Mitochondria and reperfusion injury

The viability of the ischemic myocardium is jeopardized by alterations, such as ATP decrease and elevation in intracellular [Ca²⁺], that are related to derangements in mitochondrial function. Besides these established notions, the elucidation of the apoptotic cascade and the availability of novel methodologies for in situ studies prompted new interest in mitochondria. The characterization of mitochondrial channels provided a contribution that is particularly relevant to cardiovascular research. Here we focus on the role of the permeability transition pore by analyzing the methodological requirements for its characterization, the consequences of its opening and the possible relationships with other mitochondrial functions, especially with the K_ATP channels. Published online: 9 May 2003 Correspondence to: F. Di Lisa     

Early allograft calcifications after kidney transplantation

Early allograft calcifications after kidney transplantation (KT) have already been reported, but the clinical implications of this finding are not clear thus far. Patient-related factors such as age, gender, underlying renal disease, and dialytic modality, seem to be irrelevant. It has been postulated that factors promoting the development of metastatic calcifications, including elevated calcium phosphate product and severe secondary hyperparathyroidism, could play a causal role. Here we report a case of a KT patient who developed early kidney calcifications which were associated with severe allograft dysfunction.     

Androgen receptor expression in male breast carcinoma: lack of clinicopathological association

Androgen receptor (AR) expression was retrospectively analysed in 47 primary male breast carcinomas (MBCs) using a monoclonal antibody on formalin-fixed, paraffin-embedded tissues. AR immunopositivity was detected in 16 out of 47 (34%) cases. No association was found with patient age, tumour stage, progesterone receptor (PGR) or p53 protein expression. Well-differentiated MBCs tended to be AR positive more often than poorly differentiated ones (P = 0.08). A negative association was found between ARs and cell proliferative activity: MIB-1 scores were higher (25.4%) in AR-negative than in AR-positive cases (21.11%; P = 0.04). A strong positive association (P = 0.0001) was found between ARs and oestrogen receptors (ERs). In univariate analysis, ARs (as well as ERs and PGRs) were not correlated with overall survival; tumour histological grade (P = 0.02), size (P = 0.01), p53 expression (P = 0.0008) and MIB-1 scores (P = 0.0003) had strong prognostic value. In multivariate survival analysis, only p53 expression (P = 0.002) and histological grade (P = 0.02) retained independent prognostic significance. In conclusion, the lack of association between AR and most clinicopathological features and survival, together with the absence of prognostic value for ER/PGR status, suggest that MBCs are biologically different from female breast carcinomas and make it questionable to use antihormonal therapy for patients with MBC.     

Increased epinephrine and skeletal muscle responses to hypoglycemia in non-insulin-dependent diabetes mellitus.

We evaluated skeletal muscle counterregulation during hypoglycemia in nine subjects with non-insulin-dependent diabetes mellitus (NIDDM) (HbA1c 9.4 +/- 0.5%, nl < 6.2%) compared with six normal controls, matched for age (51 +/- 3 and 49 +/- 5 yr, respectively) and body mass index (27.3 +/- 1.2 and 27.0 +/- 2.1 kg/m2). After 60 min of euglycemia (plasma insulin approximately 140 microU/ml), plasma glucose was lowered to 62 +/- 2 mg/dl by 120 min. Hypoglycemia induced a 2.2-fold greater increase in plasma epinephrine in NIDDM (P < 0.001), while the plasma glucagon response was blunted (P < 0.01). Hepatic glucose output ([3H-3]glucose) suppressed similarly during euglycemia, but during hypoglycemia was greater in NIDDM (P < 0.005). Conversely, glucose uptake during euglycemia was 150% greater in controls (P < 0.01) and remained persistently higher than in NIDDM during hypoglycemia. In NIDDM, plasma FFA concentrations were approximately fivefold greater (P < 0.001), and plasma lactate levels were approximately 40% higher than in controls during hypoglycemia (P < 0.01); the rates of glycolysis from plasma glucose were similar in the two groups despite a 49% lower rate of glucose uptake in NIDDM (3.4 +/- 0.9 vs. 6.9 +/- 1.3 mg/kg per minute, P < 0.001). Muscle glycogen synthase activity fell by 42% with hypoglycemia (P < 0.01) in NIDDM but not in controls. In addition, glycogen phosphorylase was activated by 56% during hypoglycemia in NIDDM only (P < 0.01). Muscle glucose-6-phosphate concentrations rose during hypoglycemia by a twofold greater increment in NIDDM (P < 0.01). Thus, skeletal muscle participates in hypoglycemia counterregulation in NIDDM, directly by decreased removal of plasma glucose and, indirectly, by providing lactate for hepatic gluconeogenesis. Consequently, in addition to inherent insulin resistance in NIDDM, the enhanced plasma epinephrine response during hypoglycemia may partially offset impaired glucagon secretion and counteract the effects of hyperinsulinemia on liver, fat, and skeletal muscle.