Obese-insulin resistance accelerates and aggravates cardiometabolic disorders and cardiac mitochondrial dysfunction in estrogen-deprived female rats

Women have a lower incidence of cardiovascular diseases (CVD) than men at a similar age but have an increased incidence of CVD and metabolic syndrome after menopause, indicating the possible protective effects of estrogen on cardiometabolic function. Although obesity is known to increase CVD risks, its impact on the heart on estrogen deprivation is still inconclusive. We investigated the effects of obese-insulin resistance on cardiometabolic function in estrogen-deprived ovariectomized rats. Adult female ovariectomized (O) or sham (S)-operated rats randomly received either normal diet (ND, 19.77 % fat) or high-fat diet (HF, 57.60 % fat) (n = 6/group) for 12 weeks. The heart rate variability (HRV), left ventricular (LV) performance, cardiac autonomic balance, cardiac mitochondrial function, metabolic parameters, oxidative stress, and apoptotic markers were determined at 4, 8, and 12 weeks. Insulin resistance developed at week 8 in NDO, HFS, and HFO rats as indicated by increased plasma insulin and HOMA index. However, only HFO rats had elevated plasma cholesterol level at week 8, whereas HFS rats had showed elevation at week 12. In addition, only HFO rats had depressed HRV, impaired LV performance indicated by decreased fractional shortening (%FS) and cardiac mitochondrial dysfunction indicated by increased mitochondrial ROS level, mitochondrial depolarization and swelling, as early as week 8, whereas other groups exhibited them at week 12. Either estrogen deprivation or obesity alone may impair metabolic parameters, cardiac autonomic balance, and LV and mitochondrial function. However, an obese insulin-resistant condition further accelerated and aggravated the development of these cardiometabolic impairments in estrogen-deprived rats.     

Trigeminal c-Fos expression and behavioral responses to pulpal inflammation in ferrets

Injury to peripheral dental tissues evokes dynamic alternations in central sensory pathways. We have previously reported that transient stimulation of the dental pulp with noxious heat evokes the induction of the immediate early gene product Fos in the transitional region between subnucleus interpolaris and caudalis (Vi/Vc) and subnucleus caudalis (Vc). A question arises as to whether similar changes occur in response to inflammation to the tooth pulp. In this study, the effects of pulpal inflammation produced by bacterial lipopolysaccharide (LPS) on face-grooming behavior and trigeminal Fos expression were examined. Face-grooming behaviors were recorded daily for 3 days pre- and 24, 48 and 72 h post- LPS or saline application. All animals were perfused 72 h post- LPS or saline application. Brainstems were processed for Fos-like immunoreactivity (Fos-LI). Teeth were processed for H&E staining. Histological examination of LPS-treated teeth revealed features of an acute pulpitis. Moreover, LPS-treated animals showed greater face-grooming activity (i.e. tongue protrusions) directed to the injured tooth than the sham-operated group. The number of Fos-positive neurons was greater in the trigeminal subnucleus caudalis (Vc) and the transitional regions (Vi/Vc) in LPS-treated animals compared with sham-operated animals, and greater in the deeper laminae than the superficial laminae of each trigeminal region. LPS treatment did not evoke Fos expression in the rostral trigeminal regions above Vi/Vc. These results demonstrate that LPS-induced pulpal inflammation results in significant alterations in the Vi/Vc and Vc, and such changes may underlie the observed nociceptive behavioral responses and may play an important role in producing a symptomatic pulpitis in humans.     

Clinical,radiographic, and histologic analysis of the effects of acemannan used in direct pulp capping of human primary teeth: short-term outcomes

Acemannan has been previously reported as a direct pulp-capping agent in animal study. This natural material demonstrated its biocompatibility and enhanced reparative dentin formation. The objective of this study was to investigate the action of acemannan as a direct pulp-capping material in human primary teeth with deep caries. Forty-two deeply carious mandibular primary molars from 37 children, aged 7–11 years old diagnosed with reversible pulpitis were studied. After completely removing the infected dentine, teeth with a pinpoint pulpal exposure were randomly divided into two treatment groups: acemannan or calcium hydroxide. A glass-ionomer cement base was applied to all teeth prior to restoration with stainless steel crowns. Clinical and radiographic evaluation was performed 6 months post-treatment. The teeth due to exfoliate were extracted and histopathologically evaluated for inflammation, dentine bridge formation, and soft tissue organization. At 6 months, the overall clinical and radiographic success rates of direct pulp capping with acemannan and calcium hydroxide at 6 months were 72.73 and 70.0 %, respectively. The histopathological results indicated that the acemannan-treated group had significantly better histopathological responses compared with the calcium hydroxide-treated group (p < 0.05). These data suggest acemannan offers a valuable alternative biomaterial for vital pulp therapy in primary teeth.     

Suk-Sam-Bai: the quality of life perceptions among middle-aged women living with a disability in Isaan, Thailand

Midlife represents a time of shifting roles and biopsychosociocultural change for women. Physical disabilities compound the effect of such on daily life and quality of life. The objective of this study was to explore how middle-aged women with disabilities in Isaan perceived their current quality of life. A qualitative method was applied. Data were collected using in-depth interviews and observations. Sixteen disabled women were recruited through purposive and theoretical sampling. Qualitative data were analyzed using both thematic and content analysis. Triangulation was used to ensure data rigor. "Suk-Sam-Bai" was a term frequently used by disabled women in this study to define their quality of life. Life experiences, goals, and achievements lead to experiences of gain, maintenance, and loss in three interrelated aspects that include: fluctuations in physical capacity and health, maintaining gender role, and a caring and supportive environment. These three aspects impact on an individual's personal perception of Suk-Sam-Bai. Study findings indicate that gender and culture play significant roles in the lives of disabled women in Isaan culture. Based on study findings, providing gender- cultural sensitive nursing care is essential to delivering comprehensive and effective healthcare to women with disabilities.     

T-type calcium channel blockade improves survival and cardiovascular function in thalassemic mice

Objectives: Iron‐overload cardiomyopathy is a major cause of morbidity and mortality in patients with thalassemia. However, the precise mechanisms of iron entry and sequestration in the heart are still unclear. Our previous study showed that Fe²⁺ uptake in thalassemic cardiomyocytes are mainly mediated by T‐type calcium channels (TTCC). Nevertheless, the role of TTCC as well as other transporters such as divalent metal transporter1 (DMT1) and L‐type calcium channels (LTCC) as possible portals for iron entry into the heart in in vivo thalassemic mice under an iron‐overload condition has not been investigated. Methods: An iron‐overload condition was induced in genetically altered β‐thalassemic mice and adult wild‐type mice by feeding them with an iron diet (0.2% ferrocene w/w) for 3 months. Then, blockers for LTCC (verapamil and nifedipine), TTCC (efonidipine), and DMT1 (ebselen) as well as iron chelator desferoxamine (DFO) were given for 1 month with continuous iron feeding. Results: Treatment with LTCC, TTCC, DMT1 blockers, and DFO reduced cardiac iron deposit, cardiac malondialdehyde (MDA), plasma non‐transferrin‐bound iron, and improved heart rate variability and left ventricular (LV) function in thalassemic mice with iron overload. Only TTCC and DMT1 blockers and DFO reduced liver iron accumulation, liver MDA, plasma MDA, and decreased mortality rate in iron‐overloaded thalassemic mice. Conclusions: DMT1, LTCC, and TTCC played important roles for iron entry in the thalassemic heart under an iron‐overloaded condition. Unlike LTCC blocker, TTCC blocker provided all benefits including attenuating iron deposit in both the heart and liver, reduced oxidative stress, and decreased mortality in iron‐overloaded mice.     

PPARγ agonist improves neuronal insulin receptor function in hippocampus and brain mitochondria function in rats with insulin resistance induced by long term high-fat diets

We previously demonstrated that a high-fat diet (HFD) consumption can cause not only peripheral insulin resistance, but also neuronal insulin resistance. Moreover, the consumption of an HFD has been shown to cause mitochondrial dysfunction in both the skeletal muscle and liver. Rosiglitazone, a peroxizome proliferator-activated receptor-γ ligand, is a drug used to treat type 2 diabetes mellitus. Recent studies suggested that rosiglitazone can improve learning and memory in both human and animal models. However, the effects of rosiglitazone on neuronal insulin resistance and brain mitochondria after the HFD consumption have not yet been investigated. Therefore, we tested the hypothesis that rosiglitazone improves neuronal insulin resistance caused by a HFD via attenuating the dysfunction of neuronal insulin receptors and brain mitochondria. Rosiglitazone (5 mg/kg · d) was given for 14 d to rats that were fed with either a HFD or normal diet for 12 wk. After the 14(th) week, all animals were euthanized, and their brains were removed and examined for insulin-induced long-term depression, neuronal insulin signaling, and brain mitochondrial function. We found that rosiglitazone significantly improved peripheral insulin resistance and insulin-induced long-term depression and increased neuronal Akt/PKB-ser phosphorylation in response to insulin. Furthermore, rosiglitazone prevented brain mitochondrial conformational changes and attenuated brain mitochondrial swelling, brain mitochondrial membrane potential changes, and brain mitochondrial ROS production. Our data suggest that neuronal insulin resistance and the impairment of brain mitochondria caused by a 12-wk HFD consumption can be reversed by rosiglitazone.     

A synthetic peptide derived from domain III envelope glycoprotein of Dengue virus induces neutralizing antibody

Dengue virus (DENV) is an arthropod-borne human pathogen that represents a severe public health threat in both endemic and non-endemic regions. So far, there is no licensed vaccine or specific drugs available for dengue fever. A fifteen-amino-acid-long peptide that includes the NGR motif was chemically synthesized and conjugated with keyhole limpet hemocyanin. A standard immunization protocol was followed for the production of polyclonal antibodies by immunizing rabbits against the synthetic peptide. The immune response elicited high-titer polyclonal antibodies with the reactivity of the anti-peptide antibody against both synthetic peptide and four serotypes of DENV confirmed by DOT-ELISA. Neutralizing activity of anti-peptide antibody was found to be cross-reactive and effective resulting in 60% reduction of infectivity at 1:200 dilution in all four serotypes of DENV. Our findings have the potential to further improve our understanding of virus–host interactions and provide new insights into neutralizing antibodies and could also be used as a drug target.     

Factors associated with the market availability of systemic anti-infective products in Thailand (no. 743)

Background  Despite the fact that the market availability of medicines has been recognized as one of the most important components in the health-care system, its association with other factors is still in doubt. Objective  This study aimed at determining the factors associated with the number of trade names and products of systemic anti-infective medicines available for the market in Thailand. Methods  A cross-sectional study on the data from the Thai National List of Essential Medicines (Thai EML) 2008 and Thailand Index of Medical Specialties 2008 was undertaken. Results  Results showed a total of 702 trade names and 1,262 products from 137 generic drugs. Half of the products belonged to the classes of beta-lactam antibacterials (39%) and quinolone antibacterials (11.3%). The significant factors found were dosage forms of medicines, manufacturer types and category. The generic drugs that were prepared in more than one dosage form, produced by local manufacturers and categorized as essential medicines (EMs) would have a greater number of trade names and products than those done in one dosage form by foreign manufacturers and as non-EMs. Conclusion  There are at least three factors associated with the number of trade names and products of systemic anti-infective medicines, which include dosage forms of medicines, manufacturer types and EM category. These factors have involved the technical issue, private sector and Thai EML. One suggestion from this finding is to use the Thai EML as a means to control the market availability of systemic anti-infective products in the country.     

Comparison of Fos expression within the ferret's spinal trigeminal nuclear complex evoked by electrical or noxious-thermal pulpal stimulation.

Fos-like immunoreactivity (Fos-LI) was used as a marker of trigeminal neurons that responded to tooth pulp stimulation. The activation of intradental afferents was produced by electrical stimulation of the ferret's intact canine tooth, whereas natural stimuli that activate predominantly Adelta (5 mol/L CaCl2 applied to dentin) or C fibers (slow heating of the intact tooth) were used to stimulate the 2 populations of afferents selectively. Electrical stimulation evoked Fos-LI in ipsilateral dorsomedial of the trigeminal subnucleus caudalis (Vc), dorsomedial and ventrolateral of the transition zone between subnucleus interpolaris and caudalis (Vi/Vc), and the the paratrigeminal nucleus (Pa5). Osmotic stimulation evoked Fos-LI in the ipsilateral dorsomedial Vc and Vi/Vc. The spatial distribution of Fos labeling after heat stimulation was dependent on the duration and location of the stimulus application. Repeated heating of the maxillary canine for 30 minutes evoked labeling bilaterally in ventrolateral Vi/Vc. Stimulation of the maxillary and mandibular canines with heat pulses for 1 hour produced labeling in the ipsilateral dorsomedial Vc, dorsomedial Vi/Vc, and the Pa5. None of the stimulating procedures did evoke Fos expression in regions rostral to Vi/Vc. Regardless of the pulpal stimulation procedures, a similar number of Fos-positive neurons was found in the nucleus of solitary tract and the ventrolateral medulla. Although Fos expression does not reveal all neurons that respond to noxious pulpal stimulation, it marks many neuronal regions that contain neurons that respond to pulpal stimulation and injury. Our results suggest that a population of neurons in Vc and Vi/Vc contribute to painful sensations originating from the dentition. PERSPECTIVE: We demonstrated that the trigeminal nucleus caudalis and the transitional zone between trigeminal interpolaris and caudalis mediate painful sensation in the dental pulp. Both trigeminal regions might be therapeutic targets for dental pain in the future.     

Incidence of Ototoxicity in Pediatric Patients with Transfusion-Dependent Thalassemia Who Are Less Well-Chelated by Mono- and Combined Therapy of Iron Chelating Agents

Ototoxicity due to iron chelation therapy, especially deferoxamine (DFO), is frequently observed in patients who have a higher chelation index (>0.025). However, there is limited data on patients who are less well-chelated and on other chelating regimens, including deferiprone (L1), deferasirox (DFX), and a combination of DFO and L1. To determine the incidence of ototoxicity from iron chelators, we retrospectively analyzed our clinical records from January 1997 to December 2010. All transfusion-dependent thalassemia (TDT) patients received iron chelation therapy with mono DFX, DFO, L1, or a combination. All patients underwent routine otolaryngologic examination and pure-tone audiometry before starting each chelation regimen and were regularly followed every 6 months. One hundred thalassemic patients were enrolled and analyzed (48 males and 52 females), with a mean age of 12.11?±?4.48 years (range 2.5–22.5 years). Total summative duration of iron chelation therapy in all patients was 596.50 years. Nine patients were found to have conductive hearing loss. Sensorineural hearing loss (SNHL) was identified in seven patients but only four were determined to be associated with iron chelators; three patients were detected while undergoing DFO therapy and one patient with L1 therapy. None of patients undergoing DFO therapy had reached over the levels of chelation index. In our resource-limited setting with poor treatment compliance, there was a rather low incidence of ototoxicity after exposure to iron chelators. However, a routine audiometry remains recommended for early detection and intervention since SNHL still develops and results in a long-term morbidity.