Possible role of an ischemic preconditioning-like response mechanism in K(ATP) channel opener-mediated protection against streptozotocin-induced suppression of rat pancreatic islet function

Potassium channel openers (KCOs) decrease insulin secretion from beta-cells. Some KCOs also protect against damage to beta-cell function and type 1 diabetes in animal models. Previously we have found that the KCO NNC 55-0118 counteracted islet cell dysfunction, and this was associated with a lowering of the mitochondrial membrane potential (Deltapsi). Presently we aimed to explore whether inhibition of insulin secretion per se or rather inhibition of mitochondrial function correlates to counteraction of beta-cell suppression. For this we used two novel KCOs (NNC 55-0321 and NNC 55-0462), which at certain concentrations have different actions regarding insulin secretion and the Deltapsi, with NNC 55-0321 being a potent inhibitor of Deltapsi and NNC 55-0462 being a potent inhibitor of insulin secretion. At 10 microM NNC 55-0321, but not with NNC 55-0462, the islet ATP content and ATP/ADP ratio was acutely decreased. This was accompanied by a complete protection against streptozotocin-induced suppression of islet insulin secretion using the former KCO. In cardiac research KCOs have been used to induce an ischemic preconditioning (IPC) response. In line with an IPC-like mechanism we found that NNC 55-0321 induced an initial free oxygen radical formation, PKC-epsilon isoform activation and a subsequent phosphorylation of the survival promoting factor Akt. Thus, KCOs may elicit mitochondrial events that resemble classical IPC seen in cardiomyocytes, and this could explain the enhanced islet cell function observed. KCOs with this property may be particularly interesting compounds to study as a rescue therapy during acute episodes of beta-cell suppression/destruction.     

Mice lacking 12/15-lipoxygenase have attenuated airway allergic inflammation and remodeling

Arachidonate 15-lipoxygenase (LO)-1 has been implicated in allergic inflammation and asthma. The overall effect of 15-LO in allergic inflammation in vivo is, however, unclear. This study investigates systemic allergen sensitization and local allergic airway inflammation and remodeling in mice lacking the murine 12/15-LO, the ortholog to human 15-LO-1. Upon systemic sensitization with intraperitoneal ovalbumin, 12/15-LO-/- mice produced elevated levels of allergen-specific immunoglobulin E compared with wild-type (Wt) controls. However, when challenged with repeated aerosolized allergen, sensitized 12/15-LO-/- mice had an impaired development of airway allergic inflammation compared with Wt controls, as indicated by reduced bronchoalveolar lavage fluid leukocytes (eosinophils, lymphocytes, macrophages) and Th2 cytokines (IL-4, IL-5, IL-13), as well as tissue eosinophils. Allergen-induced airway epithelial proliferation was also significantly attenuated in 12/15-LO-/- mice, whereas goblet cell hyperplasia was unaffected. However, 12/15-LO-/- mice had significantly reduced luminal mucus secretions compared with Wt controls. The repeated allergen challenges resulted in a dramatic increase of alpha-smooth muscle actin-positive alveolar cells in the peripheral airways, a phenomenon that was significantly less developed in 12/15-LO-/- mice. In conclusion, our data suggest that 12/15-LO-/- mice, although having a fully developed systemic sensitization, did not establish a fully developed allergic airway inflammation and associated manifestations of central and peripheral airway remodeling. These data suggest that 12/15-LO-derived metabolites play an important pathophysiologic role in allergen-induced inflammation and remodeling. Hence, pharmacologic targeting of the human 15-LO-1 may represent an attractive therapeutic strategy to control inflammation and remodeling in asthma.     

Leakage around voice prosthesis in laryngectomees: treatment with local GM-CSF.

OBJECTIVES: The aim of this study was to investigate the possibility of treating leakage around voice prosthesis by local injection of granulocyte-macrophage colony-stimulating factor (GM-CSF). STUDY DESIGN: Three patients with nonhealing leaking tracheoesophageal (TE) fistula, resistant to common treatment, were treated with local GM-CSF. MATERIAL AND METHODS: Fistula size was measured and photo documented before and after treatment. RESULT: In all three patients, the fistula shrank, and the leakage ceased. No side effects were observed. CONCLUSION: Local injection with GM-CSF seems to be a simple and effective way of decreasing a leaking TE-fistula in laryngectomized patients. A great advantage was that the procedure could be done with the voice prosthesis in place.     

Characterization of a hairy cell leukemia-associated 5q13.3 inversion breakpoint

Previous cytogenetic analysis has indicated that chromosome anomalies involving the 5q13 band are common in hairy cell leukemia (HCL), occurring in approximately $frac13; of the patients. The data suggest that 5q13.3 is likely to harbor a gene involved in the transformational event of this disease. We selected a constitutional inv(5)(p13.1q13.3) in a patient with HCL as the starting point in an attempt to identify the relevant gene in 5q13.3. By using double color interphase fluorescence in situ hybridization (FISH) techniques, we have identified two cosmid probes from a chromosome 5-specific library that flank the 5q13.3 inversion breakpoint proximally and distally. Pulsed field gel electrophoresis (PFGE) and interphase FISH experiments suggest that the two markers are at a distance of no more than 300 kb. YAC probes covering a 21 Mb region at 5q13 were used to map the 5q13.3 inversion breakpoint and the breakpoint is located within the D5S646–D5S620 region. Two non-chimeric YACs have been identified that span the breakpoint. FISH analysis revealed that four other patients with cytogenetic aberrations of 5q carried inversions/deletions that involved the same 5q13.3 breakpoint region. The identification of a gene involved in hairy cell leukemogenesis in this region will be of major importance in the elucidation of the transformational events of HCL. Genes Chromosomes Cancer 20:337–346, 1997. © 1997 Wiley-Liss, Inc.     

Cytokine-induced PGE(2) formation is reduced from iNOS deficient murine islets

Cytokines may be involved in islet destruction during Type 1 diabetes. Exposure to interleukin-1β (IL-1β) or IL-1β plus interferon-γ (IFN-γ) of rodent islets induces expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Subsequent formation of nitric oxide (NO) and prostaglandin E₂ (PGE₂) may impair β-cell function. Using iNOS deficient (iNOS −/−) islets, we have further investigated the relation between NO formation and PGE₂ induction. We found that iNOS −/− islets responded with a reduced PGE₂ formation following IL-1β or (IL-1β + IFN-γ) treatment compared to wild-type (wt) islets, while COX-2 mRNA or protein content were unchanged. By the addition of an NO donor together with IL-1β, PGE₂ formation could be stimulated from iNOS −/− islets. We conclude that the lowered capacity of PGE₂ formation observed from cytokine exposed iNOS −/− islets is due to a decreased stimulation of PGE₂ formation by the COX-2 enzyme in the absence of NO, rather then differences in expressed COX-2 protein.     

Can echocardiography and ECG discriminate hereditary transthyretin V30M amyloidosis from hypertrophic cardiomyopathy?

Objective: Hereditary transthyretin (ATTR) amyloidosis with increased left ventricular wall thickness could easily be misdiagnosed by echocardiography as hypertrophic cardiomyopathy (HCM). Our aim was to create a diagnostic tool based on echocardiography and ECG that could optimise identification of ATTR amyloidosis.

Methods: Data were analysed from 33 patients with biopsy proven ATTR amyloidosis and 30 patients with diagnosed HCM. Conventional features from ECG were acquired as well as two dimensional and Doppler echocardiography, speckle tracking derived strain and tissue characterisation analysis. Classification trees were used to select the most important variables for differentiation between ATTR amyloidosis and HCM.

Results: The best classification was obtained using both ECG and echocardiographic features, where a QRS voltage >30?mm was diagnostic for HCM, whereas in patients with QRS voltage <30?mm, an interventricular septal/posterior wall thickness ratio (IVSt/PWt) >1.6 was consistent with HCM and a ratio <1.6 supported the diagnosis of ATTR amyloidosis. This classification presented both high sensitivity (0.939) and specificity (0.833).

Conclusion: Our study proposes an easily interpretable classification method for the differentiation between HCM and increased left ventricular myocardial thickness due to ATTR amyloidosis. Our combined echocardiographic and ECG model could increase the ability to identify ATTR cardiac amyloidosis in clinical practice.     

Short term complications of the tension free vaginal tape operation for stress urinary incontinence in women

Objective To assess the prevalence of intra- and post-operative complications with the tension free vaginal tape operation for female urinary incontinence.
Design Non-control case series.
Setting University Hospital.
Population One hundred and seventy-seven operations on women who were diagnosed urodynamically to have genuine stress incontinence. In 26 cases (15%) there was symptomatic urge incontinence.
Main outcome measures Intra- and post-operative complications in relation to individual surgeons and mode of anaesthesia (local or spinal), and continence at short term follow up.
Results Bladder or urethral perforation occurred in 26 cases (15%) and three operations were abandoned for these reasons. A failure to void after the first 24 hours was registered in 35 (20%); 21 (12%) had to undergo urethral dilatation while five patients (2.8%) had persistent urinary retention which required excision of the sling. These problems were significantly associated to the experience of surgeon. In seven cases (4%) haemorrhage required intravaginal tamponade. In three (1.7%) sling rejection occurred post-operatively. When followed up six to eight weeks post-operatively, 154 patients (88%) reported subjective cure, 21 (11%) significant improvement and two (1%) no improvement. The use of spinal anaesthesia increased the frequency of peroperative bladder perforation but affected neither the incidence of post-operative bladder obstruction nor the outcome at follow up.
Conclusions This study identifies short term complications which relate partly to the experience of the individual surgeon. Nevertheless the 88% subjective cure rate was independent of these factors.