Vessel Network Architecture of Adult Human Islets Promotes Distinct Cell-Cell Interactions In Situ and Is Altered After Transplantation.

Islet-cell hormone release is modulated by signals from endothelial and endocrine cells within the islet. However, models of intraislet vascularization and paracrine cell signaling are mostly based on the rodent pancreas. We assessed the architecture and endocrine cell interaction of the vascular network in unperturbed human islets in situ and their potential to re-establish their endogenous vascular network after transplantation in vivo. We prepared slices of fresh pancreas tissue obtained from nondiabetic patients undergoing partial pancreatectomy. In addition, we transplanted human donor islets into the anterior chamber of the mouse eye. Next, we performed three-dimensional in situ and in vivo imaging of islet cell and vessel architecture at cellular resolution and compared our findings with mouse and porcine islets. Our data reveal a significantly different vascular architecture with decreased vessel diameter, reduced vessel branching, and shortened total vessel network in human compared with mouse islets. Together with the distinct cellular arrangement in human islets, this limits ß to endothelial cell interactions, facilitates connection of α and ß cells, and promotes the formation of independent ß-cell clusters within islets. Furthermore, our results show that the endogenous vascular network of islets is significantly altered after transplantation in a donor age-related mechanism. Thus, our study provides insight into the vascular architecture and cellular arrangement of human islets with apparent consequences for intercellular islet signaling. Moreover, our findings suggest that human islet engraftment after transplantation can be improved by using alternative, less mature islet-cell sources.

Outpatient or inpatient treatment for acute pulmonary embolism: a retrospective cohort study of 439 consecutive patients.

Current guidelines consider outpatient treatment as an option for low-risk pulmonary embolism (PE), and risk assessment tools such as the HESTIA criteria can be used to identify PE patients who could feasibly be treated in an outpatient setting. Little is known about what proportion of patients in daily care this would comprise, and, in these patients, outcome data outside of clinical trials are scarce. To assess the proportion of PE patients receiving outpatient early discharge or in-hospital therapy, evaluate differences in patient characteristics between these subgroups and to assess clinical outcomes at 6 months. Monocentric, retrospective cohort study in 439 consecutive patients undergoing outpatient, early-discharge or in-hospital treatment for PE. Outcome data on recurrent VTE, pulmonary hypertension or death were collected from routine follow-up visits 6 months after VTE diagnosis. PE patients were treated as outpatient (OP; n = 49; 11.2 %); early-discharge (ED; n = 62; 14.1 %) or in-hospital (IH; n = 328; 74.7 %). Median duration of hospital stay in the ED and IH groups were 1 (IQR: 1) day and 9 (IQR: 7) days, respectively. Outcome event rates at 6 months were 3.9 % for recurrent VTE (95 % CI 2.3-6.1, similar between groups), 5.2 % for pulmonary hypertension (95 % CI 3.3-7.8, similar between groups) and 10.7 % for mortality (95 % CI 8.0-14.0). Mortality was significantly higher in IH patients (14.0 %; 95 % CI 10.5-18.3) compared to OP (0 %; 95 % CI 0.0-7.3) or ED (1.6 %; 95 % CI 0.0-8.7) patients. Mortality risk factors were high-risk ESC category (OR: 5.7), paraneoplastic VTE (OR: 3.0), need for oxygen supplementation (OR: 5.2), diabetes (OR: 2.5), age (OR per additional year: 1.1) and elevated INR (OR per 0.1 point increase: 1.5). No difference in the treatment groups for pulmonary hypertension during follow-up was found. Independent risk factors were thrombophilia (OR: 8.43), signs of right ventricular strain in baseline ECG (OR: 6.64) or echocardiography (RVESP > 40 mmHg OR: 2.99). 32 % of the OP or ED patients had at least one criterion of the HESTIA score that would have excluded them from outpatient treatment. In daily care, treating PE in an almost exclusively outpatient setting seems feasible and safe for up to 25 % of all PE patients. The HESTIA criteria seem to exclude up to 30 % of patients for whom outpatient or early-discharge treatment seems feasible and safe.

Lipidomic profiling at the interface of metabolic surgery and cardiovascular disease.

Bariatric surgery has helped patients attain not only significant and sustained weight loss but has also proved to be an effective means of mitigating or reversing various obesity-related comorbidities. The impressive rates of remission or resolution of type 2 diabetes mellitus (T2D) following bariatric surgery are well documented and have rightly received great attention. Less understood are the effects of bariatric surgery on cardiovascular disease (CVD) and its underlying risk factors. Thanks to the availability of increasingly sensitive laboratory tools, the emerging science of lipidomics and metagenomics is poised to offer significant contributions to our understanding of metabolically induced vascular diseases. They are set to identify novel mechanisms explaining how the varied approaches of bariatric surgery produce the remarkable improvements in multiple organs observed during patient follow-up. This article reviews recent and novel findings in patients through the lens of lipidomics with an emphasis on CVD.

Safety and feasibility of a diagnostic algorithm combining clinical probability, d-dimer testing, and ultrasonography for suspected upper extremity deep venous thrombosis: a prospective management study.

BACKGROUND: Although well-established for suspected lower limb deep venous thrombosis, an algorithm combining a clinical decision score, d-dimer testing, and ultrasonography has not been evaluated for suspected upper extremity deep venous thrombosis (UEDVT). OBJECTIVE: To assess the safety and feasibility of a new diagnostic algorithm in patients with clinically suspected UEDVT. DESIGN: Diagnostic management study. (ClinicalTrials.gov: NCT01324037) SETTING: 16 hospitals in Europe and the United States. PATIENTS: 406 inpatients and outpatients with suspected UEDVT. MEASUREMENTS: The algorithm consisted of the sequential application of a clinical decision score, d-dimer testing, and ultrasonography. Patients were first categorized as likely or unlikely to have UEDVT; in those with an unlikely score and normal d-dimer levels, UEDVT was excluded. All other patients had (repeated) compression ultrasonography. The primary outcome was the 3-month incidence of symptomatic UEDVT and pulmonary embolism in patients with a normal diagnostic work-up. RESULTS: The algorithm was feasible and completed in 390 of the 406 patients (96%). In 87 patients (21%), an unlikely score combined with normal d-dimer levels excluded UEDVT. Superficial venous thrombosis and UEDVT were diagnosed in 54 (13%) and 103 (25%) patients, respectively. All 249 patients with a normal diagnostic work-up, including those with protocol violations (n = 16), were followed for 3 months. One patient developed UEDVT during follow-up, for an overall failure rate of 0.4% (95% CI, 0.0% to 2.2%). LIMITATIONS: This study was not powered to show the safety of the substrategies. d-Dimer testing was done locally. CONCLUSION: The combination of a clinical decision score, d-dimer testing, and ultrasonography can safely and effectively exclude UEDVT. If confirmed by other studies, this algorithm has potential as a standard approach to suspected UEDVT. PRIMARY FUNDING SOURCE: None.

Prevalence of parvovirus B19 and human bocavirus DNA in the heart of patients with no evidence of dilated cardiomyopathy or myocarditis.

BACKGROUND: Although the DNA of parvovirus B19 (B19V) is frequently detected in patients with dilated cardiomyopathy or myocarditis, whether the parvovirus causes disease is questionable, since even in healthy individuals the virus persists in various tissues. The same question applies to human bocavirus (HBoV). We have determined the prevalence and quantity of B19V and HBoV DNA in heart tissue of patients who were not experiencing virus-related heart diseases and analyzed whether the seroprevalence corresponded to DNA prevalence in the heart. METHODS: Samples of left-atrium heart tissue and serum were obtained from 100 patients who underwent open-heart surgery. Serum immunoglobulin (Ig) G and IgM against proteins encoded by B19V and HBoV were detected by enzyme-linked immunoabsorption assay and immunoblotting. B19V and HBoV DNA concentrations were determined by quantitative real-time polymerase chain reaction (PCR) in heart tissue and serum samples. Nested PCRs for VP1, K71, and GT3 identified the B19V genotypes. RESULTS: The prevalences of serum IgG specific for B19V and HBoV were 85% and 96%, respectively. Of all the patients, 85% had B19V DNA detected in heart tissues, and 4% displayed low-level B19V viremia, whereas only 5% of heart tissue samples and none of the serum samples demonstrated HBoV DNA. The sensitivity of B19V serological testing for B19V DNA in heart samples was 0.96 (95% confidence interval, 0.92-1.0). Specificity was 0.8 (95% confidence interval, 0.6-1.0), and the positive predictive value was 0.96 (95% confidence interval, 0.92-1.0). B19V genotypes 1 and 2 were present in 11% and 89% of heart tissues samples, respectively. B19V genotype 3 was not detected in any of the samples. CONCLUSIONS: Our data suggest that B19V but not HBoV demonstrates a lifelong persistence in the heart. The detection of B19V DNA in heart tissue showed no correlation with clinical symptoms. We strongly recommend that serological testing become a standardized procedure for future studies, to obtain representative data concerning the prevalence of B19V in the heart.

Treatment of a patient with shock complicating severe falciparum malaria: a case report.

INTRODUCTION: Malaria is a potentially life-threatening disease, especially when complicated by a septic shock. When patients present in such a critical condition, the currently available literature allows a dilemma to develop as to which the correct treatment strategy is concerning fluid resuscitation. CASE PRESENTATION: A 55-year-old Caucasian man was admitted to the intensive care unit with the clinical picture of severe malaria, brought by a Plasmodium falciparum infection. On admission, the patient was confused, had high fever up to 40 degrees C, and his blood analysis revealed a severe thrombocytopenia, a parasitemia of 25.5%, and biochemical features indicative of severe malaria. The patient received quinine and underwent two automated red cell exchanges by use of a centrifuge-driven cell separator. Two days after admission, the patient developed a septic shock. He received an "early-goal" treatment, according to the surviving sepsis campaign guidelines, which propose fluid resuscitation. The existing recommendations concerning the treatment of severe malaria that favour a restrictive fluid administration were disregarded. Fluid therapy was guided by regular measurements of the central venous pressure, blood pressure and monitoring of the hemodynamic status. The patient survived the shock and the subsequent multiorgan failure, which required mechanical ventilation and dialysis. After 12 days in the intensive care unit and an additional three weeks of hospitalization, the patient was discharged to rehabilitation. CONCLUSION: The authors believe that in patients with severe malaria complicated by septic shock, the treatment of sepsis and septic shock should be the one of first priority.

Adrenal hyperplasia and adenomas are associated with inhibition of phosphodiesterase 11A in carriers of PDE11A sequence variants that are frequent in the population.

Several types of adrenocortical tumors that lead to Cushing syndrome may be caused by aberrant cyclic AMP (cAMP) signaling. We recently identified patients with micronodular adrenocortical hyperplasia who were carriers of inactivating mutations in the 2q-located phosphodiesterase 11A (PDE11A) gene. We now studied the frequency of two missense substitutions, R804H and R867G, in conserved regions of the enzyme in several sets of normal controls, including 745 individuals enrolled in a longitudinal cohort study, the New York Cancer Project. In the latter, we also screened for the presence of the previously identified PDE11A nonsense mutations. R804H and R867G were frequent among patients with adrenocortical tumors; although statistical significance was not reached, these variants affected significantly enzymatic function in vitro with variable increases in cAMP and/or cyclic guanosine 3',5'-monophosphate levels in HeLa and HEK293 cells. Adrenocortical tissues carrying the R804H mutation showed 2q allelic losses and higher cyclic nucleotide levels and cAMP-responsive element binding protein phosphorylation. We conclude that missense mutations of the PDE11A gene that affect enzymatic activity in vitro are present in the general population; protein-truncating PDE11A mutations may also contribute to a predisposition to other tumors, in addition to their association with adrenocortical hyperplasia. We speculate that PDE11A genetic defects may be associated with adrenal pathology in a wider than previously suspected clinical spectrum that includes asymptomatic individuals.