Surabhi Bhatt

Accumulation of cadmium in insulin-producing β cells

Evidence suggests that chronic low level cadmium exposure impairs the function of insulin-producing β cells and may be associated with type-2 diabetes mellitus. Herein, we describe the cadmium content in primary human islets and define the uptake kinetics and effects of environmentally relevant cadmium concentrations in cultured β cells. The average cadmium content in islets from 10 non-diabetic human subjects was 29 ± 7 nmol/g protein (range 7 to 72 nmol/g protein). Exposure of the β-cell line MIN6 to CdCl2 concentrations between 0.1 and 1.0 µmol/L resulted in a dose- and time-dependent uptake of cadmium over 72 h. This uptake resulted in an induction of metallthionein expression, likely enhancing cellular cadmium accumulation. Furthermore, cadmium accumulation resulted in an inhibition of glucose stimulated insulin secretion in MIN6 cells and primary mouse islets. Our results indicate that this impairment in β-cell function is not due to an increase in cell death or due to an increase in oxidative stress. We conclude that mouse β cells accumulate cadmium in a dose- and time-dependent manner over a prolonged time course at environmentally relevant concentrations. This uptake leads to a functional impairment of β-cell function without significant alterations in cell viability, expression of genes important for β-cell function or increase in oxidative stress.

The Inflammatory Gene Pathway Is Not a Major Contributor to Polycystic Ovary Snydrome

CONTEXT Although inflammation is clearly associated with obesity, diabetes, and insulin resistance, the role of chronic inflammation in the etiology of polycystic ovary syndrome (PCOS) is unclear. OBJECTIVE To determine whether chronic inflammation plays a causal role in the etiology of PCOS, we tested for an association between PCOS and genetic markers mapping to 80 members of the inflammatory pathway. DESIGN This was a case-control association study. SETTING The setting was an academic medical center. PATIENTS OR PARTICIPANTS A total of 905 index case patients with PCOS and 955 control women (108 intensively phenotyped subjects with normal androgen levels and regular menses and 847 minimally phenotyped subjects with regular menses and no history of PCOS). INTERVENTIONS Subjects were genotyped at single nucleotide polymorphisms mapping to 80 inflammatory genes. Logistic regression was used to test for an association between 822 single nucleotide polymorphisms and PCOS after adjustment for population stratification, body mass index, and/or age. In the index patients, we also tested for association with 11 quantitative traits (body mass index and testosterone, fasting insulin, fasting glucose, 2-hour postchallenge glucose, LH, FSH, total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels). MAIN OUTCOME MEASURES The evidence for an association with PCOS and with 11 quantitative traits was investigated. RESULTS Nominally significant evidence for an association was observed with MAP3K7, IKBKG, TNFRS11A, AKT2, IL6R, and IRF1, but no results remained statistically significant after adjustment for multiple testing. CONCLUSIONS Genetic variation in the inflammatory pathway is not a major contributor to the etiology of PCOS or related quantitative traits in women with PCOS.

Validation of Patient-Reported Outcomes Measurement Information System (PROMIS) computerized adaptive tests in cervical spine surgery

OBJECTIVE The Patient-Reported Outcomes Measurement Information System (PROMIS), which is funded by the National Institutes of Health, is a set of adaptive, responsive assessment tools that measures patient-reported health status. PROMIS measures have not been validated for surgical patients with cervical spine disorders. The objective of this project is to evaluate the validity (e.g., convergent validity, known-groups validity, responsiveness to change) of PROMIS computer adaptive tests (CATs) for pain behavior, pain interference, and physical function in patients undergoing cervical spine surgery. METHODS The legacy outcome measures Neck Disability Index (NDI) and SF-12 were used as comparisons with PROMIS measures. PROMIS CATs, NDI-10, and SF-12 measures were administered prospectively to 59 consecutive tertiary hospital patients who were treated surgically for degenerative cervical spine disorders. A subscore of NDI-5 was calculated from NDI-10 by eliminating the lifting, headaches, pain intensity, reading, and driving sections and multiplying the final score by 4. Assessments were administered preoperatively (baseline) and postoperatively at 6 weeks and 3 months. Patients presenting for revision surgery, tumor, infection, or trauma were excluded. Participants completed the measures in Assessment Center, an online data collection tool accessed by using a secure login and password on a tablet computer. Subgroup analysis was also performed based on a primary diagnosis of either cervical radiculopathy or cervical myelopathy. RESULTS Convergent validity for PROMIS CATs was supported with multiple statistically significant correlations with the existing legacy measures, NDI and SF-12, at baseline. Furthermore, PROMIS CATs demonstrated known-group validity and identified clinically significant improvements in all measures after surgical intervention. In the cervical radiculopathy and myelopathic cohorts, the PROMIS measures demonstrated similar responsiveness to the SF-12 and NDI scores in the patients who self-identified as having postoperative clinical improvement. PROMIS CATs required a mean total of 3.2 minutes for PROMIS pain behavior (mean ± SD 0.9 ± 0.5 minutes), pain interference (1.2 ± 1.9 minutes), and physical function (1.1 ± 1.4 minutes) and compared favorably with 3.4 minutes for NDI and 4.1 minutes for SF-12. CONCLUSIONS This study verifies that PROMIS CATs demonstrate convergent and known-groups validity and comparable responsiveness to change as existing legacy measures. The PROMIS measures required less time for completion than legacy measures. The validity and efficiency of the PROMIS measures in surgical patients with cervical spine disorders suggest an improvement over legacy measures and an opportunity for incorporation into clinical practice.

The use of a novel tablet application to quantify dysfunction in cervical spondylotic myelopathy patients

BACKGROUND CONTEXT Despite the prevalence and importance of myelopathy, there is a paucity of objective and quantitative clinical measures. The most commonly used diagnostic tools available are nonquantitative physical exam findings (eg, pathologic reflexes, and gait disturbance) and subjective scoring systems (eg, modified Japanese Orthopaedic Association [mJOA]). A decline in fine motor coordination is a hallmark of early myelopathy, which may be useful for quantitative testing. PURPOSE To identify if a novel tablet application could provide a quantitative measure of upper extremity dysfunction in cervical spondylotic myelopathy. STUDY DESIGN/SETTING Prospective cohort study Patient Sample: Adult patients with a diagnosis of cervical spondylotic myelopathy from a board-certified, spine surgeon were compared with age-matched, healthy, and adult control patients. OUTCOME MEASURES Self-reported function was assessed via the mJOA. Upper extremity function was measured via the fine motor skills (FiMS) tablet test. METHODS Subjects and controls prospectively completed the mJOA paper survey and the FiMS tablet testing, which consisted of four challenges. RESULTS After age-matching, 65 controls and 28 myelopathic patients were available for comparison. The mean mJOA was 13.5 ± 2.9 in the myelopathic cohort and 17.3 ± 1.1 in the control cohort (p < .0001). The average scores for challenges 1-4 in control patients were 24.4, 16.3, 3.2, and 6.6, respectively, whereas the average scores for the myelopathic patients were 16.6, 10.5, 1.4, and 1.8, respectively (p values for all four challenges <.001). Based upon the 15 control subjects who repeated FiMS testing four sequential times, intrarater reliability was excellent, yielding an interclass correlation coefficient of 0.88 CONCLUSIONS: The FiMS tablet application produced significantly lower scores in a myelopathic cohort when compared with an age-matched control cohort. This is true for all four challenges in the FiMS tablet application. The test can be completed in 1.5 minutes, producing a reliable, quantitative measure of cervical myelopathy upper extremity function. In summary, the FiMS tablet application is a novel, easily administered, objectively quantifiable test for analyzing cervical spondylotic myelopathy.

High-resolution magnetization transfer MRI in patients with cervical spondylotic myelopathy

Magnetization transfer (MT) contrast has been established as a marker of myelin integrity, and cervical spondylotic myelopathy is known to cause demyelination. Ten patients with clinical and magnetic resonance imaging (MRI) manifestations of cervical spondylotic myelopathy (CSM) were compared to the MRIs of seven historic healthy controls, using the magnetization transfer ratio (MTR) and Nurick scores as the primary metrics. Transverse slices through the intervertebral discs of the cervical spine were acquired using a gradient echo sequence (MEDIC) with and without an MT saturation pulse on a 3 Tesla Siemens Prisma scanner (TR = 300 ms, TEeff = 17 ms, flip angle = 30°, in-plane resolution = 0.47 × 0.47 mm2). The CSM patients tended to have a lower mean MTR (30.4 ± 6.5) than the controls (34.8 ± 3.8), but the difference was not significant (independent samples t-test, p = 0.110, Cohens d = 0.80). The mean MTR across all intervertebral disc levels was not significantly correlated to the Nurick score (Spearmans ρ = -0.489, p = 0.151). The intervertebral level with the lowest MTR in each cohort was not significantly different between groups (equal variances not assumed, t = 1.965, dof = 14.8, p = 0.068, Cohens d = 0.88), but the CSM patients tended to have a lower MTR. The mean MTR at this level was negatively correlated to the Nurick score among CSM patients (Spearmans ρ = -0.725, p = 0.018). CSM patients tended to have decreased MTR indicating myelin degradation compared to our healthy subjects, and MTR was negatively correlated with the severity of CSM.