Traumatic brain injury-induced cerebral microbleeds in the elderly

Traumatic brain injury (TBI) was shown to lead to the development of cerebral microbleeds (CMBs), which are associated with long term cognitive decline and gait disturbances in patients. The elderly is one of the most vulnerable parts of the population to suffer TBI. Importantly, ageing is known to exacerbate microvascular fragility and to promote the formation of CMBs. In this overview, the effect of ageing is discussed on the development and characteristics of TBI-related CMBs, with special emphasis on CMBs associated with mild TBI. Four cases of TBI-related CMBs are described to illustrate the concept that ageing exacerbates the deleterious microvascular effects of TBI and that similar brain trauma may induce more CMBs in old patients than in young ones. Recommendations are made for future prospective studies to establish the mechanistic effects of ageing on the formation of CMBs after TBI, and to determine long-term consequences of CMBs on clinically relevant outcome measures including cognitive performance, gait and balance function.

     

Anti-cancer action of 4-iodo-3-nitrobenzamide in combination with buthionine sulfoximine: inactivation of poly(ADP-ribose) polymerase and tumor glycolysis and the appearance of a poly(ADP-ribose) polymerase protease

E-ras 20 tumorigenic malignant cells and CV-1 non-tumorigenic cells were treated with a drug combination of 4-iodo-3-nitrobenzamide (INO(2)BA) and buthionine sulfoximine (BSO). Growth inhibition of E-ras 20 cells by INO(2)BA was augmented 4-fold when cellular GSH content was diminished by BSO, but the growth rate of CV-1 cells was not affected by the drug combination. Analyses of the intracellular fate of the prodrug INO(2)BA revealed that in E-ras 20 cells about 50% of the intracellular reduced drug was covalently protein-bound, and this binding was dependent upon BSO, whereas in CV-1 cells BSO did not influence protein binding. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was identified as the protein that covalently binds the reduction product of INO(2)BA, which is 4-iodo-3-nitrosobenzamide. Since only the enzymatically reduced drug INOBA bound covalently to GAPDH, the BSO-dependent covalent protein-drug association indicated an apparent nitro-reductase activity present in E-ras 20 cells, but not in CV-1 cells, explaining the selective toxicity. Covalent binding of INOBA to GAPDH inactivated this enzyme in vitro; INO(2)BA+BSO also inactivated cellular glycolysis in E-ras 20 cells because it provided the precursor to the inhibitory species: INOBA. Another event that occurred in INO(2)BA+BSO-treated E-ras 20 cells was the progressive appearance of a poly(ADP-ribose) polymerase protease. This enzyme was partially purified and characterized by the polypeptide degradation product generated from PARP I, which exhibited a 50kDa mass. This pattern of proteolysis of PARP I is consistent with a drug-induced necrotic cell killing pathway.     

Breast cancer detection among older Latinas: is it worth the risk?

Fifty-eight Latinas participated in focus group interviews to assess their perceptions about screening to detect breast cancer (BC). Grounded theory methods helped uncover a cultural explanatory model that explained how cultural and psychosocial dynamics influence BC screening decisions. According to this model, Latinas generally perceived BC screening as a risky behavior. Three themes emerged that influenced the amount and type of perceived risks: feeling healthy (i.e., perceptions about the etiology of the illness and its nature), feeling indecent (i.e., the behaviors involved in screening), and feeling threatened (i.e., the anticipated consequences of BC detection). Screening was perceived as risky because of many personal and interpersonal consequences associated with detecting BC. Latinas' subjective assessment that detecting BC is too risky might influence their participation in screening procedures. Health education programs should aim at helping Latinas perceive that the early detection of BC is a life-saving benefit that outweighs its perceived risks.     

Preinjury administration of the calpain inhibitor MDL-28170 attenuates traumatically induced axonal injury

Traumatic brain injury (TBI) evokes diffuse (traumatic) axonal injury (TAI), which contributes to morbidity and mortality. Damaged axons display progressive alterations gradually evolving to axonal disconnection. In severe TAI, the tensile forces of injury lead to a focal influx of Ca2+, initiating a series of proteolytic processes wherein the cysteine proteases, calpain and caspase modify the axonal cytoskeleton, causing irreversible damage over time postinjury. Although several studies have demonstrated that the systemic administration of calpain inhibitors reduces the extent of ischemic and traumatic contusional injury a direct beneficial effect on TAI has not been established to date. The current study was initiated to address this issue in an impact acceleration rat-TBI model in order to provide further evidence on the contribution of calpain-mediated proteolytic processes in the pathogenesis of TAI, while further supporting the utility of calpain-inhibitors. A single tail vein bolus injection of 30 mg/kg MDL-28170 was administered to Wistar rats 30 min preinjury. After injury the rats were allowed to survive 120 min when they were perfused with aldehydes. Brains were processed for immunohistochemical localization of damaged axonal profiles displaying either amyloid precursor protein (APP)- or RMO-14-immunoreactivity (IR), both considered markers of specific features of TAI. Digital data acquisition and statistical analysis demonstrated that preinjury administration of MDL-28170 significantly reduced the mean number of damaged RMO-14- as well as APP-IR axonal profiles in the brainstem fiber tracts analyzed. These results further underscore the role of calpain-mediated proteolytic processes in the pathogenesis of DAI and support the potential use of cell permeable calpain-inhibitors as a rational therapeutic approach in TBI.     

Differences in predictors of cervical and breast cancer screening by screening need in uninsured Latino women

BACKGROUND: Latino women experience higher mortality for cervical cancer and lower 5-year survival for breast cancer than non-Latino White women. Adherence with screening recommendations can increase chances of survival, yet the factors that influence screening behaviors in uninsured women are not well documented. METHODS: Uninsured Latino women (N = 467) recruited in four US cities participated in the study. Logistic regression was used to model adherence to recommendations by screening type (cervical or breast cancer) and screening need (needs to obtain initial screening, overdue for rescreening, up-to-date with rescreening). RESULTS: Predictors differed by type of screening and screening need. Women who reported exposure to cancer education were more likely to have had a mammogram and to be up-to-date with Pap smear screening than women without such exposure. Women who were younger, had more than a sixth grade education, and/or had children were more likely to have had a Pap smear. Older women who had been in the US the longest were more likely to be overdue for a Pap smear. Women with incomes 5000 to 7000 were more likely to have obtained a mammogram. Regional differences were found with respect to mammography screening and maintenance behaviors. CONCLUSIONS: Exposure to cancer education is an important predictor of screenings among uninsured urban Latino women. The potential of creating educational interventions that can increase screening rates among women who evidence health disparities is encouraging. Recruitment strategies to reach women in need of screenings are provided.     

Brain injury biomarkers may improve the predictive power of the IMPACT outcome calculator

Outcome prediction following severe traumatic brain injury (sTBI) is a widely investigated field of research. A major breakthrough is represented by the IMPACT prognostic calculator based on admission data of more than 8500 patients. A growing body of scientific evidence has shown that clinically meaningful biomarkers, including glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), and αII-spectrin breakdown product (SBDP145), could also contribute to outcome prediction. The present study was initiated to assess whether the addition of biomarkers to the IMPACT prognostic calculator could improve its predictive power. Forty-five sTBI patients (GCS score≤8) from four different sites were investigated. We utilized the core model of the IMPACT calculator (age, GCS motor score, and reaction of pupils), and measured the level of GFAP, UCH-L1, and SBDP145 in serum and cerebrospinal fluid (CSF). The forecast and actual 6-month outcomes were compared by logistic regression analysis. The results of the core model itself, as well as serum values of GFAP and CSF levels of SBDP145, showed a significant correlation with the 6-month mortality using a univariate analysis. In the core model, the Nagelkerke R(2) value was 0.214. With multivariate analysis we were able to increase this predictive power with one additional biomarker (GFAP in CSF) to R(2)=0.476, while the application of three biomarker levels (GFAP in CSF, GFAP in serum, and SBDP145 in CSF) increased the Nagelkerke R(2) to 0.700. Our preliminary results underline the importance of biomarkers in outcome prediction, and encourage further investigation to expand the predictive power of contemporary outcome calculators and prognostic models in TBI.     

Anatomical site differences of sodium lauryl sulfate-induced irritation: randomized controlled trial

Sodium lauryl sulphate (SLS) is a chemical used to induce skin irritation that mimics irritant contact dermatitis (ICD). ICD is a condition where direct contact with certain substances causes rash, redness, blistering, itching, dryness and cracking of the exposed skin. It is a common occupational disease and accounts for 4-7% of all dermatological consultations in U.K. This SLS induced irritation is often used to test the effectiveness of different treatments that could be used to alleviate the ICD symptoms. Irritation is usually induced on the forearms but other locations such as upper back have been used. The extent of the irritation might be different between different anatomical locations. Those differences could affect the results of the treatment testing. That means that the beneficial effects achieved by the treatment on one location may not be achieved on the other. This study, from Croatia, aimed to investigate variations in skin response to irritation and its effects on treatment in an SLS induced ICD. The irritant was applied on the forearms and the upper back of the healthy volunteers. Emollient (moisturising) cream was chosen as a treatment. One forearm and one side of the back were treated with the emollient for nine days while others were left untreated. The skin parameters that indicate the extent of the irritation and the recovery were measured using skin probes. The authors found that the upper back had stronger reaction to the irritant and faster recovery of the skin than the forearms. Also, the tested emollient cream did not improve the skin recovery. In conclusion, the anatomical location is an important factor influencing the results of the studies testing treatment effectiveness. Future studies should always accurately report the testing location. The results of the studies using this irritation model, but on different anatomical locations, are not necessarily directly comparable.     

Suddenly,a Carriage Appears: Social Support Needs of Latina Breast Cancer Survivors

Through focus groups and individual interviews, data were gathered on the emotional, informational, and instrumental support needs of 22 immigrant Latina women. A thematic analysis revealed that participants who perceived to receive social support reported less psychological distress and better adjustment to breast cancer than those who did not perceive this support. Types and sources of support varied across survivorship stages. Many needs were related to financial, linguistic, and cultural barriers participants encountered in the course of the disease. Based on the findings, we conclude with several clinical recommendations to improve the quality of life in this medically underserved population.     

Modification of growth related enzymatic pathways and apparent loss of tumorigenicity of a ras-transformed bovine endothelial cell line by treatment with 5-iodo-6-amino-1,2-benzopyrone (INH2BP)

Bovine aortic endothelial cells were converted to a highly tumorigenic cell line by transfection with Ha-ras and stimulation with thrombin. Sustained pretreatment with a non-cytotoxic concentration (600 mu M) of 5-iodo-6-amino-1,2-benzopyrone (INH2BP), a lipophilic ligand of poly(ADP-ribose) polymerase, abrogated in vivo tumorigenicity, of 10(5) cells per inoculum an effect which developed progressively during 2 to 6 weeks of drug treatment. The initial action of the drug was cytostasis, consisting of an arrest in prophase, extreme cell enlargement consistent with cytoplasmic hypertrophy, as seen by EM, and dramatic morphologic changes. Although neither DNA, RNA or protein syntheses are directly affected by INH2BP, apparently newly synthesized cellular DNA is degraded by endonucleases, which are upregulated by the inhibition of their poly-ADP-ribosylation. The drug treated cells exhibited greatly increased respiration and aerobic glycolysis, due to an augmentation of,glycolytic and respiratory enzymes in enlarged cells. These responses to the drug were reversible in cell cultures following drug removal, within 5-10 days drug exposure but the progressive loss of tumorigenicity in nude mice that developed after 3-6 weeks of drug exposure of cells, prior to inoculation to nude mice, was not reversible in vivo. Drug treatment produced a sustained 70-80% inhibition of pADPRT in intact cells at 600 mu M extracellular concentration of INH2BP. The prerequisite for the abrogation of tumorigenicity was the maintenance of pADPRT inhibition. The arrest of cell multiplication and a large decrease of Topo I, especially of Topo II and MAP kinase activities occurred without loss of enzyme protein as assayed in cell extracts of drug-treated cells. However INH2BP had no direct effect on these enzymes. Drug treatment down-regulated DNA-methyltransferase, PKC, ODC proteins, diminished cyclin A protein, but the hypophosphorylated form of Rb protein was significantly augmented. None of the enzymatic components of signal pathways so far studied, were directly affected by INH2BP. The inhibition of pADPRT by INH2BP coincided with an induction or activation of alkaline phosphatase and leucyl and glutamyl peptidase. The pADPRT content or the expression of pADPRT gene were not influenced by drug treatment, but the expression of ras gene was completely absent in nontumorigenic drug-treated cells, without a loss of ras gene from genomic DNA. Telomerase activity was not directly influenced by INH2BP treatment when assayed in diluted cell extracts, but the addition of homogeneous pADPRT to cell extracts, to approach physiological concentration of this protein in the cell, inhibited telomerase activity by binding of the polymer-free pADPRT to telomer templates. We conclude that inhibition of pADPRT indirectly down-regulates growth stimulatory signal pathways and sustains growth-arrested cells in culture at a pre-apoptotic threshold which explains the absence of tumorigenicity in vivo.