Evaluation of sex differences on mitochondrial bioenergetics and apoptosis in mice

It has been postulated that the differences in longevity observed between organisms of different sexes within a species can be attributed to differences in oxidative stress. It is generally accepted that differences are due to the higher female estrogen levels. However, in some species males live the same or longer despite their lower estrogen values. Therefore, in the present study, we analyze key parameters of mitochondrial bioenergetics, oxidative stress and apoptosis in the B6 (C57Bl/6J) mouse strain. There are no differences in longevity between males and females in this mouse strain, although estrogen levels are higher in females. We did not find any differences in heart, skeletal muscle and liver mitochondrial oxygen consumption (State 3 and State 4) and ATP content between male and female mice. Moreover, mitochondrial H(2)O(2) generation and oxidative stress levels determined by cytosolic protein carbonyls and concentration of 8-hydroxy-2'-deoxyguanosine in mitochondrial DNA were similar in both sexes. In addition, markers of apoptosis (caspase-3, caspase-9 and mono- and oligonucleosomes: the apoptosis index) were not different between male and female mice. These data show that there are no differences in mitochondrial bioenergetics, oxidative stress and apoptosis due to gender in this mouse strain according with the lack of differences in longevity. These results support the Mitochondrial Free Radical Theory of Aging, and indicate that oxidative stress generation independent of estrogen levels determines aging rate.     

Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90

17-Allylamino-17-demethoxygeldanamycin (17-AAG)1 is a semisynthetic inhibitor of the 90 kDa heat shock protein (Hsp90) currently in clinical trials for the treatment of cancer. However, 17-AAG faces challenging formulation issues due to its poor solubility. Here we report the synthesis and evaluation of a highly soluble hydroquinone hydrochloride derivative of 17-AAG, 1a (IPI-504), and several of the physiological metabolites. These compounds show comparable binding affinity to human Hsp90 and its endoplasmic reticulum (ER) homologue, the 94 kDa glucose regulated protein (Grp94). Furthermore, the compounds inhibit the growth of the human cancer cell lines SKBR3 and SKOV3, which overexpress Hsp90 client protein Her2, and cause down-regulation of Her2 as well as induction of Hsp70 consistent with Hsp90 inhibition. There is a clear correlation between the measured binding affinity of the compounds and their cellular activities. Upon the basis of its potent activity against Hsp90 and a significant improvement in solubility, 1a is currently under evaluation in Phase I clinical trials for cancer.     

Oxaliplatin and irinotecan plus granulocyte-colony stimulating factor as third-line treatment in relapsed or cisplatin-refractory germ-cell tumor patients: a phase II study

OBJECTIVE: To investigate the efficacy and tolerability of the combination of oxaliplatin and irinotecan in patients with relapsed or cisplatin-refractory germ cell tumors (GCT). PATIENTS AND METHODS: Eighteen patients with relapsed or cisplatin-refractory GCT were treated with oxaliplatin 85 mg/m(2) on days 1 and 15, followed by irinotecan 80 mg/m(2) on days 1, 8 and 15, every four weeks for a maximum of six cycles. RESULTS: All patients were assessable for response and toxicity. Overall, 7 patients (40%) achieved a favorable response (4 complete and 3 partial responses). One of the complete responders relapsed after 2.5 months and despite further treatment with high dose chemotherapy, he died two months later. The remaining 3 patients are continuously disease free for 11+, 14+ and 19+ months. The partial responders subsequently progressed and died after 2, 3 and 4.5 months, respectively. None of the patients with extragonadal mediastinal GCT responded to oxaliplatin and irinotecan chemotherapy. The investigated combination has a good tolerance. Neutropenia related toxicity (grade 3/4, 17%), neutropenic infections and sepsis were not common probably due to prophylactic use of hematopoietic colony stimulating factor (G-CSF). Thrombocytopenia and anemia were not a serious problem. Gastrointestinal side effects, specifically grade 3/4 diarrhea and nausea/vomiting were noted in 22% and 28% of patients, respectively. Oxaliplatin-associated neurotoxicity was rather low; grade 3 peripheral sensory neuropathy was recorded in 11% of patients. CONCLUSION: The combination of oxaliplatin and irinotecan is feasible and associated with significant clinical antitumor activity, mild and manageable toxicity and easy outpatient administration in patients with relapsed or cisplatin-refractory germ cell cancer. This combination seems to offer a possibility for long-term disease-free status (17%), despite the poor prognostic features of the study patient group.     

Endometrial hormone receptors and proliferation index in the periovulatory phase of stimulated embryo transfer cycles in comparison with natural cycles and relation to clinical pregnancy outcome

OBJECTIVE: To investigate the endometrial steroid receptors and proliferation index in GnRH analogue/hMG-stimulated cycles in comparison with natural cycles and their relation to clinical pregnancy outcome. DESIGN: Prospective observational study. SETTING: Tertiary referral center. PATIENT(S): Twenty-seven stimulated patients with GnRH agonist and hMG. Twenty normo-ovulatory patients were the natural cycle controls. INTERVENTION(S): Endometrial aspiration biopsies: in stimulated cycles on the day of oocyte retrieval within the ET cycle (Day OPU) (n = 20) or 2 days later (Day OPU + 2) (n = 7); in natural cycles on the natural day of ovulation (Day NO) (n = 10) or on the day of ovulation + 2 (Day NO + 2) (n = 10). MAIN OUTCOME MEASURE(S): Comparison of endometrial maturation, estrogen (ER) and P receptor (PR), and proliferation index by immunohistochemistry in natural and stimulated cycles, correlation with pregnancy outcome in stimulated cycles. RESULT(S): Stimulated cycles Day OPU showed significantly advanced endometrial maturation compared to natural cycles Day NO; stromal ER and glandular and stromal PR staining was lower in stimulated than in natural cycles, but higher on Day OPU than on Day NO + 2; proliferation index was lower in all stimulated cycles. Steroid receptors and proliferation index in stimulated cycles were unrelated to clinical pregnancy occurrence. CONCLUSION(S): Compared to natural cycles, ovarian stimulation induced an imbalance in endometrial ER and PR and led to a profound antimitotic effect in the peri-ovulatory phase. These parameters were, however, not predictive of clinical pregnancy in cycles with ET.     

Repeated Episodes of Respiratory Failure Due to Bilateral Vocal Cord Paralysis

Background

Bilateral vocal cord paralysis can produce severe airway obstruction, leading to acute respiratory failure. Discriminating the pathology of the upper airway from chronic obstructive diseases of the lower airways often presents a challenge for clinicians in the Emergency Department.

Objectives

To underlie the value of clinical examination and flow-volume loops in the establishment of diagnosis of upper airway obstruction.

Case Report

We describe the case of a 55-year-old female ex-smoker who presented with a long history of hoarseness and progressive exertional dyspnea. The patient developed repeated episodes of acute respiratory failure and was supported with noninvasive ventilation. The diagnosis of bilateral vocal cord paralysis was finally established by patient’s symptoms and flow-volume loops demonstrating variable extrathoracic obstruction.

Conclusion

Vocal cord paralysis is a rare and often neglected condition, contributing to repeated episodes of acute respiratory failure. Flow-volume loop is a useful tool when symptoms are suggestive of upper airway obstruction.