNFR1 and sTNFR2), interleukin-6, high-sensitive C-reactive protein, adiponectin and leptin; and (4) insulin resistance (by way of a mathematical estimation of the glucose disposal rate - eGDR-). RESULTS: Thirty-six subjects had DN and 84 did not. Subjects with DN received higher insulin doses (57.6 +/- 16.7 vs. 49.2 +/- 15.0 IU/day; P = 0.008) and had higher WHR (0.85 +/- 0.07 vs. 0.81 +/- 0.10; P = 0.007) and HbA1c values (8.5 (7.6-9.6) vs. 7.7 (7.3-8.9)%; P = 0.049) than subjects without DN. They also had higher values of sTNFR1 (2.42 +/- 0.60 vs. 1.96 +/- 0.66 microg/l; P = 0.001) and sTNFR2 (4.73 +/- 1.33 vs. 4.14 +/- 1.09 microg/l; P = 0.015), and were more insulin resistant (eGDR values: 7.28 (5.83-8.03) vs. 8.30 (7.17-9.03) mg kg(-1) min(-1); P = 0.003). The relationship between DN and either sTNFR1 or sTNFR2 remained essentially unchanged after adjusting for several confounders, including glycaemic control, WHR, lipid profile, blood pressure and other microvascular complications (OR for sTNFR1: 2.592 (1.222-5.498), P = 0.013; OR for sTNFR2: 2.124 (1.258-3.587), P = 0.005). CONCLUSIONS: The activity of the TNF-alpha system is increased in subjects with type 1 diabetes mellitus and diabetic neuropathy, regardless of their glycaemic control and cardiovascular risk factors associated with insulin resistance. These results suggest that TNF-alpha may play a pathogenic role in the development of diabetic neuropathy.

The tumour necrosis factor (TNF)-alpha system is activated in accordance with pulse pressure in normotensive subjects with type 1 diabetes mellitus.

OBJECTIVE: Pulse pressure (PP) and inflammation are important predictors of cardiovascular disease (CVD), even in the normotensive. The age-related increase in PP can be diagnosed up to 20 years earlier in subjects with type 1 diabetes mellitus (T1DM) than in the general population. Some evidence suggests that PP can stimulate inflammation. Our aim was to study the relationship between PP and plasma inflammatory proteins in normotensive subjects with T1DM. DESIGN: This was a cross-sectional study of a group of normotensive (<140/80 mmHg) subjects diagnosed with T1DM 14 years before. None of them had clinically proven CVD or inflammatory conditions or were on antiplatelet, antihypertensive, anti-inflammatory or lipid-lowering treatment. METHODS: The following information was recorded: sex, age, body-mass index (BMI), waist-to-hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure (DBP), PP, mean blood pressure (MBP), smoking, alcohol intake, insulin dose, lipid profile, HbA1c, microvascular complications, and plasma concentrations of soluble receptor types 1 and 2 of tumour necrosis factor (TNF)-alpha (sTNFR1 and sTNFR2, respectively), interleukin-6, C-reactive protein, adiponectin and leptin. RESULTS: A total of 112 subjects were evaluated (aged 27.4+/-6.6 years, 52.7% women, BMI: 20.4+/-2.7 kg/m2, WHR: 0.82+/-0.09, SBP: 112+/-12 mmHg, DBP: 68+/-9 mmHg, PP: 45+/-9 mmHg, MBP: 82+/-9 mmHg, HbA1c: 8.2% (7.3-9.0%), 41.1% microvascular complications). After adjusting for potential confounders, only inflammatory markers of the TNF-alpha system correlated significantly with PP (Pearson correlation coefficient between sTNFR1 and PP: r = 0.215, P = 0.030; and between PP and sTNFR2: r = 0.238, P = 0.020). CONCLUSION: In normotensive subjects with T1DM after 14 years of diagnosis, the activation of the TNF-alpha system is positively associated with PP levels. This finding might suggest a pathogenic role of the TNF-alpha system in the development of cardiovascular disease in T1DM.