Multidonor FMT capsules improve symptoms and decrease fecal calprotectin in ulcerative colitis patients while treated - an open-label pilot study.

Background: Growing evidence indicates that gut dysbiosis is a factor in the pathogenesis of ulcerative colitis (UC). Fecal microbiota transplantation (FMT) appears to be promising in inducing UC remission, but there are no reports regarding administration using capsules. Methods: Seven patients with active UC, aged 27-50 years, were treated with 25 multidonor FMT capsules daily for 50 days as a supplement to their standard treatment in an open-label pilot study. The primary objective was to follow symptoms through the Simple Clinical Colitis Activity Index (SCCAI). Secondary objectives were to follow changes in fecal calprotectin and microbial diversity through fecal samples and quality of life through the Inflammatory Bowel Disease Questionnaire (IBDQ). Participants were followed through regular visits for six months. Results: From a median of 6 at baseline, the SCCAI of all participants decreased, with median decreases of 5 (p = .001) and 6 (p = .001) after 4 and 8 weeks, respectively. Three of the seven patients had flare-up/relapse of symptoms after the active treatment period. The median F-calprotectin of ≥1800 mg/kg at baseline decreased significantly during the treatment period, but increased again in the follow-up period. The median IBDQ improved at all visits compared to baseline. The fecal microbiota α-diversity did not increase in the study period compared to baseline. All participants completed the treatment and no serious adverse events were reported. Conclusion: Fifty days of daily multidonor FMT capsules temporarily improved symptoms and health-related life quality and decreased F-calprotectin in patients with active UC.

The Promise of Telemedicine for Movement Disorders: an Interdisciplinary Approach.

PURPOSE OF REVIEW: Advances in technology have expanded telemedicine opportunities covering medical practice, research, and education. This is of particular importance in movement disorders (MDs), where the combination of disease progression, mobility limitations, and the sparse distribution of MD specialists increase the difficulty to access. In this review, we discuss the prospects, challenges, and strategies for telemedicine in MDs. RECENT FINDINGS: Telemedicine for MDs has been mainly evaluated in Parkinson's disease (PD) and compared to in-office care is cost-effective with similar clinical care, despite the barriers to engagement. However, particular groups including pediatric patients, rare MDs, and the use of telemedicine in underserved areas need further research. Interdisciplinary telemedicine and tele-education for MDs are feasible, provide similar care, and reduce travel costs and travel time compared to in-person visits. These benefits have been mainly demonstrated for PD but serve as a model for further validation in other movement disorders.

Development of mycosis fungoides after bone marrow transplantation for chronic myeloid leukaemia: transmission from an allogeneic donor.

We report on a patient who developed donor-derived cutaneous T-cell lymphoma (CTCL) 4 years after successful treatment of chronic myeloid leukaemia with an allogeneic bone marrow transplant. The patient developed an eczematous rash unresponsive to topical therapy and immunosuppression. When CTCL was diagnosed in the recipient, his sibling donor had been attending his local dermatology unit with a maculosquamous rash, which proved subsequently to be mycosis fungoides. An identical pattern of donor and recipient clonality assessment and T-cell receptor gene sequencing indicated that the CTCL was probably transmitted in the bone marrow harvest. This suggests that CTCL cells circulate in the marrow at an early subclinical stage in this disease. This is the second case of donor-derived CTCL reported to date.

PBOX-15, a novel microtubule targeting agent, induces apoptosis, upregulates death receptors, and potentiates TRAIL-mediated apoptosis in multiple myeloma cells.

BACKGROUND: In recent years, much progress has been made in the treatment of multiple myeloma. However, a major limitation of existing chemotherapeutic drugs is the eventual emergence of resistance; hence, the development of novel agents with new mechanisms of action is pertinent. Here, we describe the activity and mechanism of action of pyrrolo-1,5-benzoxazepine-15 (PBOX-15), a novel microtubule-targeting agent, in multiple myeloma cells. METHODS: The anti-myeloma activity of PBOX-15 was assessed using NCI-H929, KMS11, RPMI8226, and U266 cell lines, and primary myeloma cells. Cell cycle distribution, apoptosis, cytochrome c release, and mitochondrial inner membrane depolarisation were analysed by flow cytometry; gene expression analysis was carried out using TaqMan Low Density Arrays; and expression of caspase-8 and Bcl-2 family of proteins was assessed by western blot analysis. RESULTS: Pyrrolo-1,5-benzoxazepine-15 induced apoptosis in ex vivo myeloma cells and in myeloma cell lines. Death receptor genes were upregulated in both NCI-H929 and U266 cell lines, which displayed the highest and lowest apoptotic responses, respectively, following treatment with PBOX-15. The largest increase was detected for the death receptor 5 (DR5) gene, and cotreatment of both cell lines with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), the DR5 ligand, potentiated the apoptotic response. In NCI-H929 cells, PBOX-15-induced apoptosis was shown to be caspase-8 dependent, with independent activation of extrinsic and intrinsic apoptotic pathways. A caspase-8-dependent decrease in expression of Bim(EL) preceded downregulation of other Bcl-2 proteins (Bid, Bcl-2, Mcl-1) in PBOX-15-treated NCI-H929 cells. CONCLUSION: PBOX-15 induces apoptosis and potentiates TRAIL-induced cell death in multiple myeloma cells. Thus, PBOX-15 represents a promising agent, with a distinct mechanism of action, for the treatment of this malignancy.

Amniotic fluid index curves in the obese gravida.

OBJECTIVE: To determine whether amniotic fluid volume as measured by amniotic fluid index (AFI) is influenced by maternal pre-gestational obesity as measured by body mass index (BMI). METHODS: This was a retrospective cohort study of pregnant women between 20 and 43 weeks gestation receiving ultrasounds with AFI measurements at Augusta University Medical Center between 2003 and 2017. A subset of 500 charts that met inclusion and exclusion criteria were reviewed to obtain maternal clinical data. The study cohort was subdivided by maternal BMI at initial obstetric visit into three groups: normal weight (18.5 kg/m2-24.9 kg/m2), overweight (25.0 kg/m2-29.9 kg/m2), and obese (≥ 30 kg/m2). Chi-square analysis was used to compare BMI groups in terms of categorical clinical characteristics and outcome variables, and analysis of variance (ANOVA) was used for continuous variables. Mixed effects regression models (MRMs) were used to evaluate AFI throughout gestation separately in each group, and MRM-based analysis of covariance was used to compare AFI throughout gestation among groups. AFI curves were constructed for the 5th, 50th, and 95th percentiles for all study subjects combined and separately for normal weight, overweight, and obese subjects. RESULTS: Fitted curves relating AFI percentiles to estimated gestational age (EGA) showed statistically significant differences among BMI groups. There was also a significant difference in AFI over gestation across the obesity groups. CONCLUSION: Fitted curves for AFI throughout pregnancy showed statistically significant differences among BMI groups.

Allogeneic hematopoietic stem cell transplantation for advanced mycosis fungoides and Sézary syndrome. An updated experience of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option in advanced-stage mycosis fungoides (MF) and Sézary syndrome (SS). This study presents an updated analysis of the initial experience of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT) describing the outcomes after allo-HSCT for MF and SS, with special emphasis on the impact of the use of unrelated donors (URD). METHODS AND PATIENTS: Eligible for this study were patients with advanced-stage MF or SS who underwent a first allo-HSCT from matched HLA-identical related or URD between January/1997 and December/2011. Sixty patients have been previously reported. RESULTS: 113 patients were included [77 MF (68%)]; 61 (54%) were in complete or partial remission, 86 (76%) received reduced-intensity protocols and 44 (39%) an URD allo-HSCT. With a median follow up for surviving patients of 73 months, allo-HSCT resulted in an estimated overall survival (OS) of 38% at 5 years, and a progression-free survival (PFS) of 26% at 5 years. Multivariate analysis demonstrated that advanced-phase disease (complete remission/partial remission >3, primary refractory or relapse/progression in patients that had received 3 or more lines of systemic treatment prior to transplant or the number of treatment lines was not known), a short interval between diagnosis and transplant (<18 months) were independent adverse prognostic factors for PFS; advanced-phase disease and the use of URDs were independent adverse prognostic factors for OS. CONCLUSIONS: This extended series supports that allo-HSCT is able to effectively rescue over one third of the population of patients with advanced-stage MF/SS. High relapse rate is still the major cause of failure and needs to be improved with better strategies before and after transplant. The negative impact of URD is a matter of concern and needs to be further elucidated in future studies.

An unusual cause of methaemoglobinaemia.

Methaemoglobinaemia is a rare condition characterised by increased quantities of haemoglobin in which the iron of haem is oxidised to the ferric (Fe3+) form. Clinically the condition presents with cyanosis and low oxygen saturations on pulse oximetry but normal oxygen saturation on arterial blood gas analysis. Most cases are acquired and are frequently drug related. We present a case of methaemoglobinaemia which presented to our hospital.

Successful outcome of patients with relapsed/refractor Hodgkin lymphoma treated with high dose chemotherapy at the National Adult Bone Marrow Transplant Unit at St. James's Hospital.

Patients with Hodgkin lymphoma who relapse or are refractory to first line multi-agent chemotherapy can be successfully salvaged with high dose therapy (HDT) and autologous stem cell transplant (ASCT). Twenty-six patients with relapsed or refractory Hodgkin lymphoma have been treated with HDT and ASCT at St James Hospital between 2000 and 2005. At day 100 post HDT-ASCT, 23 patients were in complete remission. This group included all 6 patients transplanted at first relapse, 8 of 9 with advanced disease and 9 of 11 with primary refractory disease. Patients treated in first relapse had the best outcome with an overall and progression free survival of 100% (median, 37 months). Patients with primary refractory disease had the poorest outcome with an overall survival of 76% (median, 28 months). All patients with primary refractory disease responsive to salvage chemotherapy were in remission at a median of 28 months. The presence of chemosensitive disease prior to transplantation was the most important determinant of outcome. PET-CT imaging is useful to assess chemosensititvity prior to HDT and thus predict which patients will do well post HDT-ASCT. No patient died of treatment related toxicity. The outcome of this patient series compares favourably with international figures.

Selected nitrostyrene compounds demonstrate potent activity in chronic lymphocytic leukaemia cells, including those with poor prognostic markers.

The nitrostyrene scaffold was previously identified as a lead target structure for the development of effective compounds targeting Burkitt's lymphoma. The present study aimed to develop these compounds further in haematological malignancies, including chronic lymphocytic leukaemia (CLL). Cellular viability, flow cytometry and lactate dehydrogenase assays, amongst others, were used to examine the effects of nitrostyrene compounds on CLL cells, including a cell line representing disease with poor prognosis (HG­3) and in ex vivo CLL patient samples (n=14). The results demonstrated that two representative nitrostyrene compounds potently induced apoptosis in CLL cells. The pro­apoptotic effects of the compounds were found to be reactive oxygen species and caspase­dependent, and had minimal effects on the viability of normal donor peripheral blood mononuclear cells. Nitrostyrene compounds exhibited synergistic augmentation of apoptosis when combined with the phosphatidylinositol 3­kinase inhibitor idelalisib and demonstrated potent toxicity in ex vivo CLL cells, including those co­cultured with bone marrow stromal cells, making them more resistant to apoptosis (n=8). These compounds also demonstrated activity in samples from patients with poor prognostic indicators; unmutated immunoglobulin heavy chain genes, expression of CD38 and deletions in chromosomes 17p and 11q. These results suggest that this class of pharmaceutically active compounds offer potential in the treatment of CLL.

PAX-5 is invariably expressed in B-cell lymphomas without plasma cell differentiation.

AIMS: The B-cell-specific transcription factor PAX-5 is physiologically expressed in normal B cells and silenced in plasma cells. The aim of this study was to determine whether PAX-5 expression is universal among B-cell malignancies. METHODS AND RESULTS: A wide spectrum of B-cell malignancies were subjected to immunohistochemical analysis for PAX-5 expression. The study was especially focused on cases lacking CD20, such as precursor B-cell acute lymphoblastic leukaemia (preB-ALL), CD20- B-cell lymphomas, classical Hodgkin's lymphoma (CHL) and B-cell lymphomas with significant plasmacytic differentiation. Strong PAX-5 expression was identified, without exception, in all cases of CD20+ B-lymphoproliferative disorders. It was also invariably detected in 31/31 cases of preB-ALL, 14/14 cases of CD20- diffuse large B-cell lymphoma without plasmacytic differentiation and 26/26 CD20- B-cell lymphoma status post rituximab treatment. The vast majority of CHLs had unequivocal PAX-5 expression of varying intensity (80/86). However, variants of B-cell malignancies with characteristic plasmacytic differentiation exhibited no detectable PAX-5 expression (0/17). CONCLUSIONS: PAX-5 is the most sensitive and reliable immunohistochemical marker for B-cell malignancies. Lack of PAX-5 expression correlates with the presence of marked plasma cell differentiation.

Development of a curated Hershberger database.

A systematic literature review was conducted to identify Hershberger bioassays for ∼3200 chemicals including those used to validate the OECD/US EPA guideline assay, US EPA's chemicals screened for endocrine activity, and the library of chemicals run in US EPA 's ToxCast in vitro assays. For 134 chemicals that met pre-defined criteria, experimental results were extracted into a database used to characterize uncertainty in results and evaluate the concordance of the Hershberger assay with other in vivo rodent studies that measure androgen-responsive endpoints. Of 25 chemicals tested in >1 Hershberger study, 28% had disagreements between studies (i.e. ≥1 positive and ≥1 negative study), and of the 65 chemicals tested in Hershberger studies and other in vivo studies with androgen-responsive endpoints, 43% indicated disagreements, though in some cases these may be explained by differences in study designs or physiology of the animal model. Ultimately, 49 chemicals were identified with reproducible androgen pathway responses confirmed in ≥2 in vivo rodent studies that could be considered reference chemicals useful for validating alternative methods.

Evaluation of androgen assay results using a curated Hershberger database.

A set of 39 reference chemicals with reproducible androgen pathway effects in vivo, identified in the companion manuscript [1], were used to interrogate the performance of the ToxCast/Tox 21 androgen receptor (AR) model based on 11 high throughput assays. Cytotoxicity data and specificity confirmation assays were used to distinguish assay loss-of-function from true antagonistic signaling suppression. Overall agreement was 66% (19/29), with ten additional inconclusive chemicals. Most discrepancies were explained using in vitro to in vivo extrapolation to estimate equivalent administered doses. The AR model had 100% positive predictive value for the in vivo response, i.e. there were no false positives, and chemicals with conclusive AR model results (agonist or antagonist) were consistently positive in vivo. Considering the lack of reproducibility of the in vivo Hershberger assay, the in vitro AR model may better predict specific AR interaction and can rapidly and cost-effectively screen thousands of chemicals without using animals.

Removal of erythrocyte membrane iron in vivo ameliorates the pathobiology of murine thalassemia.

Abnormal deposits of free iron are found on the cytoplasmic surface of red blood cell (RBC) membranes in beta-thalassemia. To test the hypothesis that this is of importance to RBC pathobiology, we administered the iron chelator deferiprone (L1) intraperitoneally to beta-thalassemic mice for 4 wk and then studied RBC survival and membrane characteristics. L1 therapy decreased membrane free iron by 50% (P = 0.04) and concomitantly improved oxidation of membrane proteins (P = 0.007), the proportion of RBC gilded with immunoglobulin (P = 0.001), RBC potassium content (P < 0.001), and mean corpuscular volume (P < 0.001). Osmotic gradient ektacytometry confirmed a trend toward improvement of RBC hydration status. As determined by clearance of RBC biotinylated in vivo, RBC survival also was significantly improved in L1-treated mice compared with controls (P = 0.007). Thus, in vivo therapy with L1 removes pathologic free iron deposits from RBC membranes in murine thalassemia, and causes improvement in membrane function and RBC survival. This result provides in vivo confirmation that abnormal membrane free iron deposits contribute to the pathobiology of thalassemic RBC.

Placental expression and molecular characterization of aromatase cytochrome P450 in the spotted hyena (Crocuta crocuta).

At birth, the external genitalia of female spotted hyenas (Crocuta crocuta) are the most masculinized of any known mammal, but are still sexually differentiated. Placental aromatase cytochrome P450 (P450arom) is an important route of androgen metabolism protecting human female fetuses from virilization in utero. Therefore, placental P450arom expression was examined in spotted hyenas to determine levels during genital differentiation, and to compare molecular characteristics between the hyena and human placental enzymes. Hyena placental P450arom activity was determined at gestational days (GD) 31, 35, 45, 65 and 95 (term, 110), and the relative sensitivity of hyena and human placental enzyme to inhibition by the specific inhibitor, Letrozole, was also examined. Expression of hyena P450arom in placenta was localized by immuno-histochemistry, and a full-length cDNA was cloned for phylogenetic analysis. Aromatase activity increased from GD31 to a peak at 45 and 65, apparently decreasing later in gestation. This activity was more sensitive to inhibition by Letrozole than was human placental aromatase activity. Expression of P450arom was localized to syncytiotrophoblast and giant cells of mid-gestation placentas. The coding sequence of hyena P450arom was 94% and 86% identical to the canine and human enzymes respectively, as reflected by phylogenetic analyses. These data demonstrate for the first time that hyena placental aromatase activity is comparable to that of human placentas when genital differentiation is in progress. This suggests that even in female spotted hyenas clitoral differentiation is likely protected from virilization by placental androgen metabolism. Decreased placental aromatase activity in late gestation may be equally important in allowing androgen to program behaviors at birth. Although hyena P450arom is closely related to the canine enzyme, both placental anatomy and P450arom expression differ. Other hyaenids and carnivores must be investigated to determine the morphological and functional ancestral state of their placentas, as it relates to evolutionary relationships among species in this important taxonomic group.

Wilms' tumor gene 1 (WT1) expression in childhood acute lymphoblastic leukemia: a wide range of WT1 expression levels, its impact on prognosis and minimal residual disease monitoring.

Wilms' tumor gene 1 (WT1) is overexpressed in the majority (70-90%) of acute leukemias and has been identified as an independent adverse prognostic factor, a convenient minimal residual disease (MRD) marker and potential therapeutic target in acute leukemia. We examined WT1 expression patterns in childhood acute lymphoblastic leukemia (ALL), where its clinical implication remains unclear. Using a real-time quantitative PCR designed according to Europe Against Cancer Program recommendations, we evaluated WT1 expression in 125 consecutively enrolled patients with childhood ALL (106 BCP-ALL, 19 T-ALL) and compared it with physiologic WT1 expression in normal and regenerating bone marrow (BM). In childhood B-cell precursor (BCP)-ALL, we detected a wide range of WT1 levels (5 logs) with a median WT1 expression close to that of normal BM. WT1 expression in childhood T-ALL was significantly higher than in BCP-ALL (P<0.001). Patients with MLL-AF4 translocation showed high WT1 overexpression (P<0.01) compared to patients with other or no chromosomal aberrations. Older children (> or =10 years) expressed higher WT1 levels than children under 10 years of age (P<0.001), while there was no difference in WT1 expression in patients with peripheral blood leukocyte count (WBC) > or =50 x 10(9)/l and lower. Analysis of relapsed cases (14/125) indicated that an abnormal increase or decrease in WT1 expression was associated with a significantly increased risk of relapse (P=0.0006), and this prognostic impact of WT1 was independent of other main risk factors (P=0.0012). In summary, our study suggests that WT1 expression in childhood ALL is very variable and much lower than in AML or adult ALL. WT1, thus, will not be a useful marker for MRD detection in childhood ALL, however, it does represent a potential independent risk factor in childhood ALL. Interestingly, a proportion of childhood ALL patients express WT1 at levels below the normal physiological BM WT1 expression, and this reduced WT1 expression appears to be associated with a higher risk of relapse.

MRONJ risk reduction pathway - 360 degree survey.

Introduction Bisphosphonates and denosumab reduce the risk of skeletal events in some malignancies (for example, breast, myeloma). These drugs carry a significant risk of a difficult-to-manage side effect of medication related osteonecrosis of the jaw (MRONJ). Preventive dental screening and treatment reduces the incidence of MRONJ. A managed clinical network (MCN) has been used to provide a MRONJ risk reduction pathway. A 360 degree survey was undertaken to assess the effectiveness of the pathway.Aim The aim of the 360 degree survey was to evaluate if this preventive pathway fulfilled its aims based on patient and stakeholder responses.Method A multidisciplinary, cross-service, cross-health board MRONJ preventive pathway has been developed. A 360 degree feedback survey of patients and other stakeholders was undertaken.Results Overall, this survey revealed high levels of satisfaction across patients, oncologists, community dental services, general dental services, and hospital managers.Conclusion Alternative ways of delivering MRONJ preventive pathways can be developed and assessed using iterative stakeholder feedback aided by a robust clinical governance framework.

Transformed follicular lymphoma (tFL): consolidation therapy may improve survival.

PURPOSE: Retrospective study to evaluate the outcome of patients with transformed follicular lymphoma (tFL) treated with rituximab-containing chemotherapy and consolidation. PATIENTS AND METHODS: Patients diagnosed with tFL from 2003 to 2013 treated with consolidation therapy with last follow-up in December 2015 were identified from the institutional lymphoma database and included in this study. Data collected included age, gender, stage, interval to tFL diagnosis, R-IPI score, histological diagnosis and therapy. The treatment algorithm used was stratified for age, performance status (PS) and sibling donor availability using R-chemotherapy induction followed by consolidation with allogeneic stem cell transplant (SCT), autologous SCT, Zevalin or rituximab maintenance (RM). Patients with B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and Burkitt's lymphoma (BCL-U), with FISH-proven t(14;18) and t(8;14) and their variants were excluded. RESULTS: Four hundred patients were diagnosed with FL of whom 26 (7%) developed histologically proven tFL. The group was predominantly male (73%) with a median age at transformation of 53 (range 27-72) years and 85% presented with stage III/IV disease. Thirteen (50%) patients presented with de novo tFL and the remainder had previously diagnosed FL, with a median time to transformation of 5.7 (range 1-15) years. The median follow-up time from tFL diagnosis to December 2015 is 8 (range 4-14) years. All patients received immuno-chemotherapy achieving an overall response rate (ORR) of 100%. Fourteen (54%), patients were transplant eligible and based on donor availability, six had an auto-SCT only, five had an allo-SCT only and three had a matched unrelated allo-SCT for a post-auto-SCT relapse. The 12 patients (46%) who were not transplant eligible were consolidated with rituximab maintenance (RM) in nine (35%) and Zevalin in three (11%) cases. The overall survival (OS) and progression-free survival (PFS) for the series at 5 years were, 92 and 73%, respectively. CONCLUSION: This consecutively treated series of 26 patients with tFL have had a better outcome than expected which may be due to the use of rituximab-chemotherapy and a consolidation strategy based on age, PS and availability of a sibling donor.

Circulating cholesterol levels, apolipoprotein E genotype and dementia severity influence the benefit of atorvastatin treatment in Alzheimer's disease: results of the Alzheimer's Disease Cholesterol-Lowering Treatment (ADCLT) trial.

CONTEXT: Recent evidence suggests that treatment of mild-to-moderate Alzheimer's disease (AD) with atorvastatin provides significant benefit on the Alzheimer Disease Assessment Scale-Cognitive (ADAS-cog) after 6 months. OBJECTIVE: To determine if benefit on ADAS-cog performance produced by atorvastatin is influenced by severity of cognitive impairment, circulating cholesterol levels, or apolipoprotein E genotype. DESIGN: A double-blind, placebo-controlled, randomized (1:1) trial with a 1-year exposure to atorvastatin calcium or placebo. SETTING: A single-site study at the clinical research center of the Sun Health Research Institute. PARTICIPANTS: Ninety-eight individuals with mild-to-moderate AD (MMSE score of 12-28) provided informed consent, and 67 were randomized. Stable dose use of cholinesterase inhibitors, estrogen and vitamin E was allowed, as was the use of many other medications in the treatment of co-morbidities. Participants using cholesterol-lowering medications or being treated for major depression or a psychiatric condition were excluded. INTERVENTION: Once daily atorvastatin calcium (80 mg; two 40 mg tablets) or placebo. MAIN OUTCOME MEASURES: A primary outcome measure was change ADAS-cog sub-scale score. Secondary outcome measures included scores on the MMSE, and circulating cholesterol levels. The Apolipoprotein E genotype was established for each participant. RESULTS: A significant positive effect on ADAS-cog performance occurred after 6 months of atorvastatin therapy compared with placebo. This positive effect was more prominent among individuals entering the trial with, (i) higher MMSE scores, (ii) cholesterol levels above 200 mg/dl or (iii) if they harbored an apolipoprotein-E-4 allele compared with participants not responding to atorvastatin treatment. Individuals in the placebo group tended to experience more pronounced deterioration if their cholesterol levels exceeded 200 mg/dl or they harbored an apolipoprotein-E-4 allele. CONCLUSION: Atorvastatin therapy may be of benefit in the treatment of mild-to-moderately affected AD patients, but the level of benefit produced may be predicated on earlier treatment, an individual's apolipoprotein E genotype or whether the patient exhibits elevated cholesterol levels.

Statin therapy in Alzheimer's disease.

Previous studies have suggested that statin therapy may be of benefit in treating Alzheimer's disease (AD). We initiated a double-blind, placebo-controlled, randomized (1:1) trial with a 1-year exposure to once-daily atorvastatin calcium (80 mg; two 40 mg tablets) or placebo among individuals with mild-to-moderate AD [Mini-Mental State Examination (MMSE) score of 12-28]. Stable dose use of cholinesterase inhibitors, estrogen and vitamin E was allowed, as was the use of most other medications in the treatment of co-morbidities. We demonstrated that atorvastatin treatment produced significantly (P = 0.003) improved performance on cognition and memory after 6 months of treatment (ADAS-cog) among patients with mild-to-moderate AD. This superior effect persisted at 1 year (P = 0.055). This positive effect on the ADAS-cog performance after 6 months of treatment was more prominent among individuals entering the trial with higher MMSE scores (P = 0.054). Benefit on other clinical measures was identified in the atorvastatin-treated population compared with placebo. Accordingly, atorvastatin therapy may be of benefit in the treatment of mild-to-moderately affected AD patients, but the level of benefit produced may be predicated on earlier treatment. Evidence also suggests that atorvastatin may slow the progression of mild-to-moderate AD, thereby prolonging the quality of an afflicted individual's life.