Faculty Bibliography

OBJECTIVE: To determine the relation between markers of kidney disease-estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR)-with cerebral blood flow (CBF) and white matter volume (WMV) in hypertensive adults. METHODS: We used baseline data collected from 665 nondiabetic hypertensive adults aged >/=50 years participating in the Systolic Blood Pressure Intervention Trial (SPRINT). We used arterial spin labeling to measure CBF and structural 3T images to segment tissue into normal and abnormal WMV. We used quantile regression to estimate the association between eGFR and UACR with CBF and abnormal WMV, adjusting for sociodemographic and clinical characteristics. RESULTS: There were 218 participants (33%) with eGFR <60 mL/min/1.73 m(2) and 146 participants (22%) with UACR >/=30 mg/g. Reduced eGFR was independently associated with higher adjusted median CBF, but not with abnormal WMV. Conversely, in adjusted analyses, there was a linear independent association between UACR and larger abnormal WMV, but not with CBF. Compared to participants with neither marker of CKD (eGFR >/=60 mL/min/1.73 m(2) and UACR <30 mg/g), median CBF was 5.03 mL/100 g/min higher (95% confidence interval [CI] 0.78, 9.29) and abnormal WMV was 0.63 cm(3) larger (95% CI 0.08, 1.17) among participants with both markers of CKD (eGFR <60 mL/min/1.73 m(2) and UACR >/=30 mg/g). CONCLUSIONS: Among nondiabetic hypertensive adults, reduced eGFR was associated with higher CBF and higher UACR was associated with larger abnormal WMV.

We aimed to determine whether a unique, ultra-high-field 7 T magnetic resonance imaging (MRI) scanner could detect occult cartilage and meniscal injuries in asymptomatic female dancers. This study had Institutional Review Board approval. We recruited eight pre-professional female dancers and nine non-athletic, female controls. We scanned the dominant knee on a 7 T MRI scanner using a three-dimensional fast low-angle shot sequence and a proton density, fast spin-echo sequence to evaluate cartilage and menisci, respectively. Two radiologists scored cartilage (International Cartilage Repair Society classification) and meniscal (Stoller classification) lesions. We applied two-tailed z- and t-tests to determine statistical significance. There were no cartilage lesions in dancers or controls. For the medial meniscus, the dancers demonstrated higher mean MRI score (2.38 +/- 0.61 vs 1.0 +/- 0.97, P < 0.0001) and higher frequency of mean grade 2 lesions (88% vs 11%, P < 0.01) compared with the controls. For the lateral meniscus, there was no difference in score (0.5 +/- 0.81 vs 0.5 +/- 0.78, P = 0.78) in dancers compared with the control groups. Asymptomatic dancers demonstrate occult medial meniscal lesions. Because this has been described in early osteoarthritis, close surveillance of dancers' knee symptoms and function with appropriate activity modification may help maintain their long-term knee health.

Micro-finite element analysis applied to high-resolution (0.234-mm length scale) MRI reveals greater whole and cancellous bone stiffness, but not greater cortical bone stiffness, in the distal femur of female dancers compared to controls. Greater whole bone stiffness appears to be mediated by cancellous, rather than cortical bone adaptation. INTRODUCTION: The purpose of this study was to compare bone mechanical competence (stiffness) in the distal femur of female dancers compared to healthy, relatively inactive female controls. METHODS: This study had institutional review board approval. We recruited nine female modern dancers (25.7 +/- 5.8 years, 1.63 +/- 0.06 m, 57.1 +/- 4.6 kg) and ten relatively inactive, healthy female controls matched for age, height, and weight (32.1 +/- 4.8 years, 1.6 +/- 0.04 m, 55.8 +/- 5.9 kg). We scanned the distal femur using a 7-T MRI scanner and a three-dimensional fast low-angle shot sequence (TR/TE = 31 ms/5.1 ms, 0.234 mm x 0.234 mm x 1 mm, 80 slices). We applied micro-finite element analysis to 10-mm-thick volumes of interest at the distal femoral diaphysis, metaphysis, and epiphysis to compute stiffness and cross-sectional area of whole, cortical, and cancellous bone, as well as cortical thickness. We applied two-tailed t-tests and ANCOVA to compare groups. RESULTS: Dancers demonstrated greater whole and cancellous bone stiffness and cross-sectional area at all locations (p < 0.05). Cortical bone stiffness, cross-sectional area, and thickness did not differ between groups (>0.08). At all locations, the percent of intact whole bone stiffness for cortical bone alone was lower in dancers (p < 0.05). Adjustment for cancellous bone cross-sectional area eliminated significant differences in whole bone stiffness between groups (p > 0.07), but adjustment for cortical bone cross-sectional area did not (p < 0.03). CONCLUSIONS: Modern dancers have greater whole and cancellous bone stiffness in the distal femur compared to controls. Elevated whole bone stiffness in dancers may be mediated via cancellous, rather than cortical bone adaptation.

BACKGROUND & AIMS: Trefoil factor family-1 (TFF1) is a key gastric tumor-suppressor gene. TFF1 knockout mice develop multiple gastric adenomas and carcinomas, and human gastric cancers typically lack TFF1 expression. Recently, TFF1 mutations have been found in human gastric cancer. The purpose of this study was to determine the functionality of these mutants. METHODS: Recombinant wild-type TFF1 and the gastric cancer-associated TFF1 mutants (A10D and E13K) were produced and tested for their effect on gastric cancer cell proliferation, apoptosis, and invasion. Molecular modeling was used to guide the choice of mutants and to evaluate structure-function relationships. RESULTS: Molecular modeling suggested that A10D and E13K altered the surface charge of the loop 1 region of TFF1 without disturbing protein stability. Recombinant wild-type TFF1 significantly inhibited cell growth; A10D and E13K lost this tumor-suppressive property along with the ability to block etoposide-induced apoptosis. Although wild-type TFF1 promoted cell invasion, A10D and E13K were even more pro-invasive. Invasion induced by both mutants was blocked by inhibiting PI3-kinase or phospholipase-C, but inhibiting Rho-associated kinase (ROCK) blocked only E13K-induced invasion. CONCLUSIONS: The loss of tumor-suppressor activity and gain of invasiveness from single point mutations constitute evidence for a functional role of TFF1 mutations in gastric cancer. These site-directed mutagenesis experiments provide the tools for continued probing of signal transduction mechanisms and structural elements responsible for TFF1 functions.