Cannabis arteritis presenting with Raynaud's and digital ulcerations: a case-based review of a controversial thromboangiitis obliterans-like condition.

Thromboangiitis obliterans (TAO), or Buerger's disease, is a non-atherosclerotic inflammatory disease of the small and medium-sized arteries, veins, and nerves of the legs and arms, strongly associated with the use of tobacco products in young adults. Cannabis arteritis (CA), an entity with similar clinical and pathological features, has been described in marijuana users as a subtype of TAO. Distinction between TAO and CA is challenging, given that most patients use tobacco and marijuana products concomitantly. Herein, we report the case of a male in his late forties who was referred to rheumatology with a 2-month history of hand swelling and bilateral painful digital ulcers with blue discoloration on his fingers and toes. The patient reported daily use of marijuana in blunt wraps and denied tobacco use. His laboratory work-up was negative for scleroderma and other connective tissue diseases. His angiogram confirmed the diagnosis of thromboangiitis obliterans, which was attributed to cannabis arteritis. The patient was started on aspirin and nifedipine daily and discontinued marijuana use. His symptoms resolved within 6 months and have not recurred for more than a year with continued avoidance of marijuana. Our case is one of the few that features primarily marijuana-driven CA and highlights the importance of not only considering marijuana use but also blunt wrap use in patients presenting with Raynaud's phenomenon and ulcerations as cannabis use rises globally.

PCSK9 and ANGPTL3 levels correlate with hyperlipidemia in HIV-lipoatrophy, are regulated by fasting and are not affected by leptin administered in physiologic or pharmacologic doses.

BACKGROUND: Medications leveraging the leptin, PCSK9, ANGPTL3 and FABP4 pathways are being developed for the treatment of insulin resistance and/or lipid disorders. To evaluate whether these pathways are independent from each other, we assessed the levels of PCSK9, ANGPTL3 and FABP4, in normal subjects and subjects exhibiting HIV and highly active antiretroviral therapy (HAART) induced metabolic syndrome with lipoatrophy and hypoleptinemia. Studies were performed at baseline and during food deprivation for three days with either a placebo or leptin administration at physiological replacement doses to correct fasting induced acute hypoleptinemia and in pharmacological doses. METHODS: PCSK9, ANGPTL3, FABP4 levels and their correlations to lipoproteins-metabolites were assessed in randomized placebo controlled cross-over studies: a) in 15 normal-weight individuals undergoing three-day admissions in the fed state, in complete fasting with placebo and in complete fasting with leptin treatment in physiologic replacement doses (study 1), b) in 15 individuals day baseline in a fed and three fasting admissions for three days with leptin administered in physiologic, supraphysiologic and pharmacologic doses (study 2), c) in 7 hypoleptinemic men with HIV and HAART-induced lipoatrophy treated with leptin or placebo for two months in the context of a cross over randomized trial (study 3). RESULTS: Circulating ANGPTL3, PCSK9 and FABP4 were markedly elevated in HIV-lipoatrophy and not affected by leptin treatment. PCSK9 levels correlated with lipids and markers of lipid utilization and lipolysis. ANGPTL3 levels correlated with HDL particles and their lipid composition. FABP4 levels were negatively associated with HDL diameter (HDL-D) and composition. PCSK9 and ANGPTL3 levels decreased during food deprivation by ~65 % and 30 % respectively. Leptin administration at physiologic, supraphysiologic and pharmacologic doses did not affect PCSK9, ANGPTL3 and FABP4 levels. CONCLUSIONS: PCSK9, ANGPTL3 and FABP4 levels are associated with markers of lipid metabolism and are higher in HIV-lipoatrophy. PCSK9 and ANGPTL3 but not FABP4 decrease in response to food deprivation. PCSK9 and ANGPTL3 regulation is leptin-independent, suggesting independent pathways for lipid regulation. Thus, combining treatments of leptin with PCSK9 and/or ANGPTL3 inhibitors for metabolic diseases should have additive effects and merit further investigation. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov no. NCT00140231, NCT00140205, NCT00140244.

Heel fat pad involvement in rheumatoid arthritis: a review and case series.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease affecting not only the synovial joints but also multiple extra-articular sites, including ankle and foot soft tissue. Hindfoot abnormalities usually follow those in the forefoot, with up to 4 out of 10 patients experiencing talalgia during their disease course. Enthesophytosis, retrocalcaneal bursitis, and plantar fasciitis are among the most common etiologies, while heel fat pad abnormalities like subcalcaneal bursitis are rare. Here, we report two cases of subcalcaneal bursitis, and the first case of heel fat pad and subcalcaneal bursa herniation in patients with established RA, along with a comprehensive literature review of subcalcaneal bursitis and other heel fat pad abnormalities in RA. Subcalcaneal bursitis, also referred to as panniculitis, inflammatory-edematous lesion, or adventitial (adventitious) bursitis has been reported in up to 10% of patients with RA. It appears as a compressible, heterogeneous, and hypoechoic subcalcaneal mass on ultrasound (US), with peripheral vascularization on Doppler US. Patients may present with heel discomfort. Ultrasonographic assessment is usually sufficient to confirm the presence of heel fat pad pathologies. Rest, analgesics, and mechanical aids with or without addition of disease-modifying antirheumatic drugs are usually employed, while intervention is rarely required.

Circulating levels of gastrointestinal hormones in response to the most common types of bariatric surgery and predictive value for weight loss over one year: Evidence from two independent trials.

AIMS: Bariatric surgery leads to profound and sustainable weight loss. Gastrointestinal hormones are involved in energy and glucose homeostasis, thus postoperative changes of their circulating levels may be mediating future weight loss. To investigate how the circulating concentrations of gastrointestinal hormones change in response to the most common types of bariatric operation and whether these changes can predict future weight loss. MATERIALS AND METHODS: We measured circulating GLP-1, GLP-2, oxyntomodulin, glicentin, glucagon, major proglucagon fragment (MPGF), ghrelin, GIP, PYY after overnight fasting and/or after a mixed meal test (MMT) in: a) 14 subjects that have undergone either an adjustable gastric banding [AGB] (n = 9) or a Roux-en-Y bypass (RYGB) (n = 5) (Pilot study 1), b) 28 subjects that have undergone either a vertical sleeve gastrectomy (n = 17) or a RYGB (n = 11) before and three, six and twelve months after surgery. RESULTS: In addition to the expected associations with GLP-1, the most robust increases were observed in postprandial levels of oxyntomodulin and glicentin three months after VSG or RYGB (but not after AGB) and are associated with degree of weight loss. Oxyntomodulin and glicentin levels at the third and sixth month postoperative visit are positively associated with feeling of satiety which may be underlying the observed associations with future weight loss. CONCLUSION: Beyond GLP-1, early postprandial changes in circulating oxyntomodulin and glicentin are predictors of weight loss after bariatric surgery, possibly through regulation of satiety. Further studies should focus on underlying mechanisms, and their potential as attractive therapeutic tools against obesity and related comorbidities.

Increased risk for cardiovascular disease in patients with obstructive sleep apnoea syndrome-chronic obstructive pulmonary disease (overlap syndrome).

INTRODUCTION: Accumulating evidence suggests that cardiovascular disease (CVD) is highly prevalent among patients with concurrent obstructive sleep apnoea syndrome (OSAS) and chronic obstructive pulmonary disease, otherwise known as overlap syndrome (OS). OBJECTIVES: The aim of this study was to investigate the 10-year risk for CVD in OS patients compared with OSAS patients and controls. METHODS: Consecutive patients, referred for symptoms suggestive of OSAS, were evaluated with polysomnography and pulmonary function testing. Cardiovascular risk was assessed using the Framingham risk score (FRS) and systematic coronary risk evaluation (SCORE). RESULTS: Overall, 244 participants (184 males) without CVD and diabetes were divided into 3 groups: controls (n = 63), OSAS (n = 139) and OS (n = 42). Both FRS and SCORE were found to be elevated in the OS group compared with the OSAS and control groups (P < .001 for all). In multivariate analysis, age (ß = .461, P < .001), forced expiratory volume in first second (ß = -.285, P = .036) and oxygen desaturation index (ODI) (ß = .234, P = .007) were major determinants for the SCORE, whereas age (ß = .308, P < .001) and apnoea-hypopnoea index (ß = .252, P = .010) for the FRS. CONCLUSION: In our study, an increased risk for CVD was observed in a group of patients with OS at the time of their initial evaluation. Further studies are needed in the field of OS in order to investigate, prevent and manage early CVD in this population.

Of mice and men: incretin actions in the central nervous system.

Incretins have risen to the forefront of therapies for obesity and related metabolic complications, primarily because of their efficacy and relatively few side effects. Importantly, their efficacy in altering energy balance and decreasing body weight is apparently through actions in the central nervous system (CNS); the latter may have implications beyond obesity per se, i.e. in other disease states associated with obesity including CNS-related disorders. Here, we first describe the role of the CNS in energy homeostasis and then the current state of knowledge in terms of incretin physiology, pathophysiology and efficacy in preclinical and clinical studies. In the future, more clinical studies are needed to fully map mechanistic pathways underlying incretin actions and outcomes in the human CNS. Additionally, future research will likely lead to the discovery of additional novel incretins and/or more efficacious medications with less side effects through the improvement of current compounds with properties that would allow them to have more favorable pharmacokinetic and pharmacodynamic profiles and/or by combining known and novel incretins into safe and more efficacious combination therapies leading ultimately to more tangible benefits for our patients.

Circulating levels of the components of the GH/IGF-1/IGFBPs axis total and intact IGF-binding proteins (IGFBP) 3 and IGFBP 4 and total IGFBP 5, as well as PAPPA, PAPPA2 and Stanniocalcin-2 levels are not altered in response to energy deprivation and/or metreleptin administration in humans.

OBJECTIVE: It remains unclear whether food deprivation induces changes in components of the GH/IGF-1/IGFBPs axis and if yes, which ones are mediated by leptin, an adipocyte secreted hormone regulating neuroendocrine response to energy deprivation in animals and humans. We aimed to investigate components of the axis that have not been studied to date, i.e. IGF-binding proteins (IGFBPs) and related proteases (total and intact IGFBP 3 and IGFBP 4, total IGFBP 5, PAPPA, PAPPA2 and Stanniocalcin-2), during acute (short-term fasting in healthy subjects) and chronic (women with hypothalamic amenorrhea [HA] due to excessive exercise) energy deprivation and whether metreleptin administration, in replacement, supraphysiologic or pharmacologic levels, may mediate any changes of circulating levels of the above molecules in healthy individuals and in women with hypothalamic amenorrhea. METHODS: We studied: 1) 11 healthy men and women during three four day admissions i.e. a baseline admission in the fed isocaloric state and two admissions in the complete food deprivation state for 72-h with either placebo (resulting in a hypoleptinemic state) or metreleptin administration in doses designed to normalize circulating leptin levels for the duration of the study, 2) 15 healthy men and women during three 72-hour long admissions in a complete food deprivation state receiving three escalating doses of metreleptin designed to bring circulating leptin levels to physiologic, supraphysiologic, or pharmacologic levels, and 3) 18 women with HA randomized to either metreleptin treatment in replacement doses or placebo for nine months. RESULTS: There were no significant changes in the circulating profiles of the above molecules in the fasting vs. fed state and/or with metreleptin administration during acute and chronic energy deprivation. CONCLUSIONS: The studied components of the GH/IGF-1/IGFBPs axis are not affected by energy deprivation, leptin deficiency associated with energy deprivation, or by metreleptin administration in physiologic, supraphysiologic or pharmacologic doses.

Pharmacotherapy of obesity: Available medications and drugs under investigation.

Obesity is a chronic disease with a continuously rising prevalence that currently affects more than half a billion people worldwide. Energy balance and appetite are highly regulated via central and peripheral mechanisms, and weight loss triggers a homeostatic response leading to weight regain. Lifestyle and behavioral modifications are the cornerstones of obesity management; however, they often fail to achieve or sustain long-term weight loss. Pharmacotherapy added onto lifestyle modifications results in an additional, albeit limited, weight reduction. Regardless, this weight reduction of 5-10% conveys multiple cardiovascular and metabolic benefits. In this review, evidence on the food and drug administration (FDA)-approved medications, i.e., orlistat, lorcaserin, phentermine/topiramate, liraglutide and naltrexone/bupropion, is summarized. Furthermore, anti-obesity agents in the pipeline for potential future therapeutic use are presented.