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- The Neuroimaging Signature of Frontotemporal Lobar Degeneration Associated with Granulin Mutations: An Effective Connectivity Study. [JOURNAL ARTICLE]
- J Nucl Med 2013 May 17.
It has been suggested that monogenic frontotemporal lobar degeneration (FTLD) due to Granulin (GRN) mutations might present a specific pattern of atrophy, as compared with FTLD GRN-negative disease. Recent literature has suggested that the study of functional neural networks, rather than regional structural damage, might better elucidate the pathogenic mechanisms, showing complex relationships among structural alterations observed with conventional neuroimaging. The aim of this study was to evaluate effective brain connectivity in FTLD patients carrying GRN mutations (GRN+), compared with FTLD patients without pathogenetic GRN mutations (GRN-) and healthy controls (HCs).
METHODS:Twenty-six FTLD patients (13 GRN+ and 13 GRN- matched for age, sex, and phenotype) and 13 age- and sex-matched HCs underwent brain perfusion SPECT. Brain regions involved in FTLD (dorsolateral, anterior cingulate, orbitofrontal, posterior temporal, temporal pole, and parietal) were used as regions of interest to identify functionally interconnected areas. An effective connectivity (path) analysis was defined with a PC algorithm (named after its inventors Peter Spirtes and Clark Glymour) search procedure and structural equation fitting. Statistically significant differences among the 3 groups were determined.
RESULTS:The best-fitting model was obtained by the data-driven approach, and brain connectivity pathways resembling state-of-the-art anatomic knowledge were obtained. When GRN+ and GRN- groups were considered, the former presented a selective bilateral parietotemporal disconnection, compared with GRN- patients. Furthermore, in FTLD GRN+ patients an increased compensative connectivity of the temporal regions (temporal pole and posterior temporal cortices) was observed.
CONCLUSION:The present work suggests that impairment of effective functional connectivity of the parietotemporal regions is the hallmark of GRN-related FTLD. However, compensative mechanisms-which should be further investigated-may occur.
- An Integrated Health Care System's Approach to Development of a Process to Collect Patient Functional Outcomes on Total Joint Replacement Procedures. [JOURNAL ARTICLE]
- Am J Med Qual 2013 May 17.
Health care organizations are challenged to find ways to measure not only process of care but also outcomes of care. Gundersen Health System's Orthopaedic Surgery Department in the La Crosse, Wisconsin area developed a process to collect outcomes of care for patients having hip or knee arthroplasty procedures and planned to use these data to determine impact on patients' lives. The Hip Osteoarthritis Outcomes Score and Knee Osteoarthritis Outcomes Score, adapted from the widely used Western Ontario and McMaster Universities Osteoarthritis Index, were collected preoperatively and at 1 year postoperatively. From these data, the health system determined that patients were experiencing significant improvement in 4 of 5 scales. Further recommendations include evaluating the impact of patients' age, sex, and preoperative body mass index on outcomes, as well as evaluating the impact of more patient involvement in goal setting on recovery time and functional outcomes.
- Functional and structural brain changes in anti-NMDAR encephalitis. [JOURNAL ARTICLE]
- Ann Neurol 2013 May 20.
OBJECTIVE:Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune encephalitis with a characteristic neuropsychiatric syndrome and severe and prolonged clinical courses. In contrast, standard clinical MRI remains normal in the majority of patients. Here, we investigated structural and functional brain changes in a cohort of patients with anti-NMDAR encephalitis.
METHODS:Twenty-four patients with established diagnosis of anti-NMDAR encephalitis and age- and gender-matched controls underwent neuropsychological testing and multimodal MRI, including T1w/T2w structural imaging, analysis of resting state functional connectivity, analysis of white matter using diffusion tensor imaging, and analysis of grey matter using voxel-based morphometry.
RESULTS:Patients showed significantly reduced functional connectivity of the left and right hippocampus with the anterior default mode network. Connectivity of both hippocampi predicted memory performance in patients. Diffusion tensor imaging revealed extensive white matter changes, which were most prominent in the cingulum and which correlated with disease severity. In contrast, no differences in T1w/T2w structural imaging and grey matter morphology were observed between patients and controls.
INTERPRETATION:Anti-NMDAR encephalitis is associated with characteristic alterations of functional connectivity and widespread changes of white matter integrity despite normal findings in routine clinical MRI. These results may help to explain the clinico-radiological paradox in anti-NMDAR encephalitis and advance the pathophysiological understanding of the disease. Correlation of imaging abnormalities with disease symptoms and severity suggests that these changes play an important role in the symptomatology of anti-NMDAR encephalitis. ANN NEUROL 2013. © 2013 American Neurological Association.
- Health literacy: A primer for pharmacists. [JOURNAL ARTICLE]
- Am J Health Syst Pharm 2013 Jun 1; 70(11):949-955.
PURPOSE:The literature surrounding health literacy and its importance in everyday practice are reviewed.
SUMMARY:Health literacy includes a patient's reading, writing, and numeracy skills, as well as his or her cultural experiences, understanding of health concepts and pathophysiology, and basic communication skills. Over one third of the American population lack the skills necessary to understand health information, make health care decisions, or follow medication instructions. Independent risk factors for low health literacy include poor socioeconomic status, ethnicity, older age, and limited education. Mounting evidence suggests that low health literacy leads to poor health outcomes, increased mortality, increases in health care costs, and poorly self-managed chronic diseases. Communication with a pharmacist to gain clarification of medication instructions is often the last opportunity to ensure that patients understand how to use their medications appropriately. Low health literacy is not always easily recognized, as patients use well-practiced coping mechanisms or avoidant behaviors. Clear communication strategies help patients become more involved in their care plans and increase positive interactions. Tools to assess health literacy have been developed and can be used by pharmacists to guide education and counseling. Advanced methods of written and oral communication should be used to improve patient comprehension and understanding.
CONCLUSION:Tools such as simple word-recognition tests or comprehensive tests of functional health literacy can be used in daily practice to assess patients' health literacy. Being familiar with communication techniques such as the Indian Health Service, teach back, and Ask Me 3 can help facilitate individualized medication-related education and maximize patient comprehension.
- Functional outcomes and quality of life in patients treated with laparoscopic total colectomy for colonic inertia. [JOURNAL ARTICLE]
- Surg Today 2013 May 19.
PURPOSE:To assess the functional outcomes and quality of life in patients with laparoscopic total colectomy for slow-transit constipation (STC).
METHODS:All patients undergoing laparoscopic colectomy with ileorectal anastomosis for colonic inertia at two referral centers were analyzed. Their preoperative, intraoperative and postoperative details were recorded with a one-year follow-up. Their quality of life was assessed using the SF-36 questionnaire.
RESULTS:Between 2004 and 2007, 710 patients were evaluated. Eight female patients (1.1 %) fulfilled the criteria for STC without obstructive defecation syndrome. Their mean age was 38 years ± 15 (range from 22 to 62). The conversion rate was 12.5 %. The morbidity rate was 37.5 %, and mortality was nil. The preoperative abdominal pain was 6.6 ± 0.3 and had decreased to 3.6 ± 2.3 postoperatively (P = 0.008). At 1 year, the defecation frequency per week had increased from 0.84 ± 0.24 to 6.75 ± 3.4 (P = 0.001). Three patients developed nocturnal leakage (37.5 %). Eighty-eight percent of the patients recommend the procedure. All parameters of the SF-36 questionnaire had improved at the one-year follow-up examination.
CONCLUSION:Laparoscopic colectomy for slow-transit constipation is safe and increased the number of evacuations per week. Although nocturnal leakage may occur, these patients experience improvements in their quality of life.
- Influence of CYP2D6-genotype on tamoxifen efficacy in advanced breast cancer. [JOURNAL ARTICLE]
- Breast Cancer Res Treat 2013 May 18.
The influence of CYP2D6 genotype on the efficacy of tamoxifen (Tam) has been extensively analyzed in early breast cancer with conflicting results. However, there is only scarce data regarding this potential influence in advanced breast cancer (ABC). We hypothesize that Tam is more effective in patients with a functional CYP2D6 allele than in patients with impaired CYP2D6 activity. ABC patients with prior or ongoing palliative Tam treatment (20 mg/d) were eligible. Genomic DNA was extracted from blood (n = 51) and formalin-fixed, paraffin-embedded tissue (n = 43). CYP2D6*2, *3, *4, *5, *6, *10, *17, *29, *41, CYP2D6 duplication and multiplication were determined in blood and CYP2D6*4 in tissue samples. Primary endpoint was progression free survival (PFS); secondary endpoints included clinical benefit (CB), and overall survival (OS). The clinical charts were retrospectively analyzed regarding survival and treatment effects. Genotyping was performed blinded and clinical data were analyzed separately. 94 patients were identified with a median age of 59 years (29-90 years). In 6 patients genotyping did not show conclusive results, therefore these patients were excluded from further analysis. Genotyping results were as follows: 1.1 % ultrarapid, 84.1 % extensive, 3.4 % intermediate, and 11.4 % poor metabolizers. Patients without any fully functional allele (IM/IM, IM/PM, PM/PM) had a significant shorter PFS and OS compared to patients with at least one functional allele (EM/EM, EM/IM, EM/PM) (PFS: p = 0.017; HR = 2.19; 95 % CI 1.15-4.18; OS: p = 0.028; HR = 2.79; 95 % CI 1.12-6.99). The CB rate was 73 % for EM-group and 38.5 % for IM + PM-group (p = 0.019). Our results show a significant influence of the CYP2D6 genotype on the efficacy of Tam in the treatment of ABC. In contrast to the adjuvant setting, the evidence in the palliative setting is congruent. CYP2D6 testing in ABC should be considered.
- The differential effects of acute right- vs. left-sided vestibular failure on brain metabolism. [JOURNAL ARTICLE]
- Brain Struct Funct 2013 May 18.
The human vestibular system is represented in the brain bilaterally, but it has functional asymmetries, i.e., a dominance of ipsilateral pathways and of the right hemisphere in right-handers. To determine if acute right- or left-sided unilateral vestibular neuritis (VN) is associated with differential patterns of brain metabolism in areas representing the vestibular network and the visual-vestibular interaction, patients with acute VN (right n = 9; left n = 13) underwent resting state (18)F-FDG PET once in the acute phase and once 3 months later after central vestibular compensation. The contrast acute vs. chronic phase showed signal differences in contralateral vestibular areas and the inverse contrast in visual cortex areas, both more pronounced in VN right. In VN left additional regions were found in the cerebellar hemispheres and vermis bilaterally, accentuated in severe cases. In general, signal changes appeared more pronounced in patients with more severe vestibular deficits. Acute phase PET data of patients compared to that of age-matched healthy controls disclosed similarities to these patterns, thus permitting the interpretation that the signal changes in vestibular temporo-parietal areas reflect signal increases, and in visual areas, signal decreases. These data imply that brain activity in the acute phase of right- and left-sided VN exhibits different compensatory patterns, i.e., the dominant ascending input is shifted from the ipsilateral to the contralateral pathways, presumably due to the missing ipsilateral vestibular input. The visual-vestibular interaction patterns were preserved, but were of different prominence in each hemisphere and more pronounced in patients with right-sided failure and more severe vestibular deficits.
- Signalling pathways regulating muscle mass in ageing skeletal muscle. The role of the IGF1-Akt-mTOR-FoxO pathway. [JOURNAL ARTICLE]
- Biogerontology 2013 May 19.
During ageing skeletal muscles undergo a process of structural and functional remodelling that leads to sarcopenia, a syndrome characterized by loss of muscle mass and force and a major cause of physical frailty. To determine the causes of sarcopenia and identify potential targets for interventions aimed at mitigating ageing-dependent muscle wasting, we focussed on the main signalling pathway known to control protein turnover in skeletal muscle, consisting of the insulin-like growth factor 1 (IGF1), the kinase Akt and its downstream effectors, the mammalian target of rapamycin (mTOR) and the transcription factor FoxO. Expression analyses at the transcript and protein level, carried out on well-characterized cohorts of young, old sedentary and old active individuals and on mice aged 200, 500 and 800 days, revealed only modest age-related differences in this pathway. Our findings suggest that during ageing there is no downregulation of IGF1/Akt pathway and that sarcopenia is not due to FoxO activation and upregulation of the proteolytic systems. A potentially interesting result was the increased phosphorylation of the ribosomal protein S6, indicative of increased activation of mTOR complex1 (mTORC1), in aged mice. This result may provide the rationale why rapamycin treatment and caloric restriction promote longevity, since both interventions blunt activation of mTORC1; however, this change was not statistically significant in humans. Finally, genetic perturbation of these pathways in old mice aimed at promoting muscle hypertrophy via Akt overexpression or preventing muscle loss through inactivation of the ubiquitin ligase atrogin1 were found to paradoxically cause muscle pathology and reduce lifespan, suggesting that drastic activation of the IGF1-Akt pathway may be counterproductive, and that sarcopenia is accelerated, not delayed, when protein degradation pathways are impaired.
- Neutrophil-to-lymphocyte ratio predicts response to cardiac resynchronization therapy. [Journal Article]
- Med Sci Monit 2013.:373-7.
Background Neutrophil-to-lymphocyte (N/L) ratio has been associated with adverse outcomes in patients with acute coronary syndromes and increased risk for long-term mortality in patients with acute decompensated heart failure. We aimed to investigate the prognostic value of neutrophil-to-lymphocyte ratio on response to cardiac resynchronization therapy (CRT). Material and Methods Seventy consecutive patients (mean age 58±13 years; 40 men) undergoing CRT were included in the study. Hematological and echocardiographic parameters were measured before and 6 months after CRT. Echocardiographic response to CRT was defined as a ≥15% reduction in left ventricular end-systolic volume at 6-month follow-up. Results After 6 months of CRT, 49 (70%) patients were responders. After 6 months, left ventricular ejection fraction (LVEF) had significantly increased, from 21±7% to 34±11% in responder patients (p=0.001). N/L ratio decreased significantly, from 2.4±1 to 2.1±0.7 in responders (p=0.04). In multivariate analysis, significant associates of echocardiographic response to CRT was evaluated adjusting for age, etiology of cardiomyopathy, baseline LVEF, New York Heart Association functional class, C-reactive protein, and baseline N/L ratio. Baseline N/L ratio was the only predictor of response to CRT (OR 1.506, 95% CI, 1.011-2.243, p=0.035). Conclusions N/L ratio at baseline could help to identify patients with response to CRT.
- Prognostic Value of Gated SPECT after Reperfusion for Acute Myocardial Infarction. [Journal Article]
- MEDICC Rev 2013 Apr; 15(2):20-5.
INTRODUCTION Myocardial reperfusion during the course of an acute myocardial infarction improves patients' short- and long-term prognosis; coronary blood flow is successfully re-established while preserving a large amount of at-risk muscle. Clinical evolution, however, varies. Presence of residual ischemia or viable myocardial tissue affects a patient's prognosis. Assessment by noninvasive methods allows better prognostic stratification. Cardiac-gated SPECT provides appropriate parameters to support treatment selection and monitoring of these patients.