Effects Of Cumulative Doses Research Articles

The hallucinogen d-lysergic diethylamide (LSD) decreases dopamine firing activity through 5-HT1A, D2 and TAAR1 receptors

d-lysergic diethylamide (LSD) is a hallucinogenic drug that interacts with the serotonin (5-HT) system binding to 5-HT1 and 5-HT2 receptors. Little is known about its potential interactions with the dopamine (DA) neurons of the ventral tegmental area (VTA). Using in-vivo electrophysiology in male adult rats, we evaluated the effects of cumulative doses of LSD on VTA DA neuronal activity, compared these effects to those produced on 5-HT neurons in the dorsal raphe nucleus (DRN), and attempted to identify the mechanism of action mediating the effects of LSD on VTA DA neurons. LSD, at low doses (5–20μg/kg, i.v.) induced a significant decrease of DRN 5-HT firing activity through 5-HT2A and D2 receptors. At these low doses, LSD did not alter VTA DA neuronal activity. On the contrary, at higher doses (30–120μg/kg, i.v.), LSD dose-dependently decreased VTA DA firing activity. The depletion of 5-HT with p-chlorophenylalanine did not modulate the effects of LSD on DA firing activity. The inhibitory effects of LSD on VTA DA firing activity were prevented by the D2 receptor antagonist haloperidol (50μg/kg, i.v.) and by the 5-HT1A receptor antagonist WAY-100,635 (500μg/kg, i.v.). Notably, pretreatment with the trace amine-associate receptor 1 (TAAR1) antagonist EPPTB (5mg/kg, i.v.) blocked the inhibitory effect of LSD on VTA DA neurons. These results suggest that LSD at high doses strongly affects DA mesolimbic neuronal activity in a 5-HT independent manner and with a pleiotropic mechanism of action involving 5-HT1A, D2 and TAAR1 receptors.

Comprehensive Audiometric Analysis of Hearing Impairment and Tinnitus After Cisplatin-Based Chemotherapy in Survivors of Adult-Onset Cancer.

Cisplatin is widely used but highly ototoxic. Effects of cumulative cisplatin dose on hearing loss have not been comprehensively evaluated in survivors of adult-onset cancer. Comprehensive audiological measures were conducted on 488 North American male germ cell tumor (GCT) survivors in relation to cumulative cisplatin dose, including audiograms (0.25 to 12 kHz), tests of middle ear function, and tinnitus. American Speech-Language-Hearing Association criteria defined hearing loss severity. The geometric mean of hearing thresholds (0.25 to 12 kHz) summarized overall hearing status consistent with audiometric guidelines. Patients were sorted into quartiles of hearing thresholds of age- and sex-matched controls. Increasing cumulative cisplatin dose (median, 400 mg/m(2); range, 200 to 800 mg/m(2)) was significantly related to hearing loss at 4, 6, 8, 10, and 12 kHz (P trends, .021 to < .001): every 100 mg/m(2) increase resulted in a 3.2-dB impairment in age-adjusted overall hearing threshold (4 to 12 kHz; P< .001). Cumulative cisplatin doses > 300 mg/m(2) were associated with greater American Speech-Language-Hearing Association-defined hearing loss severity (odds ratio, 1.59; P = .0066) and worse normative-matched quartiles (odds ratio, 1.33; P = .093) compared with smaller doses. Almost one in five (18%) patients had severe to profound hearing loss. Tinnitus (40% patients) was significantly correlated with reduced hearing at each frequency (P< .001). Noise-induced damage (10% patients) was unaffected by cisplatin dose (P = .59). Hypertension was significantly related (P = .0066) to overall hearing threshold (4 to 12 kHz) in age- and cisplatin dose-adjusted analyses. Middle ear deficits occurred in 22.3% of patients but, as expected, were not related to cytotoxic drug dosage. Follow-up of adult-onset cancer survivors given cisplatin should include routine inquiry for hearing status and tinnitus, referral to audiologists as clinically indicated, and hypertension control. Patients should be urged to avoid noise exposure, ototoxic drugs, and other factors that further damage hearing.

Influence of inhaled corticosteroids on pubertal growth and final height in asthmatic children.

Controversial data exist on the possibility that inhaled corticosteroids (ICs) affect growth in children with mild-to-moderate asthma. We assessed whether ICs affect growth and final height (FH) in asthmatic children compared to controls. A retrospective study was conducted on 113 asthmatic children compared with 66 control children. Asthmatic children presented with mild-to-moderate asthma and had exclusive ICs. Anthropometric data of four specific time-points were collected for both groups (pre-puberty, onset and late puberty, and FH) and converted to standard deviation scores (SDS). Growth trajectories were assessed as follows: (i) in puberty, using peak height velocity (PHV) and pubertal height gain SDS (PHG-SDS); (ii) until FH achievement, using FH-SDS and FH gain SDS (FHG-SDS). Repeated measurement analysis was performed across longitudinal study visits. A general linear model (GLM) was performed in asthmatic group evaluating the effect of corticosteroid type, treatment duration, and cumulative dose on FH corrected for multiple variables. At pre-puberty, height and weight SDS were similar between the groups (p > 0.05). Height SDS progressively declined over the study period in asthmatic patients from pre-puberty to FH (p-trend < 0.05), whereas it did not change over time in controls (p-trend > 0.05), in both boys and girls. Asthmatic children had exclusive ICs [budesonide (n = 36) vs. fluticasone (n = 43) vs. mometasone (n = 34)] for a mean period of 6.25 ± 1.20 years and a mean cumulative dose of 560.07 ± 76.02 mg. They showed decreased PHG-SDS and lower PHV compared to controls (all p < 0.05). FH-SDS and FHG-SDS were significantly reduced in asthmatic group compared to controls. FH in asthmatic patients was 2.5 ± 2.89 cm lower in boys and 2.0 ± 2.03 cm lower in girls than controls. The GLM showed that FH achievement was dependent on the type of ICs, duration of the treatment, and cumulative dose (p < 0.05). ICs affect pubertal growth determining reduced final height in asthmatic children compared to controls, in a dose- and duration-dependent manner.

Subconcussive Blows to the Head: A Formative Review of Short-term Clinical Outcomes.

Given questions about "lower thresholds" for concussion, as well as possible effects of repetitive concussion and chronic traumatic encephalopathy (CTE), and associated controversy, there is increasing interest in "subconcussive" blows and their potential significance. A formative review with critical examination of the developing literature on subconcussive blows in athletes with an emphasis on clinical outcomes. Studies of biomechanical, performance and/or symptom-based, and neuroimaging data were identified via PubMed search and critically reviewed. Five studies of symptom reporting/performance and 4 studies of neuroimaging were included. The relation between biomechanical parameters and diagnosed concussion is not straightforward (ie, it is not the case that greater and more force leads to more severe injury or cognitive/behavioral sequelae). Neuropsychological studies of subconcussive blows within a single athletic season have failed to demonstrate any strong and consistent relations between number and severity of subconcussive events and cognitive change. Recent studies using neuroimaging have demonstrated a potential cumulative effect of subconcussive blows, at least in a subset of individuals. Human studies of the neurological/neuropsychological impact of subconcussive blows are currently quite limited. Subconcussive blows, in the short-term, have not been shown to cause significant clinical effects. To date, findings suggest that any effect of subconcussive blows is likely to be small or nonexistent, perhaps evident in a subset of individuals on select measures, and maybe even beneficial in some cases. Longer-term prospective studies are needed to determine if there is a cumulative dose effect.

Current Evidence for Developmental, Structural, and Functional Brain Defects following Prenatal Radiation Exposure.

Ionizing radiation is omnipresent. We are continuously exposed to natural (e.g., radon and cosmic) and man-made radiation sources, including those from industry but especially from the medical sector. The increasing use of medical radiation modalities, in particular those employing low-dose radiation such as CT scans, raises concerns regarding the effects of cumulative exposure doses and the inappropriate utilization of these imaging techniques. One of the major goals in the radioprotection field is to better understand the potential health risk posed to the unborn child after radiation exposure to the pregnant mother, of which the first convincing evidence came from epidemiological studies on in utero exposed atomic bomb survivors. In the following years, animal models have proven to be an essential tool to further characterize brain developmental defects and consequent functional deficits. However, the identification of a possible dose threshold is far from complete and a sound link between early defects and persistent anomalies has not yet been established. This review provides an overview of the current knowledge on brain developmental and persistent defects resulting from in utero radiation exposure and addresses the many questions that still remain to be answered.

A Prospective, Multicenter, 2-Year Echocardiographic Study on Valvular Heart Disease in Parkinson's Disease Patients Taking Rotigotine and Other non-Ergot Dopamine Agonists

Objectives: We explored the possible risk of valvular heart disease (VHD) in Parkinson’s disease (PD) patients taking rotigotine compared to other non-ergot dopamine agonists (DA) as requested by the EMA (European Medicines Agency) in terms of assessing the longterm safety associated with the cumulative dose of rotigotine. Methods: We performed a prospective, multicenter, open-label, 2-year echocardiographic study in PD patients taking rotigotine or other non-ergot DA (piribedil, pramipexole, ropinirole). Valvular pathology was assessed by transthoracic echocardiographic examinations according to American Society of Echocardiography recommendations and a scoring system for restrictive VHD at 1-month, 12-months and 24-months follow-up examination. Routine neurological and physical examinations with special attention toward clinical symptoms of heart failure were performed after 1, 6, 12, 18 and 24 months. Results: 102 out of 107 screened patients were enrolled into the study. Due to drop-outs along the 2-year followup, 66 patients (28 rotigotine, 38 other non-ergot DAs [3 piribedil, 20 pramipexole, 15 ropinirole]) completed the 12-months visit and 53 patients (23 rotigotine, 30 other non-ergot DAs [3 piribedil, 16 pramipexole, 11 ropinirole]) completed the 24-months visit. No patient showed clinical symptoms of heart failure or echocardiographic evidence of restrictive VHD during the 2-year period. Analyses of valve regurgitation (VR) revealed no case of severe or moderate VR in the rotigotine group. Only one patient taking pramipexole showed moderate VR at 1-month and 12-months follow-up visit decreasing to mild degree at 24-months follow-up. Conclusions: This is the first prospective study assessing the possible risk of VHD in patients taking rotigotine. We did not find valvular pathology suggestive for restrictive VHD or increased risk of cardiac VR in PD patients receiving rotigotine or other non-ergot DAs. Future studies are needed to explore the clinical relevance and the relationship between non-ergot DAs and heart failure including effects of cumulative dose or comedication with other antiparkinsonian drugs.

A randomised trial of glucocorticoids in acute-stage allergic bronchopulmonary aspergillosis complicating asthma.

Whether use of high-dose steroids in acute-stage allergic bronchopulmonary aspergillosis (ABPA) is associated with superior outcomes is not known. Herein, we compare the efficacy and safety of two glucocorticoid protocols in ABPA.Treatment-naive ABPA subjects randomly received either high-dose or medium-dose oral prednisolone. The primary outcomes were exacerbation rates and glucocorticoid-dependent ABPA after 1 and 2 years, respectively, of treatment. The secondary end-points were composite response rates after 6 weeks, improvement in lung function, time to first exacerbation, cumulative dose and adverse effects.92 subjects (high-dose n=44, medium-dose n=48) were included in the study. The numbers of subjects with exacerbation after 1 year (high-dose 40.9% versus medium-dose 50%, p=0.59) and glucocorticoid-dependent ABPA after 2 years (high-dose 11.4% versus medium-dose 14.6%, p=0.88) were similar in the two groups. Although composite response rates were significantly higher in the high-dose group, improvement in lung function and time to first exacerbation were similar in the two groups. Cumulative glucocorticoid dose and side-effects were significantly higher in the high-dose group.Medium-dose oral glucocorticoids are as effective and safer than high-dose in treatment of ABPA.

γ-H2AX responds to DNA damage induced by long-term exposure to combined low-dose-rate neutron and γ-ray radiation

Risk estimates for low-dose radiation (LDR) remain controversial. The possible involvement of DNA repair-related genes in long-term low-dose-rate neutron-gamma radiation exposure is poorly understood. In this study, 60 rats were divided into control groups and irradiated groups, which were exposed to low-dose-rate n-γ combined radiation (LDCR) for 15, 30, or 60 days. The effects of different cumulative radiation doses on peripheral blood cell (PBC), subsets of T cells of peripheral blood lymphocytes (PBL) and DNA damage repair were investigated. Real-time PCR and immunoblot analyses were used to detect expression of DNA DSB-repair-related genes involved in the NHEJ pathway, such as Ku70 and Ku80, in PBL. The mRNA level of H2AX and the expression level of γ-H2AX were detected by real-time PCR, immunoblot, and flow cytometry. White blood cells (WBC) and platelets (PLT) of all ionizing radiation (IR) groups decreased significantly, while no difference was seen between the 30 day and 60 day exposure groups. The numbers of CD3+, CD4+ T cells and CD4+/CD8+ in the PBL of IR groups were lower than in the control group. In the 30 day and 60 day exposure groups, CD8+ T cells decreased significantly. Real-time PCR and immunoblot results showed no significant difference in the mRNA and protein expression of Ku70 and Ku80 between the control groups and IR groups. However, the mRNA of H2AX increased significantly, and there was a positive correlation with dose. There was no difference in the protein expression of γ-H2AX between 30 day and 60 day groups, which may help to explain the damage to PBL. In conclusion, PBL damage increased with cumulative dose, suggesting that γ-H2AX, but neither Ku70 nor Ku80, plays an important role in PBL impairment induced by LDCR.

Vasopressin 1a receptor partial agonism increases sodium excretion and reduces portal hypertension and ascites in cirrhotic rats.

Patients and rats with cirrhosis and ascites have portal hypertension and circulatory dysfunction. Synthetic arginine vasopressin (AVP) receptor agonists able to induce systemic and mesenteric vasoconstriction have shown their usefulness in reducing portal pressure (PP) in this condition. We assessed the potential therapeutic value of a new V1 a -AVP receptor partial agonist with a preferential splanchnic vasoconstrictor effect (FE 204038) in rats with cirrhosis and ascites. The hemodynamic effects of cumulative intravenous doses of FE 204038, terlipressin, or vehicle were investigated. Mean arterial pressure and PP were continuously recorded and cardiac output and systemic vascular resistance (SVR) assessed at 30-minute intervals for 90 minutes. Urine volume, urine osmolality, and urinary excretion of sodium and creatinine were measured in basal conditions and following twice-daily subcutaneous doses of FE 204038 or vehicle. PP, mean arterial pressure, cardiac output, SVR, and ascites volume were also measured after 6 days. The expression of an array of vasoactive genes was assessed in the thoracic aorta and the mesenteric circulation of control rats and rats with cirrhosis and ascites. FE 204038 dose-dependently decreased PP, did not modify mean arterial pressure, and increased SVR. The effect of the V1a -AVP receptor partial agonist on PP was associated with an improvement in urine volume and urinary excretion of sodium during the first day of treatment. SVR was higher and cardiac output and ascites volume were lower in rats with cirrhosis and ascites treated with FE 204038. V1a -AVP receptor expression in rats with cirrhosis and ascites was markedly enhanced in the mesenteric circulation compared to the thoracic aorta. FE 204038 increases sodium excretion and reduces portal hypertension and ascites in experimental cirrhosis. V1a -AVP receptor partial agonism could be a useful pharmacological treatment in decompensated patients with cirrhosis.

Morphine-induced antinociception and reward in "humanized" mice expressing the mu opioid receptor A118G polymorphism.

The rewarding and antinociceptive effects of opioids are mediated through the mu-opioid receptor. The A118G single nucleotide polymorphism in this receptor has been implicated in drug addiction and differences in pain response. Clinical and preclinical studies have found that the G allele is associated with increased heroin reward and self-administration, elevated post-operative pain, and reduced analgesic responsiveness to opioids. Male and female mice homozygous for the "humanized" 118AA or 118GG alleles were evaluated to test the hypothesis that 118GG mice are less sensitive to the rewarding and antinociceptive effects of morphine. We found that 118AA and 118GG mice of both genders developed conditioned place preference for morphine. All mice developed tolerance to the antinociceptive and hypothermic effects of morphine. However, morphine tolerance was not different between AA and GG mice. We also examined sensitivity to the antinociceptive and hypothermic effects of cumulative morphine doses. We found that 118GG mice show reduced hypothermic and antinociceptive responses on the hotplate for 10mg/kg morphine. Finally, we examined basal pain response and morphine-induced antinociception in the formalin test for inflammatory pain. We found no gender or genotype differences in either basal pain response or morphine-induced antinociception in the formalin test. Our data suggests that homozygous expression of the GG allele in mice blunts morphine-induced hypothermia and hotplate antinociception but does not alter morphine CPP, morphine tolerance, or basal inflammatory pain response.

Significance of Echocardiography in the Assessment of Left Ventricular Function in Patients Receiving Combined Adjuvant Treatment with Anthracyclines and Trastuzumab / Značaj ehokardiografije u proceni funkcije leve komore kod bolesnica na adjuvantnoj terapji (kombinovana terapija antraciklinima i trastuzumabom)

Abstract The application of anthracycline and trastuzumab in adjuvant breast cancer treatment approach has significantly improved the survival of patients, but also carries the risk of cardiotoxicity that is manifested by reducing the ejection fraction of the heart. The aim of the study was to investigate the effect of cumulative anthracycline dose in combination therapy with trastuzumab on the left ventricular ejection fraction, and the influence of the time interval for starting the treatment with trastuzumab. The study included a group of 80 breast cancer patients (aged 28 to 75 years) who underwent the therapy with anthracyclines (IV-VI cycles) with the continuation of trastuzumab therapy for a period of one year. Ejection fraction at the end of completing the treatment period (VI anthracycline cycles and trastuzumab) was significantly lower in 68 (93%) patients compared to the value at the beginning of the study (68.2% ± 6.06 to 62.1 ± 6.1%; p &lt;0.0001; difference 6.1%). In five patients (anthracyclines and trastuzumab IV cycles) a decrease of 7.1% EF; p = 0.0043 was registered compared to the baseline values. The reduction in the ejection fraction was highest in patients in whom the trastuzumab therapy was initiated one month after the last anthracycline therapy (7.33%), and lowest in the subgroup who started receiving the therapy after three months (5.31%). In patients on cytostatic therapy, echocardiography proves the reduction in the left ventricular ejection fraction, which is cumulative and dose-dependent, and it also proves that the shorter time interval between the last cycle of anthracycline and the initial trastuzumab treatment the more it is associated with a marked decrease in the left ventricular ejection fraction.

Multivariable analysis of predictors of side effects of cabazitaxel in the Italian Expanded Access Program.

225 Background: Cabazitaxel-based chemotherapy provides a survival benefit after docetaxel failure in patients with prostate cancer. Grade 3-4 neutropenia and febrile neutropenia were relatively frequent in the registrative trial, but their incidence in clinical practice is likely to be lower, as shown by data collected in the Expanded Access Program (EAP). While cumulative doses of docetaxel are associated to neuropathy, the effect of cumulative doses of cabazitaxel is unknown. In this study, we assessed 'per cycle' incidence and predictors of toxicity in the Italian cohort of the EAP, with a focus on the effect of cumulative doses of cabazitaxel. Methods: The study population consisted of 218 Italian patients enrolled in the cabazitaxel EAP. The influence of selected variables on the most relevant side effects identified was assessed using a Generalised Estimating Equations (GEE) model at univariate and multivariate analysis. Multivariate logistic regression analysis was performed using a backward selection procedure. Variables with a p value ⩽0.1 were kept in the final model. Results: Per cycle incidence of grade 3-4 neutropenia was 8.7%, while febrile neutropenia occurred only in 0.9% of cycles and was an early event, occurring during the first three cycles only. Multivariate logistic regression analysis showed that the odds of having grade 3 – 4 neutropenia, febrile neutropenia and anemia were statistically significantly reduced by 10, 48 and 7%, respectively, every 10 mg/m2 increase of total prior dose of cabazitaxel. Interestingly, a body surface area &gt; 2 m2 was associated to increased odds of having grade 3-4 neutropenia. In this regard, it must be noted that all patients with body surface area &gt; 2 m2 had their total dose capped to 50 mg, with a mean (95% CI) and median (IQR) dose reduction of 7.1 (7.58-6.69) and 5.9 (2.76-10.27) % with respect to planned dose. Conclusions: Cumulative doses of cabazitaxel are associated to decreased risk of bone marrow toxicity. Patients with body surface area &gt;2 m2 are at increased risk of bone marrow toxicity and dose capping should be considered. These data indicate that cabazitaxel should not be arbitrarily suspended because of concerns of cumulative toxicity.

Effect of cumulative bortezomib dose on survival in multiple myeloma patients receiving bortezomib‐melphalan‐prednisone in the phase III VISTA study

This analysis, using data from the bortezomib-melphalan-prednisone (VMP) arm of the Phase III VISTA study, investigated whether increased cumulative bortezomib dose could improve overall survival (OS) in transplant-ineligible patients with previously untreated multiple myeloma. Median cumulative bortezomib dose received by the 340 patients was 39 mg/m(2); this was selected as the cut-off for defining the dose groups to be compared for OS. Patient characteristics were well balanced between dose groups except for age. OS was significantly longer in the higher (≥39 mg/m(2)) versus lower (<39 mg/m(2)) cumulative bortezomib dose group (median 66.3 vs. 46.2 months; hazard ratio (HR) 0.533, P < 0.0001; age-adjusted HR 0.561, P = 0.0002). To overcome confounding effects of early discontinuations/deaths, which were more common in the lower cumulative dose group (27 vs. 4% of patients discontinued due to adverse events (AEs) in the lower and higher cumulative dose groups, respectively), a landmark analysis was conducted at 180 days, eliminating patients who died or discontinued before this time from the analysis. OS from this landmark remained significantly longer in the higher dose group (median 60.4 vs. 50.3 months; HR 0.709, P = 0.0372). Thus, higher cumulative bortezomib dose, reflecting prolonged treatment duration and/or dose intensity, appears associated with improved OS. Approaches to achieve higher cumulative doses could include subcutaneous bortezomib administration, dose/schedule modifications, continuing therapy in responding patients, and proactive AE management.

Deterministic effects after fenestrated endovascular aortic aneurysm repair

Endovascular aortic aneurysm repairs (EVARs) with fenestrated (FEVAR) stent grafts are high radiation dose cases, yet no skin injuries were found retrospectively in our 61 cases with a mean peak skin dose (PSD) of 6.8 Gy. We hypothesize that skin injury is under-reported. This study examined deterministic effects in FEVARs after procedural changes implemented to detect skin injury. All FEVARs during a 6-month period with a radiation dose of 5 Gy reference air kerma (RAK; National Council on Radiation Protection and Measurements threshold for substantial radiation dose level [SRDL]) were included. Patients were questioned about skin erythema, epilation, and necrosis, with a physical examination of the back completed daily until discharge and then at 2 and 4 weeks and at 3 and 6 months. PSD distributions were calculated with custom software using input data from fluoroscopic machine logs. These calculations have been validated against Gafchromic (Ashland Inc, Covington, Ky) film measurements. Dose was summed for the subset of patients with multiple procedures ≤6 months of the SRDL event, consistent with the joint commission recommendations. Twenty-two patients, 21 FEVARs and one embolization, reached an RAK of 5 Gy. The embolization procedure was excluded from review. The average RAK was 7.6 ± 2.0 Gy (range, 5.1-11.4 Gy), with a mean PSD of 4.8 ± 2.0 Gy (range, 2.3-10.4 Gy). Fifty-two percent of patients had multiple endovascular procedures ≤6 months of the SRDL event. The mean RAK for this subset was 10.0 ± 2.9 Gy (range, 5.5-15.1 Gy), with a mean PSD of 6.6 ± 1.9 Gy (range, 3.4-9.4 Gy). One patient died before the first postoperative visit. No radiation skin injuries were found. Putative risk factors for skin injury were evaluated and included smoking (32%), diabetes (14%), cytotoxic drugs (9%), and fair skin type (91%). No other risk factors were present (hyperthyroidism, collagen vascular disorders). Deterministic skin injuries are uncommon after FEVAR, even at high RAK levels, regardless of cumulative dose effects. This study addresses the concern of missed injuries based on the retrospective clinical examination findings that were published in our previous work. Even with more comprehensive postoperative skin examinations and patient questioning, the fact that no skin injuries were found suggests that radiation-induced skin injuries are multifactorial and not solely dose dependent.

Antithymocyte globulin dosing effects on biopsy-proven acute rejection and infection risk.

Antithymocyte globulin (rATG) is a polyclonal antibody commonly used as induction therapy in kidney transplantation to reduce risk of allograft rejection. Currently there is no consensus on the optimal dosing. rATG is not FDA approved for induction therapy, so no dosing recommendations are provided by the manufacturer. Current kidney transplant guidelines do not provide dosing recommendations. The objective of this study was to evaluate effects of different cumulative doses of rATG on rejections and infection rates. This was a retrospective, single-center chart review that included 142 renal transplant patients from January 2007 to October 2012 who received either 3 or 5 doses of rATG. The primary outcome of biopsy-proven acute rejection (BPAR) was not significantly different between the 3-dose and 5-dose groups, (6.1% versus 7.4%, p=NS). No significant difference was seen between the 3-dose and 5-dose groups in regards to bacterial infections (33.9% versus 40.7%, p>0.05) or BK viremia (24.3% versus 18.5%, p>0.05). However, in regards to CMV viremia there was a significantly higher incidence in the 5-dose group (37% versus 15.7%, p=0.47). Five doses of rATG versus 3 doses did not provide any additional benefit in preventing BPAR.

Evaluation of Azacitidine Clinical Efficacy in Patients with Myelodysplasia Syndrome Dudina G.a., Golenkov a.K., Kataeva E.V., Mitina T.a. Moscow Regional Clinical Research Institute

Introduction: The anti-tumor effect of azacitidine in patients with myelodysplasia syndrome is based on cytotoxicity against pathologically changed hemopoetic cells of bone marrow and DNA hypomethylation. Objective: evaluation of clinical efficacy of azacitidine in patients with myeloddysplasia syndrome. Materials and methods: we have monitored 7 patients with myelodysplasia syndrome and refractory anaemia with excessive blast count, type II. IPSS with a high risk of acute leucosis development was found in 4 patients; intermediate risk was reported in 3 patients. Mean age – 62 years. Chromosomal aberrations (multiple clone transformations) were found in 4 patients during cytogenetic analysis. Normal karyotype was reported in 3 patients. Treatment regimen: azacitidine 75 mg/m² daily s/c injections, Days 1 - 7. Totally, 3 – 7 induction cycles were conducted, median (Me) – 4 cycles. Further maintenance treatment with 6-8 weeks interval was conducted in 5 patients. The mean index of haemoglobin level decrease was used to evaluate the hemopoetic ability in non-selective group; it was calculated as the ratio of the haemoglobin level at the time of discharge minus haemoglobin level at the time of the next hospitalization to the duration of the interval between treatment courses. The number of blood transfusions during the interval between treatment courses was constant: 2-3 transfusions of RBCs. Results: 4 azacitidine treatment courses resulted in decrease of blast cells number in bone marrow from 16.4 ± 0.2 % to 5.4% ± 0.7 % (р&lt;0.05). Mean index of haemoglobin level decrease after the first hospitalization was 1.9 g/l per day and 0.3 g/l per day after the 4-th treatment course (р&lt;0.05) The following results were reported using standard Cheson criteria: full response – 1 patient, hematologic improvement – 2 patients, bone marrow remission – 3 patients. Mean duration of response 8.5 months. Treatment complications: pleural empyema, abscess of left lung lower lobe after the 2-nd treatment cycle – 1 patient; broncho-pulmonary aspergillosis after 3-rd treatment cycle – 1 patient. In other patients drug toxicity that could possibly affect the interval between courses or decrease the drug dose was not reported. Delayed treatment results: 100% of patients survived the 12 – months period. Conclusions: in patients with myelodysplasia syndrome and refractory anaemia with excessive blast count, type II treatment with azacitidine (median treatment course duration – 4 months) resulted in full response in 14% of cases (1 patient), bone marrow remission was reported in 43% of cases (3 patients). Use of original method of haemoglobin level decrease index determination enables evaluation of the cumulative azacitidine dose effect on hemopoesis recovery after 4 treatment cycles. Disclosures No relevant conflicts of interest to declare.

Impaired ambulation and steroid therapy impact negatively on bone health in multiple sclerosis.

The prevalence of osteopenia and osteoporosis is higher amongst patients with multiple sclerosis in comparison with the general population. In addition to the general determinants of bone health, two factors may contribute to reduced bone mineral density in multiple sclerosis: physical disability and corticosteroid therapy. The aim of this study was to examine the effect of physical disability and steroid exposure on bone health in weight-bearing bones and spine and on the incidence of low-trauma fractures in multiple sclerosis. In this retrospective analysis of prospectively collected data, associations between bone mineral density (at the femoral neck, total femur and the lumbar spine) and its change with disability or cumulative steroid dose were evaluated with random-effect models adjusted for demographic and clinical determinants of bone health. The incidence of low-trauma fractures during the study follow-up was evaluated with Andersen-Gill models. Overall, 474 and 438 patients were included in cross-sectional and longitudinal analyses (follow-up 2347 patient-years), respectively. The effect of severely impaired gait was more apparent in weight-bearing bones (P≤10(-15) ) than in spine (P=0.007). The effect of cumulative steroid dose was relatively less pronounced but diffuse (P≤10(-4) ). Risk of low-trauma fractures was associated with disability (P=0.02) but not with cumulative steroid exposure and was greater amongst patients with severely impaired gait (annual risk 3.5% vs. 3.0%). Synergistic effects were found only between cumulative steroid dose in patients ambulatory without support (P=0.02). Bone health and the incidence of low-trauma fractures in multiple sclerosis are more related to impaired gait than to extended corticosteroid therapy.

FRI0458 Current Evidence on Prognostic Factors in Patients with Polymyalgia Rheumatica (PMR): A Systematic Literature Review Informing the Acr/Eular Recommendations for the Management of PMR

BackgroundOne of the most frequent desires of patients with polymyalgia rheumatica (PMR) is to individualize their treatment based on comorbidities, co-medication and prognostic factors. The upcoming ACR/EULAR guidelines for the...

Transcranial Magnetic Stimulation in the Treatment of Neurological Disease

Transcranial magnetic stimulation (TMS) holds great potential in the treatment of a host of neurological conditions due to its ability to focally modulate—suppress or enhance—activity in targeted cortical brain regions and modify activity across specific brain networks. Results from early trials in a number of neurological indications are presented, including stroke rehabilitation, Parkinson’s disease, tinnitus, chronic pain, migraine, and epilepsy. We emphasize both the challenges, such as the limited efficacy to date in tinnitus, as well as the opportunities, such as the use of TMS in epilepsy caused by focal/cortical lesions. However, to establish TMS as a clinically valuable neurological therapeutic intervention, a number of hurdles must be overcome, including accurate targeting of the treatment, characterization of its therapeutic benefit for specific patients/symptoms, proof of efficacy in multicenter trials that are adequately blinded and powered, proof of the durability of the effects, and assessment of potential adverse effects of cumulative dose and repeated application. [ Psychiatr Ann. 2014; 44(6):299–304.]

Local radiation dose and solid second malignant neoplasms after childhood cancer in Germany: a nested case-control study.

Radiotherapy (RT) has been associated with the development of solid second malignant neoplasms (SMNs) in childhood cancer survivors. The aim of this study was to analyse the effect of cumulative doses of previous RT received at the SMN body region, at all other body regions and at body regions adjacent to the SMN, on the risk of developing a solid SMN. A total of 190 cases diagnosed with a solid second malignant neoplasm in 1980-2002 were matched with 368 controls with single neoplasm from the database of the German Childhood Cancer Registry (GCCR) (33,809 patients at cut-off date). The GCCR registers approximately 97% of all childhood malignancies which occur at an age of less than 15years in Germany since 1980. It was found that 147 (77.4%) cases had received RT compared to 208 (56.6%) controls with cumulative focus doses from 8 to 110Gy. Fifty per cent of the SMNs and 60% of RT affected the head region. RT was shown to increase the risk of a solid second tumour within the body region of radiation by 5.3% per Gy (odds ratio 1.053; 95% confidence interval 1.036-1.071). With increasing age at diagnosis and with more recent treatment eras, this effect decreased. Cumulative RT doses received at all other body regions or only at body regions adjacent to the SMN did not show an additional effect on the risk of developing an SMN. It is thus concluded that RT is the main risk factor for the development of SMNs within the irradiated body region. Late effects surveillance of former patients should give special attention to the originally irradiated parts of the body.