Effect of 3-methyl-branching on the metabolism in rat hearts of radioiodinated iodovinyl long chain fatty acids

The metabolism of two new 3-methyl-branched iodovinyl fatty acids in rat hearts was evaluated by determining the subcellular and lipid pool distribution of these radiolabeled analogues after intravenous injection. Methyl branching had been introduced into the straight chain analogue, 19-iodo-18-nonadecenoic acid (IVN), to produce the monomethyl analogue, 19-iodo-3-(R,S)-methyl-18-nonadecenoic acid (BMIVN) and the dimethyl derivative, 19-iodo-3,3-dimethyl-18-nonadecenoic acid (DMIVN) in the hope of inhibiting oxidation. Since the presence of 3-methyl branching results in delayed myocardial clearance in rats, differences were sought in the lipid and subcellular distribution of these branched analogues that might correlate with the prolonged retention and reflect differences in metabolism. Hearts of rats injected intravenously with the radiolabeled fatty acids were removed and homogenized and the homogenates partitioned between the chloroform-methanol (organic) fraction and the aqueous fraction. Comparison of the distribution of radioactivity between the organic and aqueous fractions showed that most of the DMIVN and BMIVN activity was in the organic fraction with IVN activity initially divided equally between the two fractions. Identification of the lipid components of these organic fractions showed that there was slow incorporation of DMIVN into the triglyceride and polar lipid fractions with a slow loss from the free fatty acid fraction. With the straight chain IVN analogue which shows rapid washout from rat hearts, there was loss of activity from all 3 lipid components during the 60 min. The monomethyl branched BMIVN analogue demonstrated predominant storage in the polar lipid fraction with some incorporation into triglycerides. Subcellular distribution studies of the three analogues also showed differences that correlated with the observed differences in heart retention properties. With the unbranched IVN analogue, radioactivity was found primarily in the cytoplasmic fraction 30 min after injection, whereas the branched analogues demonstrated a much higher association with the microsomal and mitochondrial fractions of the heart. In rats fed prior to injection, these differences in the subcellular distribution profiles were minimized. The lipid and subcellular distribution patterns reported here for the methyl branched analogues as compared to those of the straight chain iodovinyl fatty acid may provide some understanding as to the mechanisms of retention in rat myocardium.Research supported by the Office of Health and Environmental Research, U.S. Department of Energy, under contract DE-AC0 5-840 R21400 with Martin Marietta Energy Systems, Inc.     

An economic assessment of health care coverage for the elderly

The current array of public and private health care coverages for the elderly is so complex and confusing that consumers are unable to make effective choices. The recent "medigap market" still further confounds the operation of "economic efficiency" in competitive insurance markets; consumers are uninformed about the extent and value of their basic coverage and even more so about the vulnerabilities against which supplementary insurance is purchased. This structural impediment to effectiveness and efficiency is most critical for long-term nursing care. Future changes in public programs must recognize that comprehensive benefits must also be made comprehensible.     

Hyperbaric oxygen therapy in chronic stable multiple sclerosis: double-blind study

We carried out a randomized, double-blind, placebo-controlled trial of hyperbaric oxygen therapy (HBO) in patients with chronic stable MS. Eighty-two patients were treated in a multiplace hyperbaric chamber with gas supplied by mask. Forty-one patients received 20 consecutive daily treatments of 100% O2 followed by 7 "booster" treatments in the next 6 months; 41 control patients received "air" (12.5% O2 at 1.75 atmospheres absolute). There was no significant difference in treatment and control groups in the Extended Kurtzke Disability scores, Kurtzke Functional scores, magnetic resonance imaging, or evoked potentials after the initial 20 treatments or after the boosters. HBO is not effective in treating chronic stable MS.     

Safety and Efficacy of a Steroid Avoidance Immunosuppression Regimen in Renal Transplant Patients With De Novo or Preformed Donor-Specific Antibodies: A Single-Center Study

Although interest in the role of donor-specific antibodies (DSAs) in kidney transplant rejection, graft survival, and histopathological outcomes is increasing, their impact on steroid avoidance or minimization in renal transplant populations is poorly understood. Primary outcomes of graft survival, rejection, and histopathological findings were assessed in 188 patients who received transplants between 2012 and 2015 at the Scripps Center for Organ Transplantation, which follows a steroid avoidance protocol. Analyses were performed using data from the United Network for Organ Sharing. Cohorts included kidney transplant recipients with de novo DSAs (dnDSAs; n = 27), preformed DSAs (pfDSAs; n = 15), and no DSAs (nDSAs; n = 146). Median time to dnDSA development (classes I and II) was shorter (102 days) than in previous studies. Rejection of any type was associated with DSAs to class I HLA (P < .05) and class II HLA (P < .01) but not with graft loss. Although mean fluorescence intensity (MFI) independently showed no association with rejection, an MFI >5000 showed a trend toward more antibody-mediated rejection (P < .06), though graft loss was not independently associated. Banff chronic allograft nephropathy scores and a modified chronic injury score were increased in the dnDSA cohort at 6 months, but not at 2 years (P < .001 and P < .08, respectively). Our data suggest that dnDSAs and pfDSAs impact short-term rejection rates but do not negatively impact graft survival or histopathological outcomes at 2 years. Periodic protocol post-transplant DSA monitoring may preemptively identify patients who develop dnDSAs who are at a higher risk for rejection.     

ASO Visual Abstract: Will It Play in Peoria? A Pilot Study of a Robotic Skills Curriculum for Surgical Oncology Fellows

Annals of Surgical Oncology -     

An Evaluation of Breastfeeding Promotion Through Peer Counseling in Mississippi WIC Clinics

Objective: This study evaluates the effectiveness of a peer counseling program at increasing breastfeeding by participants in the Mississippi Special Supplemental Nutrition Program for Women, Infants and Children (WIC). Methods: Data from the 1989–1993 Pediatric Nutrition Surveillance System were analyzed to compare breastfeeding rates in clinics with and without peer counseling programs. A questionnaire completed by program staff to describe the program in greater detail helped identify characteristics associated with greater success. Results: The incidence of breastfeeding rose from 12.3% to 19.9% in those clinics with peer counseling programs, but only from 9.2% to 10.7% in clinics without a program. Clinics that started a program earlier showed greater changes in breastfeeding incidence. However, the presence of lactation specialists or consultants in the clinic appeared to be more important than the presence of less-trained peer counselors. Peer counselors who spent more than 45 minutes per participant were more effective than those spending less time. Conclusions: The peer counseling program significantly increased the incidence of breastfeeding, particularly in clinics with lactation specialists and consultants. Success can be enhanced by ensuring that peer counselors spend a great deal of time with the participants.     

Treatment of Secondary Progressive Multiple Sclerosis

Disease progression and advancing disability will supervene in the majority of multiple sclerosis patients who are followed over the long-term. This process can begin insidiously from the onset of the disease (primary progression) or after one or more clinical flares (secondary progression). The factors which lead to progression of disability are incompletely understood. The progressive forms of multiple sclerosis have been remarkably resistant to treatment. The legacy of heroic immunosuppression as a treatment for the disease progression has been modest indeed although there is some recent enthusiasm for immunosuppression with agents like mitoxantrone. In the last decade, the treatment of relapsing forms of multiple sclerosis has been revitalised by the interferons and glatiramer acetate. The robust treatment effect on the magnetic resonance imaging burden of the disease and the modest treatment effect in the suppression of clinical attacks have raised hopes that these agents might stall the disease in its progressive phase. Recent clinical trials with the interferons are indeed showing promise for modest clinical efficacy in patients selected for treatment on the basis of chronic progression. Given the weakness of the current treatment, the essence of disease management remains the handling of the complications of the disease. The management of bladder disturbances, spasticity, pain, depression, emotional lability, paroxysmal disorders, fatigue and heat intolerance, tremor and sexual dysfunction is reviewed.     

Ascorbate compartmentalization in the CNS

Ascorbic acid, found physiologically as the ascorbate anion, is an abundant water-soluble antioxidant. It is concentrated in the intracellular compartment of all tissues in the body. The CNS has particularly high levels of ascorbate. Recent data from this laboratory indicate that ascorbate is distinctly compartmentalized between neurons and glia, with an average intracellular concentration of 10 mM in neurons and 1 mM in glial cells. These data can be contrasted with those for another important low molecular weight antioxidant, glutathione, which is somewhat more concentrated in glia than in neurons. The present review summarizes evidence for ascorbate compartmentalization between neurons and glia and considers these data in light of evidence for the roles of ascorbate as a neuroprotective antioxidant and as a neuromodulator in the CNS.     

Opioid peptide receptor studies, 11: involvement of Tyr148, Trp318 and His319 of the rat mu-opioid receptor in binding of mu-selective ligands

Previous data obtained with the cloned rat mu opioid receptor demonstrated that the "super-potent" opiates, ohmefentanyl (RTI-4614-4) and its four enantiomers, differ in binding affinity, potency, efficacy, and intrinsic efficacy. Molecular modeling (Tang et al., 1996) of fentanyl derivatives binding to the mu receptor suggests that Asp147, Tyr148, Trp318, and His319 are important residues for binding. According to this model, Asp147 interacts with the positively charged opiate agonist to form potent electrostatic and hydrogen-bonding interactions. In this study, the role of weak electrostatic and hydrogen-bonding "pi-pi" interactions of the O atom of the carbonyl group and the phenyl ring structures of RTI-4614-4 and its four enantiomers with residues Tyr148, Trp318, and His319 were explored via site-directed mutagenesis. Tyr148 (in transmembrane helix 3 {TMH3}), Trp318 (TMH7), and His319 (TMH7) were individually replaced with phenylalanine or alanine. Receptors transiently expressed in COS-7 cells were labeled with [125I]IOXY according to published procedures. Mutation of Tyr148 to phenylalanine reduced the binding affinities of some mu-selective agonists (2-7 fold) but did not alter the affinities of DAMGO, naloxone, and the non-selective opiates etorphine and buprenorphine. In contrast, this mutation significantly increased the binding affinities (decreased the Kd values) of [D-Ala2,D-Leu5]enkephalin, IOXY, and dermorphin. Mutation of Trp318 decreased opioid receptor binding to almost undetectable levels. Substitution of alanine for His319 significantly reduced binding affinities for the opioid ligands tested (1.3- to 48-fold), but did not alter the affinities of naloxone and bremazocine. These results indicate the importance of Tyrl48 and His319 for the binding of fentanyl derivatives to the mu receptor. Functional studies using the mutant receptors will provide additional insight into the mechanism of action of RTI-4614-4 and its four enantiomers.