Circulatory effects of apnoea in elite breath‐hold divers

Aim: Voluntary apnoea induces several physiological adaptations, including bradycardia, arterial hypertension and redistribution of regional blood flows. Elite breath‐hold divers (BHDs) are able to maintain very long apnoea, inducing severe hypoxaemia without brain injury or black‐out. It has thus been hypothesized that they develop protection mechanisms against hypoxia, as well as a decrease in overall oxygen uptake. Methods: To test this hypothesis, the apnoea response was studied in BHDs and non‐divers (NDs) during static and dynamic apnoeas (SA, DA). Heart rate, arterial oxygen saturation (SaO₂), and popliteal artery blood flow were recorded to investigate the oxygen‐conserving effect of apnoea response, and the internal carotid artery blood flow was used to examine the mechanisms of cerebral protection. Results: The bradycardia and peripheral vasoconstriction were accentuated in BHDs compared with NDs (P < 0.01), in association with a smaller SaO₂ decrease (?2.7% vs. ?4.9% during SA, P < 0.01 and ?6% vs. ?11.3% during DA, P < 0.01). Greater increase in carotid artery blood flow was also measured during apnoea in BHDs than in controls. Conclusion: These results confirm that elite divers present a potentiation of the well‐known apnoea response in both SA and DA conditions. This response is associated with higher brain perfusion which may partly explain the high levels of world apnoea records.     

Elastolysis induces collagenolysis in a gingival lamina propria model

Elastin peptides were previously reported to increase MMP expression in several cell types. We found binding of these peptides to their receptors led to enhanced MMP-3 and MMP-1 expression, but not activation, in human gingival fibroblasts cultured on plastic dishes. We hypothesized that these peptides, in a more physiological environment, might additionally trigger an MMP-3/MMP-1 activation cascade, leading to matrix lysis, as occurs in periodontitis. To test this hypothesis, we used contracted and attached lattices as gingival lamina propria equivalents. In such 3D models, supplementation of elastin peptides and plasminogen triggered an MMP-3/MMP-1 activation cascade and significant down-regulation of TIMPs production, further leading to intense collagen degradation. We propose that elastolysis, as occurs in periodontitis, potentiates collagenolysis, thus promoting disease progression.     

Monitoring of ventilation during the early part of cardiopulmonary exercise testing: the first step to detect central sleep apnoea in chronic heart failure

BACKGROUND AND PURPOSE: To evaluate the prediction of nocturnal central sleep apnoea (CSA) syndrome from the presence of periodic breathing (PB) on diurnal monitoring of pre-exercise (cardiopulmonary exercise test [CPX]) parameters. CSA syndrome is commonly found in congestive heart failure (CHF) patients and has several prognostic and therapeutic implications but is frequently undiagnosed. Awake PB pattern is sometimes observed during the CPX cardiopulmonary monitoring period of gas exchanges in CHF patients referred to the stress test laboratory for routine peak VO2 determination. PATIENTS AND METHODS: Forty-five consecutive ambulatory patients (2 women/43 men; 60.2+/-11.7 years old) with clinically moderate to severe CHF (New York Heart Association [NYHA] class II/III: 22/23; mean+/-standard deviation left ventricular ejection fraction [LVEF]: 30.5+/-6.6%) underwent a classical maximal CPX test including a 2-min period (pre-test) of gas exchange monitoring and nocturnal ambulatory polygraphic monitoring. PB was defined when a cyclical pattern of VE, VO2, VCO2, was visually noted during the pre-exercise period and/or during the first 4 min of the CPX. CSA syndrome was retained as a central apnoea-plus-hypopnea index (cAHI) equal to or more than 10/h. The sleep study scoring procedure was done independently of the knowledge of the CPX results. Sensitivity, specificity and predictive values were calculated and receiver operating characteristic (ROC) curve analysis was constructed. RESULTS: Peak VO2 reached 16.4+/-5.2 mL kg(-1)min(-1) (55% of the theoretical value adjusted for gender and age). The polygraphy was completed and validated (at least five consecutive hours of sleep) in all cases. CSA syndrome was found in 28 (62%) patients (mean cAHI: 19.3+/-8.6/h). Sensitivity for the prediction of CSA syndrome reached 92.9% (two false-negative patients with a cAHI of nine) and specificity 94.1% with a predictive accuracy of 93.3%. The only false-positive patient suffered a moderate but significant obstructive sleep apnoea syndrome. Using ROC curve analysis, the W value reached 0.99 for the prediction of CSA from the presence of PB. The presence of CSA syndrome, using logistic regression analysis, is associated with a more severe functional status (NYHA: p<0.01, peak VO2: p<0.002), a lower basal and peak end-expiratory CO2 pressure (PETCO2, all p<0.03), a worse LVEF (p<0.01) and age equal to or more than 60 years (p<0.03). CONCLUSIONS: The observation of PB in the preliminary period of the CPX test in CHF patients appeared highly predictive of the presence of CSA syndrome during sleep and could prompt the use of polygraphic monitoring in severe CHF patients.     

Phase I/II pharmacokinetic study of pemetrexed and epirubicin in patients with locally advanced or metastatic breast cancer

BACKGROUND: Pemetrexed and epirubicin are each active in patients with advanced/metastatic breast cancer (MBC). This phase I/II study evaluated these drugs as a combination regimen. PATIENTS AND METHODS: Women with locally advanced or MBC were enrolled. Pemetrexed 400-600 mg/m2 and epirubicin 60-90 mg/m2 were administered on day 1 every 21 days. The recommended phase II dose was evaluated in a 2-stage design. RESULTS: Phase I enrolled 34 patients and evaluated 5 dose levels. Dose-limiting toxicities were neutropenia and febrile neutropenia. Patients received a median of 7.5 cycles (range, 1-8 cycles), and promising efficacy (partial response [PR], 32%; stable disease [SD], 50%) was observed. Pharmacokinetics of pemetrexed was unchanged when combined with epirubicin. Selected phase II regimen (pemetrexed 600 mg/m2 and epirubicin 75 mg/m2) was administered to 22 patients (median, 4.5 cycles; range 1-13 cycles). Five patients experienced a PR (23%), and 10 experienced SD (46%). This response was below the predefined efficacy requirements for subsequent enrollment, and accrual was stopped. Median time to progression was 5.3 months (95% CI, 3.1-8.9 months), and median time to treatment failure was 3.5 months (95% CI, 2.6-5.9 months). CONCLUSION: The regimen is safe but cannot be recommended as first-line chemotherapy in advanced breast cancer because of the low response rate.     

Interferon-alpha gene therapy by lentiviral vectors contrasts ovarian cancer growth through angiogenesis inhibition

Ovarian cancer represents a suitable disease for gene therapy because of the containment of neoplastic cells in the peritoneal cavity even at advanced tumor stages. The aim of this study was to investigate whether intraperitoneal administration of a lentiviral vector encoding murine interferon-alpha (LV-IFN) could have therapeutic activity in a transplantable ovarian cancer model. Multiple injections of low amounts of LV-IFN into severe combined immunodeficiency (SCID) mice bearing IGROV-1 or OC316 ovarian cancer cells elicited remarkable antitumor activity, leading to prolongation of survival in the majority of animals. A definitive cure was obtained in animals bearing PD-OVA#1 tumors, generated by injecting tumor cells isolated from the ascitic fluid of a patient into SCID mice. Interferon-alpha levels were detected in the peritoneal fluids but not in the serum of treated mice, indicating that production of the cytokine is mainly local, by both tumor and normal cells of the host. Antitumor effects were associated with a remarkable decrease in the formation of hemorrhagic ascites, an increase in ischemic tumor necrosis, and a reduction in microvessel density. In conclusion, our findings show that intracavitary IFN-alpha gene therapy, using a lentiviral vector, provides strong antitumor effects in murine models of ovarian cancer and reinforces the evidence that angiogenesis inhibition is a promising strategy for the treatment of localized tumors.     

Oestrus cycle perturbations and hypotrophy of clitoral glands in malaria-infected female BALB/c mice

An experimental host-parasite association involving BALB/c female mice infected with Plasmodium vinckei petteri was used with the aim of investigating the morphological and physiological alterations induced by the parasite in the genital tract of the host. The vaginal oestrous cycle was monitored as a daily clue to the sexual physiology of the female mice, and a complete histological analysis of the genital tract was performed 36 days following parasite inoculation. The oestrous cycle showed strong transitory alterations during the first 30 days following infection. The occurrence of oestrus days increased during the first 10 days post-infection and then decreased to a subnormal value during the following 20 days. Infected mice also showed a remarkable hypotrophy of their clitoral glands 30 days after the beginning of the malarial infection. A probable cause of such perturbations is a significant hormonal imbalance triggered by the erythrocytic proliferation of the Plasmodium. The relationship between the immune response of the host and these physiological and morphological alterations, as well as the outcomes of these alterations on the sexuality of the rodent host are discussed.     

Paracoccidioidomycosis and larynx carcinoma

Report of a case of paracoccidioidomycosis associated with a carcinoma: both located in the larynx in a patient whose therapeutic response to antifungal treatment produced a recovery of physical conditions. This case shows the importance of taking into account the diagnosis of paracoccidioidomycosis in all patients with problems in the larynx, especially those who inhabit or inhabited endemic areas of Paracoccidioides brasiliensis.