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Background Although cerebral lesions ≥3mm on imaging are associated with incident stroke, lesions < 3mm are typically ignored. Objective To examine stroke risks associated with subclinical brain lesions by size (< 3 mm only, lesions ≥3 mm only, both < 3 mm and ≥3 mm) and white matter hyperintensities (WMH). Design Community cohort, Atherosclerosis Risk in Communities (ARIC) Study Setting Two ARIC sites with magnetic resonance imaging (MRI) data (1993–95) Participants 1,884 (99%) adults (50–73 years, 40% men; 50% black) with MRI and no prior stroke; average 14.5 years follow-up. Measurements MRI lesions: none (n=1611), < 3 mm only (n=50), ≥3 mm only (n=185), or both < 3 and ≥3 mm lesions (n=35); WMH score (0–9 scale). Outcomes: incident stroke (n=157), overall mortality (n=576), stroke mortality (n=50). Hazard Ratios (HR) estimated with proportional hazards models. Results Compared to no lesions, stroke risk was tripled with lesions < 3mm only (HR=3.47, 95% CI:1.86-6.49), doubled with lesions ≥3 mm only (HR=1.94, 95% CI:1.22-3.07), and was 8-fold higher with both < 3 mm and ≥3 mm-sized lesions (HR=8.59, 95% CI:4.69-15.73). Stroke risk doubled with WMH ≥3 (HR=2.14, 95% CI:1.45-3.16). Stroke mortality risk tripled with lesions < 3 mm only (HR=3.05, 95% CI:1.04-8.94), doubled with lesions ≥3 mm (HR=1.9, 95% CI:1.48-2.44) and was seven-times higher with both lesion sizes (HR=6.97, 95% CI:2.03-23.93). Limitations Few stroke events (n=147), especially hemorrhagic (n=15); limited numbers of participants with only lesions ≤3mm (n=50) or with both lesions ≤3mm and 3–20mm (n=35). Conclusions Very small cerebrovascular lesions may be associated with increased risks of stroke and mortality; having both < 3 mm and ≥3 mm lesions may represent a particularly striking risk increase. Larger studies are needed to confirm findings and provide more precise estimates.

Chronic uremia is associated with secondary hyperparathyroidism (HPT). The purpose of the present investigation was to study the reversibility of secondary HPT after reversal of uremia by an isogenic kidney transplantation in the rat. Secondary HPT was induced in two models: Model A comprised 5/6 nephrectomized rats kept on a standard diet (N = 12; PTH 210 +/- 43 pg/ml; plasma urea 24 +/- 2 mmol/liter; and normal control rats, N = 12; PTH 45 +/- 5 pg/ml; plasma urea 6 +/- 0.2 mmol/liter); and Model B comprised 5/6 nephrectomized rats kept on a high phosphorus diet (N = 12; PTH 769 +/- 157 pg/ml; plasma urea 18 +/- 2 mmol/liter). The parathyroid function was examined by measuring the secretory response of PTH to an acute induction of hypo- and hypercalcemia. Acute hypocalcemia in the hyperphosphatemic uremic rats did not significantly increase serum PTH levels (N = 6, delta Ca2+ -0.56 mmol/liter; maximal PTH 1045 +/- 164 pg/ml; basal PTH 690 +/- 134 pg/ml; NS). During hypercalcemia the PTH levels were significantly higher than in the normal controls (N = 6; minimal PTH 24 +/- 5 pg/ml vs. normal controls 5 +/- 0.2 pg/ml, P < 0.05). After 20 weeks of uremia, the uremia was reversed by the isogenic kidney transplantation. One week after reversal of the uremia the PTH levels became normal in both models A and B (28 +/- 6 and 63 +/- 16 pg/ml, respectively) and the kidney transplanted rats from model B had a normal secretory response of PTH to both hypo- and hypercalcemia. To study whether both parathyroid cell hypertrophy and hyperplasia could be down-regulated, 8 uremic glands (N = 9) or 20 normal glands (N = 6) were implanted into one normal rat. Within two weeks the rats regained normocalcemia and PTH levels remained normal from the third day after the increase of glandular mass. The 20 gland rats all had normal PTH suppressibility in response to calcium (minimal PTH 5 +/- 0.3 pg/ml). In conclusion, experimental severe secondary hyperparathyroidism is reversible very quickly after the reversal of uremia. Hyperphosphatemia in uremia is important for the non-suppressibility of the parathyroid glands to calcium. In non-uremic rats even severe parathyroid hyperplasia can be controlled, resulting in normal plasma PTH and Ca2+ levels and in a normal response to hypercalcemia. Thus, the minimal PTH secretion obtained during the induction of hypercalcemia is not an expression of the parathyroid mass.

Despite there being no PTH in the circulation a rapid increase of plasma Ca2+ occurs immediately after a brief induction of hypocalcaemia. The kidneys are not responsible for this phenomenon. The present results suggest the existence of a mechanism other than the effect of PTH, which is responsible for the rapid minute-to-minute regulation of plasma Ca2+ in the rat.

Introduction: The prognosis of glioblastoma (GBM) treated with standard-of-care maximal surgical resection and concurrent adjuvant temozolomide (TMZ)/radiotherapy remains very poor (less than 15 months). GBMs have been found to contain a small population of cancer stem cells (CSCs) that contribute to tumor propagation, maintenance, and treatment resistance. The highly invasive nature of high-grade gliomas and their inherent resistance to therapy lead to very high rates of recurrence. For these reasons, not all patients with similar diagnoses respond to the same chemotherapy, schedule, or dose. Administration of ineffective anticancer therapy is not only costly but more importantly burdens the patient with unnecessary toxicity and selects for the development of resistant cancer cell clones. We have developed a drug response assay (ChemoID) that identifies the most effective chemotherapy against CSCs and bulk of tumor cells from of a panel of potential treatments, offering great promise for individualized cancer management. Providing the treating physician with drug response information on a panel of approved drugs will aid in personalized therapy selections of the most effective chemotherapy for individual patients, thereby improving outcomes. A prospective study was conducted evaluating the use of the ChemoID drug response assay in GBM patients treated with standard of care. Methods: Forty-one GBM patients (mean age 54 years, 59% male), all eligible for a surgical biopsy, were enrolled in an Institutional Review Board–approved protocol, and fresh tissue samples were collected for drug sensitivity testing. Patients were all treated with standard-of-care TMZ plus radiation with or without maximal surgery, depending on the status of the disease. Patients were prospectively monitored for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). Odds ratio (OR) associations of 12-month recurrence, PFS, and OS outcomes were estimated for CSC, bulk tumor, and combined assay responses for the standard-of-care TMZ treatment; sensitivities/specificities, areas under the curve (AUCs), and risk reclassification components were examined. Results: Median follow-up was 8 months (range 3-49 months). For every 5% increase in in vitro CSC cell kill by TMZ, 12-month patient response (nonrecurrence of cancer) increased two-fold, OR = 2.2 (P = .016). Similar but somewhat less supported associations with the bulk tumor test were seen, OR = 2.75 (P = .07) for each 5% bulk tumor cell kill by TMZ. Combining CSC and bulk tumor assay results in a single model yielded a statistically supported CSC association, OR = 2.36 (P = .036), but a much attenuated remaining bulk tumor association, OR = 1.46 (P = .472). AUCs and [sensitivity/specificity] at optimal outpoints (>40% CSC cell kill and >55% bulk tumor cell kill) were AUC = 0.989 [sensitivity = 100/specificity = 97], 0.972 [100/89], and 0.989 [100/97] for the CSC only, bulk tumor only, and combined models, respectively. Risk categorization of patients w...

BackgroundTo understand how blood pressure (BP) from midlife and beyond is related to cognition in older age, a lifespan approach is needed. We assessed the associations of BP levels and variability from midlife on with subsequent cognitive change.Methods and ResultsThe ARIC (Atherosclerosis Risk in Communities) Study participants underwent 4 clinic BP measurements (visit 1, 2, 3, and 4 BPs) between 1987 and 1998, and their mean levels and average real variability (ARV) were assessed as exposures. A global cognitive z score, estimated from the Delayed Word Recall Test, Digit Symbol Substitution Test, and Word Fluency Test scores, was calculated at 1996 to 1998 (visit 4) and 2011 to 2013 (visit 5). Among 11 408 participants (mean age, 54 years; 56% women; 21% black race), mean systolic BP (SBP)/diastolic BP (DBP) level was 123/72 mm Hg, and ARVSBP/ARVDBP was 11/7 mm Hg. With linear mixed models, 1‐SD increases of ARVSBP (standardized regression coefficient [95% confidence interval], −0.03 [−0.04 to −0.01] points) and ARVDBP (standardized regression coefficient [95% confidence interval], −0.02 [−0.03 to −0.002] points; both P<0.05), but not mean SBP or DBP levels, were associated with lower global cognitive z scores at visit 4. In contrast, mean SBP (standardized regression coefficient [95% confidence interval], −0.04 [−0.06 to −0.02] points) or DBP (standardized regression coefficient [95% confidence interval], 0.04 [0.02–0.06] points; both P<0.001) level, but not ARVSBP or ARVDBP, was associated with change in global cognitive z scores from visits 4 to 5.ConclusionsGreater visit‐to‐visit SBP or DBP variability from midlife on is modestly associated with lower cognitive function, whereas higher mean SBP and lower DBP levels from midlife to later life are modestly associated with cognitive decline in later life.

The authors assessed the process of blood pressure (BP) measurement and level of adherence to recommended procedures at representative sites throughout a large academic health sciences center. A casual observer assessed the setting and observed the process, noting the equipment, technique, and BP recorded by site personnel. A trained observer then repeated the patient's BP measurement following American Heart Association recommendations. Significant biases were observed between measurements by site personnel and the trained observer. Site personnel reported on average an increased systolic BP (SBP) of 5.66 mm Hg (95% confidence interval [CI], 3.09-8.23; P<.001) and a decreased diastolic BP (DBP) of )2.96 mm Hg (95% CI, )5.05 to )0.87; P=.005). Overall, 41% of patients had a !10-mm Hg difference in SBP between measurements. Similarly, 54% had differences of !5 mm Hg in DBP between measurements. Inaccurate BP measurement and poor technique may lead to misclassification, misdiagnosis, and inappropriate medical decisions. Concordance of measured SBP between our site personnel and trained observer was less than optimal. Several areas for improvement were identified. Routine calibration and use of system-wide standardized equipment, establishment of BP measurement protocols, and periodic technique and equipment recertification can be addressed in future quality initiatives. J Clin Hypertens (Greenwich). 2012;14:222-227. Ó2012 Wiley Periodicals, Inc.Blood pressure (BP) measurement is perhaps the most commonly performed procedure in the clinical encounter and one of the most important measurements in clinical medicine.1 Despite clear guidelines on appropriate techniques for BP measurement, 2,3 these recommendations rarely are followed by health care providers or personnel.1 There are numerous factors that influence accuracy of BP readings including those related to the patient, observer, instruments, and technique.2-4 Adequate rest time, diurnal variation, clinic atmosphere, pain, anxiety, smoking, and conversation all can have a significant impact on BP readings.4 Factors directly related to the observer include training, end-digit preference, and impaired hearing.2,3,5 Instrument accuracy, background noise, clothing interference, inappropriate cuff size and placement, posture, and inflation-deflation rate can influence BP measurements. Lack of repeated measurements further compounds the obtainment of an accurate reading.3 These multiple sources of potential error encountered in daily clinical practice emphasize the possibility for inaccurate results that can influence patient management. Accurate measurement of BP is essential in staging hypertension, ascertaining BP-related risk, and guiding management. Health care providers and personnel should be keenly aware of the need to carefully follow standardized procedures in order to achieve accurate and reproducible BPs. Despite education, clinic personnel who are aware of guidelines often do not follow them to the degree necessary to produce repeatable measures, and it h...

Background and Aims Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) or biopsy is widely practiced. Optimal sonographic visualization of the needle is critical for image guided interventions. There are several commercially available needles but no bench-top testing and direct comparison of these needles to reveal their inherent echogenicity. The aims are to provide bench-top data that can be used to guide clinical applications and to promote future device research and development. Methods Descriptive bench-top testing and comparison. Bench-top testing of 8 commonly used EUS-FNA needles (all of 22 gauge in size): SonoTip Pro Control (Medi-Globe); Expect Slimline (Boston Scientific); EchoTip, EchoTip Ultra, EchoTip ProCore High Definition, (Cook Medical); ClearView (Conmed); EZ Shot2 (Olympus); BNX (Beacon Endoscopic); and 2 new prototype needles that are coated by echogenic polymers by Medi-Globe. Blinded evaluation of standardized and unedited videos by 43 EUS endoscopists and 17 radiologists specialized in gastrointestinal ultrasound examination that is unfamiliar with EUS needle devices. Results There was no significant difference in the ratings and rankings of these needles between endosonographers and radiologists. Overall, one prototype needle was rated as the best, ranking 10% to 40% higher than all other needles (p<0.01). Among the commercially available needles, the EchoTip Ultra needle and the ClearView needle were top choices. The EZ Shot 2 needle was ranked statistically lower than other needles (30%–75% worse, p<0.001). Conclusions All FNA needles have their inherent and different echogenicity, and these differences are similarly recognized by EUS endoscopists and radiologists. Needles with polymeric coating from the entire shaft to the needle tip may offer better echogenicity.