Investigating the Z-scan technique for quantifying circulating cell-free DNA (ccfDNA) extracted from blood plasma as a potential biomarker for various cancers.

The Z-scan technique is a nonlinear optical method that has found applications in characterizing various materials, particularly those exhibiting nonlinear optical response (NLOR). This study applies the continuous wave (CW) Z-scan technique to examine the NLOR in terms of the nonlinear optical phase shifts(ΔΦ0) exhibited by the ccfDNA extracted from blood plasma samples collected from a group constituting 30 cancer-diagnosed patients and another group constituting 30 non-diagnosed individuals. The cancer group exhibited significantly higherΔΦ0versus incident power slopes compared to the non-cancer group (0.34 versus 0.12) providing a clear distinction between the two groups. The receiver operating characteristic (ROC) curve analysis of the results indicates a clear separation between cancer and non-cancer groups, along with a 94% accuracy rate of the data. The Z-scan results are corroborated by spectrophotometric analysis, revealing a consistent trend in the concentration values of ccfDNA samples extracted from both cancerous and non-cancerous samples, measuring 3.24 and 1.41 respectively. Additionally, more sensitive fluorometric analyses of the respective samples demonstrate significantly higher concentrations of ccfDNA in the cancer group, further affirming the correlation with the Z-scan results. The study suggests that the Z-scan technique holds promise as an effective method for cancer detection, potentially contributing to improved oncology diagnosis and prognosis in the future.

Prevalence of Virulence Genes in Acinetobacter baumannii Isolated from Clinical Samples in Mymensingh Medical College Hospital, Bangladesh.

Acinetobacter baumannii is an opportunistic bacterial pathogen that is the most important cause of hospital-acquired infections. The objective of this study was to evaluate the predominance and determination of virulence encoding genes in A. baumannii isolates. During this cross-sectional study period from February 2019 to March 2020 of 380 clinical samples including endotracheal aspirates (70), wound swab or pus (175), urine (70) and blood (65) analysed in inpatients admitted to the hospital in different unit like ICU, Surgery and Burn unit of Mymensingh Medical College Hospital. Out of 380 studied samples, 130(34.21%) strains were yielded growth. Among 130 isolates, Acinetobacter spp. was 49(37.69%). Totally, 39(79.59%) were Acinetobacter baumannii which was detected by molecular technique PCR. Further more, the determination of virulence genes csgA and fimH detected by PCR. Among two studied virulence genes, csgA (38.46%) was the most prevalent virulent genes associated with disease severity and co-morbidity of the patient in A. baumannii infections.

Molecular Detection of MBL Encoding Genes in Acinetobacter baumannii strains Isolated from Various Samples at a Tertiary Care Hospital in Mymensingh.

MBL producing Acinetobacter baumannii is a major threat for therapeutic treatment of hospital acquired infections. The aim of this study was to determine the prevalence of metallo-ß-lactamase genes VIM, IMP & SIM genes amongst isolated A. baumannii. This cross sectional study conducted in the department of Microbiology Mymensingh Medical College from March 2019 to February 2020. 49 Acinetobacter spp. were isolated from different clinical samples including endotracheal aspirates, wound swab/pus, urine and blood. Among 380 clinical samples 130 organisms were isolated growth was 34.21%. Out of 130 isolated strains, 49(37.69%) were Acinetobacter spp identified by standard bacteriological method and resistance to different antibiotics was assessed with Kirby- Bauer Disc diffusion method. Among 49 Acinetobacter spp, 39(79.59%) were Acinetobacter baumannii which was identified by molecular method PCR directing OXA-51 like gene. Multiplex PCR was done to determine MBL genes existence VIM, IMP & SIM. Ceftriaxone (79.48%) showing higher resistance and colistin (12.82%) showing lower resistance. All the strains were sensitive to tigecycline. The distribution of MBLs genes such as VIM 20(51.28%), IMP 5(12.82%) and SIM 0 (0%). This study showed that high level of antibiotic resistance and VIM was the most prevalent MBL genes among A. baumannii highlighting the need for indigenous antibiotic usage plan & infection control measures to prevent the spread of these resistance genes.

Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by baseline body mass index: an analysis of pooled data from phase 3 studies.

OBJECTIVE: Tofacitinib is an oral Janus kinase for the treatment of rheumatoid arthritis (RA). This post hoc analysis assessed whether baseline body mass index (BMI) impacts tofacitinib efficacy in patients with RA. METHODS: Pooled data from six phase 3 studies in patients receiving tofacitinib 5 mg (N=1589) or 10 mg (N=1611) twice daily or placebo (advancing to active treatment at months 3 or 6; N=680), ±conventional synthetic disease-modifying antirheumatic drugs, were stratified by baseline BMI (<25, 25 to <30, ≥30 kg/m2). Endpoints (through to month 6) were assessed descriptively: American College of Rheumatology 20/50/70 response rates; changes from baseline (∆) in Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4(ESR)), DAS28-4(C-reactive protein), Clinical Disease Activity Index (CDAI), Health Assessment Questionnaire-Disability Index (HAQ-DI) and pain; and proportions of patients achieving DAS28-4(ESR) ≥1.2 and HAQ-DI ≥0.22 decreases from baseline, low disease activity (DAS28-4(ESR) ≤3.2 or CDAI ≤10) and radiographic non-progression (Δmodified Total Sharp Score ≤0.5; months 12 and 24). Estimates were adjusted using multivariable models for selected outcomes. Univariate/multivariable regression analyses determined predictors of month 6 outcomes. RESULTS: Of 3880 patients included, 1690 (43.6%), 1173 (30.2%) and 1017 (26.2%) had baseline BMI <25, 25 to <30 and ≥30 kg/m2, respectively. Tofacitinib showed greater efficacy improvements versus placebo in each BMI category. Differences in efficacy outcomes (adjusted and unadjusted) were generally not clinically meaningful across BMI categories within treatment groups. In regression analyses, BMI was not consistently associated with selected outcomes. CONCLUSIONS: Baseline BMI did not consistently affect tofacitinib response suggesting that tofacitinib is an effective oral treatment option for adults with moderate to severe RA regardless of baseline BMI, including patients with BMI ≥30 kg/m2. TRIAL REGISTRATION NUMBERS: NCT00814307, NCT01039688; NCT00960440; NCT00847613; NCT00856544; NCT00853385.

Socio-demographic and Clinico-epidemiological Study of Scrub Typhus in A Tertiary Care Hospital of Mymensingh, Bangladesh.

Scrub typhus is one of the leading causes of undifferentiated treatable febrile illness in Asia pacific region. It is grossly under diagnosed in many tropical countries of South Asia including Bangladesh, due to wide range of non-specific clinical presentations, low index of suspicion among clinicians, limited awareness and lack of accurate diagnostic facilities. This cross sectional observational study was conducted at department of Microbiology, Mymensingh Medical College, Mymensingh, Bangladesh from March 2019 to February 2020 enrolling 113 diagnosed cases of scrub typhus by Immunochromatographic test (ICT) and / or Nested PCR to characterize the socio-demographic and clinico-epidemiological features of scrub typhus in Mymensingh area. Majority of the scrub typhus cases came from rural areas (63.83%) and there was a slight female predominance (52.21%). The young (32.74%) and the young-adult age group (28.31%) were mostly affected. Most of the scrub typhus cases were housewives (30.98%), followed by farmers (23.89%) and students (21.23%). All the enrolled cases presented with fever. Other findings were myalgia (76.10%), headache (56.63%), cough (30.97%), vomiting (12.38%) and Respiratory distress (9.73%). Typical eschar of scrub typhus was present only in 9(7.96%) cases and 4(3.53%) patients had rashes on their skin. Few cases (3.53%) had jaundice and 15.96% cases were anaemic. Oliguria (7.96%) and neck rigidity (1.76%) were also documented. Most of the Nested PCR positive scrub typhus cases were documented during late rainy season and beginning of winter months. Findings of the study may offer increased awareness about high burden of scrub typhus as well as heightened suspicion among clinicians for early diagnosis, timely treatment and prevention of complications.

Detection of Biocide Resistance Genes (qacE and qacΔE1) in Pseudomonas spp Isolated from Patients with CSOM at Mymensingh Medical College Hospital, Bangladesh.

Biocides, including disinfectants and antiseptics, are used for a variety of topical and hard surface applications in health care facilities. Biocides play a significant role for preventing and controlling nosocomial infections. However, failures in the antimicrobial activities of biocides have been reported. The resistance mechanism to disinfectants is usually determined by genes which are related to resistance to quaternary ammonium compounds, namely, qacE, qacΔE1 that are found in Gram-negative bacteria. The aim of this study is to detect the prevalence of Biocides resistance genes, qacE and qacΔE1, in clinical isolates of Pseudomonas spp. It was carried out from March 2017 to July 2018 in the department of Microbiology, Mymensingh Medical College, Mymensingh, Bangladesh. Samples were collected from Outpatient of ENT department, MMCH. In this study, 300 clinical samples of CSOM cases were tested by the PCR method. The present study shows detection of biocide resistance genes (qacE, qacΔE1) among 87 isolated Pseudomonas spp by uniplex PCR. Among 72 clinical isolates of Pseudomonas aeruginosa 67(93.05%) had the gene qacEΔ1 and 25(34.72%) had the gene qacE. In addition other 15 Pseudomonas spp 3(20%) isolates had the qacEΔ1 gene and 2(13.33%) isolates had the qacE gene. In this study there is a marked difference in detection of the qacEΔ1 gene between the MDR and non MDR P. aeruginosa isolates. The qacEΔ1 was identified in 50 of 54(92.59%) MDR isolates and 7 of 18(38.89%) non MDR strains respectively. While gene qacE was detect 25(46.29%) MDR isolates and did not show any qacEΔ1gene in non MDR isolates. This study shows that the genes, qacE, qacΔE1 are widespread among Pseudomonas aeruginosa, they are higher in MDR strains than non MDR strains.

Rapid Serologic and Molecular Diagnosis of Scrub Typhus among Suspected Febrile Patients Visiting Mymensingh Medical College Hospital.

Scrub typhus, caused by the bacterium- Orientia tsutsugamushi is one of the leading causes of undifferentiated treatable febrile illness in Asia pacific region. It is grossly under diagnosed in many tropical countries of South Asia including Bangladesh, due to wide range of non-specific clinical presentations, low index of suspicion among clinicians, limited awareness and lack of accurate diagnostic facilities. This cross-sectional descriptive study was conducted at Department of Microbiology, Mymensingh Medical College to diagnose scrub typhus by rapid Immunochromatographic test (ICT) as well as molecular detection of O. tsutsugamushi by Nested PCR and automated nucleotide sequencing among suspected febrile patients in Mymensingh, Bangladesh during 2019-20. Blood samples were collected from 402 febrile patients of suspected Rickettsial illness, referred from inpatient and outpatient departments of Medicine and Pediatrics, Mymensingh Medical College Hospital (MMCH). Among the enrolled 402 patients, 89 samples (22.13%) were seropositive by Immunochromatographic test (ICT) and 65 samples (16.16%) were positive for O. tsutsugamushi DNA by Nested PCR, targeting 47KDa gene. Therefore, 113/402 (28.10%) samples were positive for scrub typhus by PCR and/ or ICT. Highest number of patients was detected positive by nested PCR during the first 5-10 days of fever but only 2 cases were positive after 20 days. In case of ICT, highest positivity for only IgM (8.13%) and both antibodies (2.43%) were documented in first 5-10 days of fever, but IgG positivity was highest (41.66) in >20 days of fever. From 65 PCR positive samples, automated nucleotide sequencing was performed on 20 randomly selected samples and all were genetically confirmed to be O. tsutsugamushi.

Prevalence of ESBL Encoding Genes in Acinetobacter baumannii Strains Isolated from Various Samples of a Tertiary Care Hospital in Mymensingh.

The aim of this study was to find the prevalence of ESBL genes among A. baumannii isolates. In this cross sectional study, 49 Acinetobacter spp. were isolated from various clinical samples from March 2019 to February 2020 conducted in the department of Microbiology, Mymensingh Medical College, Mymensingh, Bangladesh. Clinical samples including endotracheal aspirates, wound swab/pus, urine and blood. A total of 380 samples were analyzed. Growth was obtained in 34.21% of the samples yielding 130 organisms. Out of 130 organisms, 49(37.69%) were Acinetobacter spp. Among 49 Acinetobacter spp, 39(79.59%) were Acinetobacter baumannii which was identified by PCR targeting OXA-51 like gene. Amplification of the ESBL encoding genes, namely CTX-M, TEM, SHV done by molecular technique PCR. The most antibacterial resistance was against ceftriaxone (79.48%) and lower resistance only showed in colistin (12.82%). All the isolates were sensitive to tigecycline. The distribution of ESBLs genes such as TEM 20(51.28%), CTX-M 16(41.02%) and SHV 0(0%). The high resistance to most of the antibiotics among the studied strains and also a high prevalence of TEM gene in A. baumannii strains found in our study gives alarming sign towards the treatment complexity of these strains.

Multivessel Spontaneous Coronary Artery Dissection With Coronary Artery Fibromuscular Dysplasia.

A 53-year-old woman underwent a cardiac catheterization for evaluation of acute coronary syndrome. The coronary angiogram revealed evidence of spontaneous coronary artery dissection in multiple coronary arteries including the left anterior descending artery, posterior descending artery, and posterior left ventricular artery. Further diagnostic imaging revealed associated bilateral vertebral artery and renal artery fibromuscular dysplasia (FMD). Follow-up coronary angiogram 6 weeks later revealed a "string of beads" appearance of the posterior descending artery. This case highlights the importance of extra-coronary imaging for FMD and demonstrates angiogram findings suggestive of coronary FMD.

Une femme de 53 ans a été soumise à un examen par cathétérisme cardiaque afin d'évaluer le syndrome coronarien aigu dont elle est atteinte. L'angiographie coronarienne a révélé des signes de dissection spontanée de l'artère coronaire dans de multiples artères coronaires, y compris l'artère interventriculaire antérieure, l'artère interventriculaire postérieure et l'artère ventriculaire gauche postérieure. D'autres images diagnostiques ont révélé la présence d'une dysplasie fibromusculaire (DFM) bilatérale connexe des artères rénales et vertébrales. L'artère interventriculaire postérieure avait l'aspect d'un « collier de perles ¼ à l'angiographie coronarienne de suivi effectué six semaines plus tard. Ce cas souligne l'importance de l'imagerie extracoronaire pour la détection d'une DFM et montre que les résultats de l'angiographie sont indicatifs d'une DFM coronaire.

Detection of Antimicrobial Resistance Pattern and ESBL Production among Clinical Isolates of Salmonella Species in Mymensingh, Bangladesh.

The occurrence of antimicrobial resistance in Salmonella enterica serovars (both typhoidal and non-typhoidal Salmonellae) is a major public health problem especially in developing countries, which have been associated with treatment failures. Therefore, the study was undertaken to determine the current antimicrobial resistance pattern and extended spectrum ß-lactamase (ESBL) production among clinical isolates of Salmonella spp. during 2019-2020 in Mymensingh, Bangladesh. In this cross sectional study, 36 Salmonella enterica isolates were obtained from blood and stool culture of suspected 200 enteric fever and 100 gastroenteritis patients attending at Mymensingh Medical College Hospital, Mymensingh, Bangladesh. Isolated Salmonella species were identified by biochemical tests and Polymerase Chain Reaction (PCR). Disk diffusion test was performed by modified Kirby Bauer method. Minimum Inhibitory Concentration (MIC) of ceftriaxone was detected by agar dilution method. Double disk synergy test was used as a screening test for ESBL production. PCR was done for detection of blaTEM, blaSHV and blaCTX-MU genes. The isolates showed 25% resistance to Ceftriaxone and 58.3% to Azithromycin. The highest sensitivity rates were 88.9% to Meropenem and 83.3% to Amikacin. Whereas 6(16.7%) isolates were Multi Drug Resistant (MDR). Eight (8) isolates were confirmed as ESBL producer by DDST. The marked increase in MIC was observed between 8->512µg/ml to ceftriaxone. blaTEM, blaSHV and blaCTX-MU genes were detected in 3, 5 and 8 isolates respectively. In conclusion, the current study observed, higher level of resistance to ceftriaxone and azithromycin. At the same times 22.2% isolates showed ESBL production, which is a cause for concern as it may lead to treatment failure. On the other hand the study also showed the re-emergence of chloramphenicol and Sulfamethoxazole-Trimethoprim sensitivity.

Predominance of Leptospira wolffii in north-central Bangladesh, 2019.

Leptospira was detected in 48.9% of blood samples from 182 febrile patients in north-central Bangladesh in 2019. Most Leptospira were classified as L. wolffii (93%) on the basis of phylogenetic analysis of 16S ribosomal RNA genes, while others were assigned to L. borgpetersenii and L. meyeri.

Exploring Armenian Ethnicity as an Independent Risk Factor for Cardiovascular Disease: Findings from a Prospective Cohort of Patients in a County Hospital.

OBJECTIVES: While several studies have examined the risk of cardiovascular disease (CVD) in larger racial and ethnic groups within the United States, limited information is available on smaller sub-populations, such as Armenians, with high rates of CVD in their home country. This study examined the association between Armenian ethnicity and a positive exercise treadmill test (ETT). DESIGN: Prospective cohort study of patients at a 377-bed county hospital in Los Angeles, California from 2008-2011. SETTING: All patients were interviewed at the time of ETT to assess their cardiovascular risk factors at the cardiac laboratory of the hospital. PARTICIPANTS: 5,006 patients between 18-89 years of age, of whom 12.6% were of Armenian ethnicity and 54.4% were female.Main Outcome Measure: ETT results as a proxy for CVD risk. RESULTS: After adjusting for cardiovascular risk factors, Armenian ethnicity was significantly associated with higher odds of positive ETT (OR = 1.40, p = 0.01). Known coronary artery disease CAD (OR = 2.28, p < 0.01), hyperlipidemia (OR = 1.37, p < 0.01), and hypertension (OR = 1.24, p = 0.05) were significantly associated with higher odds of a positive ETT. In subgroup analyses, hyperlipidemia was the only significant predictor of positive ETT (OR = 1.92, p = 0.02) among Armenians, while patient history of CAD (OR = 2.49, p < 0.01), hyperlipidemia (OR = 1.29, p = 0.03), and age (OR = 1.04, p < 0.01) were significant predictors among non-Armenians. Armenian ethnicity remained associated with higher odds of positive ETT (OR = 1.40, p < 0.01) when patients with CAD were excluded. CONCLUSION: Armenian ethnicity may be an independent risk factor for CVD, influenced by the uniformity of the genetic pool and cultural and dietary exposures.

Revascularization Versus Medical Therapy in Patients Aged 80 Years and Older with Acute Myocardial Infarction.

BACKGROUND/OBJECTIVES: Older patients are underrepresented in acute coronary syndrome clinical trials. We sought to evaluate the benefits of revascularization in patients aged 80 years and older presenting with acute myocardial infarction (AMI). DESIGN: Retrospective study utilizing inverse probability of treatment weighting (IPTW). SETTING: Single tertiary referral center for an integrated healthcare system in southern California. PARTICIPANTS: Patients undergoing invasive coronary angiography for AMI between 2009 and 2019, and subsequently treated with percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), or medical therapy alone. MEASUREMENTS: All-cause mortality, nonfatal myocardial infarction (MI), and repeated revascularization. RESULTS: A total of 1,433 patients aged 80 years or older (median age = 83.5 years; 66% male) presenting with AMI who underwent treatment with PCI (50%), CABG (12%), or medical therapy alone (38%) were included. Those treated with medical therapy were more likely to be Black, had one or more chronic total occlusions in any vessel, had more comorbidities, and had lower left ventricular ejection fraction. Baseline characteristics were well balanced after IPTW adjustment. Median follow-up was 2.6 years. Revascularization (PCI or CABG) was associated with reduced mortality (hazard ratio (HR) = 0.66; 95% confidence interval (CI) = 0.60-0.73) and nonfatal MI (HR = 0.68; 95% CI = 0.58-0.78), but an increased need for repeated revascularization (HR = 1.60; 95% CI = 1.15-2.23). Separately comparing PCI or CABG alone versus medical therapy yielded similar results. Revascularization was associated with lower mortality in all subgroups, except in Black patients and those with prior CABG. CONCLUSION: Revascularization is superior to medical therapy in reducing all-cause mortality and nonfatal MI in patients aged 80 years and older with AMI. Age alone should not preclude patients from potentially beneficial invasive therapies.

Defying the Odds of Sudden Cardiac Death in Hypertrophic Cardiomyopathy.

We report an unusual case of a patient with hypertrophic obstructive cardiomyopathy, anomalous aortic origin of a coronary artery, obesity hypoventilation syndrome, and acquired long QT syndrome who was able to defy the odds of sudden cardiac death in the rarest of circumstances. (Level of Difficulty: Advanced.).

Heterogeneity of treatment effect in SPRINT by age and baseline comorbidities: The greatest impact of intensive blood pressure treatment is observed among younger patients without CKD or CVD and in older patients with CKD or CVD.

The Systolic Blood Pressure Intervention Trial (SPRINT), a large randomized controlled trial funded by the National Institutes of Health, randomized 9361 patients with hypertension over 50 years of age and at least one cardiovascular risk factor to intensive (SBP < 120 mm Hg) or standard (SBP < 140 mm Hg) blood pressure treatment. The trial found a significant reduction in primary cardiovascular and mortality outcomes in the intensive treatment group. We performed an IRB-approved post hoc analysis of the SPRINT trial data, recently made available through the NEJM SPRINT Data Analysis Challenge. Our subgroup analysis stratified subjects by age (≥75 years vs. <75 years) and presence or absence of pre-existing chronic kidney disease (CKD) or cardiovascular disease (CVD). We found that intensive blood pressure control was associated with a significantly lower rate of the primary CVD outcome and all-cause mortality in subjects age <75 years with no prior CVD or CKD and in subjects age ≥75 years with pre-existing CVD or CKD.

Switching From Immediate-Release to Delayed-Release Prednisone in Moderate to Severe Rheumatoid Arthritis: A Practice-Based Clinical Study.

INTRODUCTION: Rheumatoid arthritis (RA) produces debilitating morning stiffness. Exogenous glucocorticoids can help with these symptoms when timed appropriately. Bedtime dosing of delayed-release prednisone (DR-prednisone) matches the rise of inflammatory cytokines before awakening and can improve stiffness and other RA symptoms. A prospective open-label study was conducted in patients currently on stable doses of immediate-release prednisone (IR-prednisone) who were switched to DR-prednisone to analyze the incremental benefit of better timed and lower dose glucocorticoid therapy. METHODS: Twelve US sites enrolled patients with moderate-severe RA into a 12-week prospective study. Patients were switched from IR- to DR-prednisone while maintaining other existing background therapies. Change from baseline in morning stiffness severity, morning stiffness duration, swollen and tender joint counts (S-TJC), 28 joint disease activity score (DAS28), and patient/physician global assessment (PGA/PhGA), among others, were measured. Post-hoc analyses were performed on those completing 10 weeks of treatment and those with >60 min of morning stiffness at baseline. RESULTS: Fifty-six patients had at least one follow-up visit and were similar in demographics to previous controlled trials with DR-prednisone with regard to baseline age and DAS28-CRP but had lower morning stiffness and RA duration. DR-prednisone produced a trend toward lower morning stiffness severity and duration with a reduction in daily prednisone dose of almost 1 mg. Patients treated with DR-prednisone for ≥10 weeks demonstrated significant reductions in morning stiffness duration, SJC, TJC, DAS28-CRP, and PhGA (all p ≤ 0.04). Patients treated for ≥10 weeks with >60 min of baseline morning stiffness produced similar results in these measures as well as a 21% reduction in morning stiffness severity (p = 0.02). CONCLUSION: Patients switched to DR-prednisone from IR-prednisone in this practice-based study maintained or improved their outcomes across a variety of domains, and results were comparable to previous controlled trials in which patients completed at least 10 weeks of treatment. FUNDING: Horizon Pharma USA, Inc. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02287610.

Metabolism and disposition of MM-433593, a selective FAAH-1 inhibitor, in monkeys.

MM-433593 is a highly potent and selective inhibitor of fatty acid amide hydrolase-1 (FAAH-1) with potential utility as an orally administered treatment of pain, inflammation, and other disorders. In this study, we investigated the metabolism and pharmacokinetics of MM-433593 in monkeys, and compared plasma and urine metabolites of this compound to the in vitro metabolites produced by monkey hepatocytes. Intravenous administration of MM-433593 to cynomolgus monkeys produced a rapid distribution phase and slower elimination phase with a mean systemic clearance rate of 8-11 mL/min/kg. Absolute oral bioavailability was determined to be 14-21% with maximum plasma concentrations reached ∼3 h (T max) following a 10 mg/kg oral dose. The average terminal half-life of MM-433593 was 17-20 h, and there were no qualitative sex differences in the metabolite profile of MM-433593. The major site of metabolism was oxidation of the methyl group at the five position of the indole ring, which was confirmed by chromatography and mass spectrometry comparison to a synthesized authentic standard. This metabolite was further oxidized to the corresponding carboxylic acid and/or conjugated with sulfate, glucuronide, or glutathione. In all, 18 metabolites were found in plasma and urine. In vitro incubations of MM-433593 with monkey hepatocytes yielded 13 metabolites, all of which were found in vivo, indicating a good correlation between the in vitro and in vivo metabolism data. A comprehensive pathway for the metabolism of MM-433593 is proposed, including a plausible, five-step biotransformation for the formation of N-acetylcysteine conjugate metabolite (M18) from the hydroxylated parent (M5).

Cognition, glucose metabolism and amyloid burden in Alzheimer's disease.

The authors investigated relationships between glucose metabolism, amyloid load, and measures of cognitive and functional impairment in Alzheimer's disease (AD). Patients meeting criteria for probable AD underwent (11)C-labeled Pittsburgh Compound-B ([(11)C]PIB) and 18F-fluorodeoxyglucose ([(18)F]FDG) positron emission tomography (PET) imaging and were assessed on a set of clinical measures. The Pittsburgh Compound-B (PIB) Distribution volume ratios and fluorodeoxyglucose (FDG) scans were spatially normalized and average PIB counts from regions-of-interest (ROI) were used to compute a measure of global PIB uptake. Separate voxel-wise regressions explored local and global relationships between metabolism, amyloid burden, and clinical measures. Regressions reflected cognitive domains assessed by individual measures, with visuospatial tests associated with more posterior metabolism, and language tests associated with metabolism in the left hemisphere. Correlating regional FDG uptake with these measures confirmed these findings. In contrast, no correlations were found between either voxel-wise or regional PIB uptake and any of the clinical measures. Finally, there were no associations between regional PIB and FDG uptake. We conclude that regional and global amyloid burden does not correlate with clinical status or glucose metabolism in AD.