The impact of whole human blood on the kinetic inertness of platinum(IV) prodrugs - an HPLC-ICP-MS study

The potential advantage of platinum(IV) complexes as alternative to classical platinum(II)-based drugs relies on their kinetic stability in the body before reaching the tumor site and on their activation by reduction inside cancer cells. In this study, an analytical workflow was developed to investigate the reductive biotransformation and kinetic inertness of platinum(IV) prodrugs comprising different ligand coordination spheres (respectively, lipophilicity and redox behavior) in whole human blood. The distribution of the platinum(IV) complexes in blood pellet and plasma was determined by inductively coupled plasma-mass spectrometry (ICP-MS) after microwave digestion. An analytical approach based on reversed-phase (RP)-ICP-MS was used to monitor the parent compound and the formation of metabolites using two different extraction procedures. The ligand coordination sphere of the platinum(IV) complexes had significant impact on their accumulation in red blood cells and on their degree of kinetic inertness in whole human blood. The most lipophilic platinum(IV) compound featuring equatorial chlorido ligands showed a pronounced penetration into blood cells and a rapid reductive biotransformation. In contrast, the more hydrophilic platinum(IV) complexes with a carboplatin- and oxaliplatin-core exerted kinetic inertness on a pharmacologically relevant time scale with notable amounts of the compound accumulated in the plasma fraction

Dacryocystitis presenting as post-septal cellulitis: a case report

Dacryocystitis is relatively common, the majority of patients present with pre-septal cellulitis and not an orbital abscess due to anatomical barriers. The authors report a case of dacryocystitis presenting as post-septal cellulitis in a postmenopausal lady with an underlying malignancy. Following antibiotic therapy and elective dacryocystorhinostomy the patient is still under follow-up, and has no further recurrence of symptoms. Orbital abscess in postmenopausal women presenting with dacryocystitis should be considered, as prompt recognition and early surgical intervention is required to prevent visual loss

Measuring Health Related Quality of Life for Dengue Patients in Iquitos, Peru

Previous studies measuring the health-related quality of life (HRQoL) of individuals with dengue focused on treatment seeking populations. However, the vast majority of global dengue cases are unlikely to be detected by health systems. Representative measurements of HRQoL should therefore include patients with disease not likely to trigger treatment-seeking behavior. This study based in Iquitos, Peru used the Quality of Wellbeing Scale-Self Administered, a survey that enquires about not only physical health, but also psychological health, self-care, mobility, and usual social activities, and rates HRQoL between 0 (death) and 1 (optimum function), to evaluate the impact of dengue on HRQoL. In order to enroll treatment and non treatment-seeking participants, three modalities of participant recruitment were used. In addition to clinic and community-based febrile surveillance, a contact-cluster methodology was also employed to identify infected individuals less likely to seek treatment. We measured changes in HRQoL and identified common areas of health impairment in 73 virologically confirmed dengue cases at 3 time points during the participant\u27s illness; the early-acute (days 0-6 post symptom onset), late-acute (days 7-20), and convalescent illness phases (days 21 +). Participants reported HRQoL related impairments at significantly higher frequency during the early-acute versus convalescent illness phase (Fisher\u27s exact: P\u3c0.01). There was substantial heterogeneity in scores during each illness phase with median scores in the early-acute, late-acute and convalescent phases of 0.56 (IQR: 0.41-0.64), 0.70 (IQR: 0.57-0.94), and 1 (IQR: 0.80-1.00), respectively. In all illness phases participants recruited in clinics had on average the lowest HRQoL scores where as those recruited in the contact clusters had the highest. Only 1 individual who was recruited in the contact-clusters had no reduction in HRQoL score during their illness. These data illustrate that dengue should be considered as a disease that may have significant implications for not only physical health but also psychological health and social functioning. The impact of dengue on the HRQoL of non-treatment-seeking individuals, although lower than the impact among treatment-seeking individuals, is not necessarily trivial

Coffee Consumption and the Incidence of Colorectal Cancer in Women

Background. Higher coffee consumption has been associated with decreased incidence of colorectal cancer. Our objective was to examine the relationship of coffee intake to colorectal cancer incidence in a large observational cohort of postmenopausal US women. Methods. Data were collected for the Women’s Health Initiative Observational Study providing a follow-up period of 12.9 years. The mean age of our sample (N=83,778 women) was 63.5 years. Daily coffee intake was grouped into 3 categories: None, moderate (>0–<4 cups), and high (4+ cups). Proportional hazards modeling was used to evaluate the relationship between coffee intake and colorectal cancer. Results. There were 1,282 (1.53%) new cases of colorectal cancer during follow-up. Compared to nondrinkers, moderate and high coffee drinkers had an increased incidence of colorectal cancer in multivariate analysis (HR 1.15, 1.02–1.29; HR 1.14, 0.93–1.38). Moderate drip brew coffee intake (HR 1.20, 1.05–1.36) and high nondrip brew coffee intake (HR 1.43, 1.01–2.02) were associated with increased odds. Conclusion. Our results suggesting increased incidence of colorectal cancer associated with higher coffee consumption contradict recent meta-analyses but agree with a number of other studies showing that coffee increases risk or has no effect. Brew method results are novel and warrant further research

Improving Fecal Occult Blood Testing Compliance Using a Mailed Educational Reminder

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the United States. Randomized controlled trials have shown that annual screening fecal occult blood testing (FOBT) reduces CRC mortality and incidence. However, patient compliance with FOBT is low. To determine whether a mailed educational reminder increases FOBT card return rates and to examine predictors of FOBT compliance. Blinded, randomized, controlled trial at the Veteran Affairs Medical Center, San Diego, California. Seven hundred and seventy-five consecutive patients ≥50 years of age referred by their primary care physicians for FOBT. Patients were randomly assigned to the usual care group or the intervention group. Ten days after picking up the FOBT cards, a 1-page reminder with information related to CRC screening was mailed to the intervention group only. The primary outcome was proportion of returned FOBT cards after 6 months. Patient demographic, clinical characteristics and prior FOBT completed were collected for multivariate regression analysis. At 6 months after card distribution, 64.6% of patients in the intervention group returned cards compared with 48.4% in the control group (P &lt; 0.001). Patients who received a mailed reminder (OR 2.02; 95% CI: 1.48–2.74) or have a prior history of returning the FOBT cards (OR 1.87; 95% CI: 1.29–2.70) were more likely to return the FOBT cards. Patients with current or recent illicit drug use were less likely to return the FOBT cards (OR 0.26; 95% CI: 0.13–0.50). A simple mailed educational reminder significantly increases compliance with FOBT for CRC screening

Evaluating a Measure of Social Health Derived from Two Mental Health Recovery Measures: The California Quality of Life (CA-QOL) and Mental Health Statistics Improvement Program Consumer Survey (MHSIP)

Social health is important to measure when assessing outcomes in community mental health. Our objective was to validate social health scales using items from two broader commonly used measures that assess mental health outcomes. Participants were 609 adults receiving psychological treatment services. Items were identified from the California Quality of Life (CA-QOL) and Mental Health Statistics Improvement Program (MHSIP) outcome measures by their conceptual correspondence with social health and compared to the Social Functioning Questionnaire (SFQ) using correlational analyses. Pearson correlations for the identified CA-QOL and MSHIP items with the SFQ ranged from .42 to .62, and the identified scale scores produced Pearson correlation coefficients of .56, .70, and, .70 with the SFQ. Concurrent validity with social health was supported for the identified scales. The current inclusion of these assessment tools allows community mental health programs to include social health in their assessments

Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness

Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually. The diseases are caused by infection with the kinetoplastid parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., respectively. These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drugs that modulate the activity of a conserved parasite target. However, no such molecular targets or broad spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases