Quantitative evaluation of the relaxivity effects of iodine on GD-DTPA enhanced MR arthrography

PURPOSE: To quantify the effect of iodine on the gadolinium (Gd) contrast-enhanced signal in MR arthrography. MATERIALS AND METHODS: Saline solutions of Gd contrast agent (0-1 mmol/liter) were mixed with iodinated contrast agent (0-185 mmol/liter). The T1 and T2 relaxation constants of these solutions were measured at 1.5T. Different types of commonly used iodinated contrast agents as well as sodium iodide (NaI) solutions were also analyzed. RESULTS: Iodine caused significant T2 shortening and some T1 shortening in Gd contrast solutions. Both contrast agents independently obeyed the standard relaxation relation, and their mixture obeyed a modified version of this relation. The side chains in various iodine molecules and their viscosities affected the relaxation properties differently. For various spin-echo (SE) sequences, the signal from synovial fluid containing different concentrations of the two contrast agents was calculated. The T2-weighted signal appeared to be most affected by the increase in iodine concentrations. In the absence of Gd contrast, all SE sequences showed an initial increase in signal from iodine contrast. CONCLUSION: A generalized relation for the relaxivities of Gd contrast in the presence of iodine was established. The side chains of iodine contrast were found to alter the relaxivities of Gd contrast. Imaging with proton density (PD)-weighted SE with only iodine contrast agent was found to be feasible.     

De novo discovery of serotonin N-acetyltransferase inhibitors

Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT) is a member of the GCN5 N-acetyltransferase (GNAT) superfamily and catalyzes the penultimate step in the biosynthesis of melatonin; a large daily rhythm in AANAT activity drives the daily rhythm in circulating melatonin. We have used a structure-based computational approach to identify the first druglike and selective inhibitors of AANAT. Approximately 1.2 million compounds were virtually screened by 3D high-throughput docking into the active site of X-ray structures for AANAT, and in total 241 compounds were tested as inhibitors. One compound class, containing a rhodanine scaffold, exhibited low micromolar competitive inhibition against acetyl-CoA (AcCoA) and proved to be effective in blocking melatonin production in pineal cells. Compounds from this class are predicted to bind as bisubstrate inhibitors through interactions with the AcCoA and serotonin binding sites. Overall, this study demonstrates the feasibility of using virtual screening to identify small molecules that are selective inhibitors of AANAT.     

Facilitators and barriers to implementing pharmacist-prescribed hormonal contraception in California independent pharmacies

ABSTRACT

In 2013, California passed legislation to expand the scope of pharmacist practice, including authorizing pharmacists to prescribe hormonal contraception. Pharmacist-prescribed contraception was largely unavailable across the state in 2017. This study aimed to identify barriers and facilitators to offering this service in California independent pharmacies. To do so, we thematically analyzed qualitative data from structured interviews with 36 pharmacists working in independent pharmacies in 2016–17. We found that pharmacists anticipated general benefits from expanding their roles to prescribe contraception, including increasing health care access and decreasing costs. In contrast, described barriers were concrete, including lack of financial incentives and business risks for independent pharmacies. Specific barriers to prescribing hormonal contraception included time required to screen and counsel women about contraception and concerns that pharmacist-prescribed contraception would increase liability and lead to patients seeking health care less frequently. This study suggests that incentives and barriers identified by the respondents are likely to have varied and unequal impacts, with immediate barriers being potentially prohibitive for pharmacists to prescribe contraception. For independent pharmacies, perceived business risks and lack of insurance reimbursement may outweigh professional support for prescribing contraception, limiting the public health impact of legislation that should increase contraceptive access.     

A novel in situ gel for sustained drug delivery and targeting

The objective of this study was to develop a novel chitosan-glyceryl monooleate (GMO) in situ gel system for sustained drug delivery and targeting. The delivery system consisted of 3% (w/v) chitosan and 3% (w/v) GMO in 0.33M citric acid. In situ gel was formed at a biological pH. In vitro release studies were conducted in Sorensen's phosphate buffer (pH 7.4) and drugs were analyzed either by HPLC or spectrophotometry. Characterization of the gel included the effect of cross-linker, determination of diffusion coefficient and water uptake by thermogravimetric analysis (TGA). Mucoadhesive property of the gel was evaluated in vitro using an EZ-Tester. Incorporation of a cross-linker (glutaraldehyde) retarded the rate and extent of drug release. The in vitro release can further be sustained by replacing the free drug with drug-encapsulated microspheres. Drug release from the gel followed a matrix diffusion controlled mechanism. Inclusion of GMO enhanced the mucoadhesive property of chitosan by three- to sevenfold. This novel in situ gel system can be useful in the sustained delivery of drugs via oral as well as parenteral routes.     

Guinea Pig Lung Lavage Cells After Intranasal BCG Sensitization

Recent studies have suggested that intranasal administration of antigen can induce local cell-mediated immunity in lung lavage cells. The present study was designed to examine the changes in composition of lung lavage cells and their capacity to produce the lymphokine migration inhibitory factor after intranasal immunization with BCG in guinea pigs. Results indicate that guinea pigs responded to respiratory tract BCG infection with an increase in immunocompetent cells in the bronchoalveolar tract and with production of migration inhibitory factor. After local pulmonary BCG administration, the total number of cells increased as compared with that of the uninfected animals, the increase being statistically significant within 2 weeks. This marked increase in the total cell population is due to a more than doubling of the number of macrophages in the lavage fluid. Animals also developed at this time positive delayed hypersensitivity to intradermally administered purified protein derivative. A significant increase in the total lymphoid cells and macrophage population was observed again at 6 weeks after sensitization, suggesting that the response is biphasic in nature. At 6 weeks, however, there was also a significant rise in total lymphocytes and T cell population in addition to macrophage numbers. This increase in T cells correlated with an increase in production of migration inhibitory factor in the presence of purified protein derivative. These data suggest that the immune response of the respiratory tract after BCG challenge involves increased recruitment of immunocompetent cells locally at the site of infection and that these cells are capable of producing effector molecules in terms of the elaboration of migration inhibitory factor.     

Defective sarcoplasmic reticular calcium transport in diabetic cardiomyopathy

The effects of insulin and thyroid hormone treatments on cardiac sarcoplasmic reticular function were investigated in chronic streptozotocin-induced diabetes in rats. ATP-dependent Ca2+ transport and Ca2+-stimulated ATPase activities were depressed significantly in microsomal samples from diabetic rats in comparison with control (P less than 0.05). This defect was seen at various times of incubation (1-20 min) and different concentrations of free Ca2+ (10(-7) to 10(-5) M Ca2+) and was accompanied by changes in the protein composition and phospholipid contents of the microsomal fraction. The defect in calcium transport in microsomal vesicles was not evident until 28 days after streptozotocin (65 mg/kg iv) injection, whereas increases in plasma glucose levels due to insulin-deficiency occurred within 3 days. All changes in function and composition of the sarcoplasmic reticulum were reversed by insulin administration to the diabetic rats. Although the plasma level of thyroid hormone was decreased in the diabetic rat, thyroid hormone treatment did not restore microsomal calcium transport in the diabetic animals. The results of this study provide some evidence that the depression in cardiac sarcoplasmic reticular calcium accumulation during diabetes is a consequence of insulin deficiency and associated chronic metabolic changes but the hypothyroid condition that accompanies experimental diabetes does not appear to play any role in this defect.     

Severe and moderate haemophilia A and B in US females

Haemophilia A and B are rare X‐lined hemorrhagic disorders that typically affect men. Women are usually asymptomatic carriers, but may be symptomatic and, rarely, also express severe (factor VIII (FVIII) or factor IX (FIX) <0.01 U mL^?1) or moderately severe (FVIII/FIX 0.01–0.05 U mL^?1) phenotypes. However, data on clinical manifestations, genotype and the psychosocial ramifications of illness in severely affected females remain anecdotal. A national multi‐centre retrospective study was conducted to collect a comprehensive data set on affected US girls and women, and to compare clinical observations to previously published information on haemophilic males of comparable severity and mildly affected haemophilic females . Twenty‐two severe/moderate haemophilia A/B subjects were characterized with respect to clinical manifestations and disease complications; genetic determinants of phenotypic severity; and health‐related quality of life (HR‐QoL). Clinical data were compared as previously indicated. Female patients were older than male patients at diagnosis, but similarly experienced joint haemorrhage, disease‐ and treatment‐related complications and access to treatment. Gynaecological and obstetrical bleeding was unexpectedly infrequent. F8 or F9 mutations, accompanied by extremely skewed X‐chromosome inactivation pattern (XIP), were primary determinants of severity. HR‐QoL was diminished by arthropathy and viral infection. Using systematic case verification of participants in a national surveillance registry, this study elucidated the genetics, clinical phenotype and quality of life issues in female patients with severe/moderate haemophilia. An ongoing international case‐controlled study will further evaluate these observations. Novel mechanistic questions are raised about the relationship between XIP and both age and tissue‐specific FVIII and FIX expression.