Stress profile in essential hypertension.

This study was undertaken to test the hypothesis that basal sympathetic activity and sympathetic reactivity to stress are increased in patients with essential hypertension. One hundred and fifteen randomly selected patients with essential hypertension and an equal number of age- and sex-matched normal controls were included in this study. Various parameters, viz., heart rate, respiratory rate, blood pressure, peripheral skin temperature, electromyographic activity of the frontalis muscle, skin conductance (measured by electrodermography), and blood pressure, were measured in the resting state in both groups. These parameters were then measured during the performance of various stressful activities, such as mental arithmetical calculations, thinking of unpleasant thoughts, staring at a fixed point, catching of a dropped object, and reading aloud for 1 min each, and again over a 1-min quiet period following each stressful activity. Changes in various parameters in the two groups were analyzed and compared. Baseline heart rate, respiratory rate, electromyographic activity and peripheral skin temperature were higher-while skin conductance was lower-in the hypertensive group than in the control group. The increases in systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, electromyographic activity, and peripheral skin temperature in response to stress were greater in hypertensive patients than in controls, while skin conductance showed a higher elevation in controls than in hypertensive patients. In conclusion, sympathetic nervous system activity is increased in patients with essential hypertension. The reduced skin conductance and high peripheral skin temperature in these patients may be due to a possible dermal neurovascular dysfunction.     

Correlation of her-2/neu gene amplification with other prognostic and predictive factors in female breast carcinoma

The purpose of this study was to determine if any relationship exists between Her-2/neu gene amplification and estrogen receptor (ER), progesterone receptor (PR), MIB-1, grade, size and age in female breast cancer. Five hundred and eighteen female patients with invasive breast carcinoma, 390 ductal and 128 lobular, in which assessment of Her-2/neu amplification by fluorescence in-situ hybridization (FISH) has been performed, were reviewed retrospectively. Each patient was further assessed for ER, PR, MIB-1, grade, size and age at diagnosis. Chi-square analysis was then used to correlate the above observations. Overall gene amplification was seen in 76 (15%) of the cases, 68 (17%) were ductal and 8 (6%) were lobular. Her-2/neu gene was amplified in 37 (10%) out of 379 ER positive cases and in 39 (28%) out of 139 ER negative cases. Her-2/neu was amplified in 22 (7%) out of 301 PR positive cases and in 54 (25%) out of 217 PR negative cases. Amplification occurred in 18 (8%) out of 222 negative MIB-1 cases and amplified in 58 (20%) out of 296 positive cases. Amplification was seen in 5 (10%) out of 49 grade I tumors, 17 (12%) out of 143 grade II tumors and 54 (27%) out of 198 grade III tumors. Lobular carcinomas were not graded. Amplification was present in 52 (15%) out of 346 T1 lesions, in 17 (13%) out of 130 T2 lesions, in 5 (17%) out of 30 T3 lesions and in 2 (17%) out of 12 T4 lesions. Her-2/neu was amplified in 67 (14%) out of 467 woman 41 years and older, and in 9 (18%) out of 51 women 40 years and younger. Comparison of these frequencies using chi-square test revealed statistically significant correlation between Her-2/neu amplification and ductal versus lobular carcinoma (p<0.0003), ER (p=0.0001) and PR (p<0.0001) negative tumors, over-expression of MIB-1 (p<0.0005) and high tumor grade (p=0.0009), while size of the tumor (p=0.08) and age of the patients (p=0.67) were not statistically significant. Correlation was found between Her-2/neu amplification and tumor type, high histological grade, ER and PR negative tumors, and high proliferative MIB-1 index. No correlation was found between size of the tumor and age of the patient with Her-2/neu amplification.     

Gender significance of ST-segment deviation detected by ambulatory (Holter) monitoring

OBJECTIVE: To evaluate the gender influence in diagnostic and prognostic value of Holter-detected ST-segment deviation. METHODS: Two-hundred seventy-seven consecutive patients (196 men) who underwent coronary angiography for evaluation of chest pain were studied with 24-h Holter monitoring within 72 h of coronary angiography, and were followed up for 65+/-21 months. RESULTS: Men had a higher prevalence of coronary artery disease (169 of 196, 86%) compared to that of women (54 of 81, 67%), p<0.00025. Thirty-three (17%) men and 15 (19%) women had ST-segment deviation during 24-h recording. The sensitivity, specificity and positive predictive values of ST-segment deviation (elevation, depression, or both) for the detection of significant coronary artery disease were similar in men and women. The negative predictive values were significantly higher in women than men for ST-segment deviation (36% vs. 15%, p<0.001), ST-segment elevation (35% vs. 14%, p<0.001), and ST-segment depression (34% vs. 15%, p<0.001). Similarly, the diagnostic accuracies were significantly higher in women than men for ST-segment deviation (44% vs. 29%, p<0.025), ST-segment elevation (38% vs. 19%, p<0.001), and ST-segment depression (40% vs. 24%, p<0.025). There was no significant difference in composite end-point of events (mortality, nonfatal myocardial infarction, unstable angina, and coronary revascularization) in men versus women with ST-segment deviation (elevation, depression, or both). CONCLUSION: Holter-detected ST-segment deviation has a higher negative predictive value and diagnostic accuracy for detection of significant coronary artery disease in women than in men, although the prognostic values are not significantly different between men and women.     

The development of new density gradient media for purifying human islets and islet-quality assessments

Successful islet transplantation is dependent on the quality and quantity of islets infused. Islets are purified on density gradients, but procedures currently used have limited capacity for pancreatic digests, islet yield, and viability. We aimed to improve islet purification with a modified gradient medium. Biocoll was diluted in University of Wisconsin solution to create linear density gradients of 1.065 to 1.095 g/mL. Properties of islets purified from 22 human pancreas digests with modified medium were compared with 15 preparations using standard medium. The modification increased the capacity of gradients for pancreatic digests from 20 to 60 mL, islet yield increased from 218,000 to 435,318 per isolation, and viability increased from 65.4% to 92.1%. Islet fractions contained greater than 95% of recovered insulin. Islets showed good physiologic responses to secretagogues and restored normoglycemia in streptozotocin-induced diabetic severe combined immunodeficiency disease mice. The new medium enhances yield, purity, and viability of human islet preparations for clinical islet transplantation.     

Pharmacoepidemiology of anemia in kidney transplant recipients

ABSTRACT. Anemia has long been known to be a complication of end-stage renal disease (ESRD), and it has been linked to cardiovascular morbidity and mortality. Although kidney transplant recipients (KTR) are prone to experiencing cardiovascular outcomes, little is known about the epidemiology of anemia in this population. With few exceptions, studies to date have not fully evaluated the associations between posttransplant anemia (PTA) and medications commonly used in KTR, particularly immunosuppressant drugs, angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB). The authors aimed to specifically investigate possible associations between these drugs and PTA. Detailed medical information was retrospectively collected on 374 consecutive KTR from our transplant clinic. Univariate/multivariate linear regression models were used to test for associations between hematocrit (HCT) and other covariates, and logistic regression models were used to detect independent predictors of PTA, defined as HCT <33%. The mean time since transplantation was 7.7 yr, and mean creatinine was 2.2 mg/dl. The prevalence of PTA was 28.6%. Ten percent of all patients were on erythropoietin therapy, but only 41.6% of patients whose HCT was <30 received this treatment. From multivariate analyses, the authors found that female gender and lower renal function were associated with lower HCT (both P < 0.001). Patients on ACEI had significantly lower HCT (P = 0.005) compared with patients without such treatment. In addition, a significant curvilinear dose-response relationship was found between ACEI dose and HCT. Among the immunosuppressant drugs, mycophenolate mofetil (P = 0.05) and tacrolimus (P = 0.02) were associated with a lower HCT. The authors conclude that PTA is prevalent and undertreated in KTR. Several medications that are possibly modifiable correlates of PTR deserve further study.     

Blockade of ubiquitin-conjugating enzyme CDC34 enhances anti-myeloma activity of Bortezomib/Proteasome inhibitor PS-341

The ubiquitin-conjugating enzyme CDC34 (UBC3) is linked to cell cycle progression in diverse cell types; however, its role in multiple myeloma (MM) pathogenesis is unclear. Here, we show that CDC34 is highly expressed in patient MM cells and MM cell lines versus normal cells. Blocking CDC34 using a dominant-negative strategy enhances the anti-MM activity of Bortezomib/Proteasome inhibitor PS-341, dexamethasone (Dex) and 2-Methoxyestradiol (2ME2). The expression of wild-type CDC34 reduces Dex-induced cytotoxicity in MM cells. Moreover, inhibition of CDC34 enzymatic activity abrogates interleukin-6-induced protection against Dex-induced apoptosis. Together, these findings provide evidence that (1) CDC34 expression is associated with growth and survival of MM cells and (2) blocking CDC34 activity not only enhances anti-MM activity of Bortezomib and 2ME2 but also overcomes IL-6-triggered Dex-resistance.     

Regulation of junior doctors' work hours: an analysis of British and American doctors' experiences and attitudes

Regulations of junior doctors' work hours were first enacted in the United States (US) and United Kingdom (UK) over a decade ago, with the goals of improving patient care and doctors' well-being while maintaining a high quality of medical training. This study examines experiences and attitudes regarding the implementation of these regulations among physicians and surgeons at two teaching hospitals, one in South-East England, and the other in New England, US. This paper presents the findings of a survey questionnaire and a series of in-depth interviews administered to a sample of junior doctors and the consultants responsible for their supervision. The study finds that the different policy mechanisms employed in the two countries have had different degrees of success in reducing the work hours of junior doctors. The results also indicate, however, that even in settings in which hours have been reduced significantly, the regulations have only had limited effects on the quality of medical care, junior doctors' well-being, and the quality of medical education. A number of barriers to the success of the regulations in achieving their objectives are identified, and the relative merits of political action and professional self-regulation are discussed. This research suggests that recently enacted policies requiring further reductions in junior doctors' hours in both the US and UK may face similar barriers when implemented. Understanding the lessons that emerge from implementation of the original regulations is essential if future reforms are to succeed and a high-quality system of health care is to be sustained.     

Insulin-like growth factor-1 induces adhesion and migration in human multiple myeloma cells via activation of beta1-integrin and phosphatidylinositol 3'-kinase/AKT signaling

Insulin-like growth factor-1 (IGF-I) is a growth and survival factor in human multiple myeloma (MM) cells. Here we examine the effect of IGF-I on MM cell adhesion and migration, and define the role of beta1 integrin in these processes. IGF-I increases adhesion of MM.1S and OPM6 MM cells to fibronectin (FN) in a time- and dose-dependent manner, as a consequence of IGF-IR activation. Conversely, blocking anti-beta1 integrin monoclonal antibody, RGD peptide, and cytochalasin D inhibit IGF-I-induced cell adhesion to FN. IGF-I rapidly and transiently induces association of IGF-IR and beta1 integrin, with phosphorylation of IGF-IR, IRS-1, and p85(PI3-K). IGF-I also triggers phosphorylation of AKT and ERK significantly. Both IGF-IR and beta1 integrin colocalize to lipid rafts on the plasma membrane after IGF-I stimulation. In addition, IGF-I triggers polymerization of F-actin, induces phosphorylation of p125(FAK) and paxillin, and enhances beta1 integrin interaction with these focal adhesion proteins. Importantly, using pharmacological inhibitors of phosphatidylinositol 3'-kinase (PI3-K) (LY294002 and wortmannin) and extracellular signal-regulated kinase (PD98059), we demonstrate that IGF-I-induced MM cell adhesion to FN is achieved only when PI3-K/AKT is activated. IGF-I induces a 1.7-2.2 (MM.1S) and 2-2.5-fold (OPM6) increase in migration, whereas blocking anti-IGF-I and anti-beta1 integrin monoclonal antibodies, PI3-K inhibitors, as well as cytochalasin D abrogate IGF-I-induced MM cell transmigration. Finally, IGF-I induces adhesion of CD138+ patient MM cells. Therefore, these studies suggest a role for IGF-I in trafficking and localization of MM cells in the bone marrow microenvironment. Moreover, they define the functional association of IGF-IR and beta1 integrin in mediating MM cell homing, providing the preclinical rationale for novel treatment strategies targeting IGF-I/IGF-IR in MM.     

Assessment of Markov-dependent stochastic models for drug administration compliance

OBJECTIVE: There are few analytical results that describe patient compliance with drug administration regimens. The purpose of this paper is to develop and assess stochastic approaches for mathematical modelling of patient compliance with administration regimens. METHODS: Two stochastic models based on Markov-dependent random variables and on the Ising model were assessed for their ability to describe the variable nature of drug compliance. RESULTS: Both models use only experimentally accessible data, and their predictions were tested against published clinical compliance data obtained from electronic monitoring devices. The models satisfactorily fitted administration interval distribution data from several patients treated with diltiazem, a calcium channel antagonist, or zidovudine, an antiretroviral agent. The Ising model provides additional analytical expressions for the distribution of success runs and 'drug holidays' in administration regimens. These distribution predictions were tested with success run data for diltiazem and drug holiday data for two nonsteroidal anti-inflammatory drugs, piroxicam and tenoxicam. CONCLUSIONS: Stochastic models can provide useful insights into drug compliance, and can be used to identify the administration patterns that are more likely to occur during drug self-administration in populations.