Prolonged treatment of genetically obese mice with conjugated linoleic acid improves glucose tolerance and lowers plasma insulin concentration: possible involvement of PPAR activation

Background

Studies in rodents and some studies in humans have shown that conjugated linoleic acid (CLA), especially its trans -10, cis -12 isomer, reduces body fat content. However, some but not all studies in mice and humans (though none in rats) have found that CLA promotes insulin resistance. The molecular mechanisms responsible for these effects are unclear, and there are conflicting reports on the effects of CLA on peroxisomal proliferator-activated receptor-γ (PPARγ) activation and expression. We have conducted three experiments with CLA in obese mice over three weeks, and one over eleven weeks. We have also investigated the effects of CLA isomers in PPARγ and PPARα reporter gene assays.

Results

Inclusion of CLA or CLA enriched with its trans -10, cis -12 isomer in the diet of female genetically obese (lep ^ob /lep ^ob ) mice for up to eleven weeks reduced body weight gain and white fat pad weight. After two weeks, in contrast to beneficial effects obtained with the PPARγ agonist rosiglitazone, CLA or CLA enriched with its trans -10, cis -12 isomer raised fasting blood glucose and plasma insulin concentrations, and exacerbated glucose tolerance. After 10 weeks, however, CLA had beneficial effects on glucose and insulin concentrations. At this time, CLA had no effect on the plasma TNFα concentration, but it markedly reduced the plasma adiponectin concentration. CLA and CLA enriched with either isomer raised the plasma triglyceride concentration during the first three weeks, but not subsequently. CLA enriched with its trans -10, cis -12 isomer, but not with its cis -9, trans -11 isomer, stimulated PPARγ-mediated reporter gene activity; both isomers stimulated PPARα-mediated reporter gene activity.

Conclusions

CLA initially decreased but subsequently increased insulin sensitivity in lep ^ob /lep ^ob mice. Activation of both PPARγ and PPARα may contribute to the improvement in insulin sensitivity. In the short term, however, another mechanism, activated primarily by trans -10, cis -12-CLA, which probably leads to reduced adipocyte number and consequently reduced plasma adiponectin concentration, may decrease insulin sensitivity.     

Vaccination with different HSV-1 glycoproteins induces different patterns of ocular cytokine responses following HSV-1 challenge of vaccinated mice.

We previously reported that vaccination of BALB/c mice with different baculovirus expressed HSV-1 glycoproteins induced varying degrees of protection against HSV-1 ocular challenge, ranging from complete protection to no protection, to exacerbation of eye disease. To correlate specific local immune responses with protection and exacerbation of corneal scarring, we examined immune cell infiltrates in the cornea after ocular HSV-1 challenge of vaccinated mice. Mice were vaccinated with gD, which completely protects against corneal scarring, gG, which produces no protection against corneal scarring, or gK, which exacerbates corneal scarring. Cryostat sections of cornea were taken at different times after challenge and examined for infiltrating cells containing IL-2, IL-4, IFN-gamma, IL-6, or TNF-alpha. No corneal infiltrates were seen before challenge or 1 day after ocular challenge in any groups. By days 3-7, many cells containing IL-4 and IFN-gamma, but few cells containing IL-2, had infiltrated into the corneas of gG or mock vaccinated mice. At the same times, many cells containing IL-2, but few cells containing IL-4 or IFN-gamma, were seen in the corneas of gD vaccinated mice. In contrast, the corneas of mice vaccinated with gK contained large amounts of IL-2, IFN-gamma, and IL-4. Our results suggest that: (1) corneas from gD vaccinated mice had no corneal disease and developed a response highly biased toward IL-2 responses; (2) corneas from gG or mock vaccinated eyes had significant corneal disease and developed a mostly IL-4 and IFN-gamma cytokine response; and (3) corneas from gK vaccinated mice had exacerbated corneal disease and developed strong IL-2, IL-4 and IFN-gamma cytokine responses.     

Hepatic injuries of hexachloroethane smoke inhalation: the first analytical epidemiological study

There has been no human epidemiological data regarding the hepatic injuries of hexachloroethane-zinc oxide (HC/ZnO) inhalation. This is the first epidemiological study to investigate whether HC/ZnO inhalation exposure can induce hepatic dysfunction in exposed soldiers. Twenty soldiers, exposed to high concentration of HC/ZnO smoke for 3-10 min in a narrow tunnel (0.6 m in width) during military training, were recruited as exposed group and they were divided into high-exposed group (n=10) and low-exposed group (n=10) by the distance from the explosion locale as a surrogate of exposure condition. Another 64 soldiers, not visiting the explosion areas, were recruited as referents. Venous blood was collected for liver function analyses. After log transformation of alanine aminotransferase (ALT) and adjustment for potential confounders, serum ALT in high-exposed soldiers was statistically significantly higher than those of referents for the 3 weeks following exposure. The serum ALT in low exposed soldiers was statistically significantly higher than those of referents at the 3rd week following exposure. The mean ALT levels also showed decreasing gradients by the distance from exposure locale. In addition, the proportions of abnormality on ALT (>40U/L) were also significantly different among three exposure conditions. Follow-up study showed that the hepatic dysfunction started from 1 to 2 weeks and peaked from 3rd to 5th week after exposure. ALT level was then returned to normal within 6-8 weeks after removing from HC/ZnO smoke exposure. No sequelas in hepatic dysfunction were found until 72 weeks follow-up. CONCLUSION: We concluded that inhalation of HC/Zn smoke can induce acute, dose-dependent and definite temporal relationship hepatic dysfunction.     

The risk of cancer among patients with sleep disturbance: a nationwide retrospective study in Taiwan

PurposeTo investigate the risk of cancer among patients with nonapnea sleep disorders (SDs).MethodsWe included newly diagnosed SD patients aged 20 years and older without antecedent cancer between 2000 and 2010 from the National Health Insurance Research Database. Standardized incidence ratios (SIRs) of cancers were calculated to compare the cancer incidence of patients with SD with that of the general population.ResultsDuring the 10-year study period, 2062 cancers developed among 63,381 SD patients, who were observed for 382,826 person-years (median follow-up of 6.23 years). The SIR for all cancers was 1.19 (95% confidence interval [CI], 1.14–1.24). For specific cancer types, SD patients exhibited an increased SIR for liver and lung cancers (1.44; 95% CI, 1.28–1.61 and 1.34; 95% CI, 1.18–1.51, respectively).ConclusionsWe observed that overall cancer risk is increased among Asian SD patients. In terms of individual cancers, the risks of liver and lung cancers were elevated. Clinicians should be aware of the possibility of increased liver and lung cancers among SD patients in Taiwan. A prospective study is necessary to confirm these findings.     

Perinatal characteristics and risk of polio among Swedish twins

Perng W, Cnattingius S, Iliadou A, Villamor E. Perinatal characteristics and risk of polio among Swedish twins. Paediatric and Perinatal Epidemiology 2012; 26: 218–225. Prenatal exposure to adverse environmental conditions is related to increased adult mortality in regions where infections are highly prevalent, yet there is little evidence of the impact of perinatal conditions on the risk of severe infections throughout life. Using prospectively collected data from 21 604 like‐sexed Swedish twins of known zygosity born in 1926–1958, we examined the risk of polio in relation to perinatal characteristics using cohort and nested co‐twin case–control analyses. Polio incidence was determined through an interview in 1998, and linkage with the Swedish national inpatient and death registries. There were 133 cases of polio. In the cohort analysis, birth length, birthweight and head circumference were positively associated with polio risk. After adjustment for sex, birth year, gestational age at birth and within‐twin pair correlations, twins of shortest length (<44 cm) had a 67% ([95% CI: 6%, 88%]; P = 0.04) lower risk of polio compared with the reference group (47–49 cm). After additional adjustment for birth length, every 100‐g increase in birthweight was related to a 34% increased risk of polio ([95% CI: ?1%, 82%]; P = 0.06), and every 10‐mm increase in head circumference was related to a 17% greater risk of polio ([95% CI: 5%, 31%]; P = 0.004). In co‐twin control analyses among 226 disease‐discordant twins, birth length, birthweight and head circumference were 0.3 cm (P = 0.19), 84 g (P = 0.07) and 3 mm (P = 0.08) higher in cases than controls, respectively. Similar associations were observed among monozygotic (n = 84) and dizygotic (n = 142) twins. These findings suggest that early intrauterine growth restriction may be inversely related to the incidence of polio.     

Trastuzumab-induced cardiotoxicity in elderly women with HER-2-positive breast cancer: a meta-analysis of real-world data

Background: We conducted a meta-analysis to assess the overall risk of cardiac toxicity associated with trastuzumab treatment in elderly breast cancer patients.

Methods: We searched databases from PubMed, EMBASE and Cochrane Central Registry of Controlled Trials to identify relevant studies. Statistical analyses were conducted to calculate the incidence rate, overall hazard ratio (HR) and 95% CIs using a fixed effects model.

Results: A total of 116,342 and 360 elderly patients from five cohort studies and two randomized clinical trials (RCTs) were included for analysis. The pooled incidences of symptomatic congestive heart failure (CHF) and CHF/HF/CM were 6.4% (95% CI 4.1% – 9.4) and 16.4% (95% CI 16.19% – 16.61) in patients with median age of 67.5 years from two RCTs and in patients with median age of 67.5 (60 – 75), 71 (66 – 80+), 74.5 (65 – 89), 75 (66 – 81+) and 79.5 (60 – 99) from five cohort studies, respectively. Trastuzumab was significantly correlated with an increased risk of defined cardiac toxicities in five cohort studies (HR = 1.89, 95% CI 1.72 – 2.07, p < 0.00001) and two RCTs (HR = 3.00, 95% CI 1.71, 5.26, p < 0.00001). Sub-group analysis showed that the anthracycline-based chemotherapy increased the risk of CHF/HF and CM in patients among five cohort studies (HR = 2.16, 95% CI: 1.8 – 1.87, p < 0.00001).

Conclusion: Trastuzumab is likely associated with an increased risk of cardiac toxicity in elderly patients with HER-2-positive breast cancer. Carefully monitoring cardiac function in elderly patients receiving trastuzumab, particularly with concurrent use of anthracycline, is warranted.     

Role of open lung biopsy in patients with diffuse lung infiltrates and acute respiratory failure.

BACKGROUND AND PURPOSE: Open lung biopsy (OLB) is the standard procedure for the diagnosis of specific parenchymal lung diseases. The purpose of this study was to investigate the influence of OLB on subsequent treatment strategy and outcome in patients with diffuse lung infiltrates and acute respiratory failure. METHODS: This retrospective review included 32 patients (aged 50.6 +/- 21.7 years) with acute respiratory failure and diffuse pulmonary infiltrates who underwent OLB from 1990-2002. Data analyzed included diagnoses, treatment alterations, 30-day survival, oxygenation status, and histologic results. RESULTS: Specific diagnoses were made in 53.1% of patients (17/32), 23 (71.9%) of whom had acute respiratory distress syndrome (ARDS). Diagnostic yields did not differ with immunity status or ARDS. OLB led to specific decisions of treatment in 46.9% of patients (15/32), and only 7 of these 32 patients (21.8%) survived. Overall mortality was 56.2% (18/32) and was not influenced by pre-OLB oxygenation or histologic results. Although perioperative complications affected 40.6% of patients (13/32), none of the deaths were surgery-related. Complication rates were significantly higher in patients with ARDS (p = 0.04). CONCLUSIONS: OLB is associated with a low perioperative mortality rate and acceptable morbidity rate in patients with diffuse lung infiltrates and acute respiratory failure, including those patients with ARDS. In this study, a specific diagnosis was obtained by OLB in more than half of patients with diffuse pulmonary infiltrates and ARDS. In addition, OLB resulted in either use of a new therapeutic strategy or elimination of unnecessary treatment in nearly one-half of patients (46.9%).