Does anxiety, depression, and sleep levels affect the quality of life in patients diagnosed with multiple sclerosis?

OBJECTIVE: Multiple sclerosis (MS) is a chronic disease characterized by relapses and remissions, causing physical disability and affecting individuals psychosocially. In this study, we aimed to assess anxiety and depression levels, sleep, and quality of life in MS patients. PATIENTS AND METHODS: The study included 66 participants, 30 healthy controls, and 36 patients diagnosed with MS. All participants were administered the Sociodemographic and Clinical Data Form, Multiple Sclerosis Quality of Life Instrument (MSQOL-54), Pittsburgh Sleep Quality Index (PSQI), Expanded Disability Status Scale (EDSS), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI). RESULTS: The PSQI, EDSS, BDI, and BAI scores of MS patients were found to be significantly higher, while the MSQOL-54 score was considerably lower than the healthy control group (p<0.001). In the patient group, there was a positive correlation between PSQI score and BDI (r=0.599, p<0.001) and BAI (r=0.633, p<0.001), while there was a negative correlation between PSQI and MSQOL-54 (r=0.705, p<0.001) and the duration of MS diagnosis (r=-0.364, p=0.029). A positive correlation was found between the EDSS score and BDI (r=0.401, p=0.015) and the number of hospitalizations (r=0.566, p<0.001). There was a significant negative correlation observed between MSQOL-54 and BDI (r=-0.807, p<0.001) as well as BAI (r=-0.834, p<0.001). There is a significant positive relationship between BDI and BAI (r=0.828, p<0.001). CONCLUSIONS: Our research revealed that individuals diagnosed with multiple sclerosis exhibit elevated levels of anxiety and depression symptoms when compared to a healthy control group. Additionally, they tend to experience lower sleep quality and overall quality of life. The provision of necessary psychiatric interventions to these patients following their diagnosis can enable them to accept the disease and actively participate in treatment, thereby positively impacting their quality of life.

The roles of Klotho and FGF-23 in bipolar manic episode.

OBJECTIVE: Bipolar disorder (manic episode) is an essential psychiatric disorder with unknown etiology, in which inflammation is considered to play a role. Klotho and FGF-23 are known to be associated with inflammation. Therefore, this study aimed to determine the link between Klotho and FGF-23 levels and bipolar disorder. PATIENTS AND METHODS: In this study, 42 men with BD and 41 healthy controls were enrolled, followed up, and/or treated at the High-Security Forensic Psychiatry Clinic. Sociodemographic data form, Young Mania Rating Scale, and Hamilton Depression Rating Scale were applied to all participants. RESULTS: Klotho and FGF-23 levels were significantly increased in patients with BD manic episodes. There was no correlation between Klotho and FGF-23 levels and clinical parameters. For Klotho and FGF-23, cutoff values of 69 and 1,646 yielded 67.4% sensitivity and 72.1% specificity and 81.4% sensitivity and 51.2% specificity, respectively. CONCLUSIONS: Klotho and FGF-23 may play critical roles in the etiopathology of manic episodes and are potential candidate biomarkers for bipolar disorder. This relationship might contribute to the etiopathogenesis of the disease and determine its treatment. Anti-Klotho and anti-FGF-23 administration may be a future treatment for controlling the course of the disease.

Prevention of urinary infection through the incorporation of silver-ricinoleic acid-polystyrene nanoparticles on the catheter surface.

Nosocominal infections associated with biofilm formation on urinary catheters cause serious complications. The aim of this study was to investigate the feasibility of the polyurethane (PU) catheter modified with tetracycline hydrochloride (TCH) attached Ag nanoparticles embedded PolyRicinoleic acid-Polystyrene Nanoparticles (PU-TCH-AgNPs-PRici-PS NPs) and the influence on antimicrobial and antibiofilm activity of urinary catheters infected by Escherichia coli and Staphylococcus aureus. For this purpose, AgNPs embedded PRici graft PS graft copolymers (AgNPs-PRici-g-PS) were synthesized via free radical polymerization and characterized by FTIR, HNMR and DSC. AgNPs-PRici-PS NPs were prepared and optimized by the different parameters and the optimized size of nanoparticle was found as about 150 ± 1 nm. The characterization of the nanoparticles and the morphological evaluation were carried out by FTIR and SEM. Short term stability of nanoparticles was realised at 4°C for 30 days. In vitro release profiles of TCH and Ag NPs were also investigated. The formation of biofilm on PU modified TCH-Ag NPs-PRici-PS NPs, was evaluated and the biocompatibility test of the nanoparticles was realized via the mouse fibroblast (L929) and mouse urinary bladder cells (G/G An1). This is the first time that TCH-AgNPs-PRici-PS NPs used in the modification of PU catheter demonstrated high antimicrobial and antibiofilm activities against the urinary tract infection.

The efficacy of pregabalin for treating pain associated with diabetic peripheral neuropathy in subjects with type 1 or type 2 diabetes mellitus.

OBJECTIVE: The objective of this study was to compare the efficacy and safety of pregabalin for painful diabetic peripheral neuropathy (pDPN) in subjects with type 1 (T1DM) or 2 diabetes mellitus (T2DM). METHODS: Pooled data from 10 randomized clinical trials (pregabalin-treated T1DM and T2DM subjects with pDPN) were analyzed for change from baseline (CFB) scores (pain and sleep disturbance) using mixed model repeated measures (MMRM) through Week 12 and last observation carried forward (LOCF). Adverse events (AEs) were recorded. RESULTS: Pregabalin-treated (T1DM 156 [8.7%]; T2DM 1632 [91.3%]) and placebo subjects (T1DM 92 [9.6%]; T2DM 868 [90.4%]) had comparable baseline demographic characteristics between treatment groups within the same diabetes type. T2DM (vs. T1DM) subjects were ∼10 years older. With pregabalin and placebo, respectively, mean ± SD baseline pain (T1DM: 6.2 ± 1.4 and 6.5 ± 1.6; T2DM: 6.5 ± 1.5 and 6.4 ± 1.5) and sleep scores (T1DM: 5.2 ± 2.4 and 5.2 ± 2.7; T2DM: 5.3 ± 2.5 and 5.1 ± 2.5) were comparable. Using MMRM, mean CFB treatment differences (pregabalin minus placebo) were significantly different for pain and sleep with either diabetes types (all weeks p < .05). With LOCF, pregabalin's odds ratios (ORs) of achieving 30% pain reduction were similar with T2DM (OR, 1.91, 95% CI [1.61, 2.27]) and T1DM (2.01 [1.18, 3.44]) (both p ≤ .01). Pregabalin's ORs of 30% improvement in sleep quality were 1.81 (95% CI, 1.06, 3.09) with T1DM and 2.01 (1.69, 2.39) with T2DM (both p < .05). AEs were consistent with the known safety profile of pregabalin. CONCLUSIONS: Pregabalin significantly improved pain and sleep quality, without a clinically meaningful difference between diabetes types. ClinicalTrial.gov registration: NCT00156078, NCT00159679, NCT00143156, NCT00553475.

A Comparative Study of Receptor-Targeted Magnetosome and HSA-Coated Iron Oxide Nanoparticles as MRI Contrast-Enhancing Agent in Animal Cancer Model.

Magnetosomes are specialized organelles arranged in intracellular chains in magnetotactic bacteria. The superparamagnetic property of these magnetite crystals provides potential applications as contrast-enhancing agents for magnetic resonance imaging. In this study, we compared two different nanoparticles that are bacterial magnetosome and HSA-coated iron oxide nanoparticles for targeting breast cancer. Both magnetosomes and HSA-coated iron oxide nanoparticles were chemically conjugated to fluorescent-labeled anti-EGFR antibodies. Antibody-conjugated nanoparticles were able to bind the MDA-MB-231 cell line, as assessed by flow cytometry. To compare the cytotoxic effect of nanoparticles, MTT assay was used, and according to the results, HSA-coated iron oxide nanoparticles were less cytotoxic to breast cancer cells than magnetosomes. Magnetosomes were bound with higher rate to breast cancer cells than HSA-coated iron oxide nanoparticles. While 250 µg/ml of magnetosomes was bound 92 ± 0.2%, 250 µg/ml of HSA-coated iron oxide nanoparticles was bound with a rate of 65 ± 5%. In vivo efficiencies of these nanoparticles on breast cancer generated in nude mice were assessed by MRI imaging. Anti-EGFR-modified nanoparticles provide higher resolution images than unmodified nanoparticles. Also, magnetosome with anti-EGFR produced darker image of the tumor tissue in T2-weighted MRI than HSA-coated iron oxide nanoparticles with anti-EGFR. In vivo MR imaging in a mouse breast cancer model shows effective intratumoral distribution of both nanoparticles in the tumor tissue. However, magnetosome demonstrated higher distribution than HSA-coated iron oxide nanoparticles according to fluorescence microscopy evaluation. According to the results of in vitro and in vivo study results, magnetosomes are promising for targeting and therapy applications of the breast cancer cells.

Antibacterial Nanostructured Polyhydroxybutyrate Membranes for Guided Bone Regeneration.

The principle of guided bone regeneration (GBR) in orthopedic, cranio-maxillofacial and dental tissue engineering applications is to create a secluded space for the treatment of large bone defects while excluding fibrous connective tissue formation at the defect area. In dental surgeries, a GBR membrane is placed near the dental implant in post-extraction sockets to grow new bone at the implant site, along with inhibiting infection due to the microbial nature of the mouth flora. Poly[(R)-3-hydroxybutyric acid] (PHB) is a natural polyester synthesized by a wide variety of microorganisms which has been proposed for various biomedical applications. In this study, to improve the performance of PHB as a GBR, a NaOH based alkaline treatment was designed to create nanofeatured PHB membranes. The newly fabricated nanofeatured PHB membranes were investigated for GBR applications. The results showed that a quick, simple, and inexpensive sodium hydroxide treatment modified the nanostructured surface morphology and chemistry of the PHB membranes by inducing hydrolysis of the ester bonds in the PHB backbone creating carboxylic surface functional groups, which increased the hydrophilicity of the PHB surfaces. Cytocompatibility studies showed increased proliferation of human osteoblasts (bone forming cells) on the NaOH treated PHB membranes compared to the untreated ones. Importantly, in vitro bacterial studies with Staphylococcus aureus (S. aureus) indicated that the NaOH-treated PHB surfaces inhibited S. aureus growth more than 60% after 48 hours of culture compared to the untreated PHB membrane. Thus, this study, for the first time, showed that nanofeatured PHB membranes modified with a NaOH treatment may be a useful anti-bacterial, osteoconductive GBR membrane for numerous orthopedic, cranio-maxillofacial and dental tissue engineering applications.

Nanofeatured silk fibroin membranes for dermal wound healing applications.

As an effort to create the next generation of improved skin graft materials, in this study, we modified the surfaces of a previously investigated material, silk fibroin, using a NaOH alkaline treatment to obtain a biologically inspired nanofeatured surface morphology. Such surfaces were characterized for roughness, energy, and chemistry. In addition, keratinocyte (skin-forming cells) adhesion and proliferation on such nanofeatured silk fibroin wound dressings were studied in an initial attempt to determine the promotion of an epidermal cover on the wound bed to form a new epidermal barrier. Dermal fibroblast adhesion and proliferation were also studied to assess the ability of nanostructured silk fibroin to replace damaged dermal tissue in chronic wounds (i.e., for diabetic foot ulcers). Results demonstrated for the first time that keratinocyte and fibroblast cell density was greater on nanofeatured silk fibroin membranes compared with non-treated silk fibroin surfaces. The enhancement in cellular functions was correlated with an increase in silk surface nanotopography, wettability and change in chemistry after NaOH treatment. Due to the present promising results, the newly developed nanofeatured silk fibroin membranes are exciting alternative skin graft materials which should be further studied for various skin patch and wound dressing applications.

Nanostructured anti-bacterial poly-lactic-co-glycolic acid films for skin tissue engineering applications.

Major issues faced with the use of today's skin grafts are infection, scar tissue formation, insufficient keratinocyte (or skin producing cells) proliferation and high production costs. To overcome these limitations, we propose here for the first time, a nanofeatured poly(lactide-co-glycolide) (PLGA) membrane as a next generation antibacterial skin graft material. An alkaline surface treatment method was used to create random nanofeatures on PLGA membranes where sodium hydroxide (NaOH) concentration and exposure times were altered to control surface morphology. Most significantly, and without the use of antibiotics, results showed a decrease in Staphylococcus aureus (a dangerous pathogen infecting skin grafts) growth for up to ∼40% after 2 days of culture on nanofeatured PLGA membranes compared to untreated controls. Results also showed that while bacteria growth was stunted, mammalian cell growth was not. Specifically, cell culture results showed an increase in human epidermal keratinocyte density, while the density of scar tissue forming human dermal fibroblasts, did not change on nanofeatured PLGA surfaces compared to the untreated controls after 3 days of culture. These findings indicate that the alkaline treatment of PLGA membranes is a promising quick and effective manner to limit scar tissue formation and bacterial invasion while increasing skin cell proliferation for improving numerous wound-healing applications.

Comparative evaluation of cyclosporine A/HPßCD-incorporated PLGA nanoparticles for development of effective ocular preparations.

To improve poor water solubility of cyclosporine A (CsA), hydroxypropyl-beta-cyclodextrin (HPßCD) was incorporated into the nanoparticle formulation. Solid complexes of CsA with HPßCD in different ratios were prepared by the kneading method. CsA containing alone or in combination with HPßCD in poly-lactide-co-glycolide (P-CsA or P-CsA-HPßCD) nanoparticles were prepared by the emulsification solvent evaporation method. The mean size of CsA-loaded NPs was found to be approximately 220 nm. The solubility of CsA was significantly improved and the phase solubility diagram of CsA-HPßCD systems showed an A(L) type phase. Nanoparticles showed high CsA encapsulation efficiency (88%) and production yield (89%). Release rate was increased by the presence of HPßCD and total cumulative release ranged from 75% to 96% in 24 h. In vitro cytotoxicity study assay resulted in a low toxicity for all types of nanoparticles. After 6 h incubation period, the cellular uptake was found at 33% and 32% for P-CsA and P-HPßCD-CsA nanoparticles, respectively.

Development and characterization of Cyclosporine A loaded nanoparticles for ocular drug delivery: Cellular toxicity, uptake, and kinetic studies.

Dry eye syndrome is a common disorder of the tear film caused by decreased tear production or increased evaporation. The objective of this study was to evaluate the potential effectiveness of Cyclosporine A (CsA) nanoparticles (NPs) for the treatment of inflammation of the eye surface. Topical CsA is currently the only and safe pharmacologic treatment of severe dry eye symptoms. The NPs were prepared using either poly-lactide-co-glycolide (PLGA) or a mixture of PLGA with Eudragit®RL or were coated with Carbopol®. The mean size of CsA loaded NPs was within the range from 148 to 219nm, except for the Carbopol® coated NPs (393nm). The drug entrapment efficiency was very high (from 83 to 95%) and production yield was found between 75 and 92% in all preparations. The zeta potential of the Eudragit® RL containing NPs was positive (19-25mV). The NPs formulations exhibited a biphasic drug release with initial burst followed by a very slow drug release and total cumulative release within 24h ranged from 75 to 90%. Kinetically, the release profiles of CsA from NPs appeared to fit best with the Weibull model. The viability of L929 cells was decreased by increasing the concentration of the various NPs examined as well as the incubation time. The amount of NPs uptake was related to the polymer type used. The highest degree of cellular uptake (52.2%), tear film concentration of the drug (366.3ng/g) and AUC(0→24) (972.6ngh/g) value were obtained from PLGA: Eudragit® RL (75:25)-CsA NPs formulations. The change of surface characteristics of NPs represents a useful approach for improvement of ocular retention and drug availability.

Regulation of tumor angiogenesis by EZH2.

Although VEGF-targeted therapies are showing promise, new angiogenesis targets are needed to make additional gains. Here, we show that increased Zeste homolog 2 (EZH2) expression in either tumor cells or in tumor vasculature is predictive of poor clinical outcome. The increase in endothelial EZH2 is a direct result of VEGF stimulation by a paracrine circuit that promotes angiogenesis by methylating and silencing vasohibin1 (vash1). Ezh2 silencing in the tumor-associated endothelial cells inhibited angiogenesis mediated by reactivation of VASH1, and reduced ovarian cancer growth, which is further enhanced in combination with ezh2 silencing in tumor cells. Collectively, these data support the potential for targeting ezh2 as an important therapeutic approach.

Pregabalin in partial seizures: a pragmatic 21-week, open-label study (PREPS).

BACKGROUND AND PURPOSE: Pregabalin has demonstrated efficacy in controlled trials as adjunctive treatment in patients with refractory seizures. METHODS: This open-label, 21-week study in adults with at least two partial seizures in the last 2 months, who were inadequately controlled with one to three antiepileptic drugs, evaluated pregabalin 150-600 mg/day (dosed twice daily). The study comprised a prospective or retrospective 8-week baseline phase, and 9-week dose optimization and 12-week maintenance periods. The primary assessment was the mean percentage change in 28-day seizure frequency between baseline and end-point (last 12 weeks of treatment, last observation carried forward, modified intention-to-treat population). RESULTS: Four hundred and seventy-six patients from Europe were included in this study (51% men; mean age/epilepsy duration 40.1/24.1 years). The median baseline seizure frequency was 5.5/28 days. Amongst the patient population, 78% completed the 21-week treatment period; 7% discontinued for lack of efficacy and 12% because of adverse events (AEs). The mean last pregabalin dose was 359 mg/day. The mean (95% CI) reduction in seizure frequency was 36% (31%; 41%). The median reduction was 33%, and 39% of patients had a >or=50% reduction in seizure frequency. There were 19% and 8% of patients free of seizures during their last 4 and 12 weeks of treatment, respectively. The three most common AEs were dizziness (17%), somnolence (13%) and weight increase (13%). CONCLUSIONS: This open-label study of pregabalin demonstrated efficacy that was consistent with that observed in previous controlled epilepsy trials. Pregabalin was well tolerated. The AE profile was also consistent with that reported in previous trials.

Pregabalin for painful HIV neuropathy: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Pregabalin is effective in several neuropathic pain syndromes. This trial evaluated its efficacy, safety, and tolerability for treatment of painful HIV-associated neuropathy. METHODS: This randomized, double-blind, placebo-controlled, parallel-group trial included a 2-week double-blind dose-adjustment (150-600 mg/day BID) phase, a 12-week double-blind maintenance phase, and an optional 3-month open label extension phase. The primary efficacy measure was the mean Numeric Pain Rating Scale (NPRS) score, an 11-point numeric rating scale. Secondary measures included Patient Global Impression of Change (PGIC) and sleep measurements. RESULTS: Baseline mean NPRS score was 6.93 for patients randomized to pregabalin (n = 151) and 6.72 for those to placebo (n = 151). Pregabalin average daily dosage (SD) was 385.7 (160.3) mg/d. At endpoint, pregabalin and placebo showed substantial reductions in mean NPRS score from baseline: -2.88 vs -2.63, p = 0.3941. Pregabalin had greater improvements in NPRS score relative to placebo at weeks 1 (-1.14 vs -0.69, p = 0.0131) and 2 (-1.92 vs -1.43, p = 0.0393), and at weeks 7 (-3.22 vs -2.53 p = 0.0307) and 8 (-3.33 vs -2.53, p = 0.0156). At all other time points, differences between groups were not significant. Sleep measurements and 7-item PGIC did not differ among treatment groups; however, collapsed PGIC scores showed 82.8% of pregabalin and 66.7% of placebo patients rated themselves in 1 of the 3 "improved" categories (p = 0.0077). Somnolence and dizziness were the most common adverse events with pregabalin. CONCLUSIONS: Pregabalin was well-tolerated, but not superior to placebo in the treatment of painful HIV neuropathy. Factors predicting analgesic response in HIV neuropathy warrant additional research. CLASSIFICATION OF EVIDENCE: This Class II trial showed that pregabalin is not more effective than placebo in treatment of painful HIV neuropathy.

Antimicrobial activity of cefazolin-impregnated mesh grafts.

BACKGROUND: The aim of this study is the preparation and characterization of cefazolin-impregnated meshes (Surgipro; Tyco Healthcare USSC, Norwalk, CT, USA) to be used as antimicrobial devices. METHODS: During the impregnation, poly(DL-lactide-co-glycolide) solution with cephazolin in dichloromethane was used as coating material. In vitro release experiment was carried out first; later cefazolin-impregnated meshes were evaluated for the characteristics of antimicrobial efficacy and in the last part of the study native and cefazolin-impregnated meshes were implanted in the rats. Cefazolin content was proposed as the effective parameter to control the cefazolin release rate and it was concluded that the higher amounts of initial cefazolin content caused higher release rates. In all cases (or with different cefazolin content for each mesh), the release rates were very rapid in the first 24 h and in the following periods rather slow release rates were obtained. RESULTS: Antimicrobial activity was increased in the case of cefazolin-impregnated form and this efficiency was also increased by the higher amount of cefazolin in certain mesh pieces. Similar antimicrobial activities were observed in the in vitro studies. CONCLUSION: In this study, almost all of the cefazolin-impregnated mesh grafts showed very high antimicrobial activity compared with the bare mesh (or mesh without cefazolin).

Chitosan-coated alginate microspheres for embolization and/or chemoembolization: in vivo studies.

In this study, chitosan-coated alginate microspheres were prepared by the ionic complexation of alginate and chitosan biopolymers to use in embolization and/or chemoembolization studies. Biopolymeric microspheres were prepared by the ionic gelation technique of alginate with a suitable divalent cation (i.e. CaCl2) in a suspension medium composed of mineral oil and petroleum ether including emulsifier (i.e. Tween-80) and then obtained microspheres were coated with chitosan in an aqueous chitosan solution while the medium was magnetically stirred. The obtained microspheres are in the size range of 100-400 microm and they can be prepared as required by changing the preparation conditions (i.e. stirring rate, concentration of biopolymers, molecular weight and concentration of chitosan, etc.). In the in vivo studies, New Zealand rabbits were used as the test animals. Both complete and partial embolization of the kidney were achieved by using the microspheres. The renal angiograms obtained before/after embolization and the histopathological observations showed the feasibility of the chitosan-coated alginate microspheres as an alternative embolization and/or chemoembolization agent.

Bioadhesive drug carriers for postoperative chemotherapy in bladder cancer.

Transurethral resection (TUR) is the primary mode of therapy for both diagnosis and treatment of bladder cancer. Due to the recurrency of tumoral tissues after TUR further treatment is necessary which is usually in the form of intravesical chemotherapy or immunotherapy. But these therapies have some disadvantages such as disturbancy to patients, adjustment of the suitable dosage, loss of active agents without using. In this study, an alternative approach was proposed and pharmaco-therapeutic agent delivery systems which will supply the suitable dosage of the agent for a certain time period were designed to solve those problems. For this aim, Mitomycin-C loaded alginate and chitosan carriers were prepared to use as an alternative system in the post-operative chemotherapy in bladder cancer. The carriers were prepared in the form of cylindirical geometries to facilitate the insertion of the carrier in in vivo studies. The effects of some parameters (i.e., polymer MW, cross-linker concentration, Mitomycin-C/polymer ratio etc.) over the morphology, swelling behavior, bioadhesion and in-vitro drug release rate of the carriers were evaluated. The obtained results for chitosan and alginate carriers were concluded comparatively.

Norfloxacin-loaded chitosan sponges as wound dressing material.

The aim of this study was the preparation and characterization of chitosan sponges including a model antibiotic (i.e., norfloxacin). The chitosan sponges were prepared by a solvent evaporation method. The matrix was also cross-linked during the preparation. The results indicated that the chitosan sponges were in the fibrillar structure. The swelling behavior, norfloxacin loading, in vitro release characteristics, and antibacterial activity were determined. The effects of cross-linker concentration, norfloxacin/chitosan ratio, chitosan molecular weight, and base concentration were investigated. The most effective parameter was found to be the degree of neutralization. It was also observed that the equilibrium swelling ratio decreased with increasing cross-linking density. The norfloxacin release was found to be swelling controlled initially and diffusion controlled at the extended release periods. It was also found that the antibacterial activity was directly proportional to the release rate.

Functional, cognitive and behavioral effects of donepezil in patients with moderate Alzheimer's disease.

OBJECTIVE: To investigate the efficacy and safety of donepezil in a subgroup of patients with Alzheimer's disease (AD) of moderate severity from a previous trial. METHODS: Two hundred and seven patients with moderate AD (standardized Mini-Mental State Examination [sMMSE] score 10-17) were randomized to treatment in this 24-week, double-blind, placebo-controlled trial. Patents received either donepezil, 5 mg/day for the first 28 days and 10 mg/day thereafter according to the clinician's judgement (n = 102), or placebo (n = 105). The primary outcome measure was the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC-plus) at week 24 using a last observation carried forward (LOCF) analysis. RESULTS: Baseline patient demographics were similar between treatment groups. Mean age was 74.3 years (range 48-92). Least-squares (LS) mean sMMSE scores at baseline were 13.6 +/- 0.3 for the donepezil group and 13.9 +/- 0.3 for the placebo group. LS mean CIBIC-plus scores for donepezil-treated patients were improved from, or close to, baseline severity at all visits, and were significantly different from placebo at weeks 8, 12, 18, and 24 (week 24 LOCF mean difference = 0.53, p = 0.0003). LS mean change from baseline scores on the sMMSE and Severe Impairment Battery (SIB) for the donepezil group improved throughout the study, and were significantly different from placebo at each visit for the sMMSE (week 24 LOCF mean difference = 2.06, p = 0.0002) and from week 8 for the SIB (week 24 LOCF mean difference = -4.44, p = 0.0026). LS mean change scores on the Disability Assessment for Dementia remained at or above baseline levels throughout the study for the donepezil group, while the placebo group showed a steady decline; treatment differences were significant at each visit (week 24 LOCF mean difference = -9.25, p < 0.0001). LS mean change scores on the Neuropsychiatric Inventory 12-item total improved throughout the study for the donepezil group and were significantly different from placebo at weeks 4 and 24 (week 24 LOCF mean difference = 5.92, p = 0.0022). Eighty-one per cent of donepezil-treated and 89% of placebo-treated patients completed the trial, with 9% and 5%, respectively, discontinuing due to adverse events (AEs). Eighty-two per cent of donepezil-treated and 80% of placebo-treated patients experienced AEs, the majority of which were rated mild in severity and, in general, were similar between treatment groups. CONCLUSION: The significant treatment responses observed with donepezil in these patients reinforce the findings from earlier studies that show donepezil to have important benefits, compared wih placebo, across functional, cognitive, and behavioral symptoms, with good tolerability, in patients with AD of moderate severity.

Venous invasion may predict lymph node metastasis in early rectal cancer.

AIM: The aim of this study was to evaluate the role of histopathological and demographic characteristics in predicting lymph node metastasis in patients with adenocarcinoma of the rectum confined to the mucosal and submucosal layers. METHODS: Fifty-nine patients with early rectal cancer underwent resection of the rectum including lymph nodes and five showed lymph node metastasis (8.6%). Pathology slides of these patients were reviewed by a single pathologist. Demographic and clinical characteristics of these 59 patients were correlated with the existence of nodal metastasis. Formal tests of comparability were carried out by using Fisher's exact test. Logistic regression models were fitted to data to examine possible relationships with 12 covariates measured from each patient and to obtain corresponding odds ratios (as well as a 95% confidence interval for the odds ratios). These covariates included age at surgery, gender, morphology, histology, degree of differentiation, Haggitt's classification for polyps according to the level of invasion, lymphatic and venous invasion, desmoplastic reaction, degree of lymphocytic invasion, presence of lymphoid follicles and presence of infiltrating or pushing margins. RESULTS: A significantly higher rate of lymph node metastasis occurs in the presence of venous invasion (P < 0.01). Venous invasion was present in three of five (60%) patients with lymph node metastasis and only four of 54 (7%) patients without lymph node metastasis. Other variables did not achieve statistical significance. CONCLUSIONS: Only the presence of venous invasion was found to be highly significant. The odds ratio of lymph node metastasis increased 18-fold for a patient who had venous invasion compared with a patient who did not. This suggests that the presence of venous invasion in early rectal cancer may provide valuable information to determine which patients would benefit from radical surgery, or adjuvant radiation therapy after sphincter-sparing surgery owing to an increased risk of lymph node metastasis.

Comparison of diagnostic markers with repeated measurements: a non-parametric ROC curve approach.

In this paper we study a class of non-parametric statistics for comparing diagnostic markers with repeated measurements. Using adapted definitions of specificity and sensitivity, we suggest methods to compare the average of sensitivities across all specificities or a range of specificities. The theory allows for correlations introduced by the fact that markers may be obtained from the same patient at multiple visits and that both markers being compared may be obtained from the same patient. Results of the Monte Carlo simulations and an example from a breast cancer setting are provided.