The effect of salsalate on insulin action and glucose tolerance in obese non-diabetic patients: results of a randomised double-blind placebo-controlled study

Aim/hypothesis  Low-grade inflammation may contribute to obesity-related insulin resistance and has been associated with increased risk of type 2 diabetes mellitus. The present study evaluated whether treatment with salsalate, a traditional anti-inflammatory medication, would improve insulin action in obese non-diabetic individuals. Methods  The study was a randomised, double-blind, placebo-controlled, parallel trial conducted at the inpatient clinical research unit of the NIDKK (Phoenix, AZ, USA). Participants were 54 adults (18 to 45 years of age) with BMI ≥ 30 kg/m². The intervention was salsalate (3 g/day, n = 28) or identical placebo (n = 26) for 7 days. The allocation was kept concealed by giving the investigator only a number corresponding to a vial of placebo or salsalate sequentially randomised in blocks by sex. Main outcomes were changes in insulin action assessed as rate of glucose disposal (R _d) by euglycaemic–hyperinsulinaemic clamp (insulin infusion rate 40 mU m⁻² min⁻¹) and glucose tolerance by 75 g OGTT. Results  The study was completed by 47 participants, of which 40 were analysed (salsalate n = 22, placebo n = 18). Salsalate treatment resulted in decreased fasting plasma glucose concentration (mean [SD]; 4.83 [0.28] vs 5.11 [0.33] mmol/l, p = 0.001) and glucose AUC during the OGTT (p = 0.01), and in increased R _d (20 [8] vs 18 [6] μmol [kg estimated metabolic body size]⁻¹ min⁻¹, p = 0.002), while there was no significant change in these variables with placebo (p > 0.3 for all). The effect of salsalate on R _d disappeared (p = 0.9) after normalising to increased insulin concentrations (701 [285] vs 535 [201] pmol/l, p < 0.0001) measured during the clamp. No side effects of salsalate were observed during the study. Conclusions/interpretation  The glucose-lowering potential of salicylates appears to be due to effects on insulin concentration rather than improved insulin action. Salicylate-based compounds may be useful for the treatment and prevention of type 2 diabetes. Trial registration: ClinicalTrials.gov NCT 00339833. Funding: Intramural research programme of the NIDDK/NIH/DHHS. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users. J. Koska and E. Ortega contributed equally to this work.     

Intranasal delivery to the central nervous system: Mechanisms and experimental considerations

The blood–brain barrier (BBB) limits the distribution of systemically administered therapeutics to the central nervous system (CNS), posing a significant challenge to drug development efforts to treat neurological and psychiatric diseases and disorders. Intranasal delivery is a noninvasive and convenient method that rapidly targets therapeutics to the CNS, bypassing the BBB and minimizing systemic exposure. This review focuses on the current understanding of the mechanisms underlying intranasal delivery to the CNS, with a discussion of pathways from the nasal cavity to the CNS involving the olfactory and trigeminal nerves, the vasculature, the cerebrospinal fluid, and the lymphatic system. In addition to the properties of the therapeutic, deposition of the drug formulation within the nasal passages and composition of the formulation can influence the pathway a therapeutic follows into the CNS after intranasal administration. Experimental factors, such as head position, volume, and method of administration, and formulation parameters, such as pH, osmolarity, or inclusion of permeation enhancers or mucoadhesives, can influence formulation deposition within the nasal passages and pathways followed into the CNS. Significant research will be required to develop and improve current intranasal treatments and careful consideration should be given to the factors discussed in this review. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1654–1673, 2010     

Expression of idiotypic antibodies-1 and -2 and breastfeeding in relation to antibody levels against Haemophilus influenzae type B in children

The aim of the study was to determine the concentrations of serum antibodies against Haemophilus influenzae type b in preschool children in relation to the distribution of idiotypic antibodies 1 and 2 (Id-1 and Id-2) and the exposure to breastfeeding in infancy. Sera were obtained from 74 control children recruited in an earlier case-control study before the introduction of general Hib vaccination. Duration of breastfeeding was monitored, and prevalence of noninvasive infections was registered. Concentrations of IgG1 and IgG2 anti-Hib, as well as of total Id-1 and Id-2, were determined in ELISA. The expression of Id-1 antibodies increased with age in contrast to the Id-2 antibodies that were found only in children up to 24 months of age. Expression of Id-1 antibodies was positively correlated with higher anti-Hib levels of both the IgG1 and IgG2 isotype. Children expressing Id-2 antibodies showed higher IgG2 anti-Hib concentrations than those who did not have Id-2 (P = 0.001). The concentrations of neither Id-1 nor Id-2 antibodies were related to the duration of breastfeeding. Duration of breastfeeding was related to increased anti-Hib IgG2 in healthy children above 18 months of age. These study shows that the expression of idiotype-1 and idiotype-2 antibodies was associated with higher IgG2 anti-Hib concentration and that breastfeeding could enhance the anti-Hib IgG2 production in children.     

Expression of the reverse tetracycline-transactivator gene causes emphysema-like changes in mice

The doxycycline-inducible, gene regulatory system allows tight control of transgene expression for the study of organ development and disease pathogenesis. Multiple recent reports have employed this model to investigate various lung diseases including emphysema. For our study, we used this transgenic system to test whether prolonged, lung-specific, overexpression of the serine protease urokinase plasminogen activator (uPA) would result in alveolar wall destruction. Double transgenic mice were generated that possessed: (1) the rat Clara cell secretory protein promoter controlling the reverse tetracycline transactivator gene (CCSP:rtTA) and (2) the tetracycline operator controlling the murine uPA cDNA (tet[O]:muPA). Mice were treated with doxycycline beginning at age 6 wk to initiate uPA overexpression. Single transgenic and wild-type animals served as controls. A second group of double transgenic and control animals were maintained off of doxycycline. At ages 10, 18, and 30 wk, the mice underwent measurements of alveolar size, lung compliance, and total lung capacity. We found that, although the uPA overexpressing mice demonstrated an emphysema phenotype, similar abnormalities occurred in the CCSP-rtTA control animals. These CCSP-rtTA-related alterations occurred even without doxycycline exposure. Evaluation of a second transgenic line possessing the human surfactant protein C promoter controlling rtTA expression also exhibited lung abnormalities consistent with emphysema. These findings indicate that pulmonary epithelial expression of rtTA alone causes an emphysema phenotype in mice. Therefore, when using this system to study emphysema pathogenesis, the inclusion of proper controls is essential for accurate data interpretation.     

The spectrum of WRN mutations in Werner syndrome patients

The International Registry of Werner syndrome (www.wernersyndrome.org) has been providing molecular diagnosis of the Werner syndrome (WS) for the past decade. The present communication summarizes, from among 99 WS subjects, the spectrum of 50 distinct mutations discovered by our group and by others since the WRN gene (also called RECQL2 or REQ3) was first cloned in 1996; 25 of these have not previously been published. All WRN mutations reported thus far have resulted in the elimination of the nuclear localization signal at the C-terminus of the protein, precluding functional interactions in the nucleus; thus, all could be classified as null mutations. We now report two new mutations in the N-terminus that result in instability of the WRN protein. Clinical data confirm that the most penetrant phenotype is bilateral ocular cataracts. Other cardinal signs were seen in more than 95% of the cases. The median age of death, previously reported to be in the range of 46-48 years, is 54 years. Lymphoblastoid cell lines (LCLs) have been cryopreserved from the majority of our index cases, including material from nuclear pedigrees. These, as well as inducible and complemented hTERT (catalytic subunit of human telomerase) immortalized skin fibroblast cell lines are available to qualified investigators.     

The efficacy of traditional, low-cost and nonsplint therapies for temporomandibular disorder: a randomized controlled trial

BACKGROUND: Treatment recommendations for patients with painful temporomandibular disorders (TMDs) range from conservative treatments such as physiotherapy to aggressive and irreversible treatments such as restorative reconstruction and joint surgery. METHODS: The authors randomized 200 subjects diagnosed with TMD into three groups: usual conservative, dentist-prescribed self-care treatment without any intraoral splint appliance (UT); UT plus a conventional flat-plane hard acrylic splint (HS); and UT plus a soft vinyl (a low-cost athletic mouth guard) splint (SS). Subjects completed questionnaires and clinical examinations at three, six and 12 months. RESULTS: The authors observed no significant differences among the groups in TMD-related pain levels or other common signs and symptoms of TMD at baseline (BL) or at any follow-up. The changes from BL were comparable for all three groups. The authors did not note any significant differences at any follow-up for compliance with study protocols or for occurrences of adverse effects from either splint type. For HS versus SS, there were significant differences in rates of splint use, but these differences were not accompanied by differences in either self-reported symptoms or in clinical findings. CONCLUSIONS: All patients improved over time, and traditional splint therapy offered no benefit over the SS splint therapy. Neither splint therapy provided a greater benefit than did self-care treatment without splint therapy. CLINICAL IMPLICATIONS: These findings suggest that clinicians who treat patients with TMD should consider prescribing low-cost nonsplint self-care therapy for most patients.     

Methamphetamine administration reduces hippocampal vesicular monoamine transporter-2 uptake

Repeated high-dose injections of methamphetamine (METH) rapidly decrease dopamine uptake by the vesicular monoamine transporter-2 (VMAT-2) associated with dopaminergic nerve terminals, as assessed in nonmembrane-associated vesicles purified from striata of treated rats. The purpose of this study was to determine whether METH similarly affects vesicular uptake in the hippocampus; a region innervated by both serotonergic and noradrenergic neurons and profoundly affected by METH treatment. Results revealed that repeated high-dose METH administrations rapidly (within 1 h) reduced hippocampal vesicular dopamine uptake, as assessed in vesicles purified from treated rats. This reduction was likely associated with serotonergic nerve terminals because METH did not further reduce vesicular monoamine uptake in para-chloroamphetamine-lesioned animals. Pretreatment with the serotonin transporter inhibitor fluoxetine blocked both this acute effect on VMAT-2 and the decrease in serotonin content observed 7 days after METH treatment. In contrast, there was no conclusive evidence that METH affected vesicular dopamine uptake in noradrenergic neurons or caused persistent noradrenergic deficits. These findings suggest a link between METH-induced alterations in serotonergic hippocampal vesicular uptake and the persistent hippocampal serotonergic deficits induced by the stimulant.     

Is Hospice Associated with Improved End‐of‐Life Care in Nursing Homes and Assisted Living Facilities?

OBJECTIVES: To examine whether hospice enrollment for nursing home (NH) and residential care/assisted living (RC/AL) residents near the end of life is associated with symptoms and symptom management, personal care, spiritual support, and family satisfaction. DESIGN: Structured, retrospective telephone interviews with family and staff who attended to NH and RC/AL residents in the last month of life. SETTING: A stratified sample of 26 NH and 55 RC/AL facilities in four states. Participants: Family members (n=97) and long-term care (LTC) staff (n=104) identified as most involved in care of 124 residents who died over a 15-month period. MEASUREMENTS: A variety of reported measures of care and symptoms before death, including the Discomfort Scale for Dementia of the Alzheimer's Type. RESULTS: Of 124 decedents, 27 (22%) received hospice services. Dementia was less common in hospice enrollees than in decedents who did not receive hospice care. Hospice enrollees more often had moderate/severe pain and dyspnea and received pain treatment and were more likely to receive assistance with mouth care and eating and drinking. There were no differences related to unmet need, and observed differences were largely eliminated when comparisons were limited to residents whose deaths were expected. CONCLUSION: Rates of hospice use observed in this study (22%) were considerably higher than previously reported, although persons with dementia may continue to be underreferred. Hospice use is targeted to dying residents with higher levels of reported pain and dyspnea. Because difference in care largely disappears in cases when death was expected, LTC staff seem to be well positioned to provide end-of-life care for their residents and are advised to remain sensitive to instances in which death may be expected.