Beta cell count instead of beta cell mass to assess and localize growth in beta cell population following pancreatic duct ligation in mice.

BACKGROUND: Pancreatic-tail duct ligation (PDL) in adult rodents has been reported to induce beta cell generation and increase beta cell mass but increases in beta cell number have not been demonstrated. This study examines whether PDL increases beta cell number and whether this is caused by neogenesis of small clusters and/or their growth to larger aggregates. METHODOLOGY: Total beta cell number and its distribution over small (<50 µm), medium, large (>100 µm) clusters was determined in pancreatic tails of 10-week-old mice, 2 weeks after PDL or sham. PRINCIPAL FINDINGS: PDL increased total beta cell mass but not total beta cell number. It induced neogenesis of small beta cell clusters (2.2-fold higher number) which contained a higher percent proliferating beta cells (1.9% Ki67+cells) than sham tails (<0.2%); their higher beta cell number represented <5% of total beta cell number and was associated with a similar increase in alpha cell number. It is unknown whether the regenerative process is causally related to the inflammatory infiltration in PDL-tails. Human pancreases with inflammatory infiltration also exhibited activation of proliferation in small beta cell clusters. CONCLUSIONS/SIGNIFICANCE: The PDL model illustrates the advantage of direct beta cell counts over beta cell mass measurements when assessing and localizing beta cell regeneration in the pancreas. It demonstrates the ability of the adult mouse pancreas for neogenesis of small beta cell clusters with activated beta cell proliferation. Further studies should investigate conditions under which neoformed small beta cell clusters grow to larger aggregates and hence to higher total beta cell numbers.

Susceptibility of pancreatic beta cells to fatty acids is regulated by LXR/PPARalpha-dependent stearoyl-coenzyme A desaturase.

Chronically elevated levels of fatty acids-FA can cause beta cell death in vitro. Beta cells vary in their individual susceptibility to FA-toxicity. Rat beta cells were previously shown to better resist FA-toxicity in conditions that increased triglyceride formation or mitochondrial and peroxisomal FA-oxidation, possibly reducing cytoplasmic levels of toxic FA-moieties. We now show that stearoyl-CoA desaturase-SCD is involved in this cytoprotective mechanism through its ability to transfer saturated FA into monounsaturated FA that are incorporated in lipids. In purified beta cells, SCD expression was induced by LXR- and PPARalpha-agonists, which were found to protect rat, mouse and human beta cells against palmitate toxicity. When their SCD was inhibited or silenced, the agonist-induced protection was also suppressed. A correlation between beta cell-SCD expression and susceptibility to palmitate was also found in beta cell preparations isolated from different rodent models. In mice with LXR-deletion (LXRbeta(-/-) and LXRalphabeta(-/-)), beta cells presented a reduced SCD-expression as well as an increased susceptibility to palmitate-toxicity, which could not be counteracted by LXR or PPARalpha agonists. In Zucker fatty rats and in rats treated with the LXR-agonist TO1317, beta cells show an increased SCD-expression and lower palmitate-toxicity. In the normal rat beta cell population, the subpopulation with lower metabolic responsiveness to glucose exhibits a lower SCD1 expression and a higher susceptibility to palmitate toxicity. These data demonstrate that the beta cell susceptibility to saturated fatty acids can be reduced by stearoyl-coA desaturase, which upon stimulation by LXR and PPARalpha agonists favors their desaturation and subsequent incorporation in neutral lipids.

Steroid-resistant sarcoidosis: is antagonism of TNF-alpha the answer?

Steroid-resistant sarcoidosis has conventionally been treated with various drugs, including methotrexate, azathioprine, cyclophosphamide, cyclosporine, antimalarial drugs and thalidomide, with variable success. There is a compelling need for more efficient and safer alternatives to these agents. Several lines of evidence suggest a critical role of TNF-alpha (tumour necrosis factor-alpha) in the initiation and organization of sarcoid granulomas. Inhibition of TNF-alpha with monoclonal antibodies has therefore received attention as a potential treatment option in therapy-resistant sarcoidosis. A number of case reports and small case series describe successful treatment of refractory disease with infliximab. Preliminary evidence from an RCT (randomized controlled trial) with infliximab in pulmonary sarcoidosis suggests a modest improvement in functional and radiological parameters. In contrast, the results with etanercept have been disappointing, perhaps related to differences in the mechanism of TNF-alpha blockade. The experience with adalimumab in sarcoidosis is too limited to draw conclusions. An open-label study and an RCT evaluating the efficacy of adalimumab in sarcoidosis with pulmonary and cutaneous involvement respectively, have been initiated. Although TNF-alpha antagonists appear relatively safe, especially when compared with conventional agents, caution is warranted in view of the increased incidence of tuberculosis, which may be a particular diagnostic challenge in patients with sarcoidosis. Pending publication of the RCTs, the use of TNF-alpha blockade in sarcoidosis should remain in the realm of experimental treatment.

Peripherally inserted veno-venous ultrafiltration for rapid treatment of volume overloaded patients.

BACKGROUND: Veno-venous ultrafiltration may benefit patients with acute or chronic circulatory volume overload. Use of conventional systems, however, may be cumbersome, requiring physician placement of a double-lumen central venous catheter and use of a dedicated dialysis technician and apparatus. METHODS: A simplified peripheral ultrafiltration system including a miniaturized disposable circuit was evaluated in patients with volume-overload states. Separate intravenous catheters (16-18 G) for withdrawal and return of blood (blood flow