Control Levels In Patients Research Articles

Abstract 4160: A new orotopically applied vasoconstrictor drug significantly confers normal oral mucosa resistance to radio-damage

Abstract Introduction: Oral mucositis (OM) represents one of the most debilitating and troublesome adverse effects of chemoradiotherapy frequently encountered in patients. Most ionizing radiation-induced oral mucosa cell death results from radiation-induced reactive oxygen species (ROS) attack of DNA bases and molecular oxygen (O2) “fixation” of the ROS damage, which results in DNA breakage. Our earlier work showed complete suppression of radiation-induced oral mucositis in rodents by transient reduction of ROS related DNA damage when the animals were pre-treated with a topically-applied vasoconstrictor before irradiation. In this study, we have initiated a Phase IIa clinical investigation to determine whether orotopical vasoconstrictor application conferred the same resistance to radio-damage in normal oral mucosa of patients receiving whole-body radiation prior to bone marrow transplantation. Patients and Methods: In two years, 58 patients received the cyclophosphamide +TBI conditioning regimen. A clinical trial (NCT02434146) was approved by the University of Wisconsin Review Board to test the ability of five increasing doses of the NG-11-1 topical vasoconstrictor formulation to suppress the incidence and severity of OM. For a control cohort, records of five patients who received the cyclophosphamide+TBI regimen at UW were analyzed, records including weights, daily OM scores, use of total parenteral nutrition (TPN) were collected for comparison to the NG-11-1 treatment group. For the “topical NG-11-1 treated” group, each patient received the lowest of the five projected concentrations of NG-11-1 vasoconstrictor. The study physician directed 30 spray pulses to the buccal, lingual and sub-lingual surfaces. The formulation contains a blue coloring that enables directing and judging drug coverage. Orotopical NG-11-1 was applied: i) 15-20 min before IV cyclophosphamide was initiated, ii) 25-30 min after IV cyclophosphamide was initiated, and iii) 15-20 min before every 1.5 Gy irradiation. Pain score and OM score were collected before and after treatments and during follow-up clinic re-visits for 2 weeks. Results: The mean of “Grade 3 oral mucositis duration (days)” in NG-11-1 vasoconstrictor drug treated patients was significantly lower (P=0.047) than that of control patients. And, the mean of “total mucositis duration (days)” in NG-11-1 treated patients was significantly lower (P=0.043) than the level of control patients. Thirdly, either nasogastric feeding or total parenteral nutrition was required in 60% of control patients, however, none of the NG-11-1-treated patients required this intervention. Conclusions: These clinical results showing significant suppression of OM severity are consistent with the same degree of NG-11-1 dose-dependent suppression of radiation-induced oral mucositis that we observed in our previous mouse OM model studies. Citation Format: Amanda Graul-Conroy, Margo Hoover-Regan, Paul M. Sondel, Natalie S. Callander, Walter L. Longo, Ningfeng F. Li, William E. Fahl. A new orotopically applied vasoconstrictor drug significantly confers normal oral mucosa resistance to radio-damage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4160.

Quality of life of asthmatic patients after complex rehabilitation treatment

Asthma is a serious public health challenge for all age groups around the world. Heightened attention surrounds the use of the natural therapeutic factors that potentially make medication more cost-efficient in the treatment of diseases. Our research has tried to reveal how the medical conditions, quality of life of asthmatic patients change after medical treatments that are accompanied by climate therapy. Asthma patients (514 patients) participated in a 3-week complex therapy at Mátra Health Resort. Beyond medical examinations and treatments, patients were involved in breathing exercises on the curing terraces or outdoors twice a day, they were to attend the rehabilitative physical exercises led by a physiotherapist once a day, were given dietetic and lifestyle advice and provided with diets that were fitted to their individual medical conditions. Their respiratory function was examined before the commencement of the cure as well as after the therapy just before departing from the institution. The patients' exercise capacities were assessed with the 6-minute walk test before the treatment and then 3 weeks later. For the patients, a questionnaire was compiled to reveal information in relation to their conditions in the first 6 months after leaving the institution. Our results show that values of respiratory function in the sample and 6-minute walk test significantly improved with the treatment. After leaving the institute, the results of the Asthma Control Test in the 1st month after treatment revealed a significantly better quality of life and better control-level of patients than after the 3rd month. Orv Hetil. 2018; 159(27): 1103-1112.

Abstract P158: Lipid Management Challenges in Different Clinical Settings

Background: Availability of lipid profile during a patient’s clinic encounter can improve decision-making in regards to therapy, and help achieve therapeutic goals. Methods: Encounters from 2 clinics run by one cardiologist; a University-based clinic and a Veterans Administration (VA) clinic were compared for availability of cholesterol profiles and level of cholesterol control in patients with coronary disease. Results: There were 93 out of 300 encounters (31%) with documented coronary disease (CAD) in the University clinic and 77 out of 134 encounters (57%) in the VA clinic. University patients with CAD had 61% (57/93) lipid documentation during their encounters, while VA patients had 99% (76/77) documentation. The average total cholesterol and LDL for University patients was 179 ± 42 mg/dL and 111 ± 35 mg/dL respectively, compared with 154 ± 38 mg/dL and 93 ± 35 mg/dL for the VA patients respectively (P < 0.01 for each category). Only 39% (22/57) of the University-based patients achieved LDL < 100 mg/dL, compared with 66% (51/77) of VA patients. Blood pressures, which were consistently documented every clinic visit in both clinics, averaged 128/76 mmHg in the University clinic compared with 131/75 mmHg in the VA clinic, with no statistically significant difference. Conclusion: Better control of cholesterol levels is seen in the VA-based clinic compared with the University-based clinic. This may partially be explained by the availability of laboratory results through a unified computer system, allowing more prompt decision-making with regards to medication changes and intensified dietary counseling during the clinic encounter. This may not be always available in other settings where laboratory tests are performed by a different provider utilizing a different reporting system which may not be readily shared or available to the treating cardiologist. Other factors could include variable compliance with laboratory appointments and access to medications. Our findings support establishing means for cardiologists to have access to patients’ laboratory results during their encounter to help more efficient decision making.

The effect of splenectomy on the levels of PCV-13-induced memory B- and T cells.

Splenectomised patients are associated with lifelong risk of fatal overwhelming post-splenectomy infection (OPSI), which is mostly caused by Streptococcus pneumoniae. Today OPSI cases can still be reported even in patients with appropriate vaccination. In our study, the levels of vaccine-specific memory B- and T cells were compared between control and splenectomised patients to enlighten the underlying reason. Five healthy and 14 post-traumatic splenectomised individuals were vaccinated with 13-valent pneumococcal conjugate vaccine (PCV-13) followed by 23-valent pneumococcal polysaccharide vaccine (PPV-23). The levels of memory B- and T cells were compared by ELISPOT analysis. Splenectomised patients generated reduced levels of memory IgG B cells in response to PCV-13 vaccination, while the memory IFN-γ T-cell levels were undetectable in asplenic patients. This was despite the detection of vaccine-induced memory T-cell levels in control patients, which were analysed simultaneously following the same experimental protocol. Our results suggest that spleen is important, but not essential, for survival and/or generation of memory IgG B cells. In contrast, it seems to be indispensable for PCV-13-specific memory TH 1-cell levels. Studies enhancing the levels of vaccine-induced memory cells and further enlightening the immune responses in asplenic individuals are required to develop more effective vaccination strategies against OPSI.

Serum magnesium levels and its correlation with level of control in patients with asthma: A hospital-based, cross-sectional, prospective study.

Context:Magnesium (Mg) is an intracellular cation which takes part in various functions including smooth muscle contractility. Studies have shown that serum Mg level has no significant effect on asthma severity. There are only sparse data on the effect of serum Mg level on asthma control.Aims:The aim of this study was to evaluate the effect of serum Mg level on asthma control.Settings and Design:This hospital-based cross-sectional study was conducted at the Department of Respiratory Medicine, Kasturba Medical College, Manipal.Subjects and Methods:Our participants were adult asthma patients over 18 years of age. Asthma control was assessed using a questionnaire. Serum Mg level was estimated. The study was approved by the Institutional Ethics Committee, and informed consent was obtained from the participants.Statistical Analysis Used:Welch's ANOVA test was used to analyze the correlation between serum Mg level and level of control of asthma.Results:We screened 256 patients who met the inclusion criteria. After 96 patients were removed based on exclusion criteria, 160 patients were grouped into three based on the level of symptom control. Forty-eight patients belonged to the “well controlled” group, 59 in “partly controlled” group, and the remaining 53 in “uncontrolled” group. The mean serum Mg level (mg/dl) was 2.08 ± 0.37, 2.07 ± 0.28, and 1.83 ± 0.34 in well, partly, and uncontrolled groups, respectively. As the level of control of asthma decreased from well controlled to uncontrolled, the level of mean serum Mg also decreased.Conclusions:Serum Mg levels have a positive correlation with the level of symptom control in asthma. In uncontrolled asthma, serum Mg is significantly low. Hence, it might be useful as a biomarker in assessing control or severity of asthma.

Levels of l-arginine and l-citrulline in patients with erectile dysfunction of different etiology.

Nitric oxide is a physiologic signal essential to penile erection. l-citrulline (l-Cit) is converted into l-arginine (l-Arg), the precursor from which nitric oxide is generated. The level of l-Arg and l-Cit in the field of male sexual function remains relatively underexplored. The aim of the study was to evaluate the level of serum l-Arg and of l-Cit in a group of patients with erectile dysfunction. Diagnosis and severity of erectile dysfunction was based on the IIEF-5 and its etiology was classified as arteriogenic (A-ED), borderline (BL-ED), and non-arteriogenic (NA-ED) with penile echo-color-Doppler in basal condition and after intracaversous injection of prostaglandin E1. Serum l-Arg and l-Cit concentrations were measured by a cation-exchange chromatography system. l-Arg and l-Cit levels of men with A-ED were compared with those of male with BL-ED and NA-ED. Median level of l-Arg and l-Cit in 122 erectile dysfunction patients (41 A-ED, 23 ED-BL, 58 NA-ED) was 82.7 and 35.4μmol/L, respectively. l-Arg and l-Cit levels in control patients were not significantly different (p=0.233 and p=0.561, respectively) than in total erectile dysfunction patients. l-Arg and l-Cit levels in control patients were significantly higher (p<0.001 and p<0.018, respectively) than in A-ED patients, but no difference (p>0.50) was observed in controls and in both BL-ED and NA-ED patients. Patients with severe/complete-erectile dysfunction (IIEF-5<10) had l-Arg or l-Cit level significantly lower (-17%, p<0.03; -13%, p<0.04) and were more frequent (p<0.01 and p<0.04) under the respective median level (82.7 and 35.4μmol/L) than those with mild-erectile dysfunction (IIEF-5=16-20). l-Arg and l-Cit levels in A-ED were significantly lower (p<0.007 and p<0.001, respectively) than in NA-ED patients. Penile echo-color-Doppler revealed that A-ED (peak systolic velocity≤25cm/sec) was more frequent in men with l-Arg under 82.7μmol/L or l-Cit under 35.4μmol/L and in the same population, the median peak systolic velocity values were lower in l-Arg deficient (29 vs. 35; p<0.04) and also in l-Cit deficient (31 vs. 33, p>0.3) but without reaching the statistical significance. Our study shows that a significant proportion of erectile dysfunction patients have low l-Arg or l-Cit level and that this condition is more frequent in patients with arteriogenic etiology. Low levels of these nitric oxide synthase substrates might increase the erectile dysfunction risk by reducing the concentration of nitric oxide.

Effect of sitagliptin on blood glucose control in patients with type 2 diabetes mellitus who are treatment naive or poorly responsive to existing antidiabetic drugs: the JAMP study.

BackgroundTo investigate the ameliorating effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood glucose control in patients with type 2 diabetes mellitus who were previously untreated with or who have a poor responsive to existing antidiabetic drugs.MethodsSitagliptin (50 mg/day) was added on to the pre-existing therapy for type 2 diabetes and changes in the glycated hemoglobin (HbA1c) level after 3 months of treatment were compared with the baseline and performed exploratory analysis.ResultsHbA1c levels were significantly decreased after 1 month of treatment compared to baseline, with a mean change in HbA1c level from baseline of −0.73% (range, −0.80 to −0.67) in the entire study population at 3 months. Patients who received a medium dose of glimepiride showed the least improvement in HbA1c levels. The percentage of patients who achieved an HbA1c level of <7.0% significantly increased after 1 month of treatment, reaching 53.1% at 3 months. The percentage of patients who achieved a fasting blood glucose level of <130 mg/dL significantly increased after 1 month of treatment, reaching 50.9% at 3 months.ConclusionsSitagliptin improved the HbA1c level and rate of achieving the target control levels in patients with type 2 diabetes mellitus who were previously untreated with, or poorly responsive to, existing antidiabetic drugs. Thus, sitagliptin is expected to be useful in this patient group. However, the additional administration of sitagliptin in patients treated with medium-dose glimepiride only slightly improved blood glucose control when corrected for baseline HbA1c level.Electronic supplementary materialThe online version of this article (doi:10.1186/s12902-016-0149-z) contains supplementary material, which is available to authorized users.

Grado en que se alcanzan los objetivos de control en pacientes con diabetes de tipo 2 en diferentes grupos poblacionales

IntroductionThere is evidence of increased macro- and micro-vascular risk in diabetic patients. The objective of this study was to determine the level of control in patients in different population groups with type 2 diabetes. Material and methods. DesignDescriptive cross-sectional study. Location: Primary care. Madrid Health Service. Year: 2014. Subjects: Patients over 14 years with type 2 diabetes. Number of patientes: n=6674. MeasurementsVariables on the degree of control (HbA1c, systolic blood pressure [SBP], diastolic blood pressure [DBP], LDL-c) and variables on patient characteristics (demographic, other cardiovascular risk factors, complications). ResultsThe mean age of patients with controlled HbA1c was 67.8 years vs. 62.9 years in the uncontrolled (P<.001). Patients diagnosed with hypertension have a higher percentage of control with respect to the undiagnosed in HbA1c, SBP, DBP and LDL-c: 51 vs. 37%, 62 vs. 43%, 75 vs. 47% and 57 vs. 44% respectively; diagnosed with dyslipidaemia: 51 vs. 39%, 60 vs. 49%, 70 vs. 56% and 56 vs. 46%. With a diagnosis of macroangiopathy: 46 vs. 45%, 58 vs. 54%, 71 vs. 62% and 15 vs. 60%. All differences were statistically significant (P<.001). Over 50% of patients without a diagnosis of hypertension had an SBP> 140mmHg or DBP> 90mmHg. Over 25% of patients with hypertension or DL and uncontrolled levels were not receiving drug treatment. ConclusionControl was improved in all groups, especially in younger patients, with particularly high cardiovascular risk by the presence of other cardiovascular risk factors or macroangiopathy. A significant percentage of patients with uncontrolled BP and cLDL were not diagnosed or receiving drug treatment.

Thrombelastography-Based Dosing of Enoxaparin for Thromboprophylaxis in Trauma and Surgical Patients: A Randomized Clinical Trial.

Prophylactic enoxaparin is used to prevent venous thromboembolism (VTE) in surgical and trauma patients. However, VTE remains an important source of morbidity and mortality, potentially exacerbated by antithrombin III or anti-Factor Xa deficiencies and missed enoxaparin doses. Recent data suggest that a difference in reaction time (time to initial fibrin formation) greater than 1 minute between heparinase and standard thrombelastogram (TEG) is associated with a decreased risk of VTE. To evaluate the effectiveness of TEG-adjusted prophylactic enoxaparin dosing among trauma and surgical patients. This randomized clinical trial, conducted from October 2012 to May 2015, compared standard dosing (30 mg twice daily) with TEG-adjusted enoxaparin dosing (35 mg twice daily) for 185 surgical and trauma patients screened for VTE at 3 level I trauma centers in the United States. The incidence of VTE, bleeding complications, anti-Factor Xa deficiency, and antithrombin III deficiency. Of the 185 trial participants, 89 were randomized to the control group (median age, 44.0 years; 55.1% male) and 96 to the intervention group (median age, 48.5 years; 74.0% male). Patients in the intervention group received a higher median enoxaparin dose than control patients (35 mg vs 30 mg twice daily; P < .001). Anti-Factor Xa levels in intervention patients were not higher than levels in control patients until day 6 (0.4 U/mL vs 0.21 U/mL; P < .001). Only 22 patients (11.9%) achieved a difference in reaction time greater than 1 minute, which was similar between the control and intervention groups (10.4% vs 13.5%; P = .68). The time to enoxaparin initiation was similar between the control and intervention groups (median [range] days, 1.0 [0.0-2.0] vs 1.0 [1.0-2.0]; P = .39), and the number of patients who missed at least 1 dose was also similar (43 [48.3%] vs 54 [56.3%]; P = .30). Rates of VTE (6 [6.7%] vs 6 [6.3%]; P > .99) were similar, but the difference in bleeding complications (5 [5.6%] vs 13 [13.5%]; P = .08) was not statistically significant. Antithrombin III and anti-Factor Xa deficiencies and hypercoagulable TEG parameters, including elevated coagulation index (>3), maximum amplitude (>74 mm), and G value (>12.4 dynes/cm2), were prevalent in both groups. Identified risk factors for VTE included older age (61.0 years vs 46.0 years; P = .04), higher body mass index (calculated as weight in kilograms divided by height in meters squared; 30.6 vs 27.1; P = .03), increased Acute Physiology and Chronic Health Evaluation II score (8.5 vs 7.0; P = .03), and increased percentage of missed doses per patient (14.8% vs 2.5%; P = .05). The incidence of VTE was low and similar between groups; however, few patients achieved a difference in reaction time greater than 1 minute. Antithrombin III deficiencies and hypercoagulable TEG parameters were prevalent among patients with VTE. Low VTE incidence may be due to an early time to enoxaparin initiation and an overall healthier and less severely injured study population than previously reported. clinicaltrials.gov Identifier: NCT00990236.

THE IMPACT OF SUBLINGUAL ALLERGEN IMMUNOTHERAPY ON ASTHMA CONTROL AND THE QUALITY OF LIFE LEVEL IN PATIENTS WITH ALLERGIC ASTHMA AND SENSITIZATION TO TREES POLLEN

Background. To Evaluate the effects of trees pollen sublingual products on the control and quality of life in patients with allergic asthma and proven sensitization to pollens of trees. Methods. We enrolled 56 patients in open prospective study and divided into 2 groups to assess the effectiveness of therapy with sublingual allergen. Groups were matched on estimated parameters of quality of life, level of control and forced expiratory volume in the first second. Results. Statistically significant improvement of quality of life parameters and the level of control within the group receiving sublingual immunotherapy was obtained. Significant difference in the average dose of received inhaled corticosteroids was established in the treatment group comparing to control. Conclusion. Sublingual allergen specific immunotherapy has a positive impact on quality of life and level of control in patients with allergic asthma and proven sensitization to pollens of trees, and decreasing the dose of inhaled corticosteroids.

The level of control of mild asthma in general practice: an observational community-based study

Objective: The aim of the present community-based study was to evaluate the level of asthma control in patients with mild asthma, regularly treated with inhaled steroids (ICS). Method: This observational cross-sectional study included patients registered in the general practitioner (GP) database and with at least three prescriptions of ICS in the last 12 months. Patients were asked to refer to the doctor’s office for a standardised interview. The level of asthma control was self-measured by the patients using the Asthma Control Test (ACT)™ (Quality Metric, Inc.). Results: The study included 950 asthmatic patients, referred by 540 GPs: 54.5% were females, mean age was 51 (±19.1) years; 59.5% were non-smokers, 22.5% were current smokers and 18.0% were former smokers; 81.1% of the patients were on ICS in the last 4 weeks. Only 38.6% of patients had a spirometry in the last 12 months. According to the ACT, 13.7% of the asthmatic patients were totally controlled, 51.0% well controlled, and 35.3% poorly controlled. Smoking habit, older age (>60) and living in Central or Southern Italy were associated with poorer control. In the last 12 months 4.5% of patients had an asthma-related hospitalisation, 5.3% an emergency visit and 18.9% a specialist visit. Conclusions: More than one of three patients had poor asthma control, despite being considered by their GPs as mild asthmatics and treated with ICS. Asthmatic patients need to be regularly re-evaluated. Treatment is often inadequate and should be targeted to improve control and reduce asthma morbidity (SAM104964).

Diagnosis and inflammatory response of patients with candiduria

Candiduria is common in hospitalised patients, but the clinical relevance is still unclear. This study was done to further our knowledge on detection of and host responses to candiduria. Urines and clinical data from 136 patients in whom presence of yeast was diagnosed by microscopic urinalysis were collected. Diagnosis by standard urine culture methods on blood and MacConkey agar as well as on fungal culture medium (Sabouraud dextrose agar) was compared. Inflammatory parameters (IL-6 and IL-17, Ig) were quantified in the urine and compared with levels in control patients without candiduria. Standard urine culture methods detected only 37% of Candida spp. in urine. Sensitivity was especially low (23%) for C. glabrata and was independent of fungal burden. Candida specific IgG but not IgA was significantly elevated when compared with control patients (P < 0.0001 and 0.07 respectively). In addition, urine levels of IL-6 and IL-17 were significantly higher in candiduric patients when compared with control patients (P < 0.001). Multivariate analysis documented an independent association between an increased IgG (odds ratio (OR) 136.0, 95% confidence interval (CI) 25.7-719.2; P < 0.0001), an increased IL-17 (OR 17.4, 95% CI 5.3-57.0; P < 0.0001) and an increased IL-6 level (OR 4.9, 95% CI 1.9-12.4; P = 0.001) and candiduria. In summary, our data indicate that clinical studies on candiduria should include fungal urine culture and that inflammatory parameters may be helpful to identify patients with clinically relevant candiduria.

Lower serum UA levels in Parkinson's disease patients in the Chinese population

Parkinson's disease (PD) is the second most common neurodegenerative disease in the world, and oxidative stress plays an important role in its pathogenesis. Uric acid (UA) is a product of purine metabolism and is a natural antioxidant that can relieve the oxidative stress that occurs in PD. Recent studies have indicated that the serum UA level are associated with a risk of PD and PD progression of motor symptoms and have proposed UA as a possible biomarker of the underlying pathophysiology of PD. In our study, we investigated the association between serum UA level and PD in a Chinese population. We found that the serum UA levels in PD patients were lower than the levels in control patients and were correlated with PD progression and duration in the Chinese population. These associations were observed in both genders, but hyperuricemia is more strongly associated with lower rates of PD among men compared to women and older people compared to younger people. Our results indicate that UA could be an important biomarker of PD and that the serum UA level could be a useful biomarker of PD diagnosis and disease progression.

149 Prevalence of Vitamin D Deficiency Among Hemodialysis Patients and Response to Cholecalciferol

PREVALENCE OF VITAMIN D DEFICIENCY AMONG HEMODIALYSIS PATIENTS AND RESPONSE TO CHOLECALCIFEROL Maria Krassilnikova, Anita Mehrotra, Peter Heeger. Mount Sinai School of Medicine, New York, NY, USA The purpose of this study was to determine the prevalence of 25OH Vitamin D deficiency in hemodialysis patients, identify associated factors, and assess response to repletion with cholecalciferol (D3). We consented 52 outpatients at the Mount Sinai Dialysis unit between August and November 2010 for Vitamin D testing. Those patients found to have 25OH Vit D levels < 25 ng/mL were eligible for randomization to treatment with D3 (50,000 IU weekly) or control (standard of care). 25OH Vitamin D levels were measured in a subset of patients (n = 14) after six weeks of follow-up. The prevalence of Vit D deficiency was 94.2%, as defined by a 25OH Vit D level < 30ng/mL, and 26.9% of patients had Vit D levels < 10ng/mL. Mean and median Vit D levels were 16.1 and 14.1 ng/mL, respectively. Selected clinical characteristics of the patient cohort are given in the table below. There was no association between Vit D level and age, gender, race, or dialysis vintage, but Vit D levels negatively correlated with BMI (Spearman’s ρ = -0.355, p = 0.011). After six weeks of D3 repletion (n = 9), 25OH Vit D increased from a mean of 13.7 ng/mL to 36.6 ng/mL (p = 0.001), with no change in serum Ca or 1,25OH Vit D requirements. No change was noted in the Vit D level of control patients (13.3 ng/mL to 13.1 ng/mL, p = 0.943, n = 5). We demonstrate a higher prevalence of Vit D deficiency among hemodialysis patients than previously reported, and an ability to correct this deficiency with oral D3. A study of the effects of D3 repletion on the immune system in these patients is ongoing. Age, years (mean +/SD) 57 +/12 Gender: Male (%) 28 (53.8%) Race: Black (%) 29 (55.8%)

Oxidative Stress-Mediated Brain Dehydroepiandrosterone (DHEA) Formation in Alzheimer?s Disease Diagnosis

Neurosteroids are steroids made by brain cells independently of peripheral steroidogenic sources. The biosynthesis of most neurosteroids is mediated by proteins and enzymes similar to those identified in the steroidogenic pathway of adrenal and gonadal cells. Dehydroepiandrosterone (DHEA) is a major neurosteroid identified in the brain. Over the years we have reported that, unlike other neurosteroids, DHEA biosynthesis in rat, bovine, and human brain is mediated by an oxidative stress-mediated mechanism, independent of the cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) enzyme activity found in the periphery. This alternative pathway is induced by pro-oxidant agents, such as Fe2+ and β-amyloid peptide. Neurosteroids are involved in many aspects of brain function, and as such, are involved in various neuropathologies, including Alzheimer’s disease (AD). AD is a progressive, yet irreversible neurodegenerative disease for which there are limited means for ante-mortem diagnosis. Using brain tissue specimens from control and AD patients, we provided evidence that DHEA is formed in the AD brain by the oxidative stress-mediated metabolism of an unidentified precursor, thus depleting levels of the precursor in the blood stream. We tested for the presence of this DHEA precursor in human serum using a Fe2+-based reaction and determined the amounts of DHEA formed. Fe2+ treatment of the serum resulted in a dramatic increase in DHEA levels in control patients, whereas only a moderate or no increase was observed in AD patients. The DHEA variation after oxidation correlated with the patients’ cognitive and mental status. In this review, we present the cumulative evidence for oxidative stress as a natural regulator of DHEA formation and the use of this concept to develop a blood-based diagnostic tool for neurodegenerative diseases linked to oxidative stress, such as AD.

Role of Th17 cells in human autoimmune arthritis

To delineate the role of Th17 cells in the pathogenesis of autoimmune arthritides. Th17 cells were analyzed in well-defined homogeneous cohorts of patients with the prototypical autoimmune arthritides rheumatoid arthritis (RA) and psoriatic arthritis (PsA), grouped according to patients who had very early active RA (n = 36; mean disease duration 2.8 months, Disease Activity Score in 28 joints 5.0) and those who had very early active PsA (n = 20; mean disease duration 2.3 months), none of whom had received treatment with glucocorticoids or disease-modifying antirheumatic drugs, as well as patients with established RA (n = 21; mean disease duration 68 months) who were considered either responders or nonresponders to therapy. Groups of healthy individuals and patients with osteoarthritis (a noninflammatory arthritis) were used as control cohorts. Expression of T lineage-specific transcription factors (RORC, T-bet, GATA-3, and FoxP3) and the response of CD4 T cells to Th17 cell-inducing conditions were analyzed in vitro. The frequencies of Th17 cells and levels of interleukin-17 strongly correlated with systemic disease activity at both the onset and the progression of RA or PsA. The values were reduced to control levels in patients with treatment-controlled disease activity. Th17 cells were enriched in the joints, and increased frequencies of synovial Th17 cells expressed CCR4 and CCR6, indicative of selective migration of Th17 cells to the joints. The intrinsically elevated expression of RORC, accompanied by biased Th17 cell development, and the resistance of Th17 cells to a natural cytokine antagonist in patients with RA and patients with PsA were suggestive of the underlying molecular mechanisms of uncontrolled Th17 activity in these patients. Th17 cells play an important role in inflammation in human autoimmune arthritides, both at the onset and in established disease.

Persistent plasminogen activator inhibitor 1 gene expression in cardiac transplant recipients with idiopathic dilated cardiomyopathy

Plasminogen activator inhibitor 1 is the primary regulator of urokinase plasminogen activator and tissue plasminogen activator. Plasminogen activator inhibitor 1 is essential in the control of the thrombotic/fibrinolytic balance and is a marker of endothelial cell injury. Idiopathic dilated cardiomyopathy is reportedly associated with endothelial cell dysfunction. Whether endothelial cell damage plays a role in patients with dilated cardiomyopathy after cardiac transplantation remains unknown. In this study explanted hearts of cardiac transplant recipients with ischemic cardiomyopathy and dilated cardiomyopathy, as well as control myocardial tissue, were investigated for expression of urokinase plasminogen activator, tissue plasminogen activator, urokinase plasminogen activator receptor, and plasminogen activator inhibitor 1 and 2. Furthermore, plasminogen activator inhibitor 1 expression was examined in endomyocardial biopsy specimens and sera of patients with ischemic cardiomyopathy and those with dilated cardiomyopathy during the first posttransplantation year. The effect of the patient's serum on endothelial cells was assessed in vitro to examine the role of circulating endothelial cell damage-related factors. Plasminogen activator inhibitor 1 expression was upregulated in ischemic cardiomyopathy and dilated cardiomyopathy myocardial tissue versus that seen in control tissue. After transplantation, plasminogen activator inhibitor 1 expression returned to control levels in patients with ischemic cardiomyopathy. In patients with dilated cardiomyopathy, plasminogen activator inhibitor 1 expression increased at 24 weeks after transplantation in both biopsy specimens and sera versus that seen in control tissue. Sera of patients with dilated cardiomyopathy, but not that of patients with ischemic cardiomyopathy, inhibited vascular endothelial growth factor A-induced proliferation of endothelial cells, although downstream target gene activation of early growth response factor 1 and NGFI-A binding protein 2 was not affected. These data suggest for the first time that the endothelial cell damage-related process recurs in patients with dilated cardiomyopathy after transplantation, which, independently of vascular endothelial growth factor, is associated with increased plasminogen activator inhibitor 1 expression, and that this pathology might play a role in allograft remodeling in patients with dilated cardiomyopathy.

INVESTing in Hypertension

Hypertension is a common risk factor for peripheral arterial disease (PAD), and the majority of patients with PAD are hypertensive. Recent consensus-based recommendations from the American Heart Association [1] indicate that the goal of antihypertensive therapy in patients with PAD should be to achieve a blood pressure (BP) less than 130/80 mm Hg. However, evidence from clinical trials for the optimal level of BP control in patients with PAD is lacking.

Nonlinear Response of the Anterior Cingulate and Prefrontal Cortex in Schizophrenia as a Function of Variable Attentional Control

Previous studies have reported abnormal prefrontal and cingulate activity during attentional control processing in schizophrenia. However, it is not clear how variation in attentional control load modulates activity within these brain regions in this brain disorder. The aim of this study in schizophrenia is to investigate the impact of increasing levels of attentional control processing on prefrontal and cingulate activity. Blood oxygen level-dependent (BOLD) responses of 16 outpatients with schizophrenia were compared with those of 21 healthy subjects while performing a task eliciting increasing levels of attentional control during event-related functional magnetic resonance imaging at 3 T. Results showed reduced behavioral performance in patients at greater attentional control levels. Imaging data indicated greater prefrontal activity at intermediate attentional control levels in patients but greater prefrontal and cingulate responses at high attentional control demands in controls. The BOLD activity profile of these regions in controls increased linearly with increasing cognitive loads, whereas in patients, it was nonlinear. Correlation analysis consistently showed differential region and load-specific relationships between brain activity and behavior in the 2 groups. These results indicate that varying attentional control load is associated in schizophrenia with load- and region-specific modification of the relationship between behavior and brain activity, possibly suggesting earlier saturation of cognitive capacity.

Genome-wide expression analysis of peripheral blood identifies candidate biomarkers for schizophrenia

The aim of this study was to analyze gene expression in blood of patients with newly-diagnosed schizophrenia during their first psychotic episode and subsequent remission. Whole blood samples were obtained from 32 untreated patients presenting with their first psychotic episode suggestive of schizophrenia and 32 age- and gender-matched controls. Using Affymetrix micoarrays, we identified significantly altered expression of 180 gene probes in psychotic patients compared to controls. A subset of four significantly changed genes was further confirmed with QRT-PCR. The following genes were significantly altered in patients: glucose transporter, SLC2A3 ( p < 0.001) and actin assembly factor DAAM2 ( p < 0.001) were increased, whereas translation, zinc metallopeptidase, neurolysin 1 and myosin C were significantly decreased ( p < 0.05). Expression of these candidate markers was also analyzed in a longitudinal study (12–24 months) in 12 patients who achieved full remission. Interestingly, expression of DAAM2 returned to control levels in patients who were in remission after their first psychotic episode, suggesting that its expression correlates with diseases progression and/or response to treatment. In summary, we identified changes of gene expression from peripheral blood which might help discriminate patients with schizophrenia from controls. While these results are promising, especially for DAAM2 whose polymorphic variants have been found significantly associated with schizophrenia, it will be important to analyze larger cohorts of patients in order to firmly establish changes in gene expression as blood markers of schizophrenia.