Noradrenergic fibers are associated with beta-cell dedifferentiation and impaired beta-cell function in humans.

AIMS/HYPOTHESIS: Type 2 diabetes (T2D) is characterized by a progressive loss of beta-cell function, and the "disappearance" of beta-cells in T2D may also be caused by the process of beta -cell dedifferentiation. Since noradrenergic innervation inhibits insulin secretion and density of noradrenergic fibers is increased in type 2 diabetes mouse models, we aimed to study the relation between islet innervation, dedifferentiation and beta-cell function in humans. METHODS: Using immunohistochemistry and electron microscopy, we analyzed pancreata from organ donors and from patients undergoing pancreatic surgery. In the latter, a pre-surgical detailed metabolic characterization by oral glucose tolerance test (OGTT) and hyperglycemic clamp was performed before surgery, thus obtaining in vivo functional parameters of beta-cell function and insulin secretion. RESULTS: The islets of diabetic subjects were 3 times more innervated than controls (0.91 ±â€¯0.21 vs 0.32 ±â€¯0.10, n.fibers/islet; p = 0.01), and directly correlated with the dedifferentiation score (r = 0.39; p = 0.03). In vivo functional parameters of insulin secretion, assessed by hyperglycemic clamp, negatively correlated with the increase in fibers [beta-cell Glucose Sensitivity (r = -0.84; p = 0.01), incremental second-phase insulin secretion (r = -0.84, p = 0.03) and arginine-stimulated insulin secretion (r = -0.76, p = 0.04)]. Moreover, we observed a progressive increase in fibers, paralleling worsening glucose tolerance (from NGT through IGT to T2D). CONCLUSIONS/INTERPRETATION: Noradrenergic fibers are significantly increased in the islets of diabetic subjects and this positively correlates with beta-cell dedifferentiation score. The correlation between in vivo insulin secretion parameters and the density of pancreatic noradrenergic fibers suggests a significant involvement of these fibers in the pathogenesis of the disease, and indirectly, in the islet dedifferentiation process.

Comparison between intrarticular injection of hyaluronic acid, oxygen ozone, and the combination of both in the treatment of knee osteoarthrosis.

This study aimed to compare short-term clinical outcomes between intra-articular injection of hyaluronic acid (HA), oxygen ozone (O2O3), and the combination of both, in patients affected by osteoarthrosis (OA) of the knee. Seventy patients (age 45-75 years) with knee OA were randomized to intra-articular injections of HA (n=23), or O2O3 (n=23) or combined (n=24) one per week for 5 consecutive weeks. KOOS questionnaire and visual analog scale (VAS), before treatment (pre) at the end (post), and at 2 months after treatment ended (follow-up) were used as outcome measures. Analysis showed a significant effect (P < 0.05) of the conditions (pre, post and follow-up) in all parameters of the KOOS score and a significant effect (P < 0.05) of groups (HA, O2O3 and combined) for pain, symptoms, activities of daily living and quality of life. The combined group scores were higher compared to the HA and O2O3 groups, especially at follow-up. The combination of O2O3 and HA treatment led to a significantly better outcome especially at 2-month follow-up compared to HA and O2O3 given separately to patients affected by OA of the knee.

Fenestrated fontan procedure: evolution of technique and occurrence of paradoxical embolism.

The Fenestrated Fontan procedure (FFP) has improved outcome in high risk patients. The technique is evolving, however, and complications are not fully known. Over a 3-year period 13 patients (mean age 35 +/- 29 months) underwent an FFP in our institution. In the first two patients the fenestration had to be created because of high right atrial pressure and low cardiac output; in 11 patients the FFP was planned. In three patients the sutures for the adjustable fenestration were crossing the defect. In 10 patients, purse-string sutures were placed around but not across the defect. Because large fenestrations were created in 11 patients (8-12 mm) Glenn shunts were performed to improve arterial saturation. The postoperative course was relatively uneventful, with chest tubes being removed 1-8 days (mean 4 +/- 3 days) postoperatively and the hospital stay ranging from 7 to 27 days (mean 14 +/- 6 days). One patient had bleeding and another had a mediastinal abscess. The first patient died (7.6%) because of hemodynamic instability due to prolonged cardiopulmonary bypass from the creation and enlargement of the fenestration. One patient had a paradoxical cerebral embolism from clots that formed on the sutures crossing the fenestration. Because of this problem the remaining patients were placed on salicylates while awaiting closure of their fenestration. All 12 patients had their fenestrations closed, performed under local anesthesia in 9, at mediastinal abscess drainage in 1, and spontaneously in 2. We conclude that creation of large fenestrations in combination with Glenn shunts and the use of adjustable fenestrations are viable modifications of the FFP. The use of purse-string sutures around the fenestration and antiplatelet drugs can probably minimize the occurrence of paradoxical embolism.

Fungal sepsis: multisite colonization versus fungemia.

The indications for therapy and the best treatment regimens for systemic fungal infections are not well defined. The purpose of this study was to evaluate retrospectively patient management and outcome in critically ill patients with multiple sites of fungal colonization and/or fungemia. Medical records of 36 fungemic patients and 76 patients without fungemia who had two or more anatomic sites colonized with fungal organisms were reviewed. There were 53 males and 59 females, with a mean age of 58 years (range 15-86). Eighty-four patients (74%) underwent 238 operations (41% elective, 59% emergent). Gastrointestinal (37%), thoracic (15%), and orthopedic (13%) procedures were most common. Concomitant, nonfungal bacteremia was present in 56 patients (50%). Seventy-one patients (63%) received systemic antifungal therapy. Mortality differences between patients with fungemia (17/36; 47%) and fungus-colonized patients (31/76; 41%) were not statistically significant. Amphotericin B treatment of fungemia reduced mortality overall (26% vs 71%, P < 0.05) and compared with fungemic patients receiving other antifungals (26% vs 50%, P < 0.05). Among fungus-colonized patients, mortality was higher with amphotericin B than without (70% vs 36%, P < 0.05) and was not changed by treatment with other antifungals (37% vs 34%). Increased gastrointestinal operations, wound infections, and intraperitoneal fungi and bacteria in fungus-colonized patients receiving amphotericin B suggest that these patients were the most critically ill. The mortality of multisite fungal colonization is as high as that of fungemia. Only amphotericin B improves survival in fungemia. The best treatment for multisite colonization is not clear from the data.

Hemodynamic effects of carbon dioxide pneumoperitoneum during mechanical ventilation and positive end-expiratory pressure.

Laparoscopy is frequently used for diagnosis and treatment of critically ill trauma patients. Its effects on cardiopulmonary performance in the intensive care unit patient population, however, are not well-defined. This study evaluated the effects of positive end-expiratory pressure (PEEP) and carbon dioxide (CO2) pneumoperitoneum on hemodynamic function during mechanical ventilation. Five anesthetized, mechanically ventilated adult swine were monitored with pulmonary artery and arterial catheters at 0, 5, 10, 15, and 20 cm H2O PEEP without, and then with 15 mm Hg CO2 pneumoperitoneum. A hemodynamic profile, analyses of arterial and mixed venous blood gases and mixed venous hemoglobin oxygen saturation values were obtained at each data point. Compared with the non-insufflated group, CO2 pneumoperitoneum significantly increased central venous pressure, mean arterial pressure, mean pulmonary artery pressure, pulmonary vascular resistance index, and stroke index for the range of PEEP levels. With PEEP of 10 cm H2O, hemodynamic changes in non-insufflated animals were not statistically significant, but with CO2 pneumoperitoneum, stroke index and left ventricular stroke work index were decreased at 5 cm H2O PEEP, as was cardiac index at 10 cm PEEP. Pulmonary gas exchange was not affected by CO2 pneumoperitoneum. The results indicate that, in this paradigm, CO2 pneumoperitoneum for laparoscopy increases ventricular afterload and exacerbates the adverse effects of PEEP. These findings could be clinically significant in critically ill patients.