Faculty Bibliography

The use of isobaric tags such as iTRAQ allows the relative and absolute quantification of hundreds of proteins in a single experiment for up to eight different samples. More classical techniques such as 2-DE can offer a complimentary approach for the analysis of complex protein samples. In this study, the proteomes of secreted and cytosolic proteins of genetically closely related strains of Mycobacterium tuberculosis were analyzed. Analysis of 2-D gels afforded 28 spots with variations in protein abundance between strains. These were identified by MS/MS. Meanwhile, a rigorous statistical analysis of iTRAQ data allowed the identification and quantification of 101 and 137 proteins in the secreted and cytosolic fractions, respectively. Interestingly, several differences in protein levels were observed between the closely related strains BE, C28 and H6. Seven proteins related to cell wall and cell processes were more abundant in BE, while enzymes related to metabolic pathways (GltA2, SucC, Gnd1, Eno) presented lower levels in the BE strain. Proteins involved in iron and sulfur acquisition (BfrB, ViuB, TB15.3 and SseC2) were more abundant in C28 and H6. In general, iTRAQ afforded rapid identification of fine differences between protein levels such as those presented between closely related strains. This provides a platform from which the relevance of these differences can be assessed further using complimentary proteomic and biological modeling methods

Background: Several studies have attempted to investigate the underlying mechanisms of cognitive deficits by different MRI techniques. In this respect, atrophy has been recognized to be one of the best correlates for cognitive changes whilst other MRI measures are less closely related. Since whole brain N-acetyl-aspartate (WBNAA) is used to quantify diffuse neuronal cell injury and has been described to precede brain atrophy in MS one intriguing question is whether WBNAA levels are associated with cognitive abnormalities. Objective: To study the relation between WBNAA, T1w and T2w lesion volume (LV) and cognitive core functions in MS. Methods: 82 MS-patients from our outpatient clinic (mean age 48.9 yrs; 56 female/26 male; CIS = 1; RRMS = 64; SPMS = 17) were prospectively studied. Besides application of different MRI measures (T1w and T2w LV, non-localized proton MR spectroscopy), participants were examined with a set of neuropsychological tests (MUSIC, SDMT). Spearman's rank correlation (one-sided) was used to analyze the associative strength between cognitive and MRI measures. Results: Significant correlations were found between WBNAA, short-term memory (STM) (p = 0.04) and executive functions (p = 0.04). In contrast, T1w and T2w LV did not show relations to these cognitive domains but were significantly correlated with SDMT (p < 0.001), speed (p<= 0.001), mental flexibility (p<= 0.034) and long-term memory (LTM) (p<= 0.041). There was no correlation between WBNAA and T1w and T2w LV, respectively. Discussion: This is one of the first studies on the relation between white matter lesion load, diffuse neuronal damage and cognitive parameters in MS. Interestingly, WBNAA correlated with measures of STM and executive functions but not with those of processing speed, mental flexibility and LTM. In contrast the three latter domains were exclusively related to T1w and T2w LVs. It is conceivable, that different neuropsychological domains are more strongly related to features of predominant neuronal vs. white matter damage. Thus, since WBNAA represents a non-regional parameter of neuronal destruction it can be concluded from the cognitive results that brain tissue alteration most probably occurs within frontal and prefrontal areas leading to functional disconnection. This study might also explain why results of MR correlative studies with cognitive performance need a careful consideration but also offer new means to understand the integration of pathology and clinical phenotypes

Background: Fatigue is one of the most common and disabling symptoms in multiple sclerosis (MS), while its underlying mechanisms are still not clear. There is some evidence from MR-spectroscopy that neuronal damage measured by the decline of the amino acid N-acetyl-aspartate (NAA) is associated with increased fatigue in MS. However, other groups found that fatigue in MS can be caused by white matter lesions related disruption of cortico-subcortical pathways. The aim of the present study was to determine whether MR-markers of subcortical white matter disruption like T2w and T1w lesion burden or a measure of the diffuse global neuronal damage (NAA) correlate more closely with fatigue. Materials and Methods: Eighty - two MS patients (57 female) of mean age 49.4 (23-69) years, with CIS (1) RRMS (64) and SPMS (17) with an average disease duration of 17.7 (3-50) years and mean EDSS of 2.9 (0-6.5), were enrolled. There normalized whole brain NAA (WBNAA) amount was obtained with non localized proton MR spectroscopy. T2w and T1w lesion load were obtained from respective MR images by a semi-automated procedure. Fatigue was measured with the FSMC scale. In a multiple linear regression model, correlations between FSMC sum score and T2w lesion load, WBNAA and disease duration were analyzed. Additionally, t-tests between fatigued and non-fatigued patients for T2w and T1w lesion load, WBNAA, disease duration and EDSS were performed. Results: A significant positive correlation between fatigue measured by the FSMC sum score and T2w lesion load (p = 0.029), but not with WBNAA (p = 0.68) or disease duration (p = 0.07) was found. The t-test for T2w (p = 0.0095) and T1w (p = 0.0165) lesion load and EDSS (p= 0.0147) revealed significant differences between MS-patients with and without fatigue. No differences were found for WBNAA in the two groups. Discussion: In our cohort conventional MR-markers, namely T1w and T2w lesion load, and the EDSS correlated more closely with MS fatigue, as objective mesures of neuroaxonal loss. In our global approach diffuse neuronal damage as measured by WBNAA was not a contributor to MS fatigue. This may point to the importance of subcortical disconnection of functional networks as a mechanism contributing to fatigue in MS

BACKGROUND: Currently used treatment response criteria in multiple myeloma (MM) are based in part on serum monoclonal protein (M-protein) measurements. A drawback of these criteria is that response is determined solely by the best level of M-protein reduction, without considering the serial trend. The authors hypothesized that metrics incorporating the serial trend of M-protein would be better predictors of progression-free survival (PFS). METHODS: Fifty-five patients with measurable disease at baseline (M-protein > or = 1 g/dL) who received > or = 4 cycles of treatment from 2 clinical trials in previously untreated MM were included. Three metrics based on the percentage of M-protein remaining relative to baseline (residual M-protein) were considered: metrics based on the number of times residual M-protein fell within prespecified thresholds, metrics based on area under the residual M-protein curve, and metrics based on the average residual M-protein reduction between Cycles 1 and 4. The predictive value of these metrics was assessed in Cox models using landmark analysis. RESULTS: The average residual M-protein reduction was found to be significantly predictive of PFS (P = .02; hazard ratio, 0.37), in which a patient with a 10% lower average residual M-protein reduction from Cycle 1 to 4 was estimated to be at least 2.7x more likely to develop disease progression or die early. None of the other metrics was predictive of PFS. The concordance index for the average residual M-protein reduction was 0.63, compared with 0.56 for best response. CONCLUSIONS: The average residual M-protein reduction metric is promising and needs further validation. This exploratory analysis is the first step in the search for treatment-based trend metrics predictive of outcomes in MM

BACKGROUND: The second best conduit for coronary artery bypass graft surgery (CABG) is unclear. We sought to determine if the use of a second arterial conduit, the radial artery (RA), would improve long-term survival after CABG using the left internal thoracic artery (LITA) and saphenous vein (SV). METHODS: We compared the 14-year outcomes in propensity-matched patients undergoing isolated, primary CABG using the LITA, RA, and SV versus CABG using the LITA and only SV. In all, 826 patients from each group had similar propensity-matched demographics and multiple variables. The primary endpoint was all-cause mortality obtained using the Social Security Death Index. RESULTS: Perioperative outcomes including in hospital mortality (0.1% for the RA patients and 0.2% for the SV patients) were similar. Kaplan-Meier survival at 1, 5, and 10 years was 98.3%, 93.9%, and 83.1% for the RA group versus 97.2%, 88.7%, and 74.3% for the SV group (log rank, p = 0.0011). Cox proportional hazards models showed a lower all-cause mortality in the RA group (hazard ratio 0.72, confidence interval: 0.56 to 0.92, p = 0.0084). Ten-year survivals showed a 52% increased mortality for the SV patients (25.7%) versus the RA patients (16.9%; p = 0.0011). For symptomatic patients, RA patency was 80.7%, which was not different than the LITA patency rate of 86.4% but was superior to the SV patency rate of 46.7% (p < 0.001). CONCLUSIONS: Using the LITA, SV, and a RA conduit for CABG results in significantly improved long-term survival compared with using the LITA and SV. The use of two arterial conduits offers a clear and lasting survival advantage, likely due to the improved patency of RA grafts. We conclude that RA conduits should be more widely utilized during CABG

BACKGROUND: It is uncertain whether training improves physicians' obesity counseling. OBJECTIVE: To assess the impact of an obesity counseling curriculum for residents. DESIGN: A non-randomized, wait-list/control design. PARTICIPANTS: Twenty-three primary care internal medicine residents; 12 were assigned to the curriculum group, and 11 were assigned to the no-curriculum group. Over a 7-month period (1-8 months post-intervention) 163 of the residents' obese patients were interviewed after their medical visits. INTERVENTION: A 5-hour, multi-modal obesity counseling curriculum based on the 5As (Assess, Advise, Agree, Assist, Arrange) using didactics, role-playing, and standardized patients. MAIN MEASURES: Patient-report of physicians' use of the 5As was assessed using a structured interview survey. Main outcomes were whether obese patients were counseled about diet, exercise, or weight loss (rate of counseling) and the quality of counseling provided (percentage of 5As skills performed during the visit). Univariate statistics (t-tests) were used to compare the rate and quality of counseling in the two resident groups. Logistic and linear regression was used to isolate the impact of the curriculum after controlling for patient, physician, and visit characteristics. KEY RESULTS: A large percentage of patients seen by both groups of residents received counseling about their weight, diet, and/or exercise (over 70%), but the quality of counseling was low in both the curriculum and no curriculum groups (mean 36.6% vs. 31.2% of 19 possible 5As counseling strategies, p = 0.21). This difference was not significant. However, after controlling for patient, physician and visit characteristics, residents in the curriculum group appeared to provide significantly higher quality counseling than those in the control group (std beta = 0.18; R(2) change = 2.9%, P < 0.05). CONCLUSIONS: Residents who received an obesity counseling curriculum were not more likely to counsel obese patients than residents who did not. Training, however, is associated with higher quality of counseling when patient, physician, and visit characteristics are taken into account

Language barriers may contribute to the under-detection of depression in Latinos and Asians. A total of 782 English, Spanish, and Chinese-speaking primary care patients were enrolled in a randomized controlled trial. Language discordant patients were randomized to Remote Simultaneous Medical Interpreting (RSMI) or usual and customary (U&C) interpreting. The Beck Depression Inventory-Fast Screen (BDI-FS) was administered. Patients were tracked for 1 year. A total of 462 patients completed the BDI-FS. Thirty-three percent had a positive (>/=4) screen. Twenty-seven percent of BDI-FS positive patients were diagnosed with depression. Among BDI-FS positive patients, Chinese-speakers were less likely to be diagnosed compared with English speakers (31% vs. 10%, P < 0.05). There was a trend towards greater diagnosis with RSMI (27% detection with RSMI vs. 20% U&C, P = 0.41). The diagnosis of depression among BDI-FS positive patients in our population was low, particularly among Chinese-speakers. RSMI could be an important part of a multi-faceted approach to improving the detection of depression