Treatment with dapagliflozin increases FGF-21 gene expression and reduces triglycerides content in myocardial tissue of genetically obese mice.

BACKGROUND: The association between obesity and some cardiovascular complications such as heart failure (HF) is well established, and drugs affecting adiposity are supposed to be promising treatments for these conditions. The sodium-glucose cotransporter-2 inhibitors (SGLT2i) are antidiabetic drugs showing benefits in patients with HF, despite the underlying mechanisms have not been completely understood yet. SGLT2i are supposed to promote systemic effects, such as triglycerides mobilization, through the enhancement of fibroblast growth factor-21 (FGF-21) activity. So, in this study, we evaluated the effects of dapagliflozin treatment on FGF-21 and related receptors (FGF-Rs) gene expression and on lipid content in myocardial tissue in an animal model of genetically induced obesity to unravel possible metabolic mechanisms accounting for the cardioprotection of SGLT2i. METHODS: Six-week-old C57BL/6J wild-type mice and B6.V-LEP (ob/ob) mice were randomly assigned to the control or treatment group (14 animals/group). Treatment was based on the administration of dapagliflozin 0.15 mg/kg/day for 4 weeks. The gene expression of FGF-21 and related receptors (FGF-R1, FGF-R3, FGF-R4, and ß-klotho co-receptor) was assessed at baseline and after treatment by real-time PCR. Similarly, cardiac triglycerides concentration was measured in the control group and treated animals. RESULTS: At baseline, FGF-21 mRNA expression in the heart did not differ between lean and obese ob/ob mice. Dapagliflozin administration significantly increased heart FGF-21 gene expression, but only in ob/ob mice (p < 0.005). Consistently, when measuring the amount of triglycerides in the cardiac tissue, SGLT2i treatment reduced the lipid content in obese ob/ob mice, while no significant effects were observed in treated lean animals (p < 0.001). The overall expression of the FGF-21 receptors was only minimally affected by dapagliflozin treatment both in obese ob/ob mice and in lean controls. CONCLUSIONS: Dapagliflozin administration increases FGF-21gene expression and reduces triglyceride content in myocardial tissue of ob/ob mice, while no significant effect was observed in lean controls. These results might help understand the cardiometabolic effects of SGLT2i inducing increased FGF-21 synthesis while reducing lipid content in cardiomyocytes as a possible expression of the switch to different energy substrates. This mechanism could represent a potential target of SGLT2i in obesity-related heart diseases.

Bariatric surgery modulates plasma levels of antibodies against angiotensin II type 1 and endothelin 1 type A receptor in severe obesity.

PURPOSE: The contribution of endothelial-targeted autoantibodies against the angiotensin II type 1 receptor (anti-AT1R) and the anti-endothelin 1 type A receptor (anti-ETAR1) has been proposed in the development of cardiovascular diseases. However, no data have been reported yet in obesity. In this observational study we evaluated the relationship between anthropometric and metabolic parameters and anti-AT1R and anti-ETAR1 concentrations in a cohort of patients with severe obesity and associated comorbidities undergoing bariatric surgery. METHODS: Clinical evaluation and metabolic assessment were performed in 36 subjects referring to our Center for the Study and Integrated Treatment of Obesity at the University Hospital of Padova. Circulating inflammatory adipocytokines and the endothelial dysfunction marker asymmetric dimethylarginine (ADMA) were evaluated; plasma levels of anti-AT1R and anti-ETAR1 were also determined. 10 normal-weight subjects were considered as a control group. 29 patients out of 36 were re-evaluated after surgery. RESULTS: With respect to normal-weight controls patients showed significantly higher plasma levels of anti-AT1R (28 ± 20.4 vs 13.5 ± 2.8 U/mL, p < 0.005) and ADMA (0.8 ± 0.1 vs 0.54 ± 0.08 uM/L, p < 0.0001) but not anti-ETAR1 (14.2 ± 1.3 vs 13.3 ± 2 U/mL, p = 0.1). Anti-AT1R concentration showed an increasing trend with the worsening of glycemic status, while the presence of arterial hypertension among the patients did not affect autoantibodies levels. One year after surgery, a significant improvement in body weight and metabolic and inflammatory parameters was observed, along with a significant reduction of anti-AT1R (28.1 ± 20.4 U/mL vs 22.6 ± 16 U/mL, p < 0.05) and anti-ETAR1 (14.2 ± 1.3 U/L vs 13 ± 1.6 U/L, p < 0.01). CONCLUSIONS: Subjects with obesity present higher plasma levels of anti-AT1R which are more related to glycemic profile than blood pressure levels, and are reduced by bariatric surgery. Considering the detrimental effects of these autoantibodies on vascular health, they should be assessed as potential biomarkers in obesity and metabolic diseases.

Pythium and Phytopythium species associated with weeds collected in vegetable production fields in Brazil.

This study aimed to identify Pythium and Phytopythium species from weeds collected in vegetable fields and test their pathogenicity. Weeds with symptoms of damping-off, root rot or wilt were sampled in the Brazilian states of Ceará, Goiás and Pernambuco, as well as in the Distrito Federal, for isolation and identification of the causal agents. Once isolated, colonies with typical Pythium and Phytopythium characteristics grew in selective V8 medium. Procedures for species identification included morphology and amplification of the ITS and Cox II regions, which were compared with other accessions available at GenBank. The phylogenetic relationships among the isolates and pathogenicity to their original hosts were evaluated. Six Pythium species were identified: P. aphanidermatum, P. oopapillum, P. orthogonon, P. ultimum var. ultimum, P. myriotylum and P. sylvaticum, and two species of Phytopythium, Phy. chamaehyphon and Phy. oedochilum. In the pathogenicity tests, the 10 weed hosts showed symptoms of damping-off or root rot after inoculation, with exception of Portulaca oleraceae in which none of the isolates was pathogenic. Therefore, common weeds in vegetable fields areas can host different Pythium and Phytopythium species and play an important role in the epidemiology of vegetable diseases, in particular on pathogen survival and population increase.

Electromyographic and kinematic parameters of the shoulder in wheelchair rugby players: case reports.

Wheelchair rugby was created as part of the rehabilitation for patients with spinal cord injury. The biomechanical analysis of wheelchair propulsion (WP) in these athletes seems to be a key element to understand the reasons behind musculoskeletal injuries. This case reports study aimed to describe the electromyographic activity and kinematic parameters of the shoulder during the propulsion phases on the wheelchair in two Paralympic rugby players (A1 and A2) with spinal cord injury. Myoelectric activity (three portions of the deltoid, biceps and triceps brachii) and kinematics of the shoulder were assessed during the push (PP) and recovery (RP) phases. These variables were calculated considering ten propulsion cycles by each athlete. The results showed a different muscle activation between players, A1 described a high average amplitude of the anterior deltoid (PP = 58.44 ± 16.35%MVC; RP = 43.16 ± 13.48%MVC) in both propulsion phases, while A2 generated high average activity of triceps brachii (29.28 ± 10.63%MVC) and middle deltoid (46.53 ± 14.48%MVC), during PP and RP, respectively. At the same time, the player with a C7-T1 spinal cord injury (A2) showed a higher range of motion in the three plans, considering both propulsion phases.

Patients with gout have short telomeres compared with healthy participants: association of telomere length with flare frequency and cardiovascular disease in gout.

AIM AND BACKGROUND: Chronic inflammation associates with increased senescence, which is a strong predictor for cardiovascular disease. We hypothesised that inflammation accelerates senescence and thereby enhances the risk of cardiovascular disease in gout. METHODS: We assessed replicative senescence by quantifying telomere length (TL) in a discovery cohort of 145 Dutch patients with gout and 273 healthy individuals and validated our results in 474 patients with gout and 293 healthy participants from New Zealand. Subsequently, we investigated the effect of cardiovascular disease on TL of all participants. Also, we measured TL of CD4+ and CD8+ T lymphocytes, B lymphocytes, monocytes, natural killer cells and plasmacytoid dendritic cells. Additionally, we assessed the potential temporal difference in TL and telomerase activity. RESULTS: TL in PBMCs of healthy donors decreased over time, reflecting normal ageing. Patients with gout demonstrated shorter telomeres (p=0.001, R2=0.01873). In fact, the extent of telomere erosion in patients with gout was higher at any age compared with healthy counterparts at any age (p<0.0001, R2=0.02847). Patients with gout with cardiovascular disease had the shortest telomeres and TL was an independent risk factor for cardiovascular disease in patients with gout (p=0.001). TL was inversely associated with the number of gouty flares (p=0.005). CONCLUSIONS: Patients with gout have shorter telomeres than healthy participants, reflecting increased cellular senescence. Telomere shortening was associated with the number of flares and with cardiovascular disease in people with gout.

Acute and chronic nociceptive phases observed in a rat hind paw ischemia/reperfusion model depend on different mechanisms.

Complex regional pain syndrome type 1 (CRPS1) may be evoked by ischemia/reperfusion, eliciting acute and chronic pain that is difficult to treat. Despite this, the underlying mechanism of CRPS1 has not been fully elucidated. Therefore, the goal of this study is to evaluate the involvement of inflammation, oxidative stress, and the transient receptor potential ankyrin 1 (TRPA1) channel, a chemosensor of inflammation and oxidative substances, in an animal model of chronic post-ischemia pain (CPIP). Male Wistar rats were subjected to 3 h hind paw ischemia/reperfusion (CPIP model). Different parameters of nociception, inflammation, ischemia, and oxidative stress were evaluated at 1 (acute) and 14 (chronic) days after CPIP. The effect of a TRPA1 antagonist and the TRPA1 immunoreactivity were also observed after CPIP. In the CPIP acute phase, we observed mechanical and cold allodynia; increased levels of tumor necrosis factor-α (hind paw), ischemia-modified albumin (IMA) (serum), protein carbonyl (hind paw and spinal cord), lactate (serum), and 4-hydroxy-2-nonenal (4-HNE, hind paw and spinal cord); and higher myeloperoxidase (MPO) and N-acetyl-ß-D-glucosaminidase (NAGase) activities (hind paw). In the CPIP chronic phase, we detected mechanical and cold allodynia and increased levels of IMA (serum), protein carbonyl (hind paw and spinal cord), and 4-HNE (hind paw and spinal cord). TRPA1 antagonism reduced mechanical and cold allodynia 1 and 14 days after CPIP, but no change in TRPA1 immunoreactivity was observed. Different mechanisms underlie acute (inflammation and oxidative stress) and chronic (oxidative stress) phases of CPIP. TRPA1 activation may be relevant for CRPS1/CPIP-induced acute and chronic pain.

Ibuprofen intake increases exercise time to exhaustion: A possible role for preventing exercise-induced fatigue.

Although the intake of nonsteroidal anti-inflammatory drugs (NSAIDs) intake by athletes prevents soreness, little is known concerning their role in exercise performance. This study assessed the effects of ibuprofen intake on an exhaustive protocol test after 6 weeks of swimming training in rats. Animals were divided into sedentary and training groups. After training, animals were subdivided into two subsets: saline or ibuprofen. Afterwards, three repeated swimming bouts were performed by the groups. Ibuprofen (15 mg/kg) was administered once a day. Pain measurements were performed and inflammatory and oxidative stress parameters were assayed in cerebral cortex and gastrocnemius muscle. Training, ibuprofen administration, or both combined (P < 0.05; 211 ± 18s, 200 ± 31s, and 279 ± 23s) increased exercise time to exhaustion. Training decreased the acetylcholinesterase (AChE) activity (P < 0.05; 149 ± 11) in cerebral cortex. Ibuprofen intake decreased the AChE activity after exhaustive protocol test in trained and sedentary rats (P < 0.05; 270 ± 60; 171 ± 38; and 273 ± 29). It also prevented neuronal tumor necrosis factor-α (TNF-α) and interleukin (IL 1ß) increase. Fatigue elicited by this exhaustive protocol may involve disturbances of the central nervous system. Additive anti-inflammatory effects of exercise and ibuprofen intake support the hypothesis that this combination may constitute a more effective approach. In addition, ergogenic aids may be a useful means to prevent exercise-induced fatigue.

Brain anatomical substrates of mirror movements in Kallmann syndrome.

Among male patients affected by Kallmann syndrome, a genetically determined disease due to defective neural migration leading to hypogonadropic hypogonadism and hypo/anosmia, about 40% present the peculiar phenomenon of mirror movements, i.e. involuntary movements mirroring contralateral voluntary hand movements. Several pathogenic hypotheses have been proposed, but the ultimate neurological mechanisms are still elusive. The aim of the present study was to investigate brain anatomical substrates of mirror movements in Kallmann syndrome by means of a panel of quantitative MRI analyses. Forty-nine male Kallmann syndrome patients underwent brain MRI. The study protocol included 3D-T1-weighted gradient echo, fluid attenuated inversion recovery and diffusion tensor imaging. Voxel-based morphometry, sulcation, curvature and cortical thickness analyses and tract based spatial statistics were performed using SPM8, Freesurfer and FSL. All patients underwent a complete physical and neurological examination including the evaluation of mirror movements (according to the Woods and Teuber criteria). Kallmann syndrome patients presenting with mirror movements (16/49, 32%) displayed the following brain changes: 1) increased gray matter density in the depth of the left precentral sulcus behind the middle frontal gyrus; 2) decreased cortical thickness in the precentral gyrus bilaterally, in the depth of right precentral sulcus and in the posterior portion of the right superior frontal gyrus; and 3) decreased fractional anisotropy in the left hemisphere involving the temporal lobe and peritrigonal white matter. No differences were shown by cortical curvature and sulcation analyses. The composite array of brain changes observed in Kallmann syndrome patients with mirror movements likely represents the anatomical-structural underpinnings leading to the peculiar derangement of the complex circuitry committed to unilateral hand voluntary movements.

Normal spermatogenesis and sperm function in a subject affected by cerebellar ataxia due to congenital vitamin E deficiency.

Vitamin E possesses potent beneficial effects on mammalian spermatogenesis and sperm quality. Subjects affected by cerebellar ataxia due to congenital isolated vitamin E deficiency (AVED) show vitamin E deficiency caused by a selective impaired gastrointestinal absorption of vitamin E for a mutation in the gene for α-tocopherol transfer protein leading to impairment of vitamin E absorption and decreased vitamin E plasma levels. Here, we present a 34-year-old male patient with AVED showing normal seminal parameters and normal gonadotrophins, testosterone and inhibin B plasma levels. The normal standard seminal parameters of this patient with AVED possibly question the role of vitamin E in human spermatogenesis.

Supercritical extraction from vinification residues: fatty acids, α-tocopherol, and phenolic compounds in the oil seeds from different varieties of grape.

Supercritical fluid extraction has been widely employed in the extraction of high purity substances. In this study, we used the technology to obtain oil from seeds from a variety of grapes, from vinification residues generated in the Southern region of the state of Rio Grande do Sul, Brazil. This work encompasses three varieties of Vitis vinifera (Moscato Giallo, Merlot, and Cabernet Sauvignon) and two of Vitis labrusca (Bordô e Isabel), harvested in 2005 and 2006. We obtained the highest oil content from Bordô (15.40%) in 2005 and from Merlot (14.66%), 2006. The biggest concentration of palmitic, stearic, and linoleic acids was observed in Bordô, 2005, and in Bordô, Merlot, and Moscato Giallo, 2006. Bordô showed the highest concentration of oleic acid and α-tocopherol in both seasons too. For the equivalent of procyanidins, we did not notice significant difference among the varieties from the 2005 harvest. In 2006, both varieties Isabel and Cabernet Sauvignon showed a value slightly lower than the other varieties. The concentration of total phenolics was higher in Bordô and Cabernet Sauvignon. The presence of these substances is related to several important pharmacological properties and might be an alternative to conventional processes to obtain these bioactives.

Fetal dose estimation for Virtual Tangential-fields Arc Therapy whole breast irradiation by optically stimulated luminescence dosimeters.

Breast cancer is the most frequently diagnosed tumor in pregnant women and radiation therapy should carefully be weighted up because of the dose to the fetus. The aim of this study was to investigate fetal dose in a patient treated with Virtual Tangential-fields Arc Therapy (ViTAT), an innovative technique for whole breast irradiation. Optically stimulated luminescence detectors (OSLDs) were calibrated on a Varian TrueBeam linac, with both a 6X and 6XFFF beam quality, and used for out-of-field measurements. Fetal dose related with ViTAT technique was compared to the standard 3D conformal radiation therapy technique (3DCRT). The fetal dose delivered with a ViTAT technique planned with 6XFFF beam was also investigated. Measurements were taken on a phantom composed of Rando Alderson Phantom slices and solid water slabs. OSLDs were placed in a region identified by the height of the fundus from conception to the twentieth week using a custom made PMMA grid. Due to the higher number of monitor units, the peripheral dose of ViTAT delivered with 6X beams is higher than that of 3DCRT. However, nanoDots measurements prove that ViTAT can be used in place of 3DCRT while maintaining similar fetal dose levels if 6XFFF beams are used.

Fatty Acid and Carnitine Metabolism Are Dysregulated in Systemic Sclerosis Patients.

Systemic sclerosis (SSc) is a rare chronic disease of unknown pathogenesis characterized by fibrosis of the skin and internal organs, vascular alteration, and dysregulation of the immune system. In order to better understand the immune system and its perturbations leading to diseases, the study of the mechanisms regulating cellular metabolism has gained a widespread interest. Here, we have assessed the metabolic status of plasma and dendritic cells (DCs) in patients with SSc. We identified a dysregulated metabolomic signature in carnitine in circulation (plasma) and intracellularly in DCs of SSc patients. In addition, we confirmed carnitine alteration in the circulation of SSc patients in three independent plasma measurements from two different cohorts and identified dysregulation of fatty acids. We hypothesized that fatty acid and carnitine alterations contribute to potentiation of inflammation in SSc. Incubation of healthy and SSc dendritic cells with etoposide, a carnitine transporter inhibitor, inhibited the production of pro-inflammatory cytokines such as IL-6 through inhibition of fatty acid oxidation. These findings shed light on the altered metabolic status of the immune system in SSc patients and opens up for potential novel avenues to reduce inflammation.

Bilateral pedaling asymmetry during a simulated 40-km cycling time-trial.

AIM: This study investigated the pedaling asymmetry during a 40-km cycling time-trial (TT). METHODS: Six sub-elite competitive male cyclists pedaled a SRM Training Systems cycle ergometer throughout a simulated 40-km TT. A SRM scientific crank dynamometer was used to measure the bilateral crank torque (N.m) and pedaling cadence (rpm). All data were analyzed into 4 stages with equal length obtained according to total time. Comparisons between each stage of the 40-km TT were made by an analysis of variance (ANOVA). Dominant (DO) and non-dominant (ND) crank peak torque asymmetry was determined by the equation: asymmetry index (AI%)=[(DO-ND)/DO] 100. Pearson correlation analysis was performed to verify the relationship between exercise intensity, mean and crank peak torque. RESULTS: The crank peak torque was significantly (P<0.05) greater in the 4th stage compared with other stages. During the stages 2 and 3, was observed the AI% of 13.51% and 17.28%, respectively. Exercise intensity (%VO(2max)) was greater for stage 4 (P<0.05) and was highly correlated with mean and crank peak torque (r=0.97 and r=0.92, respectively) for each stage. CONCLUSIONS: The DO limb was always responsible for the larger crank peak torque. It was concluded that pedaling asymmetry is present during a simulated 40-km TT and an increase on crank torque output and exercise intensity elicits a reduction in pedaling asymmetry.

Comparison of body adiposity index (BAI) and air displacement plethysmograph with estimations of % body fat in adults with Down's syndrome.

BACKGROUND/OBJECTIVES: The aim of this study was to verify the agreement between body fat percentage (%BF) values evaluated by air displacement plethysmograph (ADP) and body adiposity index (BAI) in adults with Down's syndrome (DS). SUBJECTS/METHODS: Forty-five adults with DS volunteered to participate in this study (19 women; age 28.7±8.5 years and 26 men; age 29.1±8.8 years). The %BF was measured by ADP (%BFADP) and estimated by anthropometric measures [%BF=(hip circumference/height)1.5-18] (%BFBAI). Agreement between methods was evaluated by paired t-test, Pearson's correlation coefficient and Bland-Altman analysis. RESULTS: Although high correlation coefficients were found between %BFADP and %BFBAI for women (r=0.78, P<0.05) and men (r=0.87, P<0.05), significant differences were observed between methods for both sexes (38.9±8.9 vs 42.5±8.5% for women, and 25.8±11.3 vs 32.6±5.4% for men in %BFADP and %BFBAI, respectively). Moreover, Bland-Altman analysis showed that the mean error estimate was +3.6 (95%CI, -7.59 to 14.79) in women and +6.74 (95%CI, -7.25 to 20.72) in men. CONCLUSIONS: The results indicate that BAI seems to be a limited method to evaluate %BF in women and in men with DS.

Serum miRNAs as potential biomarkers for the bronchiolitis obliterans syndrome after lung transplantation.

Lung transplantation (LTx) is the last treatment for patients suffering from end-stage lung diseases. Survival post-LTx is hampered by the development of the bronchiolitis obliterans syndrome (BOS) and diagnosis is often late. Given the urgent clinical need to recognize BOS patients at an early stage, we analyzed circulating miRNAs to identify possible stratification markers for BOS development post-transplantation. Therefore, pro-fibrotic (miR-21, miR-155), anti-fibrotic (miR-29a) and fibrosis-unrelated (miR-103, miR-191) miRNAs were analyzed in serum of end-stage lung disease patients and during LTx follow-up. Significant elevated levels of serum miRNAs were observed for all investigated miRNAs in both chronic obstructive pulmonary disease and interstitial lung disease patients compared to healthy controls. The same miRNAs were also significantly increased in the serum of BOS+ vs. BOS- patients. Most importantly, miR-21, miR-29a, miR-103, and miR-191 levels were significantly higher in BOS+ patients prior to clinical BOS diagnosis. We demonstrated that a selected group of miRNAs investigated is elevated in end-stage lung disease and BOS+ patients, prior to clinical BOS diagnosis. Even if further research is expedient on the prognostic value of circulating miRNAs in BOS and lung conditions in general, these results strongly suggest that circulating miRNAs could be used as potential biomarkers for BOS development.

Sex steroid imbalances in the muricid Stramonita haemastoma from TBT contaminated sites.

Imposex incidence, organotin tissue levels, and sex steroid (free and esterified testosterone and estradiol) levels were assessed in Stramonita haemastoma from Babitonga Bay (Santa Catarina State, Southern Brazil). The imposex levels showed a reduction when compared to a previous evaluation performed in the same area. In spite of that, the detected imposex incidence indicated the occurrence of tributyltin (TBT) inputs that were still able to produce endocrine disruption in local gastropods. In addition, a high level of organotins was observed in tissues of imposexed females. These females also showed a hormonal imbalance, especially in the total testosterone/total estradiol ratio. These findings obtained under realistic field conditions suggest that the steroid pathway could be responsible by the imposex induction after exposure to TBT. In this case, measurements of sex steroid levels can be an additional evidence for monitoring sites and impose affected gastropod populations.

Delivering RapidArc®: A comprehensive study on accuracy and long term stability.

PURPOSE: To establish the reliability and accuracy of a UNIQUE Linac in delivering RapidArc treatments and assess its long term stability. MATERIALS AND METHODS: UNIQUE performance was monitored and analyzed for a period of nearly two years. 2280 Dynalog files, related to 179 clinical RapidArc treatments were collected. Different tumor sites and dose scheduling were included, covering the full range of our treatment plans. Statistical distributions of MLC motion error, gantry rotation error and MU delivery error were evaluated. The stochastic and systematic nature of each error was investigated together with their variation in time. RESULTS: All the delivery errors are found to be small and more stringent tolerances than those proposed by TG142 are suggested. Unlike MLC positional errors, where a linear relationship with leaf speed holds, other Volumetric Modulated Arc Therapy (VMAT) parameters reveal a random nature and, consequently, a reduced clinical relevance. MLC errors are linearly related only to leaf speed no matter the shape of the MLC apertures. Gantry rotation and MU delivery are as accurate as major competing Linacs. UNIQUE was found to be reliable and accurate throughout the investigation period, regardless of the specific tumor sites and fractionation schemes. CONCLUSIONS: The accuracy of RapidArc treatments delivered with UNIQUE has been established. The stochastic nature of delivery errors is proven. Long term statistics of the delivery parameter errors do not show significant variations, confirming the reliability of the VMAT delivery system.

Human sperm express cannabinoid receptor Cb1, the activation of which inhibits motility, acrosome reaction, and mitochondrial function.

Cannabinoids and endocannabinoids negatively influence sperm functions. These substances have been demonstrated in many mammalian tissues, including male and female reproductive tracts, and previous studies have shown the presence of functional receptors for cannabinoids in human sperm. The present study, by means of RT-PCR and Western blot techniques, demonstrates that human sperm express the CB(1), but not CB(2), cannabinoid receptor (CB-R) subtype located in the head and middle piece of the sperm. The activation of this receptor by anandamide reduces sperm motility and inhibits capacitation-induced acrosome reaction. Activation of the CB(1)-R did not induce any variation in sperm intracellular calcium concentrations, but produced a rapid plasma membrane hyperpolarization that was reduced by the K(+) channel blocker tetraethylammonium. The effects of anandamide on human sperm motility were dependent on the reduction of sperm mitochondrial activity as determined by rhodamine 123 fluorescence. The specificity of anandamide effects in human sperm were confirmed by the effects of the CB(1)-R antagonist SR141716. These findings provide additional evidence that human sperm express functional CB(1)-R, the activation of which negatively influences important sperm functions, and suggest a possible role for the cannabinoid system in the pathogenesis of some forms of male infertility.

Review article: adipocytokines and insulin resistance.

Insulin resistance has been implicated as one possible factor that links visceral obesity to unfavourable metabolic and cardiovascular consequences. However, the mechanism whereby adipose tissue causes alterations in insulin action remains unclear. White adipose tissue is secreting several hormones, particularly leptin and adiponectin, and a variety of other protein signals: the adipocytokines. They include proteins involved in the regulation of energy balance, lipid and glucose metabolism as well as angiogenesis, vascular and blood pressure regulation. Visceral obesity and inflammation within white adipose tissue may be a crucial step contributing to the emergence of insulin resistance, type 2 diabetes and atherosclerosis. A growing list of adipocytokines involved in inflammation (IL-1beta, IL-6, IL-8, IL-10, TNF-alpha, TGF-beta,) and the acute-phase response (serum amyloid A, PAI-1) have been found to be increased in the metabolic syndrome. It is, however, unclear as to the extent adipose tissue contributes quantitatively to the elevated circulating levels of these factors in obesity and how they may affect the insulin-dependent tissues. This review describes the role of the currently known adipocytokines and hormones released by adipose tissue in generating the insulin resistance state and the chronic inflammatory profile which frequently goes together with visceral obesity.