Factors Associated with Lower Extremity Dysmorphia Caused by Lower Extremity Lymphoedema.

OBJECTIVES: Indocyanine green (ICG) lymphography has been reported to be useful for the early diagnosis of lymphoedema. However, no study has reported the usefulness of ICG lymphography for evaluation of lymphoedema with lower extremity dysmorphia (LED). This study aimed to elucidate independent factors associated with LED in secondary lower extremity lymphoedema (LEL) patients. METHODS: This was a retrospective observational study of 268 legs of 134 secondary LEL patients. The medical charts were reviewed to obtain data of clinical demographics and ICG lymphography based severity stage (leg dermal backflow [LDB] stage). LED was defined as a leg with a LEL index of 250 or higher. Logistic regression analysis was used to identify independent factors associated with LED. RESULTS: LED was observed in 106 legs (39.6%). Multivariate analysis revealed that independent factors associated with LED were higher LDB stages compared with LDB stage 0 (LDB stage III; OR 17.586; 95% CI 2.055-150.482; p = .009) (LDB stage IV; OR 76.794; 95% CI 8.132-725.199; p < .001) (LDB stage V; OR 47.423; 95% CI 3.704-607.192; p = .003). On the other hand, inverse associations were observed in higher age (65 years or older; OR 0.409; 95% CI 0.190-0.881; p = .022) and higher body mass index (25 kg/m2 or higher; OR 0.408; 95% CI 0.176-0.946; p = .037). CONCLUSIONS: Independent factors associated with LED were elucidated. ICG lymphography based severity stage showed the strongest association with LED, and was useful for evaluation of progressed LEL with LED.

Myocardial torsional deformations in cats with hypertrophic cardiomyopathy using two-dimensional speckle-tracking echocardiography.

OBJECTIVES: The objective of our study was to quantitatively measure systolic torsional deformations in cats with hypertrophic cardiomyopathy (HCM) and in controls. ANIMALS: Twenty-six client-owned cats with HCM and 14 healthy cats. HCM cats were categorized based on their symptoms (asymptomatic and symptomatic) and with or without left ventricular outflow tract obstruction (obstructive and non-obstructive). METHODS: The cats were examined for myocardial deformations using two-dimensional speckle-tracking echocardiography and were evaluated for peak systolic rotation and the rotation rate at each basal and apical view. Cats were also evaluated for the peak systolic torsion and torsion rate. RESULTS: The peak systolic apical rotation and torsion were higher in asymptomatic and symptomatic cats with HCM than in control cats. Also, the peak systolic apical rotation, apical rotation rate, torsion, and torsion rate were higher in cats with obstructive HCM than in control cats. CONCLUSIONS: Myocardial torsional deformations assessed by two-dimensional speckle-tracking echocardiography may be useful for evaluating compensatory myocardial function of HCM.

Indocyanine Green Lymphography Findings in Primary Leg Lymphedema.

OBJECTIVES: Indocyanine green (ICG) lymphography has been reported to be useful for the evaluation of secondary lymphedema, but no study has reported characteristic findings of ICG lymphography in primary lymphedema. This study aimed to classify characteristic ICG lymphography patterns in primary lymphedema. METHODS: The study was a retrospective observational study. Thirty one primary lower extremity lymphedema (LEL) patients with a total of 62 legs were studied. ICG lymphography patterns were categorized according to the visibility of lymphatics and dermal backflow (DB) extension. Clinical demographics were compared with categorized ICG lymphography patterns. RESULTS: All symptomatic legs showed abnormal patterns, and all asymptomatic legs showed normal patterns on ICG lymphography. Abnormal lymphographic patterns could be classified into proximal DB (PDB), distal DB (DDB), less enhancement (LE), and no enhancement (NE) patterns. There were significant differences between PDB (16 patients), DDB (6 patients), LE (4 patients), and NE patterns (5 patients) in age (37.3 ± 18.3 vs. 61.8 ± 19.2 vs. 50.8 ± 27.7 vs. 29.2 ± 18.0 years, p = .035), onset of edema (23.9 ± 19.4 vs. 46.8 ± 27.0 vs. 43.0 ± 31.3 vs. 6.6 ± 14.2 years, p = .020), laterality (bilateral; 18.8% vs. 66.7% vs. 75.0% vs. 0%, p » .016), cellulitis history(56.3% vs. 100% vs. 25.0% vs. 0%, p » .007), and LEL index (292.2 ± 32.8 vs. 254.2 ± 28.6 vs. 243.3 ± 9.4 vs. 295.2 ± 44.8, p = .016). CONCLUSIONS: ICG lymphography findings in primary lymphedema could be classified into four patterns withdifferent patient characteristics.

A c-fos-monomeric red fluorescent protein 1 fusion transgene is differentially expressed in rat forebrain and brainstem after chronic dehydration and rehydration.

We have previously shown that an acute osmotic stimulation induces the expression of a c-fos and monomeric red fluorescent protein 1 (mRFP1) fusion transgene in osmosensitive rat brain areas, including the supraoptic (SON) and paraventricular nuclei (PVN). However, the effects of chronic stimuli, such as dehydration, have not been investigated. In the present study, the expression patterns of the c-fos-mRFP1 fusion gene in the forebrain and the brainstem of male and female transgenic rats were studied in seven experimental groups: ad lib. water (euhydration), water deprivation for 12, 24 or 48 h (dehydration) and water deprivation for 46 h + ad lib. water for 2, 6 or 12 h (rehydration). The number of cells that express nuclear mRFP1 fluorescence was quantified in the hypothalamus, the circumventricular organs and the brainstem. Compared to the euhydrated state, the number of transgene expressing cells significantly increased in all forebrain areas and in the rostral ventrolateral medulla after dehydration and 2 h of rehydration. In the nucleus of the solitary tract and area postrema, the number of mRFP1 fluorescent cells was markedly increased after 2 h of rehydration. Although the number of mRFP1 fluorescent cells in the organum vasculosum laminae terminalis, median preoptic nucleus and subfornical organ remained significantly increased after 6 h of rehydration, reaching control levels after 12 h of rehydration, the number of mRFP1 fluorescent cells in the SON and the PVN reached control levels after 6 h of rehydration. There were no significant differences between male and female rats. These results show that the expression of the c-fos-mRFP1 fusion gene changes in the forebrain and the brainstem not only after acute osmotic stimulation, but also after chronic osmotic stimulation. Interestingly, these studies reveal the differential activation of different neuronal groups over the time course of dehydration and rehydration.

Hypothalamic brain-derived neurotrophic factor regulates glucagon secretion mediated by pancreatic efferent nerves.

Understanding the molecular mechanism of the regulation of glucagon secretion is critical for treating the dysfunction of α cells observed in diabetes. Glucagon-like peptide (GLP)-1 analogues reduce plasma glucagon and are assumed to contribute to their action to lower blood glucose. It has previously been demonstrated that the central administration of brain-derived neurotrophic factor (BDNF) improves glucose metabolism by a mechanism independent of feeding behaviour in obese subjects. Using male rats, we examined whether BDNF influences glucagon secretion from α cells via the the central nervous system. We investigate whether: (i) the central infusion of BDNF stimulates glucagon and/or insulin secretion via the pancreatic efferent nerve from the hypothalamus; (ii) the intraportal infusion of GLP-1 regulates glucose metabolism via the central and peripheral nervous system; and (iii) BDNF receptor and/or BDNF-positive fibres are localised near α cells of islets. The portal glucagon level decreased with the central administration of BDNF (n = 6, in each; P < 0.05); in contrast, there was no significant change in portal insulin, peripheral glucagon and insulin levels with the same treatment. This reduction of glucagon secretion was abolished by pancreatic efferent denervation (n = 6, in each; P < 0.05). In an immunohistochemical study, pancreatic α cells were stained specifically with BDNF and tyrosine-related kinase B, a specific receptor for BDNF, and α cells were also co-localised with BDNF. Moreover, intraportal administration of GLP-1 decreased glucagon secretion, as well as blood glucose, whereas it increased the BDNF content in the pancreas; these effects were inhibited with the central infusion of BDNF antibody (n = 6, in each; P < 0.05). BDNF and GLP-1 affect glucose metabolism and modulate glucagon secretion from pancreatic α cells via the central and peripheral nervous systems.

Successful tocilizumab and tacrolimus treatment in a patient with rheumatoid arthritis complicated by systemic lupus erythematosus.

We report a 37-year-old female of intractable rheumatoid arthritis (RA) complicated by systemic lupus erythematosus (SLE), who was successfully treated with a combination of tocilizumab (TCZ) and tacrolimus. She was diagnosed with RA when she was 21 years old, and was administered oral prednisolone, injectable gold and salazosulfapyridine, but deformity of her hands gradually developed. She developed high fever and thrombocytopenia when she was 35 years old. Renal involvement, pericarditis, positive antinuclear antibody and high level of anti-double-stranded DNA antibody were found and the patient was diagnosed with SLE. Polyarthritis and immunological abnormalities developed despite aggressive immunosuppressive therapy including high-dose corticosteroids and intravenously administered cyclophosphamide. Tacrolimus (TAC) therapy gave only partial improvement of joint symptoms. After the initiation of combination therapy with TCZ, not only was a complete remission of RA obtained, but also the serum levels of SLE markers dramatically decreased. Our report suggests the possibility that this combination therapy is effective in treating SLE as well as RA.

Monocyte chemoattractant protein-1 is associated with silent cerebral infarction in patients on haemodialysis.

BACKGROUND: In patients with chronic renal failure undergoing haemodialysis (HD), silent cerebral infarctions (SCI) are associated with high mortality. Levels of monocyte chemoattractant protein-1 (MCP-1) increase with renal dysfunction and may be a novel predictor for cerebrovascular events. We tested the hypothesis that increased MCP-1 concentration correlate with the occurrence of SCI in HD patients. METHODS: Using cranial magnetic resonance imaging (MRI) findings, 52 Japanese patients undergoing HD were divided into two groups: with SCI (61 ± 7 years, mean ± SD, n= 28) and without SCI (60 ± 6 years, n= 24). The gender, metabolic profiles and MCP-1 concentration were compared between the two groups. RESULTS: The level of MCP-1 was higher in the with-SCI group than in the without-SCI group (P < 0.0001). The proportion of smokers was higher in the with-SCI group (P < 0.05) than in the without-SCI group. Plasma level of high-density lipoprotein cholesterol was lower, while uric acid level was higher, in the with-SCI group (P < 0.05 and P < 0.05 respectively) compared to the without-SCI group. Multiple logistic regression analysis identified MCP-1 level as being significantly associated with the presence of SCI (odds ratio 1.48, 95% confidence interval = 1.10-5.75, P < 0.0001). CONCLUSIONS: This study indicates that patients with chronic renal failure who are maintained on HD exhibit an increased prevalence of SCI, and that MCP-1 is significantly associated with the presence of SCI in HD patients.

Interleukin-6 and silent cerebral infarction in hemodialysis patients: a cross-sectional study.

BACKGROUND: In patients with chronic renal failure undergoing hemodialysis (HD), silent cerebral infarctions (SCI) are associated with high mortality. Levels of interleukin-6 (IL-6) increase with renal dysfunction and may be a novel predictor for cerebrovascular events. We tested the hypothesis that increased IL-6 levels correlate with the occurrence of SCI in HD patients. METHODS: Using cranial magnetic resonance imaging findings, we divided 50 Japanese patients undergoing HD into two groups: with SCI (60 ± 7 years, mean ± SD, n = 27) and without SCI (60 ± 6 years, n = 23). We compared the gender, body mass index, metabolic profiles, IL-6 levels, and smoking habits between the two groups. RESULTS: We made the following observations: (i) The prevalence of diabetes or hypertension did not differ between the two groups, (ii) the level of IL-6 was higher in the with-SCI group than in the without-SCI group (P < 0.0001), (iii) the proportion of smokers was higher in the with-SCI group (P < 0.05), (iv) plasma level of high-density lipoprotein cholesterol was lower, whilst uric acid level was higher, in the with-SCI group (P < 0.05 and P < 0.05, respectively), and (v) multiple logistic regression analysis identified IL-6 levels as being significantly associated with the presence of SCI (odds ratio 3.13, 95% CI = 1.42-7.89, P < 0.0001). CONCLUSIONS: This study indicates that patients with chronic renal failure who are maintained on HD exhibit an increased prevalence of SCI and that IL-6 is significantly associated with the presence of SCI in HD patients.

Neuronal histamine and its receptors: implication of the pharmacological treatment of obesity.

Obesity is the effect of imbalance between energy intake and expenditure and forms a fundamental basis of the metabolic syndrome. A number of substances implicated in the regulation of energy metabolism represent opportunities for anti-obesity drug development. Neuronal histamine and its receptors have been shown to regulate energy metabolism and are considered as anti-obesity targets. Several histamine receptor subtypes have been identified; of these, histamine H1 and H3 receptors (H1-R and H3-R) have been specifically recognized as mediators of energy intake and expenditure. In addition, several histamine drugs related to H1-R and H3-R, have been shown to attenuate body weight gain both in rodent and human. These results provide the reagents for histamine receptors biology and may find applications in the treatment of obesity and related metabolic disorders. In this review, the development of agonists and antagonists of histamine receptors are provided.

Induction of heat shock proteins prevents the arrhythmogenic substrate for atrial fibrillation.

Atrial fibrillation (AF) is the commonest arrhythmia. Studies have shown that atrial tachypacing (artificial persistent AF) causes electrical remodelling. This is characterised by the shortening of the atrial effective refractory period (ERP), in which reduction in L-type Ca(2+) channel current plays an essential part. Atrial fibrosis, a feature of structural remodelling, is induced by continuous infusion of angiotensin II, and has been associated with conduction delay in atria, which promotes AF. Acute atrial ischaemia, frequently observed during development of acute coronary syndrome, has been associated with atrial conduction heterogeneity, which also promotes AF. Induction of heat shock proteins (Hsp72 and Hsp27) by hyperthermia and/or geranylgeranylacetone has demonstrated to protect the heart against such atrial remodelling. The potent protective role of Hsp72 and Hsp27 against clinical AF in patients who underwent open heart surgery has been shown. Taken together, interventions that induce heat shock responses (including induction of Hsp72 and Hsp27) may prevent newly developed AF and delay the progression of paroxysmal AF to persistent AF.

Visceral fat accumulation is a significant risk factor for white matter lesions in Japanese type 2 diabetic patients.

BACKGROUND: The presence of white matter lesions (WML) is an important prognostic factor for the development of stroke. The elevated visceral fat accumulation (VFA) has been reported to be closely related to the development of atherosclerosis. This preliminary study was therefore designed to test the hypothesis that the presence of WML correlates with VFA and insulin resistance in type 2 diabetic patients not receiving insulin treatment. MATERIAL AND METHODS: Based on brain magnetic resonance imaging (MRI), 95 type 2 diabetic patients were divided into two groups: WML-positive group (aged 59 +/- 7 years, mean +/- SD n = 37) and WML-negative group (aged 58 +/- 5, years, n = 58). The level of blood glucose was assessed by fasting plasma glucose (FPG), fasting immunoreactive insulin, homeostasis model assessment (HOMA) index, and haemoglobin A1c. The fat distribution was evaluated by measuring the visceral fat accumulation by abdominal computerized tomography at the umbilical level. RESULTS: The body mass index was higher in the WML-positive group than in the WML-negative group (P < 0.005). Plasma levels of triglycerides were higher while high-density lipoprotein cholesterol was lower in the WML-positive group than in the WML-negative group (P < 0.05 and P < 0.01, respectively). FPG (P < 0.01), insulin concentrations (P < 0.0001), HOMA index (P < 0.0001) and VFA (<0.0001) levels were higher in the WML-positive group than in the WML-negative group. Multivariate logistic analysis revealed that WML was independently predicted by the high VFA and insulin resistance (P < 0.001, P < 0.0001, respectively). CONCLUSIONS: The results of this preliminary study indicate that the presence of WML was associated with the high VFA and insulin resistance in Japanese patients with type 2 diabetes mellitus. Further larger cohort studies are warranted to confirm these findings.

New squatting test indices are useful for assessing baroreflex sensitivity in diabetes mellitus.

AIMS: The heart rate (HR) responses after performance of the squatting and standing manoeuvre are thought to be a useful tool to assess autonomic neuropathy in diabetics. Our aim was to develop new simple squatting test indices and to analyse their applicability to the assessment of baroreflex sensitivity (BRS) in patients with diabetes. METHODS: Twenty healthy volunteers (mean age 23.2 +/- 3.8 years) and 51 patients with diabetes (mean age 55.9 +/- 10.6 years) were enrolled in study 1 and study 2, respectively. Each subject stood for 3 min (basal period), then squatted down for 1 min (Sq) and stood up again for 1 min (St). In study 1, the squatting test was performed before and after pharmacological autonomic blockade. In study 2, we measured HR in each period and calculated the difference between basal HR and HRSq (DeltaHRSq) and between HRSt and HRSq (DeltaHRSt). BRS was also measured using the phenylephrine method in diabetic patients. RESULTS: In healthy individuals during autonomic blockade, HR changes were mainly controlled by the vagal tone during squatting and by the sympathetic tone during standing. In diabetic patients, DeltaHRSq and DeltaHRSt positively correlated (r = 0.86, P < 0.0001) and both DeltaHRSq and DeltaHRSt significantly correlated with BRS (r = 0.66, P < 0.0001 and r = 0.61, P < 0.0001, respectively). CONCLUSIONS: The new squatting test indices provide useful information for assessing autonomic neuropathy and for identifying diabetic patients at high risk of cardiovascular events.

Hyperhomocysteinaemia is a significant risk factor for white matter lesions in Japanese type 2 diabetic patients.

The presence of white matter lesions (WML) is an important prognostic factor for the development of stroke. Plasma total homocysteine (tHcy), which increases with diabetes, has been flagged as a novel predictor for cerebrovascular events. We tested the hypothesis that the presence of WML correlates with tHcy and insulin resistance in type 2 diabetic patients not receiving insulin treatment. Based on brain magnetic resonance imaging findings, 81 type 2 diabetic patients were divided into two groups, with-WML group (57 +/- 8 years, mean +/- standard deviation, n = 31) and without-WML group (57 +/- 6 years, n = 50). The blood glucose level was assessed by fasting plasma glucose (FPG), fasting immunoreactive insulin, Homeostasis Model Assessment (HOMA) Index and hemoglobin A1c. The body mass index was higher in the with-WML group than in the without-WML group (P < 0.05). Plasma levels of triglyceride were higher whilst high-density lipoprotein cholesterol was lower in the with-WML group than in the without-WML group (P < 0.05 and P < 0.0001 respectively). FPG (P < 0.005), insulin concentrations (P < 0.0001), HOMA Index (P < 0.0001) and tHcy (<0.0001) levels were higher in the with-WML group than in the without-WML group. Multivariate logistic analysis revealed that WML was independently predicted by the high tHcy and insulin resistance. Our findings indicate that the presence of WML was associated with the high tHcy and insulin resistance in these Japanese patients with type 2 diabetes mellitus.

Pioglitazone shift circadian rhythm of blood pressure from non-dipper to dipper type in type 2 diabetes mellitus.

BACKGROUND: Insulin resistance significantly correlated with a non-dipper type of essential hypertension. Thiazolidinediones (TZD), oral hypoglycaemic agents that act as insulin sensitizers, have been demonstrated in multiple in vivo and in vitro studies to possess antihypertensive properties. This study examined the efficacy of TZD therapy with pioglitazone at transforming the circadian rhythms of blood pressure from a non-dipper to a dipper type. MATERIALS: We examined 31 patients with type 2 diabetes mellitus during both a baseline period and a period of treatment with pioglitazone. Patients received 15 mg day(-1) pioglitazone for four weeks and 30 mg day(-1) for 12 weeks. Twenty-four hour ambulatory blood pressure monitoring (ABPM) and laboratory data (blood tests for cardiovascular risk factors) were obtained at the beginning and end of the study. RESULTS: In non-dippers (n = 16), but not dippers (n = 15), we observed a significant interaction between pioglitazone therapy and nocturnal falls in systolic and diastolic blood pressure. This examination indicated that the magnitude of the nocturnal blood pressure fall was affected by pioglitazone therapy. In non-dippers, but not dippers, a significant correlation was observed between the percent decrease in nocturnal BP and the homeostasis model assessment (HOMA) index (r = 0.774, P = 0.0007). CONCLUSIONS: The present study demonstrated that pioglitazone can restore the nocturnal BP declines in parallel to reductions in the HOMA index, suggesting that insulin resistance may play an important role in the genesis of circadian BP rhythms. TZD-based treatment may thus have the additional therapeutic advantage of reducing the risk of cardiovascular complications by transforming the circadian rhythm of BP.

Smoking is associated with insulin resistance and cardiovascular autonomic dysfunction in type 2 diabetic patients.

BACKGROUND: Smoking and cardiovascular autonomic dysfunction are associated with high mortality in type 2 diabetic patients. This study tested the hypothesis that smoking is associated with insulin resistance/hyperinsulinaemia and cardiovascular autonomic dysfunction in type 2 diabetic patients who are not treated with insulin. MATERIALS AND METHODS: The study patients were 22 current smokers with type 2 diabetes mellitus (age: 57 +/- 5 years, mean +/- SD) and 30 age-matched never-smoked patients with type 2 diabetes mellitus (control group, 57 +/- 8 years). The quality of blood glucose was assessed by fasting plasma glucose (FPG), fasting immunoreactive insulin (F-IRI), homeostasis model assessment (HOMA) index and haemoglobin A1c (HbA1c). The severity of smoking status was expressed by the Brinkman index, which is calculated as number of cigarettes per day multiplied by years of smoking. Cardiovascular autonomic function was assessed by baroreflex sensitivity (BRS), heart-rate variability, plasma norepinephrine concentration and cardiac (123)I-metaiodobenzylguanidine (MIBG) scintigraphic findings. RESULTS: Baroreflex sensitivity was lower in the current smokers group than in the never-smoked group (P < 0.05). Early and delayed (123)I-MIBG myocardial uptake values were lower (P < 0.05, and P < 0.01, respectively) and the percentage washout-rate of (123)I-MIBG was higher (P < 0.0001) in the current smokers group than in the never-smoked group. Fasting immunoreactive insulin (F-IRI) concentration (P < 0.0001) and the homeostasis model assessment (HOMA) index (P < 0.0001) were higher in the current smokers group than the never-smoked group. Multiple logistic regression analysis revealed that smoking was independently predicted by F-IRI and the percentage washout-rate of (123)I-MIBG. CONCLUSIONS: The results of the study suggested that smoking was associated with cardiovascular autonomic dysfunction and hyperinsulinaemia and that F-IRI and the percentage washout-rate of (123)I-MIBG were independent predictors of smoking in these Japanese patients with type 2 diabetes mellitus.

Evaluation of average amount of cerebral blood flow measured by brain perfusion index in patients with neuropsychiatric systemic lupus erythematosus.

We used the brain perfusion index (BPI), an indicator of the average amount of cerebral blood flow (CBF), to evaluate the usefulness of the average amount of CBF for neuropsychiatric systemic lupus erythematosus (NPSLE). Of the seventy three SLE patients examined in this study (total 100 scans), 16 patients (23 scans) had already been diagnosed with NPSLE based on clinical symptoms indicative of central nervous system involvement. In addition, 12 patients (17 scans) exhibited the antiphospholipid antibody syndrome (APS). BPI is significantly influenced by age and we therefore used the BPI ratio (ratio of age predicted BPI to measured BPI value) for each assessment. The mean BPI value of 100 scans was 11.2 +/- 2.79, and the mean BPI ratio was 0.99 +/- 0.24 in all SLE patients. The mean BPI ratio among NPSLE (0.84 +/- 0.19) was significantly lower than that of the non-NPSLE patients (1.04 +/- 0.24) (P < 0.0005). However, there was no difference in the mean BPI ratio between APS patients (0.98 +/- 0.24) and non-APS patients (0.99 +/- 0.25). These results indicate that the mean CBF assessed by the BPI ratio using SPECT is of use in the evaluation of central nervous system involvement in SLE patients.

Hypothalamic neuronal histamine regulates sympathetic nerve activity and expression of uncoupling protein 1 mRNA in brown adipose tissue in rats.

To clarify how hypothalamic neuronal histamine regulates peripheral energy expenditure, we investigated the effect of infusion of histamine into the third cerebral ventricle or discrete hypothalamic regions on sympathetic nerve activity and expression of uncoupling protein 1 (UCP1) mRNA in brown adipose tissue (BAT). Infusion of histamine (200 nmol) into the third cerebral ventricle of anesthetized rats significantly increased the electrophysiological activity of sympathetic nerves (P<0.01) and UCP1 mRNA expression in the BAT (P<0.05). Microinjection of histamine (10 nmol) into the paraventricular nucleus (PVN) and preoptic area (POA) produced similar significant increases in BAT sympathetic nerve activity (P<0.01 for each). By contrast, injection of histamine into the ventromedial hypothalamic nucleus or lateral hypothalamic area had no effect. We conclude that hypothalamic neuronal histamine may regulate energy expenditure in BAT through the activation of sympathetic nerves. The PVN and/or POA appear to be the principal hypothalamic sites that mediate the stimulatory effect of histamine on this efferent pathway.

IKBL promoter polymorphism is strongly associated with resistance to type 1 diabetes in Japanese.

Type 1 diabetes is a multifactorial disease in which the genes of the major histocompatibility complex (MHC) play a key role. Recently, non-human leukocyte antigen (non-HLA) genes in the class III region of this complex have been presumed to be associated with type 1 diabetes by linkage analyses. We investigated the possibility of the inhibitor of kappaB-like (IKBL, also known as 'NFKBIL1') gene as one of these candidates. We carried out a case-control study of 124 patients with type 1 diabetes and 330 healthy control subjects. The haplotypes of the IKBL promoter, i.e., PA (-263A, -63T), PB (-263A, -63A), PC (-263G, -63T), were assigned by the single-nucleotide polymorphisms at positions -263 and -63 from the transcription start site. The frequency of the wild-type haplotype, PA, was elevated, while that of the variant-type haplotype, PC, was lower in patients than controls. In two-locus analyses with HLA-DRB1 alleles, the PA haplotype showed linkage disequilibrium with the DRB1*0405 allele and the PC haplotype with the DRB1*1502 allele. A notable observation was that the PC haplotype was significantly associated with protection in the DRB1*1502-negative population. Our study indicates the first evidence of a possible independent association between type 1 diabetes and polymorphisms in the promoter of the IKBL gene.

Food texture differences affect energy metabolism in rats.

Dietary factors such as taste and nutrients are known to affect satiety and energy balance. We hypothesized that food texture might contribute to the regulation of energy metabolism through the process of mastication in the oral cavity as well. The effects of long-term feeding of different-textured pellets on body weight gain, adiposity, and thermogenesis were assessed. From weaning at 4 wks, rats were divided into 2 groups fed on either standard (controls) or soft pellets (soft-fed) that required less chewing with the same nutritional composition. At 26 wks, the soft-fed rats showed greater adiposity than did the controls. Daily food intake did not differ between the 2 groups. The increase in body temperature following feeding was significantly lower in the soft-fed rats. These results suggested that food texture affected energy metabolism by changing post-prandial thermogenesis. The long-term deficiency of thermogenesis associated with soft foods resulted in a greater tendency toward obesity.

Histidine induces lipolysis through sympathetic nerve in white adipose tissue.

BACKGROUND: Hypothalamic neuronal histamine has been shown to increase lipolysis in white adipose tissue. The present study aimed to clarify whether peripheral loading with L-histidine, a precursor of neuronal histamine, may affect lipid metabolism in adipose tissue. MATERIALS AND METHODS: The in vivo microdialysis study was used to assess lipolysis in rat epididymal adipose tissue by measuring the release of glycerol in response to administration of L-histidine. In addition, electrophysiological measurements were performed to record changes in activity of sympathetic nerve innervating adipose tissue following histidine treatment. RESULTS: Sequential administration of isoproterenol, a beta-adrenoceptor agonist, through the microdialysis cannula at concentrations of 10(-)8 to 10(-6) M increased the glycerol concentration in the dialysate dose-dependently (P < 0.05). Intraperitoneal administration of L-histidine at a dosage of 0.35 mmol kg(-1) also increased the glycerol concentration compared to that of phosphate buffered saline (P < 0.05). Concomitantly, the administration of histidine increased the serum concentration of free fatty acid compared to control treatment (P < 0.05). The accelerating effects of histidine on lipolysis were mimicked by the infusion of 10(2) nmol rat(-1) L-histamine into the third cerebroventricle (P < 0.05). Electrophysiological measurement demonstrated that administration of histidine at a dosage of 0.35 mmol kg(-1) increased the activity of efferent sympathetic nerve, innervating adipose tissue more than the infusion of phosphate buffered saline (P < 0.05). CONCLUSION: The present results indicate that histidine accelerates lipolysis in white adipose tissue through activation of the sympathetic nerve. The regulation of lipolysis may therefore involve histamine neurons in the brain, probably through the conversion of L-histidine to histamine in the hypothalamus.