K+ channel modulation in arterial smooth muscle

Potassium channels play an essential role in the membrane potential of arterial smooth muscle, and also in regulating contractile tone. Four types of K+ channel have been described in vascular smooth muscle: Voltage-activated K+ channels (Kv) are encoded by the Kv gene family, Ca(2+)-activated K+ channels (BKCa) are encoded by the slo gene, inward rectifiers (KIR) by Kir2.0, and ATP-sensitive K+ channels (KATP) by Kir6.0 and sulphonylurea receptor genes. In smooth muscle, the channel subunit genes reported to be expressed are: Kv1.0, Kv1.2, Kv1.4-1.6, Kv2.1, Kv9.3, Kv beta 1-beta 4, slo alpha and beta, Kir2.1, Kir6.2, and SUR1 and SUR2. Arterial K+ channels are modulated by physiological vasodilators, which increase K+ channel activity, and vasoconstrictors, which decrease it. Several vasodilators acting at receptors linked to cAMP-dependent protein kinase activate KATP channels. These include adenosine, calcitonin gene-related peptide, and beta-adrenoceptor agonists. beta-adrenoceptors can also activate BKCa and Kv channels. Several vasoconstrictors that activate protein kinase C inhibit KATP channels, and inhibition of BKCa and Kv channels through PKC has also been described. Activators of cGMP-dependent protein kinase, in particular NO, activate BKCa channels, and possibly KATP channels. Hypoxia leads to activation of KATP channels, and activation of BKCa channels has also been reported. Hypoxic pulmonary vasoconstriction involves inhibition of Kv channels. Vasodilation to increased external K+ involves KIR channels. Endothelium-derived hyperpolarizing factor activates K+ channels that are not yet clearly defined. Such K+ channel modulations, through their effects on membrane potential and contractile tone, make important contributions to the regulation of blood flow.     

Complete unloading alone may not adequately protect the left ventricle

BACKGROUND: The benefit of left ventricular (LV) unloading for preserving LV function is commonly accepted, but its efficacy remains incompletely defined. METHODS: We studied the influence of complete LV unloading on LV systolic and diastolic mechanics using an in situ isovolumic preparation with two different coronary perfusion pressures (CPPs) in 12 dogs during prolonged normothermic cardiopulmonary bypass. RESULTS: Multivariate analysis of covariance with time as a covariate revealed that a high CPP (143 +/- 36 mm Hg; n = 6) was associated with better preservation of systolic LV function over time as assessed by LV end-systolic elastance (p < 0.001) and the end-systolic pressure-volume relation physiologic intercept (p < 0.001) compared with a moderate CPP (107 +/- 18 mm Hg; p < 0.005 versus a high CPP by t-test; n = 6). Dobutamine (2 micrograms.kg-1.min-1) improved LV end-systolic elastance (p < 0.005) and LV physiologic intercept (p < 0.01) only in the high-CPP group. Conversely, impaired LV diastolic function (as measured by LV stiffness) was observed (p < 0.001) with a high CPP, but did not change with a moderate CPP. CONCLUSIONS: These observations in canine hearts suggest that complete LV unloading may not preserve LV systolic function adequately over time when CPP is maintained in the accepted clinical range. A higher CPP is required to prevent deterioration over prolonged cardiopulmonary bypass times, but diastolic dysfunction still occurs.     

Tumor necrosis factor, interleukin-2, and interferon-gamma in adult varicella

Adult varicella can be a severe illness complicated by pneumonia, encephalitis, or prolonged fever. This study measured levels of tumor necrosis factor (TNF)-alpha, interleukin-2 (IL-2), and interferon gamma (IFN-G) in a consecutive group of 31 adult varicella patients presenting within 24 hours of rash onset. All cytokines were assayed using an ELISA technique. TNF-alpha was detectable in 71% of patients with a mean level of 52 pg/ml. IL-2 was detectable in 29% with a mean level of 1040 pg/ml. IFN-gamma was detectable in only 9%. There was no correlation between TNF, IL-2, or IFN-G level and clinical severity as determined by duration and severity of cutaneous findings, duration of fever, frequency of hepatitis, or thrombocytopenia.     

Perturbation in connexin 43 and connexin 26 gap-junction expression in mouse skin hyperplasia and neoplasia

To examine the possible role of gap junctions in mouse skin tumor progression, we generated a panel of mouse skin tissue samples exhibiting normal, hyperplastic, or neoplastic changes and characterized the expression of the gap-junction genes connexin 43 (Cx43) and connexin 26 (Cx26) by in situ hybridization and immunohistochemical analyses. In normal skin, these two gap junction genes were differentially expressed; Cx43 was found predominantly in the less differentiated lower spinous layers, whereas Cx26 was found in terminally differentiating upper spinous and granular layers. In hyperplastic epidermis exhibiting an expansion of the differentiated upper layer, i.e., epidermis with a thickened granular layer or in which the granular layer was replaced with keratinocytes exhibiting tricholemmal differentiation, expression of Cx43 and Cx26 remained segregated in the lower and upper spinous layers, respectively. However, in papillomas, Cx26 was localized in the lower but not upper spinous layer, an expression pattern identical to that of Cx43. In addition, the overall expression levels of both Cx43 and Cx26 appeared to be greatly elevated in the papillomas. It is interesting that such marked alteration in the pattern of Cx26 expression occurred within the context of hyperplastic changes histologically identical to those seen in the nonpapillomous hyperplasias. Interestingly, in neoplastic skin lesions containing a squamous cell carcinoma, Cx43 and Cx26 expression was extinguished. Moreover, expression of Cx43 was also significantly reduced in adjacent apparently nonneoplastic tissues. Overall, these observations show that perturbations in gap-junction gene expression are associated with skin hyperplasia and neoplasia. Such findings suggest a possible role for gap junctions in the malignant conversion of mouse epidermal cells.     

Oncogenesis in utero: fetal death due to acute myelogenous leukaemia with an MLL translocation

The incidence of translocations involving the 11q23 gene MLL is markedly increased in leukaemias that occur in infants <1 year of age. Epidemiological and molecular data have demonstrated that at least some of these translocations occur in utero. In this report we describe a case of fetal death at 36 weeks of gestation. At autopsy the fetus was found to have widely disseminated acute myelogenous leukaemia (AML), FAB subtype M5. Molecular cytogenetic studies of nuclei recovered from paraffin-embedded tissue sections demonstrated that the leukaemic cells contained an MLL translocation. This is the first detailed report, to our knowledge, of fetal death due to acute leukaemia, and directly demonstrates oncogenesis in utero.     

A multifactorial analysis of melanoma: prognostic histopathological features comparing Clark's and Breslow's staging methods

A multifactorial analysis was used to identify the dominant prognostic variables affecting survival from a computerized data base of 339 melanoma patients treated at this institution during the past 17 years. Five of the 13 parameters examined simultaneously were found to independently influence five year survival rates: 1) pathological stage (I vs II, p = 0.0014), 2) lesion ulceration (present vs absent, p = 0.006), 3) surgical treatment (wide excision vs wide excision plus lymphadenectomy, p = 0.024), 4) melanoma thickness (p = 0.032), and 5) location (upper extremity vs lower extremity vs trunk vs head and neck, p = 0.038). Additional factors considered that had either indirect or no influence on survival rates were clinical stage of disease, age, sex, level of invasion, pigmentation, lymphocyte infiltration, growth pattern, and regression. Most of these latter variables derived their prognostic value from correlation with melanoma thickness, except sex which correlated with location (extremity lesions were more frequent on females, trunk lesions on males). This statistical analysis enabled us to derive a mathematical equation for predicting an individual patient's probability of five year survival. Three categories of risk were delineated by measuring tumor thickness (Breslow microstaging) in Stage I patients: 1) thin melanomas (<0.76 mm) were associated with localized disease and a 100% cure rate: 2) intermediate thickness melanomas (0.76-4.00 mm) had an increasing risk (up to 80%) of harboring regional and/or distant metastases and 3) thick melanomas (>/=4.00 mm) had a 80% risk of occult distant metastases at the time of initial presentation. The level of invasion (Clark's microstaging) correlated with survival, but was less predictive than measuring tumor thickness. Within each of Clark's Level II, III and IV groups, there were gradations of thickness with statistically different survival rates. Both microstaging methods (Breslow and Clark) were less predictive factors in patients with lymph node or distant metastases. Clinical trials evaluating alternative surgical treatments or adjunctive therapy modalities for melanoma patients should incorporate these parameters into their assessment, especially in Stage I (localized) disease where tumor thickness and the anatomical site of the primary melanoma are dominant prognostic factors.