Maternal and perinatal magnesium restriction predisposes rat pups to insulin resistance and glucose intolerance

According to the fetal programming hypothesis, impaired intrauterine development results in insulin resistance and associated metabolic disturbances. Recently, we reported increased body fat, a forerunner of insulin resistance, in the pups of mineral-restricted rat dams. To identify the causative mineral(s), the effect of magnesium restriction was assessed. Female weanling WNIN rats (n = 21) consumed ad libitum for 9 wk a 70% magnesium-restricted diet or were pair-fed a control (C) diet (n = 7). After 9 wk, they were mated with control males. Control dams and pups were fed the control diet throughout, whereas 7 Mg-restricted dams were switched to the control diet at parturition and their pups weaned onto the control diet (RP). Pups of the remaining 14 restricted dams were weaned onto the control diet (RW) or the Mg-restricted diet (R). All groups had 8 male pups from weaning. Pups were studied on postnatal d 90 and 180. R pups weighed less than C pups at weaning, but both RP and RW pups caught up with controls by d 90. At this time, R pups were neither insulin resistant nor glucose intolerant, but had a higher percentage of body fat and plasma triglycerides and lower lean body and fat-free mass than C pups. These variables were partially corrected in both RP and RW pups. On postnatal d 180, R, RP, and RW pups were insulin resistant and had a lower insulin response to a glucose challenge than C pups; however, glucose tolerance was impaired only in RW pups. Thus, maternal magnesium restriction irreversibly increases body fat and induces insulin resistance in pups by 6 mo of age, whereas additional perinatal Mg deficiency impairs glucose tolerance.     

R-VAPOL-phosphoric acid based 1H and 13C-NMR for sensing of chiral amines and acids

Enantiomers have significant importance in pharmaceuticals, biology and modern chemistry and therefore distinguishing and quantifying the enantiomeric forms is of utmost importance. Herein, we propose diphenyl-3,3′-biphenanthryl-4,4′-diyl phosphate (R-VAPOL-PA) as a promising chiral solvating agent to discriminate amines and acids of poly-functional groups such as chiral amines, amino alcohols and hydroxy acids. The methodological approach involves using the nature of hydrogen bonds and ion pairs as a mode of weak interactions to form diastereomers where the probe is associated with enantiomers. The resulting diastereomer difference in the NMR spectrum enables the chiral discrimination with a complete baseline peak separation and an accurate enantiomeric excess (ee) analysis. We also carried out density functional theory (DFT) calculations to understand the complex formation to explain enantiodiscrimination by analysing the formation and stability of different chiral complexes. The binding energy differences between enantiomeric forms revealed by DFT calculations are qualitatively in agreement with the diastereomer difference in the NMR spectrum and unequivocally establishes the suggested experimental protocol of R-VAPOL-PA-based enantiomeric discrimination.

R-VAPOL-chiral solvating agent for discrimination of chiral amines and acids using ¹H and ¹³C NMR.     

Spectrum of ocular toxicities from epidermal growth factor receptor inhibitors and their intermediate-term follow-up: a five-year review

Purpose

Epidermal growth factor receptor (EGFR) inhibitors and kinases are commonly used in the treatment regimen of various solid tumors including non-small cell lung, colorectal, head and neck, breast, and pancreatic cancers. The aim of this study is to describe common ocular adverse effects associated with EGFR inhibitor treatment, outline successful management options, and provide data on intermediate-term follow-up of these patients.

Methods

A retrospective chart review was performed of all patients presenting to the ophthalmology clinic with an adverse ocular effect while on an EGFR inhibitor. Duration of EGFR inhibitor treatment, symptoms, diagnosis, and treatment information were collected. Statistical analyses were done to ascertain differences in adverse effects based on duration and type of EGFR inhibitor treatment using the Fisher exact test.

Results

The two most common EGFR inhibitors in this group of patients were erlotinib and cetuximab. The most common adverse ocular effects for patients on EGFR inhibitors were dysfunctional tear syndrome (DTS), followed by blepharitis and eyelash changes (trichomegaly and trichiasis). Two patients had epithelial defects (corneal abrasions). There was no significant difference in adverse effects based on specific EGFR inhibitor medication or duration of treatment. Almost all patients were successfully managed with treatment regimens that we have outlined in this paper. Intermediate-term follow-up (range 6–17 months) showed a persistence of DTS and eyelash changes.

Conclusion

We present what is, to our knowledge, the largest reported cohort of patients with ocular toxicities from EGFR inhibitors—the spectrum of eye toxicities, their management, and the intermediate-term follow-up of patients with eye toxicities. Awareness of this information is important for oncologists and oncology nurses to facilitate proper counseling and management/referral of patients developing eye toxicity while on EGFR inhibitors.     

Effect of lowering of homocysteine levels on inflammatory markers: a randomized controlled trial

BACKGROUND: Elevated concentrations of homocysteine and low concentrations of folate may lead to a proinflammatory state that could explain their relation to vascular disease risk. We investigated the effect of lowering homocysteine concentrations by means of folic acid supplementation on markers of inflammation. METHODS: In a double-blind, randomized, placebo-controlled trial among 530 men and postmenopausal women with homocysteine concentrations of 1.8 mg/L or higher (>/=13 micromol/L) at screening, we investigated the effect of folic acid supplementation (0.8 mg/d) vs placebo for 1 year on serum concentrations of C-reactive protein, soluble intercellular adhesion molecule-1, oxidized low-density lipoprotein, and autoantibodies against oxidized low-density lipoprotein. RESULTS: After 1 year of supplementation, concentrations of serum folate increased by 400% (95% confidence interval [CI], 362%-436%), and those of homocysteine decreased by 28% (95% CI, 24%-36%) in the folic acid group compared with the placebo group. However, no changes in plasma concentrations of the inflammatory markers were observed. CONCLUSIONS: Although homocysteine is associated with vascular disease risk in the general population, marked lowering of slightly elevated homocysteine concentrations by means of 1-year folic acid supplementation does not influence inflammatory responses involving C-reactive protein, soluble intercellular adhesion molecule-1, oxidized low-density lipoprotein, and autoantibodies against oxidized low-density lipoprotein.     

TRPV1 is important for mechanical and heat sensitivity in uninjured animals and development of heat hypersensitivity after muscle inflammation

Inflammatory thermal hyperalgesia is principally mediated through transient receptor potential vanilloid 1 (TRPV1) channels, as demonstrated by prior studies using models of cutaneous inflammation. Muscle pain is significantly different from cutaneous pain, and the involvement of TRPV1 in hyperalgesia induced by muscle inflammation is unknown. We tested whether TRPV1 contributes to the development of mechanical and heat hypersensitivity of the paw in TRPV1(-/-) mice after muscle inflammation. Because TRPV1(-/-) mice lack TRPV1 at the site of inflammation (muscle) and at the testing site (paw), we do not know whether TRPV1 is important as a mediator of nociceptor sensitization in the muscle or as a heat sensor in the paw. Using recombinant herpesviruses, we reexpressed TRPV1 in TRPV1(-/-) mice in primary afferents innervating skin, muscle, or both to determine which sites were important for the behavioral deficits. Responses to repeated application of noxious mechanical stimuli to the hind paw were enhanced in TRPV1(-/-) mice; this was restored by reexpression of TRPV1 into skin. Withdrawal latencies to noxious heat were increased in TRPV1(-/-) mice; normal latencies were restored by reexpression of TRPV1 in both skin and muscle. Heat hypersensitivity induced by muscle inflammation did not develop in TRPV1(-/-) mice; mechanical hypersensitivity was similar between TRPV1(-/-) and TRPV1(+/+) mice. Heat hypersensitivity induced by muscle inflammation was restored by reexpression of TRPV1 into both muscle and skin of TRPV1(-/-) mice. These results suggest that TRPV1 serves as both a mediator of nociceptor sensitization at the site of inflammation and as a heat sensor at the paw.     

Nonassociation of homocysteine gene polymorphisms with treatment outcome in South Indian Tamil Rheumatoid Arthritis patients

The aim of the study was to look for any association of MTR 2756A>G and MTRR 66A>G gene polymorphisms with clinical phenotype, methotrexate (MTX) treatment response, and MTX-induced adverse events in South Indian Tamil patients with rheumatoid arthritis (RA). A total of 335 patients with RA were investigated. MTR 2756A>G gene polymorphism was analyzed by PCR–RFLP, and MTRR 66A>G SNP was analyzed by TaqMan 5′ nuclease assay. The allele frequencies were compared with HapMap groups. MTR 2756G allele was found to be associated with risk of developing RA. The allele frequencies of MTR 2756A>G and MTRR 66A>G SNPs in controls differed significantly when compared with HapMap groups. Neither of the SNPs influenced the MTX treatment outcome and adverse effects. Neither of the SNPs seems to be associated with MTX treatment outcome and adverse events in South Indian Tamil patients with RA.