Risk of circulatory diseases associated with proton-pump inhibitors: a retrospective cohort study using electronic medical records in Thailand.

Background: Proton-pump inhibitors (PPIs) are prescribed to treat gastric acid-related diseases, while they may also have potential risks to population health. Recent studies suggested that a potential mechanism explaining the association between PPIs and cardiovascular diseases (CVD) includes the inhibition of the nitrate-nitrite-nitric oxide (NO) pathway. However, previous observational studies showed controversial results of the association. In addition, the inhibition of the NO pathway due to PPIs use may lead to peripheral vascular diseases (PVD); however, none of the studies explore the PPI-PVD association. Therefore, this study aimed to evaluate the association of PPIs with circulatory diseases (CVD, ischemic strokes or IS, and PVD). Methods: We conducted a retrospective hospital-based cohort study from Oct 2010 to Sep 2017 in Songkhla province, Thailand. PPIs and histamine 2-receptor antagonists (H2RAs) prescriptions were collected from electronic pharmacy records, while diagnostic outcomes were retrieved from electronic medical records at Songklanagarind hospital. Patients were followed up with an on-treatment approach. Cox proportional hazard models were applied to measure the association comparing PPIs vs H2RAs after 1:1 propensity-score-matching. Sub-group analysis, multi-bias E-values, and array-based sensitivity analysis for some covariates were used to assess the robustness of associations. Results: A total of 3,928 new PPIs and 3,928 H2RAs users were included in the 1:1 propensity score-matched cohort. As compared with H2RAs, the association of PPIs with CVD, IS, and PVD, the hazard ratios were 1.76 95% CI = [1.40-2.20] for CVD, 3.53 95% CI = [2.21-5.64] for ischemic strokes, and 17.07 95% CI = [13.82-76.25] for PVD. The association between PPIs and each outcome was significant with medication persistent ratio of over 50%. In addition, the association between PPIs and circulatory diseases was robust to unmeasured confounders (i.e., smoking and alcohol). Conclusion: PPIs were associated with circulatory diseases, particularly ischemic strokes in this hospital-based cohort study, whereas, the strength of associations was robust to unmeasured confounders.

Bortezomib-induced glomerular microangiopathy complicated with monoclonal immunoglobulin deposition disease.

A 75-year-old man admitted with IgG λ-type myeloma with creatinine level of 2.3 mg/dL. Serum lactate dehydrogenase level and platelet count were normal. Urinalysis demonstrated massive proteinuria dominated by albuminuria. Weekly bortezomib and dexamethasone therapy were started to treat myeloma but failed to be continued because of rapid deterioration of renal function and increase in proteinuria 1 week after the treatment. His renal function exacerbated to require hemodialysis for a month. There was no clinical evidence of tumor lysis syndrome or thrombocytopenia throughout the course of his acute kidney injury (AKI). After he became dialysis independent, a renal biopsy was performed to clarify myeloma-related renal involvement and the cause of AKI. As a result, IgG2-λ monoclonal immunoglobulin deposition disease (MIDD) and severe endothelial injury were revealed. There was no evidence of cast nephropathy. Bortezomib-induced glomerular microangiopathy (GMA) superimposed on MIDD. Bortezomib has a potential risk to cause drug-induced GMA without systemic thrombotic microangiopathy, in which vascular endothelial growth factor-nuclear factor-κ B pathway could be involved. This is the first case of biopsy-proven bortezomib-induced GMA. If proteinuria (mainly albuminuria) increases after using bortezomib, GMA should be suspected as an adverse effect of bortezomib even absent of clinical signs of systemic thrombotic microangiopathy.

Comparative analysis of patients with upper urinary tract urothelial carcinoma in black-foot disease endemic and non-endemic area.

BACKGROUND: A high incidence of upper urinary tract urothelial carcinoma has been reported in the southwestern area of Taiwan, where arsenic water contamination was considered the main cause. However, there is no definite proof to show a correlation between arsenic water contamination and upper urinary tract urothelial carcinoma. To investigate the clinical and epidemiological features of patients with upper urinary tract urothelial carcinoma between arsenic water endemic and non-endemic areas, we analyzed patients in terms of characteristics, stratified overall survival, disease-free survival, and cancer-specific survival. METHODS: The records of a total of 1194 patients diagnosed with upper urinary tract urothelial carcinoma were retrospectively reviewed. Clinical data and current medical status were collected from the medical records. Statistical analyses were performed to determine the clinical variables and stratified survival curves between endemic and non-endemic groups. RESULTS: Female predominance was revealed in both endemic and non-endemic groups (male:female ratio = 1:1.2-1.4). No statistical differences were found in histological types, staging, and tumor size between the two groups. Nonetheless, patients with characteristics of aging and having end-stage renal disease were outnumbered in the non-endemic group, while a higher prevalence of previous bladder tumors and more ureteral tumors were found in the endemic group. Adjusted stratified cumulative survival curves suggested a poorer prognosis in endemic patients, especially in disease-free survival of early stage disease. CONCLUSIONS: A higher mortality rate with more previous bladder cancer history and ureteral tumors was seen in patients with upper urinary tract urothelial carcinoma residing in the arsenic water contamination area. This may be attributed to the long-term carcinogenic effect of arsenic underground water.

Digital ischaemia secondary to adalimumab-induced antiphospholipid syndrome.

A 50-year-old woman with a history of Crohn's disease treated with adalimumab presented with left hand pain and duskiness. Angiogram showed non-filling of the radial and digital arteries of the hand. Antiphospholipid antibody testing was positive, leading to a diagnosis of antitumour necrosis factor-induced antiphospholipid syndrome. Adalimumab was discontinued, and she was treated with the vitamin K antagonist warfarin and low-dose aspirin. Upon resolution of the antiphospholipid antibodies, she was transitioned to aspirin alone without recurrence of thrombosis.

Somatosensory predictors of response to pregabalin in painful chemotherapy-induced peripheral neuropathy: a randomized, placebo-controlled, crossover study.

Painful chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and treatment-resistant sequela of many chemotherapeutic medications. Ligands of α2δ subunits of voltage-gated Ca channels, such as pregabalin, have shown efficacy in reducing mechanical sensitivity in animal models of neuropathic pain. In addition, some data suggest that pregabalin may be more efficacious in relieving neuropathic pain in subjects with increased sensitivity to pinprick. We hypothesized that greater mechanical sensitivity, as quantified by decreased mechanical pain threshold at the feet, would be predictive of a greater reduction in average daily pain in response to pregabalin vs placebo. In a prospective, randomized, double-blinded study, 26 patients with painful CIPN from oxaliplatin, docetaxel, or paclitaxel received 28-day treatment with pregabalin (titrated to maximum dose 600 mg per day) and placebo in crossover design. Twenty-three participants were eligible for efficacy analysis. Mechanical pain threshold was not significantly correlated with reduction in average pain (P = 0.97) or worst pain (P = 0.60) in response to pregabalin. There was no significant difference between pregabalin and placebo in reducing average daily pain (22.5% vs 10.7%, P = 0.23) or worst pain (29.2% vs 16.0%, P = 0.13) from baseline. Post hoc analysis of patients with CIPN caused by oxaliplatin (n = 18) demonstrated a larger reduction in worst pain with pregabalin than with placebo (35.4% vs 14.6%, P = 0.04). In summary, baseline mechanical pain threshold tested on dorsal feet did not meaningfully predict the analgesic response to pregabalin in painful CIPN.

Incidence and evaluation of predisposition to cardiovascular toxicity in chronic myeloid leukemia patients treated with bosutinib in the real-life practice.

There is little information about cardiovascular adverse event (CV-AE) incidence in chronic myeloid leukemia (CML) patients treated with bosutinib in the real-life practice. We identified 54 consecutive CML patients treated with bosutinib, stratified according to the Systematic Coronary Risk Evaluation (SCORE) assessment, based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels. The 40-month cumulative incidence of CV-AEs was 25.2 ± 8.1%. Patients with the SCORE of high-very high showed a significantly higher incidence of CV-AEs (55 ± 12.9% vs 9 ± 9.5%; p = 0.002). Overall, 9 CV-AEs were reported, with 2 deaths attributed to CV-AE. In conclusion, the SCORE assessment before starting treatment is helpful in identifying CV-AE high-risk patients during bosutinib treatment.

[Peripheral ischemia and heart failure as complications of neoadjuvant therapy of bladder cancer]. / Perifeerinen iskemia ja sydämen vajaatoiminta virtsarakkosyövän esiliitännäishoidon komplikaationa.

Cystoctemy is the standard therapy of bladder cancer that has spread to muscle. After five years from the surgery only 50% of the patients remain alive. Owing to poor prognosis, preoperative cytostatic chemotherapy for the patients has been commenced. Severe complications associated with the therapy are rare, and the results are promising in selected patients. We describe a patient case, in which necrosis of terminal segments of fingers and heart failure developed during preoperative chemotherapy.

Cardiovascular safety of varenicline: patient-level meta-analysis of randomized, blinded, placebo-controlled trials.

Smoking is a major modifiable risk factor for cardiovascular (CV) disease. Varenicline is a pharmacological aid for smoking cessation. To explore the CV safety of varenicline, we investigated the incidence of CV events in varenicline-treated subjects across all phase 2-4 randomized placebo-controlled clinical trials of ≥12-week treatment duration conducted in smokers aged ≥18 years and sponsored by the drug manufacturer. This manuscript reports a subject-level meta-analysis of time to major adverse cardiovascular events (MACE; defined as CV-related death, nonfatal myocardial infarction, nonfatal stroke) and time to MACE+ (defined as MACE plus worsening or any procedure for peripheral vascular disease, hospitalization for angina, or performance of coronary revascularization). All events were adjudicated by an independent adjudication committee, blind to treatment assignment. Events were assessed during treatment and up to 30 days after the last treatment dose. The primary analytical method was a stratified logrank time-to-event analysis; secondary analyses were meta-analyses of incidence rate ratios and rate differences. Overall, 7002 subjects were included (varenicline: 4190; placebo: 2812) from 15 studies. MACE were reported by 13 varenicline subjects (0.31%) and 6 placebo subjects (0.21%) [hazard ratio, 1.95; 95% confidence interval (CI): 0.79-4.82; P = 0.15; risk difference, 0.006 events per subject-year; 95% CI: -0.003, 0.015, P = 0.19]. MACE+ were reported by 26 varenicline subjects (0.62%) and 12 placebo subjects (0.43%) (hazard ratio, 1.74; 95% CI: 0.91-3.34, P = 0.10; risk difference, 0.010; 95% CI: -0.002, 0.022, P = 0.11). This subject-level meta-analysis of MACE or MACE+ up to 30 days posttreatment in placebo-controlled clinical trials of varenicline found a trend toward increased incidence of these events in varenicline-treated patients that did not reach statistical significance. The overall number of events was low and the absolute risk of CV events with varenicline was small.

Gastric mucosal necrosis with vascular degeneration induced by doxycycline.

We encountered 2 patients who underwent esophagogastroduodenoscopy for epigastric abdominal pain, which showed gastric mucosal erosions covered with adherent exudate. Microscopic examination of biopsies from the lesions obtained from the 2 cases revealed characteristic pathologic abnormalities that shared striking similarities. These included superficial mucosal necrosis and capillary vascular degenerative change in a background of reactive or chemical gastropathy. Further review of records identified ongoing oral doxycycline use in both patients. After cessation of the drug both patients' symptoms resolved. A follow-up esophagogastroduodenoscopy in 1 patient showed normal gastric mucosa. This pattern of injury had not been previously described and seems to be characteristic for doxycycline-induced gastric mucosal toxicity. Recognition of the clinical, endoscopic, and pathologic features described here may facilitate prompt diagnosis and management of this condition.

Cadmium and peripheral arterial disease: gender differences in the 1999-2004 US National Health and Nutrition Examination Survey.

Gender differences in the association of blood and urine cadmium concentrations with peripheral arterial disease (PAD) were evaluated by using data from 6,456 US adults aged ≥40 years who participated in the 1999-2004 National Health and Nutrition Examination Survey. PAD was defined as an ankle-brachial blood pressure index of <0.9 in at least one leg. For men, the adjusted odds ratios for PAD comparing the highest with the lowest quintiles of blood and urine cadmium concentrations were 1.82 (95% confidence interval (CI): 0.82, 4.05) and 4.90 (95% CI: 1.55, 15.54), respectively, with a progressive dose-response relation and no difference by smoking status. For women, the corresponding odds ratios were 1.19 (95% CI: 0.66, 2.16) and 0.56 (95% CI: 0.18, 1.71), but there was evidence of effect modification by smoking: among women ever smokers, there was a positive, progressive dose-response relation; among women never smokers, there was a U-shaped dose-response relation. Higher blood and urine cadmium levels were associated with increased prevalence of PAD, but women never smokers showed a U-shaped relation with increased prevalence of PAD at very low cadmium levels. These findings add to the concern of increased cadmium exposure as a cardiovascular risk factor in the general population.

Polypoidal choroidal vasculopathy following photodynamic therapy for choroidal hemangioma.

PURPOSE: To report a case of circumscribed choroidal hemangioma (CCH) that responded to photodynamic therapy (PDT) but 3 years later developed polypoidal choroidal vasculopathy (PCV) with exudative retinopathy. METHODS: Case report. RESULTS: A 59-year-old woman with a juxtapapillary CCH in her left eye was treated with a single 83-second, 7.5 mm PDT laser spot at 689 nm (50 J/cm2) 15 minutes after the injection of intravenous verteporfin (6 mg/m2). Three years later, the patient presented with photopsia in her left eye. Fundus examination of the left eye showed CCH regressed completely to a flat atrophic scar. There was diffuse macular edema and exudative retinopathy along the inferotemporal vascular arcade. On indocyanine green angiography, there were hyperfluorescent dilated choroidal vessels inferior to the foveola with late staining and leakage consistent with PCV. Hypofluorescence superior and nasal to the optic disc at the site of the treated hemangioma, consistent with choroidal ischemia, was observed. She was treated with 1.25 mg (0.05 cc) intravitreal bevacizumab. After 21 months of follow-up, the exudative retinopathy and macular edema completely regressed. CONCLUSIONS: PDT is an effective treatment for CCH. Side effects of PDT for CCH are rare but include PCV.

Flexion contracture of the elbow due to phlebosclerosis induced by anti-cancer drug infusion.

This case report describes a patient with elbow contracture due to phlebosclerosis induced by anti-cancer drug infusion. Limitation of elbow extension was completely relieved by surgical excision of the sclerotic vein.

Alcohol consumption: risks and benefits.

Alcohol has had a long and complicated role in human society and health. Excessive use of alcohol causes enormous morbidity and mortality worldwide, but the health effects of alcohol use within recommended guidelines are diverse and complex. Established effects include increased high-density lipoprotein cholesterol and antithrombotic activity, providing plausible mechanisms for the observed association of moderate drinking with lower risk of coronary heart disease but higher risk of hemorrhagic stroke. However, moderate drinking increases sex steroid hormone levels and may interfere with folate metabolism, both of which are potential mechanisms for the observed associations of moderate drinking with several forms of cancer, particularly breast and colorectal. Genetic susceptibility to the effects of alcohol on cancer and coronary heart disease also differs across the population. Recommendations regarding moderate drinking must be individualized to reflect the potentially competing effects of alcohol on several chronic diseases.

Fluorouracil-induced hepatic artery spasm preventing yttrium-90 microsphere administration.

Coronary spasm is a recognized complication of fluorouracil (FU) chemotherapy. Spasm has been documented at other arterial sites with FU. SIR-spheres (radioactive yttrium-90 microspheres) are increasingly being used for hepatic colorectal metastasis. Various FU schedules are reported in the literature, and it is likely there will be coadministration with SIR-spheres. There is, however, little specific information in these reports as to the timing of FU and hepatic arterial spasm associated with infusion FU, which is a potential complication that should be considered.

Methylphenidate and dextroamphetamine-induced peripheral vasculopathy.

Methylphenidate and dextroamphetamine are central nervous system stimulants used in the treatment of attention deficit hyperactivity disorders in children. These medications have been associated with cerebral arteritis, renal necrotizing vasculitis, and systemic and pulmonary hypertension. We report 4 patients, 2 on methylphenidate and 2 on dextroamphetamine who presented with acral cyanosis, livedo reticularis, or Raynaud phenomenon. Two patients were found to have a positive ANA at low titers, 1 of whom had histopathologic evidence of stratum malgiphian necrosis with perivascular lymphocytic infiltration on skin biopsy. Two had positive antihistone antibodies. One patient improved after withdrawal of dextroamphetamine; others had worsening of their symptoms on higher doses of medications. These cases indicate the potential for development of acral cyanosis, livedo reticularis, or Raynaud symptoms with these medications and their potential contribution to a vasculopathy.

Defective adrenergic responses in patients with arsenic-induced peripheral vascular disease.

Blackfoot disease is an endemic arsenic-induced peripheral vascular disease in southern Taiwan. The main pathologic feature is atherosclerosis, which may relate to imbalances of the adrenergic system. The purpose of this study is to investigate the peripheral adrenergic responses of patients with blackfoot disease. Eight patients with blackfoot disease and four age-matched healthy controls were enrolled in this study. Baseline cutaneous perfusion was measured with a laser Doppler flowmeter. The response of alpha-adrenoceptors in the cutaneous microcirculation was assessed with laser Doppler flowmetry with iontophoresis of phenylephrine into the nailfold. In vitro binding with (125)I-cyanopindolol determined beta-adrenoceptor density in lymphocytes. The cyclic adenosine monophosphate (cAMP) level at baseline and after isoproterenol stimulation reflects lymphocyte beta-adrenergic responsiveness. Results revealed persistently decreased skin perfusion in patients with blackfoot disease. In contrast, there was a transient decrease in skin perfusion in healthy controls after iontophoresis of phenylephrine. Both beta-2 receptor density and isoproterenol-stimulated cAMP levels in lymphocytes decreased. Increased peripheral alpha-adrenergic response and decreased beta-2-adrenergic response are related to increased vascular tone and result in atherosclerosis. Our findings of accentuated alpha-adrenergic response in microcirculation and decreased lymphocyte beta-2-adrenoceptor response play an important role in the pathogenesis of atherosclerosis in blackfoot disease.