Exercise level and cognitive decline: the MoVIES project

Growing evidence suggests that physical exercise may be protective against cognitive impairment and decline. A prospective study of a representative rural community sample (N = 1,146) aged 65+ years examined self-reported exercise habits and measured global cognitive function using the Mini-Mental State Examination (MMSE). A composite variable "exercise level" combining type, frequency, and duration of exercise was created with three levels: "high exercise" (aerobic exercise of > or = 30 minute duration > or = 3 times a week), "low exercise" (all other exercise groups), and "no exercise." Cognitive decline was defined as being in the 90 percentile of decline in this cohort, ie, declining by 3 or more MMSE points during the 2-year interval between two assessments. In a multiple regression model, high exercise level at the baseline assessment was negatively associated with, ie, was protective against, being in the group with the greatest amount of decline at the follow-up assessment, after adjusting for likely confounders (odds ratio = 0.39; 95% confidence interval, 0.19, 0.78). When high exercise was redefined using frequency as > or = 5 days per week as the threshold, as per the Surgeon General's guidelines, both low exercise and high exercise were negatively associated with cognitive decline. Exercise may have implications for prevention of cognitive decline.     

Resistance mechanisms in clinical isolates of Candida albicans

Resistance to azole antifungals continues to be a significant problem in the common fungal pathogen Candida albicans. Many of the molecular mechanisms of resistance have been defined with matched sets of susceptible and resistant clinical isolates from the same strain. Mechanisms that have been identified include alterations in the gene encoding the target enzyme ERG11 or overexpression of efflux pump genes including CDR1, CDR2, and MDR1. In the present study, a collection of unmatched clinical isolates of C. albicans was analyzed for the known molecular mechanisms of resistance by standard methods. The collection was assembled so that approximately half of the isolates were resistant to azole drugs. Extensive cross-resistance was observed for fluconazole, clotrimazole, itraconazole, and ketoconazole. Northern blotting analyses indicated that overexpression of CDR1 and CDR2 correlates with resistance, suggesting that the two genes may be coregulated. MDR1 overexpression was observed infrequently in some resistant isolates. Overexpression of FLU1, an efflux pump gene related to MDR1, did not correlate with resistance, nor did overexpression of ERG11. Limited analysis of the ERG11 gene sequence identified several point mutations in resistant isolates; these mutations have been described previously. Two of the most common point mutations in ERG11 associated with resistance, D116E and E266D, were tested by restriction fragment length polymorphism analysis of the isolates from this collection. The results indicated that the two mutations occur frequently in different isolates of C. albicans and are not reliably associated with resistance. These analyses emphasize the diversity of mechanisms that result in a phenotype of azole resistance. They suggest that the resistance mechanisms identified in matched sets of susceptible and resistant isolates are not sufficient to explain resistance in a collection of unmatched clinical isolates and that additional mechanisms have yet to be discovered.     

Characterization of murine hematopoietic progenitor subsets involved in interleukin-3-induced interleukin-6 production

Various murine cell populations were tested for their ability to generate interleukin-6 (IL-6) in response to IL-3. Among these, bone marrow cells exhibit the most prominent IL-6 production. The responder cells in this organ have been further characterized by cell fractionation on a discontinuous Ficoll gradient, fluorescence-activated cell sorting, and in situ hybridization. These procedures have allowed us to ascribe the following features to the cells mainly responsible for IL-3-induced IL-6 production: (1) they possess a low density and a relatively high forward and perpendicular light scatter (FLS/PLS); (2) they are characterized by a high rhodamine (Rh) retention; and (3) their enrichment in various subpopulations is similar to that obtained for progenitors forming colonies in the methylcellulose assay colony-forming units (CFU-C). In contrast, IL-3 target cells in terms of IL-6 production are absent both in the mature and in the most immature bone marrow compartment. Indeed, the Rh-dull population that is enriched for cells with marrow repopulating activity does not respond to the growth factor and mature cells cannot be induced to express IL-6 as assessed by (1) FLS/PLS characteristics, (2) the monoclonal antibody ER-MP 20 recognizing monocytes and granulocytic cells, and (3) in situ hybridization. Taken together, our data support the conclusion that the bone marrow cells generating IL-6 in response to IL-3 belong to a progenitor population with enhanced mitochondrial activity, comprising probably several types of immature cells of the myeloid lineage including macrophage/granulocyte precursors.     

Simultaneous radiotherapy and cis-platinum for the treatment of brain metastases. A pilot study

Thirteen patients with the established diagnosis of brain metastases were treated with weekly intravenous or intra-arterial cis-platinum (40-60 mg/m2) during whole-brain irradiation (5,000 cGy over 5 weeks). Objective tumor response was observed in 12 patients (seven complete responses [CRs] and five partial responses [PRs]), and one patient showed stable disease (NC) following treatment. Chemotherapy- and radiation therapy-related toxicity was mild. There was no enhanced radiation therapy side effects on the normal tissues. Intracarotid cis-platinum with radiotherapy resulted in five CRs, two PRs, and one NC. Intravenous cis-platinum with conventional radiation therapy resulted in two CRs and three PRs. Responses according to tumor type were as follows: lung cancer (three adenocarcinoma, one mixed type, and one small-cell anaplastic carcinoma), two CRs and three PRs; breast cancer, one CR; thyroid cancer, one CR; unknown primary cancer, one CR; and melanoma, one NC. These results represent a relatively high CR rate (53.8%) for an otherwise barely manageable complication of malignant disease. Further controlled studies are recommended.     

Management of gastric lymphoma with chemotherapy alone

Purpose. The optimal therapy for gastric lymphoma except MALToma has not yet been established. This study was undertaken to investigate whether gastric lymphoma can be managed effectively and safely with chemotherapy alone.

Patients and methods. A total of 58 patients (median age 56 years) with newly diagnosed gastric lymphoma between 1989 - 2001 at Seoul National University Hospital and who were initially managed with chemotherapy alone were evaluated. MALToma was excluded from the pathologic review.

Results. All patients received initially anthracycline-containing chemotherapy. ECOG performance scale 0 - 1 was 88% and B symptoms were present in 41.4%. Diffuse large B cell type was the most common (74.1%). Stage IE, II₁E accounted for 51.7% and II₂E, IIIE, IV for 48.3%. The international prognostic index (IPI) of risk was low in 39.7%, low-intermediate in 22.4%, high-intermediate in 15.5% and high in 22.4%. The complete response rate after first-line chemotherapy was 71.4% and the partial response rate was 12.2%. (overall response rate: 83.6%). Among patients who did not reach the complete response, a further complete response was achieved by second-line chemotherapy including etoposide-based regimen. Ultimately, the maximum complete response rate by chemotherapy was 83.7% (92% in stage IE, II₁E, 75% in stage II₂E, IIIE, IV). Median overall survival was 47.4 months (84.7 months in stage IE, II₁E, 32.5 months in stage II₂E, IIIE, IV) and the 5-year survival rate was 46%. Bleeding as a complication occurred in 3 of 58 patients (5.6%) and these cases were controlled by embolization or conservative management. No perforation episode occurred and surgical intervention due to complication was not necessary. Organ preservation was possible in 57 of 58 patients (98%). The one gastrectomy was performed due to a partial clinical response to chemotherapy but the specimen showed pathologic CR. Multivariate analysis revealed that only IPI had a significant influence on survival.

Conclusions. Gastric lymphoma except MALToma can be managed effectively and safely with chemotherapy alone.     

Termination of life support after severe child abuse: the role of a guardian ad litem

Discontinuation of life-sustaining interventions often raises ethical concerns. In cases of severe child abuse with poor prognosis for recovery, accused parents may have a conflict of interest regarding medical decision-making for their child, because the outcome of such decisions may impact legal charges filed against them. The recently issued American Academy of Pediatrics guidelines for addressing such cases recommended the appointment of a guardian ad litem for medical decision-making. We present the case of an 8-month-old infant who was abused severely by her father, resulting in a persistent vegetative state. We describe our experience with appointing a guardian ad litem and the ethical issues involved.     

Positive selection of anti-thy-1 autoreactive B-1 cells and natural serum autoantibody production independent from bone marrow B cell development

A natural serum autoantibody specific for the Thy-1 glycoprotein (anti-Thy-1 autoantibody [ATA]) is produced by B-1 cells that are positively selected by self-antigen. Here, using ATA micro kappa transgenic mice we show that cells with this B cell receptor are negatively selected during bone marrow (BM) development. In a Thy-1 null environment, BM ATA B cells progress to a normal follicular stage in spleen. However, in a self-antigen-positive environment, development is arrested at an immature stage in the spleen, concomitant with induction of CD5. Such cells are tolerant and short-lived, different from B-1. Nonetheless, ATA-positive selection was evident by self-antigen-dependent high serum ATA production, comprising approximately 90% of serum immunoglobulin M in ATA micro kappa mice. Splenectomy did not eliminate ATA production and transfer of tolerant splenic B cells did not induce it. These findings demonstrate that B-1 positive selection, resulting in the production of natural serum ATA, arises independently from the major pathway of BM B cell development and selection.