Effect of different doses of metformin on serum testosterone and insulin in non-diabetic women with breast cancer: a randomized study

BackgroundSerum levels of insulin and testosterone may affect both breast cancer (BC) incidence and prognosis. Metformin reduces hyperglycemia and insulin levels in patients with diabetes. In women without diabetes and with polycystic ovary syndrome, metformin lowers both insulin and testosterone levels. Patients with diabetes who are treated with metformin showed a lower risk of cancer; a protective effect of metformin also was observed for BC. Recently, studies on metformin use for prevention or treatment of BC have been proposed in patients who are not diabetic. The aim of the present study was to test the effect of different doses of metformin on serum levels of insulin and testosterone in those postmenopausal patients with breast cancer and without diabetes who have basal testosterone levels ≥0.28 ng/mL (median value).Patients and MethodsA total of 125 eligible women were initially invited to take metformin 500 mg/d for 3 months. The 108 women who completed the first 3 months were invited to continue the study with metformin 1000 mg/d (500 mg twice a day [b.i.d.]) for 1 month. The women were then randomized into 2 groups, and, for the subsequent 5 months, 1 group increased the dose by taking metformin 1500 mg/d (500 mg 3 times a day [t.i.d.]), and the other group continued with metformin 1000 mg /d (500 [b.i.d.]).ResultsA total of 96 women completed the study: 43 women received 1500 mg/d, and 53 women received 1000 mg/d. The women who took 1500 mg/d showed a significant reduction of insulin level, HOMA-IR index (homeostasis model assessment-insulin resistance index), testosterone level, and free androgen index compared with women treated with 1000 mg/d. After treatment with 1500 mg/d, the insulin level decreased by 25% and the testosterone level decreased by 23%.ConclusionBoth these changes might have a prognostic importance.     

HPLC-ESIMS(n) profiling, isolation, structural elucidation, and evaluation of the antioxidant potential of phenolics from Paepalanthus geniculatus

The methanol extract of the flowers of Paepalanthus geniculatus Kunth. showed radical-scavenging activity in the TEAC assay. An analytical approach based on HPLC-ESIMS(n) was applied to obtain the metabolite profile of this extract and led to the rapid identification of 19 polyphenolic compounds comprising flavonoids and naphthopyranones. The new naphthopyranone (10, 16), quercetagetin (1, 5, 7, 13), and galetine derivatives (9, 11, 17, 19), and a flavonol glucoside cyclodimer in the truxillate form (12), were identified. Compounds 2, 6, and 7 showed the highest antioxidant capacity and ability to affect the levels of intracellular ROS in human prostate cancer cells (PC3).     

Conventional and molecular techniques for the early diagnosis of bacteraemia

Bloodstream infections account for 30-40% of all cases of severe sepsis and septic shock, and are major causes of morbidity and mortality. Diagnosis of bloodstream infections must be performed promptly so that adequate antimicrobial therapy can be started and patient outcome improved. An ideal diagnostic technology would identify the infecting organism(s) and their determinants of antibiotic resistance, in a timely manner, so that appropriate pathogen-driven therapy could begin promptly. Unfortunately, despite the essential information it provides, blood culture, the gold standard, largely fails in this purpose because time is lost waiting for bacterial or fungal growth. Several efforts have been made to optimise the performance of blood culture, such as the development of technologies to obtain rapid detection of microorganism(s) directly in blood samples or in a positive blood culture. The ideal molecular method would analyse a patient's blood sample and provide all the information needed to immediately direct optimal antimicrobial therapy for bacterial or fungal infections. Furthermore, it would provide data to assess the effectiveness of the therapy by measuring the clearance of microbial nucleic acids from the blood over time. None of the currently available molecular methods is sufficiently rapid, accurate or informative to achieve this. This review examines the principal advantages and limitations of some traditional and molecular methods commercially available to help the microbiologist and the clinician in the management of bloodstream infections.     

Cytoarchitectonic subdivisions of the dorsolateral frontal cortex of the marmoset monkey (Callithrix jacchus), and their projections to dorsal visual areas

We describe the organization of the dorsolateral frontal areas in marmoset monkeys using a combination of architectural methods (Nissl, cytochrome oxidase, and myelin stains) and injections of fluorescent tracers in extrastriate areas (the second visual area [V2], the dorsomedial and dorsoanterior areas [DM, DA], the middle temporal area and middle temporal crescent [MT, MTc], and the posterior parietal cortex [area 7]). Cytoarchitectural field 8 comprises three subdivisions: 8Av, 8Ad, and 8B. The ventrolateral subdivision, 8Av, forms the principal source of frontal projections to the "dorsal stream," having connections with each of the injected visual areas. The cytoarchitectural characteristics of 8Av suggest that this subdivision corresponds to the marmoset's frontal eye field. The intermediate subdivision of area 8 (8Ad) has efferent projections to area 7, while the dorsomedial subdivision (8B) has few or no connections with extrastriate cortex. Area 46, located rostrolateral to area 8Av, has substantial connections with the medial extrastriate areas (DM, DA, and area 7) and with MT, while the cortex lateral to 8Av (area 12/45) projects primarily to MT and to the MTc. The rostromedial prefrontal (area 9) and frontopolar (area 10) regions have very few extrastriate projections. Finally, cells in dorsal area 6 (6d) have sparse projections to DM, MT, and the MTc, as well as strong projections to DA and to area 7. These results illuminate aspects of the evolutionary development of the primate frontal cortex, and serve as a basis for further research into cognitive functions using a marmoset model.     

Poor outcome of elderly patients with platinum-sensitive recurrent ovarian cancer: Results from the SOCRATES retrospective study

Background

Elderly patients with ovarian carcinoma have a poorer prognosis compared with their younger counterpart, and this depends in most cases on undertreatment. The aim of this study was to evaluate, retrospectively, the pattern of care and the prognosis of elderly patients with platinum-sensitive recurrent ovarian cancer. The SOCRATES study retrospectively assessed the pattern of care of a cohort of patients with recurrent platinum-sensitive ovarian cancer observed in the years 2000-2002 in 37 Italian centres. Data were collected between April and September 2005.

Patients and methods

Patients with recurrent ovarian cancer with >6 months of platinum free interval were considered eligible. Four-hundred-ninety-three patient files were collected and 425 were considered eligible and analyzed. Ninety-four patients with age ≥70 years and 331 patients with age <70 years were analyzed.

Results

Recurrence free interval (RFI), PS, and number of disease sites were similar among the two groups. A lower proportion of elderly patients underwent secondary cytoreduction (8.9% compared to 23.9%; p = 0.0018). The mean number of chemotherapy lines received for recurrence was 2.7 and 2.5 in young and aged patients, respectively. Elderly patients received more frequently at second line single agent platinum than platinum-combination therapy or other non-platinum chemotherapy. The response rate to the second line chemotherapy was higher in younger patients than in the elderly population (CR + PR, younger: 67.2%; elderly: 46.5%; p = 0.0004). Median overall survival from recurrence was 30.7 months in the younger patients and 23.6 months in the elderly group (p = 0.0037). At multivariate analysis, number of disease sites (>1 vs. 1), performance status at recurrence (2-3 vs. 0-1), RFI (6-12 months vs. >12 months), age at recurrence, were independently associated with survival.

Conclusion

Elderly patients with platinum-sensitive recurrent ovarian cancer receive less surgery and chemotherapy. Response to chemotherapy is better in younger patients. Age is an unfavourable factor independently associated to a worst prognosis.     

Improving the Diagnostic Accuracy of Depression in Older Persons: The Depression in the Aged Female National Evaluation Cluster Randomized Trial

OBJECTIVES: To evaluate whether a training intervention can improve the ability of geriatricians to recognize depression in older persons.
DESIGN: Multicenter, cluster randomized clinical trial.
SETTING: Fourteen geriatric outpatient clinics in Italy, each representing the unit of randomization.
PARTICIPANTS: After training, a total of 1,914 outpatients aged 65 years and older in both arms, not on antidepressant at entry, were blindly evaluated by the clinic geriatrician, in charge of routine clinical management, and by a field researcher, who formally diagnosed depression by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), taken as the criterion standard.
INTERVENTION: After randomization, geriatricians belonging to the intervention arm were assigned to receive a residential 3-day educational program on depression. Those in the control arm received a generic course on disease management in elderly people.
MEASUREMENTS: Sensitivity and specificity of the diagnosis of depression made by geriatricians, compared with the DSM-IV diagnosis.
RESULTS: Sensitivity and specificity were significantly higher in trained than in untrained geriatricians (49 vs 35% and 91 vs 88%, respectively; P =.002 in marginal regression models). Effectiveness of training was confirmed, adjusting for age, sex, and cognitive performance ( P =.02).
CONCLUSION: The ability of geriatricians to diagnose depression in older outpatients can be improved with a specific training intervention. Improvement of diagnostic performance might translate into more-appropriate clinical management.     

Anti-leukemia activity of alloreactive NK cells in KIR ligand-mismatched haploidentical HSCT for pediatric patients: evaluation of the functional role of activating KIR and redefinition of inhibitory KIR specificity

We analyzed 21 children with leukemia receiving haploidentical hematopoietic stem cell transplantation (haplo-HSCT) from killer immunoglobulin (Ig)-like receptors (KIR) ligand-mismatched donors. We showed that, in most transplantation patients, variable proportions of donor-derived alloreactive natural killer (NK) cells displaying anti-leukemia activity were generated and maintained even late after transplantation. This was assessed through analysis of donor KIR genotype, as well as through phenotypic and functional analyses of NK cells, both at the polyclonal and clonal level. Donor-derived KIR2DL1(+) NK cells isolated from the recipient displayed the expected capability of selectively killing C1/C1 target cells, including patient leukemia blasts. Differently, KIR2DL2/3(+) NK cells displayed poor alloreactivity against leukemia cells carrying human leukocyte antigen (HLA) alleles belonging to C2 group. Unexpectedly, this was due to recognition of C2 by KIR2DL2/3, as revealed by receptor blocking experiments and by binding assays of soluble KIR to HLA-C transfectants. Remarkably, however, C2/C2 leukemia blasts were killed by KIR2DL2/3(+) (or by NKG2A(+)) NK cells that coexpressed KIR2DS1. This could be explained by the ability of KIR2DS1 to directly recognize C2 on leukemia cells. A role of the KIR2DS2 activating receptor in leukemia cell lysis could not be demonstrated. Altogether, these results may have important clinical implications for the selection of optimal donors for haplo-HSCT.     

Neurocognitive aging: prior memories hinder new hippocampal encoding

Normal aging is often accompanied by impairments in forming new memories, and studies of aging rodents have revealed structural and functional changes to the hippocampus that might point to the mechanisms behind such memory loss. In this article, we synthesize recent neurobiological and neurophysiological findings into a model of the information-processing circuit of the aging hippocampus. The key point of the model is that small concurrent changes during aging strengthen the auto-associative network of the CA3 subregion at the cost of processing new information coming in from the entorhinal cortex. As a result of such reorganization in aged memory-impaired individuals, information that is already stored would become the dominant pattern of the hippocampus to the detriment of the ability to encode new information.