Effects of prolonged cycle ergometer exercise on maximal muscle power and oxygen uptake in humans

Summary The mechanical power (W_tot, W·kg^–1) developed during ten revolutions of all-out periods of cycle ergometer exercise (4–9 s) was measured every 5–6 min in six subjects from rest or from a baseline of constant aerobic exercise [50%–80% of maximal oxygen uptake (VO_2max)] of 20–40 min duration. The oxygen uptake [VO₂ (W·kg^–1, 1 ml O₂ = 20.9 J)] and venous blood lactate concentration ([la]_b, mM) were also measured every 15 s and 2 min, respectively. During the first all-out period, W_tot decreased linearly with the intensity of the priming exercise (W_tot = 11.9–0.25·VO₂). After the first all-out period (i greater than 5–6 min), and if the exercise intensity was less than 60% VO_2max, W_tot, VO₂ and [la]_b remained constant until the end of the exercise. For exercise intensities greater than 60% VO_2max, VO₂ and [la]_b showed continuous upward drifts and W_tot continued decreasing. Under these conditions, the rate of decrease of W_tot was linearly related to the rate of increase of V [(d W_tot/dt) (W·kg^–1·s^–1) = 5.0·10^–5 –0.20·(d VO₂/dt) (W·kg^–1·s^–1)] and this was linearly related to the rate of increase of [la]_b [(d VO₂/dt) (W·kg^–1·s^–1) = 2.310^–4 + 5.910^–5·(d [la]_b/dt) (mM·s^–1)]. These findings would suggest that the decrease of W_tot during the first all-out period was due to the decay of phosphocreatine concentration in the exercising muscles occurring at the onset of exercise and the slow drifts of VO₂ (upwards) and of W_tot (downwards) during intense exercise at constant W_tot could be attributed to the continuous accumulation of lactate in the blood (and in the working muscles).     

Recovery of the endogenous beta cell function in the NOD model of autoimmune diabetes

In light of accumulating evidence that the endocrine pancreas has regenerative properties and that hematopoietic chimerism can abrogate destruction of beta cells in autoimmune diabetes, we addressed the question of whether recovery of physiologically adequate endogenous insulin regulation could be achieved in the nonobese diabetic (NOD) mice rendered allogeneic chimerae. Allogeneic bone marrow (BM) was transplanted into NOD mice at the preclinical and overtly clinical stages of the disease using lethal and nonlethal doses of radiation for recipient conditioning. Islets of Langerhans, syngeneic to the BM donors, were transplanted under kidney capsules of the overtly diabetic animals to sustain euglycemia for the time span required for recovery of the endogenous pancreas. Nephrectomies of the graft-bearing organs were performed 14 weeks later to confirm the restoration of endogenous insulin regulation. Reparative processes in the pancreata were assessed histologically and immunohistochemically. The level of chimerism in NOD recipients was evaluated by flow cytometric analysis. We have shown that as low as 1% of initial allogeneic chimerism can reverse the diabetogenic processes in islets of Langerhans in prediabetic NOD mice, and that restoration of endogenous beta cell function to physiologically sufficient levels is achievable even if the allogeneic BM transplantation is performed after the clinical onset of diabetes. If the same pattern of islet regeneration were shown in humans, induction of an autoimmunity-free status by establishment of a low level of chimerism, or other alternative means, might become a new therapy for type 1 diabetes.     

Stem cell therapy for neurodegenerative diseases: the issue of transdifferentiation

In the past few years research on stem cells has exploded as a tool to develop potential therapies to treat incurable neurodegenerative diseases. Stem cell transplantation has been effective in several animal models, but the underlying restorative mechanisms are still unknown. Several events such as cell fusion, neurotrophic factor release, endogenous stem cell proliferation, and transdifferentiation (adult cell acquisition of new unexpected identities) may explain therapeutic success, in addition to replacement of lost cells. This issue needs to be clarified further to maximize the potential for effective therapies. Preliminary stem transplantation trials have already been performed for some neurodegenerative diseases. There is no effective pharmacological treatment for amyotrophic lateral sclerosis, but recent preliminary data both in experimental and clinical settings have targeted it as an ideal candidate disease for the development of stem cell therapy in humans. This review summarizes recent advances gained in stem cell research applied to neurodegenerative diseases with a special emphasis to the criticisms put forward.     

Isokinetic knee joint test in "gonalgia sine materia"

Fifty-four subjects, aged between 20 and 35 years, divided into two subgroups, respectively 30 healthy subjects (17 males and 13 females) and 24 subjects with "gonalgia sine materia" (13 males and 11 females) underwent isokinetic exercise test in order to compare their dominant limb with the not dominant one as regard as the strength of extensor and flexor muscles of the knee. No statistically significant difference was found in any of the studied parameters in the comparison between the dominant limb and the not dominant one, both within the subgroup of healthy subjects and within the subgroup of subjects with "gonalgia sine materia". Authors conclude that psychological features may play a preeminent role in the genesis, as well as in the maintenance of "gonalgia sine materia", thus confirming previous data available in medical literature.     

Cell proliferation in breast cancer is a major determinant of clinical outcome in node-positive but not in node-negative patients.

The growth rate of a tumor cell population depends on two major factors: the percentage of proliferating cells (cell growth fraction) and the rapidity of their duplication (cell proliferation rate). The authors evaluated the prognostic and predictive value of both kinetics parameters in a large series of breast cancer patients (n=504). The cell growth fraction was determined by MIB-1 immunostaining, the cell proliferation rate by AgNOR analysis. Ki-67 LI (labeling index) and AgNOR area were significantly associated with histotype, histologic grade, tumor size, estrogen/progesterone receptor status, patient age, and lymph node involvement (P<0.005). In the entire series of patients, both kinetics variables were significantly and independently associated with the clinical outcome, but their prognostic relevance was quite different when node-negative and node-positive patients were considered separately. Although in node-positive patients Ki-67 LI and AgNOR area were the unique independent predictors of disease-free and overall survival, they were excluded by the multivariate Cox model in node-negative patients, where only tumor size and estrogen receptor status retained a significant P-value. These results show that in breast carcinoma the cell growth fraction and the cell proliferation rate have a different prognostic impact with respect to the lymph node status and are major determinants of clinical outcome in node-positive patients only. Within this subgroup, the rapidity of cell proliferation as assessed by AgNOR analysis also served as a sensitive predictor of the response to adjuvant treatments.     

Distribution of cytoskeletal and contractile proteins in normal and tumour bearing salivary and lacrimal glands

Summary We have evaluated by means of immunocytochemistry the distribution of various cytoskeletal and contractile proteins (cytokeratins, vimentin, desmin and -smooth muscle actin) in 23 salivary or lacrimal gland primary tumours (15 pleomorphic adenomas and 8 carcinomas in pleomorphic adenoma), one third of which contained areas of normal gland. Normal epithelial luminal cells were stained by cytokeratin antibodies with a general specificity, while myoepithelial cells were selectively stained by a monoclonal antibody (SK2-27) reacting in immunoblots with cytokeratin polypeptides 14, 16 and 17, according to the classification of Moll et al. (1982) and by an antibody directed against -smooth muscle actin (Skalli et al. 1986). In pleomorphic adenomas, both epithelial and myoepithelial cells displayed typical topographic distributions; moreover, myoepithelial cells showed two distinct cytoskeletal phenotypes. These findings could account in part for the heterogeneity of aspects observed in this tumour. In carcinomas, malignant cells were always positive to cytokeratin antibodies with general specificity and myoepithelial cells were absent as judged by anticytokeratin SK2-27 and anti--smooth muscle actin immunostainings. However, interestingly, there was in all cases a strong positivity for -smooth muscle actin in stromal cells, similarly to what has previously been described for mammary carcinoma (Skalli et al. 1986). Our findings may be useful for the interpretation of the histogenesis of salivary and lacrimal tumour and stromal cells.     

Efficacy of human recombinant erythropoietin plus IFN-alpha in patients affected by chronic hepatitis C.

Determination of serum iron levels in patients affected by chronic hepatitis C is considered fundamental for studying the response to interferon-alpha (IFN-alpha) treatment. IFN could induce anemia, which is promptly corrected by exogenous administration of recombinant human erythropoietin (rHuEPO). The aim of our study was to verify the possible beneficial effect of rHuEPO in patients affected by chronic hepatitis C and treated with IFN. Seventy consecutive patients (42 males and 28 females, mean age 46.4+/-5.2 years) affected by chronic hepatitis C were enrolled. In all patients, chronic hepatitis C was diagnosed on the basis of clinical and biological findings (alanine aminotransferase [ALT] serum levels at least 2-fold higher than normal values for at least 12 months and the presence of anti-HCV antibodies). All patients were negative for hepatitis B virus (HBV) infection, hepatitis D virus (HDV infection, and HIV infection. Statistical analysis was carried out using the Wilcoxon nonparametric sum rank test, the Spearman correlation rank test, and the Friedman ANOVA and Kendall coefficient of concordance. At the end of the treatment, our study series showed significant differences in serum levels of AST (p < 0.001), iron (p < 0.001), and ferritin (p < 0.001). At the end of the follow-up period, significant differences were seen in ALT, aspartate (AST), and iron ferritin and transferrin levels. All differences favored patients who received IFN-alpha and rHuEPO. We think that the depletion of circulating iron may improve the immune response impaired by iron accumulation in the liver. Our study confirms the important role played by iron in the response to IFN treatment, suggesting that the use of rHuEPO induces a better response to IFN in patients with chronic hepatitis C by activation of erythropoiesis.