Adiponectin Gene Variant rs3774261, Effects on Lipid Profile and Adiponectin Levels after a High Polyunsaturated Fat Hypocaloric Diet with Mediterranean Pattern

The role of ADIPOQ gene variants on metabolic improvements after weight change secondary to different hypocaloric diets remained unclear. We evaluate the effect of rs3774261 of ADIPOQ gene polymorphism on biochemical improvements and weight change after high polyunsaturated fat hypocaloric diet with a Mediterranean dietary pattern for 12 weeks. A population of 361 obese subjects was enrolled in an intervention trial with a calorie restriction of 500 calories over the usual intake and 45.7% of carbohydrates, 34.4% of fats, and 19.9% of proteins. The percentages of different fats was; 21.8% of monounsaturated fats, 55.5% of saturated fats, and 22.7% of polyunsaturated fats. Before and after intervention, an anthropometric study, an evaluation of nutritional intake and a biochemical evaluation were realized. All patients lost weight regardless of genotype and diet used. After 12 weeks with a similar improvement in weight loss (AA vs. AG vs. GG); total cholesterol (delta: −28.1 ± 2.1 mg/dL vs. −14.2 ± 4.1 mg/dL vs. −11.0 ± 3.9 mg/dL; p = 0.02), LDL cholesterol (delta: −17.1 ± 2.1 mg/dL vs. −6.1 ± 1.9 mg/dL vs. −6.0 ± 2.3 mg/dL; p = 0.01), triglyceride levels (delta: −35.0 ± 3.6 mg/dL vs. 10.1 ± 3.2 mg/dL vs. −9.7 ± 3.1 mg/dL; p = 0.02), C reactive protein (CRP) (delta: −2.3 ± 0.1 mg/dL vs. −0.2 ± 0.1 mg/dL vs. −0.2 ± 0.1 mg/dL; p = 0.02), serum adiponectin (delta: 11.6 ± 2.9 ng/dL vs. 2.1 ± 1.3 ng/dL vs. 3.3 ± 1.1 ng/dL; p = 0.02) and adiponectin/leptin ratio (delta: 1.5 ± 0.1 ng/dL vs. 0.3 ± 0.2 ng/dL vs. 0.4 ± 0.3 ng/dL; p = 0.03), improved only in AA group. AA genotype of ADIPOQ variant (rs3774261) is related with a significant increase in serum levels of adiponectin and ratio adiponectin/leptin and decrease on lipid profile and C-reactive protein (CRP).     

Effect of verapamil, a calcium antagonist, on the gastric secretion stimulated by histamine or sham-feeding

While "in vitro" studies suggest that cholinergic but not histamine stimulation of the parietal cell is closely related to the flow of extracellular Ca++ into the cell, human studies show a great deal of discrepancy. We evaluated the effects of verapamil, a Ca++ channel antagonist, on gastric secretion stimulated by histamine and sham feeding in 19 patients with duodenal ulcers. Verapamil (200 mcg/kg/h in continuous perfusion) had no effect either on acid production or the volume of secretion in 10 duodenal ulcer patients during simultaneous perfusion of three progressive doses of histamine. However, it significantly inhibited both SAO (51.83%; p less than 0.01) and the volume of secretion in the sham feeding period (28.39%; p less than 600.05), in a group of nine duodenal ulcer patients. These findings suggest that the Ca++ acts as an intracellular mediator in the stimulation/secretion relationship for cholinergic but not histaminergic stimulation in humans.     

A Phase II trial of flavopiridol (NSC #649890) in patients with previously untreated metastatic androgen-independent prostate cancer.

PURPOSE: Flavopiridol is a cyclin-dependent kinase inhibitor with preclinical activity against prostate cancer cell lines. A Phase II trial was conducted to determine the activity of flavopiridol in patients with metastatic hormone-refractory prostate cancer. EXPERIMENTAL DESIGN: A total of 36 patients was enrolled from several institutions and treated with a 72-h continuous infusion of flavopiridol every 14 days at the eventual starting dose of 40 mg/m(2)/day. Dose escalation up to 60 mg/m(2)/day was permitted if no significant toxicity was observed. Responses were assessed every 12 weeks. Only those patients completing four courses of the 72-h infusion were considered evaluable for response because the primary objective was to determine progression-free survival at 6 months given the cytostatic nature of the agent. RESULTS: This study was conducted in a two-stage fashion. During the first stage, at least 20 evaluable patients needed to be enrolled to assess response. There were 22 of 36 patients evaluable for response. No objective responses were observed. Only 4 patients had stable disease for 16, 26, 29, and 48 weeks, respectively, stopping the trial by design as only 3 of 22 (14%) of the patients met the 6-month progression-free survival end point. The most common toxicities were diarrhea (grade 1 and 2) and nausea, although some grade 3 and 4 diarrhea (11 and 6%, respectively) were evident. CONCLUSIONS: Flavopiridol has disappointing single-agent activity in hormone-refractory prostate cancer when administered at this dose and schedule. Its use in prostate cancer should be reserved for evaluation in combination therapies or alternative schedules.     

Tirapazamine plus carboplatin and paclitaxel in advanced malignant solid tumors: a california cancer consortium phase I and molecular correlative study.

PURPOSE: Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells and has supra-additive toxicity with platinums and taxanes in preclinical studies. We conducted a Phase I study of tirapazamine, carboplatin, and paclitaxel and assessed potential plasma markers of hypoxia as surrogates for response. EXPERIMENTAL DESIGN: Forty-two patients with advanced solid tumors were treated at four dose levels; parallel dose escalations were carried out in chemotherapy-naive and previously treated subjects. Pre and post-therapy plasma levels of the hypoxia-induced proteins plasminogen activator inhibitor-1 and vascular endothelial growth factor were measured. RESULTS: Three of four chemotherapy-na?ve patients developed dose-limiting toxicities at dose level 4 (grade 3 stomatitis/infection, grade 3 emesis, and grade 4 febrile neutropenia). Four of seven previously treated patients developed dose-limiting toxicities at dose level 3, including one death [grade 3 myalgia, grade 3 infection/grade 4 neutropenia, grade 3 infection/grade 4 neutropenia, and grade 5 infection (death)/grade 4 neutropenia]. Of 38 patients assessable for response, 3 had a complete response, 1 a partial response, 1 an unconfirmed partial response, and 23 had stable disease in at least one evaluation; 10 quickly progressed. One complete responder had normalization of vascular endothelial growth factor and plasminogen activator inhibitor-1 levels. CONCLUSION: Dose levels 3 (carboplatin AUC of 6, 225 mg/m(2) paclitaxel, and 330 mg/m(2) tirapazamine) and 2 (carboplatin AUC 6, 225 mg/m(2) paclitaxel, and 260 mg/m(2) tirapazamine) are the maximum tolerated doses for chemotherapy naive and patients treated previously, respectively. Dose level 3 is the experimental arm of a Phase III Southwest Oncology Group trial (S0003) in advanced non-small cell lung cancer. Potential markers of tumor hypoxia may be useful correlates in studies of hypoxic cytotoxins and are being prospectively investigated in S0003.     

The cyclin-dependent kinase inhibitor UCN-01 plus cisplatin in advanced solid tumors: a California cancer consortium phase I pharmacokinetic and molecular correlative trial.

BACKGROUND: UCN-01 (7-hydroxy-staurosporine) is a novel antineoplastic agent targeting cyclin-dependent kinases, which shows potent in vitro and in vivo activity against a broad range of tumor types. Our group has previously shown that UCN-01 potentiates the apoptotic response of agents such as cisplatin in vitro by preventing sequence-specific abrogation of G2 arrest caused by DNA-damaging chemotherapies. PATIENTS AND METHODS: This National Cancer Institute-sponsored phase I trial was designed to determine the safety, maximum tolerated dose, and pharmacokinetics of escalating doses of cisplatin in combination with UCN-01 in patients with advanced malignant solid tumors, as well as to do molecular correlative studies on tumor specimens. Cisplatin was infused over 1 hour before UCN-01 (45 mg/m2/d) given as a 72-hour continuous infusion. Escalation of cisplatin was planned through five dose levels at 20, 30, 45, 60, and 75 mg/m2. RESULTS: Ten patients were accrued. Accrual was halted at dose level 2 (cisplatin, 30 mg/m2) due to dose-limiting toxicities consisting of grade 5 sepsis with respiratory failure associated with grade 3 creatinine (one patient) and grade 3 atrial fibrillation (one patient). Plasma and salivary pharmacokinetics of UCN-01 were unaffected by cisplatin. Pretreatment and posttreatment tumor biopsies showed that UCN-01 was active against a key molecular target, the checkpoint kinase Chk1.CONCLUSIONS: This phase I trial failed to achieve targeted therapeutic dose levels of cisplatin when combined with prolonged infusion UCN-01. However, because preclinical data indicate that UCN-01 potentiates response to platinum, further studies with alternative dose schedules of the combination, or with other platinum analogues, are warranted.     

The potential of non-myeloablative heterochronous autologous hematopoietic stem cell transplantation for extending a healthy life span

Aging is a complex multifactorial process, a prominent component being the senescence of the immune system. Consequently, immune-related diseases develop, including atherosclerosis, cancer, and life-threatening infections, which impact on health and longevity. Rejuvenating the aged immune system could mitigate these diseases, thereby contributing to longevity and health. Currently, an appealing option for rejuvenating the immune system is heterochronous autologous hematopoietic stem cell transplantation (haHSCT), where healthy autologous bone marrow/peripheral blood stem cells are collected during the youth of an individual, cryopreserved, and re-infused when he or she has reached an older age. After infusion, young hematopoietic stem cells can reconstitute the compromised immune system and improve immune function. Several studies using animal models have achieved substantial extension of the life span of animals treated with haHSCT. Therefore, haHSCT could be regarded as a potential procedure for preventing age-related immune defects and extending healthy longevity. In this review, the pros, cons, and future feasibility of this approach are discussed.     

Cirurgia cardíaca na estenose aórtica severa: o que mudou com o advento do tratamento percutâneo?

Introduction and objectiveTranscatheter aortic valve implantation (TAVI) is an alternative therapeutic approach to patients not considered suitable for surgical aortic valve replacement (SAVR) due to their high operative risk. We sought to assess the impact of TAVI on the profile and operative results of patients with severe aortic stenosis undergoing SAVR.MethodsA total of 214 patients were included, of whom 103 consecutive patients underwent isolated SAVR in 2005 and 111 in 2009. Patients’ demographic and operative data were collected retrospectively. Operative and one-year mortality and morbidity were analyzed.ResultsPatients’ mean age was 70 years, and 56% were female. Following the introduction of a TAVI program, patients undergoing conventional surgery were older, with more comorbidities. Overall 30-day and one-year mortality were 2.8% and 7.0%, respectively. After the introduction of TAVI, the observed mortality rate for SAVR decreased, but not significantly (operative mortality: 3.9% before TAVI vs. 1.8% after TAVI, p=NS; one-year mortality: 10% vs. 4.5%, p=NS). Striking differences were observed in morbidity (operative morbidity: 23.3% before TAVI vs. 13.5% after TAVI, p=0.047, and one-year morbidity: 20.4% vs. 9.9%, p=0.032).ConclusionsSince the introduction of a TAVI program at our center, the number of patients undergoing SAVR has increased, with a slight rise in surgical risk, but without worsening the final operative results. The implementation of a TAVI program has thus had a positive impact on the volume of procedures, patient selection and outcomes in SAVR.     

Incidence and prevalence of autoimmune hepatitis in the area of the Hospital de Sagunto (Spain)

Thirteen cases of autoimmune hepatitis (AIH) were diagnosed from 1990 to 2003 in the area of the Hospital de Sagunto (Valencia, Spain), which attends a population of 112,003 inhabitants aged more than 14 years (54,622 males and 57,381 females). The diagnostic criteria of the International Autoimmune Hepatitis Group were used and patients who, despite having a probable diagnosis of AIH, presented hepatitis C virus infection were excluded. The diagnosis was probable in one patient and definitive in 12. All patients, 11 females and two males aged 45.9 12.2 years (range: 28-66), were classified as AIH type 1. Among the population aged more than 14 years, the mean annual incidence of AIH was 0.83 cases/100,000 inhabitants (95% CI, 0.44-1.42) (range: 0-2.68), showing a significant trend to increase (b = 0.132; p = 0.019). The incidence was higher in women than in men (RR = 5.24; 95% CI, 1.16-23.62). The mean annual incidence was 1.37 (95% CI, 0.68-2.46) (range: 0-3,49) in women and was 0.26 (95% CI, 0.02-0.96) (range: 0-1.83) in men. By age, the maximum mean annual incidence was observed in the group aged 55-64 years (1.6 cases/100,000 inhabitants). The prevalence of AIH in September 2003 was 11.61 cases/100,000 inhabitants aged more than 14 years (95% CI, 6.78-19.86). The prevalence was 3.66 (95% CI, 1-13.35) in men and was 19.17 (95% CI, 10.70-34.33) in women.