Benefits and Risks of Weight-Loss Treatment for Older, Obese Women

Background: A key issue in the treatment of obesity in older adults is whether the health benefits of weight loss outweigh the potential risks with respect to musculoskeletal injury. Objective: To compare change in weight, improvements in metabolic risk factors, and reported musculoskeletal adverse events in middle-aged (50-59 years) and older (65-74 years), obese women. Materials and methods: Participants completed an initial 6-month lifestyle intervention for weight loss, comprised of weekly group sessions, followed by 12 months of extended care with biweekly contacts. Weight and fasting blood samples were assessed at baseline, month 6, and month 18; data regarding adverse events were collected throughout the duration of the study. Results: Both middle-aged (n = 162) and older (n = 56) women achieved significant weight reductions from baseline to month 6 (10.1 +/- 0.68 kg and 9.3 +/- 0.76 kg, respectively) and maintained a large proportion of their losses at month 18 (7.6 +/- 0.87 kg and 7.6 +/- 1.3 kg, respectively); there were no significant differences between the two groups with respect to weight change. Older women further experienced significant reductions in systolic blood pressure, HbA(1c), and C-reactive protein from baseline to month 6 and maintained these improvements at month 18. Despite potential safety concerns, we found that older women were no more likely to experience musculoskeletal adverse events during the intervention as compared with their middle-aged counterparts. Conclusion: These results suggest that older, obese women can experience significant health benefits from lifestyle treatment for obesity, including weight loss and improvements in disease risk factors. Further investigation of the impact of weight loss on additional health-related parameters and risks (eg, body composition, muscular strength, physical functioning, and injuries) in older adults is needed.National Heart, Lung and Blood Institute R18HL73326University of FloridaDivision of Statistics and Scientific Computatio

Gaining the hard yard: pre-clinical evaluation of lentiviral-mediated gene therapy for the treatment of β-thalassemia

Gene therapy is one potential novel therapeutic avenue for the treatment of inherited monogenic disorders. Diseases of the blood are frequent targets for gene therapy because it is relatively easy to harvest haematopoietic stem cells (HSCs) from the bone marrow, genetically modify the cells ex vivo, and then re-administer the corrected cells back into the patient via intra-venous injection. In this Closeup, Milsom and Williams discuss the work of Roselli et al, who describe the pre-clinical evaluation of the treatment for β-thalassemia in erythroid cells via the genetic correction of patient HSCs using a lentiviral vector

Disrupted Signaling through the Fanconi Anemia Pathway Leads to Dysfunctional Hematopoietic Stem Cell Biology: Underlying Mechanisms and Potential Therapeutic Strategies

Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. FA patients suffer to varying degrees from a heterogeneous range of developmental defects and, in addition, have an increased likelihood of developing cancer. Almost all FA patients develop a severe, progressive bone marrow failure syndrome, which impacts upon the production of all hematopoietic lineages and, hence, is thought to be driven by a defect at the level of the hematopoietic stem cell (HSC). This hypothesis would also correlate with the very high incidence of MDS and AML that is observed in FA patients. In this paper, we discuss the evidence that supports the role of dysfunctional HSC biology in driving the etiology of the disease. Furthermore, we consider the different model systems currently available to study the biology of cells defective in the FA signaling pathway and how they are informative in terms of identifying the physiologic mediators of HSC depletion and dissecting their putative mechanism of action. Finally, we ask whether the insights gained using such disease models can be translated into potential novel therapeutic strategies for the treatment of the hematologic disorders in FA patients

Is there a link between overactive bladder and the metabolic syndrome in women? : A systematic review of observational studies

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.To conduct a systematic review to determine whether there is an association between metabolic syndrome (MetS) and lower urinary tract symptoms (LUTS) or overactive bladder (OAB) in women. We systematically reviewed English language observational studies on the effect of MetS (or component factors) on the presence of OAB or LUTS in women. We searched PubMed, Web of Science and The Cochrane Library with no date restrictions, checked reference lists and undertook citation searches in PubMed and Google Scholar. Studies were assessed for risk of bias. Because of heterogeneity, results were not pooled, but are reported narrativelyPeer reviewe

New insight into the causes, consequences, and correction of hematopoietic stem cell aging

Aging of hematopoietic stem cells (HSCs) is characterized by lineage bias, increased clonal expansion, and functional decrease. At the molecular level, aged HSCs typically display metabolic dysregulation, upregulation of inflammatory pathways, and downregulation of DNA repair pathways. Cellular aging of HSCs, driven by cell-intrinsic and cell-extrinsic factors, causes a predisposition to anemia, adaptive immune compromise, myelodys, plasia, and malignancy. Most hematologic diseases are strongly associated with age. But what is the biological foundation for decreased fitness with age? And are there therapeutic windows to resolve age-related hematopoietic decline? These questions were the focus of the International Society for Experimental Hematology (ISEH) New Investigator Committee Fall 2022 Webinar. This review touches on the latest insights from two leading laboratories into inflammatory- and niche-driven stem cell aging and includes speculation on strategies to prevent or correct age-related decline in HSC function

Hypoxic modulation of exogenous nitrite-induced vasodilation in humans

Peer reviewedPublisher PD

Effects of a weight loss plus exercise program on physical function in overweight, older women: a randomized controlled trial

BACKGROUND: Obesity and a sedentary lifestyle are associated with physical impairments and biologic changes in older adults. Weight loss combined with exercise may reduce inflammation and improve physical functioning in overweight, sedentary, older adults. This study tested whether a weight loss program combined with moderate exercise could improve physical function in obese, older adult women. METHODS: Participants (N = 34) were generally healthy, obese, older adult women (age range 55-79 years) with mild to moderate physical impairments (ie, functional limitations). Participants were randomly assigned to one of two groups for 24 weeks: (i) weight loss plus exercise (WL+E; n = 17; mean age = 63.7 years [4.5]) or (ii) educational control (n = 17; mean age = 63.7 [6.7]). In the WL+E group, participants attended a group-based weight management session plus three supervised exercise sessions within their community each week. During exercise sessions, participants engaged in brisk walking and lower-body resistance training of moderate intensity. Participants in the educational control group attended monthly health education lectures on topics relevant to older adults. Outcomes were: (i) body weight, (ii) walking speed (assessed by 400-meter walk test), (iii) the Short Physical Performance Battery (SPPB), and (iv) knee extension isokinetic strength. RESULTS: Participants randomized to the WL+E group lost significantly more weight than participants in the educational control group (5.95 [0.992] vs 0.23 [0.99] kg; P < 0.01). Additionally, the walking speed of participants in the WL+E group significantly increased compared with that of the control group (reduction in time on the 400-meter walk test = 44 seconds; P < 0.05). Scores on the SPPB improved in both the intervention and educational control groups from pre- to post-test (P < 0.05), with significant differences between groups (P = 0.02). Knee extension strength was maintained in both groups. CONCLUSION: Our findings suggest that a lifestyle-based weight loss program consisting of moderate caloric restriction plus moderate exercise can produce significant weight loss and improve physical function while maintaining muscle strength in obese, older adult women with mild to moderate physical impairments

Induction of Histiocytic Sarcoma in Mouse Skeletal Muscle

Myeloid sarcomas are extramedullary accumulations of immature myeloid cells that may present with or without evidence of pathologic involvement of the bone marrow or peripheral blood, and often coincide with or precede a diagnosis of acute myeloid leukemia (AML). A dearth of experimental models has hampered the study of myeloid sarcomas and led us to establish a new system in which tumor induction can be evaluated in an easily accessible non-hematopoietic tissue compartment. Using ex-vivo transduction of oncogenic Kras(G12V) into p16/p19−/− bone marrow cells, we generated transplantable leukemia-initiating cells that rapidly induced tumor formation in the skeletal muscle of immunocompromised NOD.SCID mice. In this model, murine histiocytic sarcomas, equivalent to human myeloid sarcomas, emerged at the injection site 30–50 days after cell implantation and consisted of tightly packed monotypic cells that were CD48+, CD47+ and Mac1+, with low or absent expression of other hematopoietic lineage markers. Tumor cells also infiltrated the bone marrow, spleen and other non-hematopoietic organs of tumor-bearing animals, leading to systemic illness (leukemia) within two weeks of tumor detection. P16/p19−/−; Kras(G12V) myeloid sarcomas were multi-clonal, with dominant clones selected during secondary transplantation. The systemic leukemic phenotypes exhibited by histiocytic sarcoma-bearing mice were nearly identical to those of animals in which leukemia was introduced by intravenous transplantation of the same donor cells. Moreover, murine histiocytic sarcoma could be similarly induced by intramuscular injection of MLL-AF9 leukemia cells. This study establishes a novel, transplantable model of murine histiocytic/myeloid sarcoma that recapitulates the natural progression of these malignancies to systemic disease and indicates a cell autonomous leukemogenic mechanism.Stem Cell and Regenerative Biolog