Calcium and neuronal cytoskeletal proteins: alterations with aging

Calcium plays a major role in regulating cellular function. Alterations in calcium systems may underlie some of the physiological changes associated with aging. Calcium activates calmodulin-dependent protein kinase, and this enzyme mediates some effects of calcium on cellular function. Calcium/calmodulin-dependent kinase II may play a significant role in specific cytoskeletal abnormalities of normal aging and selected neurodegenerative diseases.     

Mouse model of oral infection with virulent type A Francisella tularensis

Francisella tularensis is a gram-negative facultative intracellular pathogen and the causative agent of tularemia. Little is known about the immunopathogenesis of oral infection with this pathogen. Here, for the first time, we examined the susceptibility of mice to intragastric inoculation with virulent type A F. tularensis and characterized the course of infection and the associated host responses. Both immunocompetent and immunodeficient mice were relatively susceptible to intragastric inoculation of type A F. tularensis with a 50% lethal dose (LD(50)) of 10(6) organisms, which was 100,000-fold higher than the LD(100) for intradermal or respiratory routes of infection. Mice deficient in gamma interferon or tumor necrosis factor receptors 1 and 2 were more susceptible than wild-type controls to oral infection with a high dose of the pathogen. After oral inoculation, F. tularensis appeared first in the mesenteric lymph nodes (MLN) and then rapidly spread to the livers and spleens, where the organism multiplied to high numbers and induced marked neutrophilic infiltration and severe tissue necrosis. Infected mice showed rapid increases in tissue cytokine mRNA expression, which peaked in the MLN at 2 days postinfection (dpi) and in the liver and spleen at 3 dpi. The levels of gamma interferon, interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor alpha, macrophage inflammatory protein 1alpha, KC, interferon-inducible protein 10, and monocyte chemotactic protein 1 were elevated from day 2 postinoculation onward. Moreover, mice intradermally immunized with the live vaccine strain of F. tularensis showed little survival advantage over naive mice after oral challenge with type A F. tularensis. These results suggest that type A F. tularensis is an effective oral pathogen that can cause fatal systemic infection and could pose a public health concern, particularly to immunocompromised individuals, if ingested in contaminated water and food.     

Three-dimensional internal mammary lymphoscintigraphy: implications for radiation therapy treatment planning for breast carcinoma

Conservative surgery combined with radiation therapy for the treatment of early breast carcinoma has been shown to achieve both a high rate of local tumor control and good cosmetic results with a minimum of complications. Whether the internal mammary lymph nodes (IMNs) should be included in the treatment volume is a topic of considerable controversy. Radionuclide internal mammary node lymphoscintigraphy (IMN-LS) can locate these nodes in three dimensions. We have analyzed the results of IMN-LS in 167 patients imaged at the Dana-Farber Cancer Institute and treated at the Joint Center for Radiation Therapy between 1977 and 1980. The location of the IMNs was found variable from patient to patient. At least one IMN was not included within tangential fields arbitrarily arranged to have a medial entrance point 3.0 cm across the midline in 17% of evaluable patients. However, 48% and 66% of patients had IMNs that could be adequately treated with fields positioned only 1.0 cm or 2.0 cm across midline, respectively. We conclude that when treatment of the IMNs is warranted, IMN-LS not only assures their complete coverage in the majority of patients but also may help reduce the amount of heart and lung irradiated.     

The effect of young age on tumor recurrence in the treated breast after conservative surgery and radiotherapy

Prognostic factors for local recurrence following conservative surgery and radiation therapy for patients with early breast cancer have not been fully established. To evaluate the importance of young age as a prognostic factor for local recurrence, we reviewed the results of treatment of 597 patients with 607 UICC-AJCC Stage I or II breast cancers, 47 of which were diagnosed when the patient was less than 35 years old. All were treated with excisional biopsy and a total dose to the site of the primary tumor of 60 Gy or more. The median follow-up in survivors was 63 months. Patient age and the presence of an extensive intraductal component (EIC) were both highly associated with the likelihood of tumor recurrence in the treated breast. Patients under 35 had an actuarial 5-year recurrence rate of 26%, compared to 10% for older patients (p = 0.002). Patients with an EIC had a breast recurrence rate of 25%, compared to 5% when EIC was absent (p less than 0.0001). Although the incidence of an EIC was higher in the younger subgroup (44% vs. 31%), this alone did not account for the difference in in breast recurrence rates, since younger patients had a higher recurrence rate than older patients even when an EIC was absent (22% vs. 3%, p = 0.0003). We conclude that the age of the patient is an important prognostic factor for local recurrence following conservative surgery and radiation therapy. This finding is in part attributed to the observation that younger women are more likely to have tumors with an EIC than older women, but even when an EIC is absent, they may be at an increased risk of local recurrence. However, caution is required in interpreting these findings with regard to selecting among treatment options until further data are available comparing the results of conservative surgery and radiation therapy to those of mastectomy in younger patients.     

Time-Compressed Speech Identification Is Predicted by Auditory Neural Processing,Perceptuomotor Speed,and Executive Functioning in Younger and Older Listeners

Journal of the Association for Research in Otolaryngology - Older adults typically have difficulty identifying speech that is temporally distorted, such as reverberant, accented, time-compressed,...     

Toward a research agenda for competency-based medical education

Competency-based medical education (CBME) is both an educational philosophy and an approach to educational design. CBME has already had a broad impact on medical schools, residency programs, and continuing professional development in health professions around the world. As the CBME movement evolves and CBME programs are implemented, a wide range of emerging research questions will warrant scholarly examination. In this paper, we describe a proposed CBME research agenda developed by the International CBME Collaborators. The resulting framework includes questions about the meaning of key concepts of CBME and their implications for learners, faculty members, and institutional structures. Other research questions relate to the learning process, the meaning of entrustment decisions, fundamental measurement issues, and the nature and definition of standards. The exploration of these questions will help to solidify the theoretical foundation of CBME, but many issues related to implementation also need to be addressed. These pertain to, among other things, nurturing independent learning, assembling and using assessment results to make decisions about competence, structuring feedback, supporting remediation, and how best to evaluate the longer-term outcomes of CBME. High-quality research on these questions will require rigorous outcome measures with strong validity evidence. The complexity of CBME necessitates theoretical and methodological diversity. It also requires multi-institutional studies that examine effects at multiple levels, from the learner to the team, the institution, and the health care system. Such a framework of research questions can guide and facilitate scholarly discourse on the theoretical and practical body of knowledge related to competency-based health professions education.     

Strength of cement-metal interfaces in fatigue: comparison of smooth, porous and precoated specimens

Radiographic follow-up studies of cemented total hip arthroplasty have shown that failure of the cement-metal interface of the femoral component is as high as 25% at 10 years. Recent analyses of clinically successful cemented femoral components obtained in toto with the surrounding cement and femurs after many years of in-vivo service have suggested that the mechanism of the initiation of failure of fixation of cemented femoral components is debonding at the cement-metal interface. Since this critical interface is subjected primarily to cyclic loading, the evaluation of different surface preparations should be studied in fatigue, not static testing. In the current study, several contemporary methods for increasing the strength of the cement-metal interface were evaluated by testing the interfacial fatigue pushout strength under varying conditions of cyclic loading. The effect of a smooth 'implant finish' surface, a surface coated with polymethylmethacrylate (PMMA precoated surface), a combination of a textured surface with PMMA precoat, and a porous titanium mesh coated surface were examined. Precoating the metal with a thin film of PMMA significantly increased the number of compressive fatigue loading cycles required for failure of the cement-metal interface under cyclic loading compared to a smooth, uncoated surface. Adding indentations to the surface and then precoating with PMMA further significantly increased the fatigue life of the cement-metal interface. The strongest interface in fatigue was the titanium fibermesh-cement interface.     

The effects of unilateral and multifocal lesions on the WAIS-R: a factor analytic study of stroke patients.

An exploratory maximum likelihood factor analysis of the inter-correlations among the 11 subtests of the WAIS-R was undertaken for 167 patients who had a primary diagnoses of cerebrovascular accident (right hemisphere, n = 79; left hemisphere, n = 55; diffuse or multifocal, n = 33). On the WAIS-R, this sample performed below normative standards (average scaled score = 7.1), but demonstrated a pattern of variability among subtests similar to the normative groups. Interestingly, VIQ-PIQ discrepancy analyses revealed V > P profiles for patients with lesions in either or both hemispheres. The best fit for the WAIS-R matrix was an oblique two-factor model comprised of the Verbal and Performance subtests. This factor solution, which was moderately correlated (.52), accounted for 58.8% of the total variance. The stability of a two-factor structure in this neurologic impaired population suggests that the WAIS-R is a robust measure, even when used within such a rehabilitation population. Only two of the eleven subtests (i.e., Comprehension and Picture Arrangement), however, were related to lesion site. Rehabilitation settings may need to rely more on neuropsychological procedures that measure the more "fluid" areas of neurocognitive ability, in contrast to the WAIS-R which appears less sensitive to the neurological impairment associated with stroke.