Transmission of hepatitis A in hamburg, germany, 1998-1999--A prospective population based study

To study the pattern of transmission of HAV in a large urban community a prospective cohort study was conducted in Hamburg between 1 January 1998 and 31 December 1999. Four hundred and eleven patients were classified as hepatitis A cases comprising 144 foreign and 267 German persons. Univariate analyses were carried out to examine differences between socio-demographic, clinical and behavioural characteristics. To determine independent predictors for HAV infection a multiple logistic-regression model was used. The principal risk factor was travel to areas where hepatitis A is endemic, with 32.6% (n = 134/411) of all documented cases of hepatitis A. Foreign patients who had acquired the infection abroad, mostly children, accounted for the majority of these cases. Of all 411 cases, 42 (10.2%) were associated with parenteral drug, followed by day-care or school contact (8.3%; n = 34). Outbreaks contributed to 11.4% of cases (n = 47), but only 7.1% (n = 29) were household contacts. The low incidence rate among exposed persons in the households of those infected was similar in the groups of foreign and German nationals (17/384 = 4.4% and 12/231 = 5.2%, respectively), which may demonstrate a good hygienic level in general. Our findings suggest that preventive measures such as the improvement of hygienic conditions in a defined general population may contribute to a reduced incidence of hepatitis A. Nevertheless, because hygienic standards may change with time, this policy should be supplemented by targeted vaccination of groups at risk.     

The rat prepubertal uterine myometrium and not the luminal epithelium is predominantly affected by a chronic dietary genistein exposure

Current knowledge about dietary soy isoflavone-induced hormonal effects and potential priming effects for the responsiveness of the organism to other estrogens is insufficient. The present study examined the effects of pre- and postnatal soy isoflavone exposure on estrogen responsiveness by estrogen receptor agonists in the uteri of prepubertal Wistar rats. To this end, offspring were generated from dams already maintained on three dietary groups, (1) a phytoestrogen-free diet, (2) a soy isoflavone-rich diet with 232?ppm daidzein and 240?ppm genistein or (3) a custom-made diet supplemented with 700?ppm genistein (GEN). Then, F1 females continuously exposed to isoflavones from GD1 to PND21 and non-exposed controls were subjected to an immature uterotrophic assay to compare physiological parameters and the response to subcutaneous treatment with 17β-estradiol, GEN or an estrogen receptor subtype (ERα and ERβ)–specific agonist. Uterine wet weight (UWW), luminal epithelial height (LEH) and myometrial thickness (MMT) were determined. In addition, isoflavone plasma levels and mRNA expression profiles of relevant steroid receptors and of molecular markers for proliferation and estrogenicity were assessed for all groups. The influence of dietary isoflavones on the sensitivity to various estrogenic stimuli in these prepubertal animals was minor. Yet, the uterus of immature rats with high chronic GEN exposure alone showed already an increase in UWW, LEH and MMT. The myometrial response to GEN was more pronounced than that of the luminal epithelium, which may be due to a non-uniform distribution of steroid receptors, in particular the progesterone receptor. In conclusion, although the impact of a continuous, prenatally initiated exposure to dietary isoflavones on the uterine physiology of juvenile rats is modest, the possible priming effects of this exposure for beneficial or adverse late-onset consequences in adults should not be neglected.     

Cadmium modulates expression of aryl hydrocarbon receptor-associated genes in rat uterus by interaction with the estrogen receptor

Estrogen-like effects of the heavy metal cadmium have been reported in both in vitro and in vivo studies. Yet, the molecular mechanisms involved in the hormonal activity of cadmium ions have not been fully elucidated. There are extensive data on cross-talk between aryl hydrocarbon receptor (AhR) and estrogen receptor (ER). Recently, 17β-estradiol (E₂) was found to modulate the expression of AhR and AhR-regulated genes in rat uterus (Kretzschmar et al. in Mol Cell Endocrinol 321:253–257, 2010). Thus, we hypothesized that cadmium may also affect AhR signaling and examined whether cadmium or E₂ modulate AhR-associated genes via the ER in rat uterus. Ovariectomized Wistar rats received E₂ (0.5 mg/kg bw) or cadmium chloride (0.05 and 2 mg/kg bw i.p.) alone and in combination with the pure anti-estrogen ZK191703. We also co-treated a group with E₂ and cadmium 2 mg/kg bw to assess how they act in concert. Uterus wet weight, uterus epithelial height, complement C3 mRNA, and progesterone receptor (PR) protein expression served as estrogen response parameters, and expression of Mt1a mRNA was analyzed as a cadmium responsive gene. The expression of AhR protein and AhR-associated gene expression, i.e., Ahr, Arnt1, Arnt2, Cyp1a1, and Gsta2, were analyzed to examine effects on AhR-mediated signaling pathways in the uterus of all groups. Both, E₂ and cadmium induced C3 and PR expression, and this was antagonized by ZK191703. Mt1a expression was clearly induced by cadmium but slightly reduced by E₂ compared to controls. Uterine Ahr, Arnt1, Arnt2, and Cyp1a1 expression was modulated by E₂ via the ER since down-regulation by E₂ was reversed by anti-estrogen. Cadmium apparently also modulated Cyp1a1 expression via the ER. Furthermore, cadmium-induced AhR was antagonized by E_2, and anti-estrogen-induced Gsta2 expression was antagonized by cadmium. Together our findings provide evidence for cross-talk of ER and AhR in the rat uterus.     

Regulation of gene expression by 8-prenylnaringenin in uterus and liver of Wistar rats

The potential estrogenic activity of 8-prenylnaringenin has been investigated using several in vitro test systems. 8-Prenylnaringenin is a natural secondary product of the female blossoms of hops. The aim of the present study was to characterize 8-prenylnaringenin for its estrogenic effects in vivo. A three day uterotrophic assay was carried out on ovariectomized young female rats. A single dose of 8-prenylnaringenin (10 mg/day/kg body mass) was administered subcutaneously. 17beta-Estradiol (0.03 mg/day/kg body mass; subcutaneous administration) was used as a positive control. Uterine wet weight, endometrial and vaginal epithelial height were determined by histological methods. Gene expression in uterus and in liver was assessed using realtime RT-PCR. Both estradiol and 8-prenylnaringenin significantly stimulated uterine wet weight accompanied by a proliferative response. The three day treatment resulted in a statistically significant increase of the uterine epithelial height as well as of the vaginal epithelial height, the latter being the more sensitive parameter. In the uterus of ovariectomized animals estrogen receptor-alpha and clusterin gene expression were down regulated following treatment with estradiol, whereas expression of complement C3 was up-regulated. In response to treatment with 8-prenylnaringenin the same gene expression pattern was detectable, but less pronounced. The levels of estrogen receptor-alpha mRNA in rat liver were very low and therefore could not be quantitatively assessed. Like in the uterine tissue, estradiol down regulated clusterin expression. The response to 8-prenylnaringenin was weaker but still significant. Conversely, 8-prenylnaringenin was found to be more potent than estradiol in inducing expression of IGFBP-1. In summary, the multiparametric assessment of the estrogenic activity of 8-prenylnaringenin provides overwhelming evidence that 8-prenylnaringenin has largely to be regarded as a pure estrogen agonist and is therefore a questionable candidate molecule for hormone replacement therapy.     

Comparative responses of three rat strains (DA/Han,Sprague-Dawley and Wistar) to treatment with environmental estrogens

The rat uterotrophic assay is a widely used screening test for the detection of estrogenic, endocrine-disrupting chemicals. Although much attention has been paid to identifying protocol variables and reproducibility between laboratories the question whether toxicodynamic and toxicokinetic variations of different strains may affect their sensitivity to estrogenic stimuli has been rarely addressed. We have compared the estrogenic activity of the environmental chemicals genistein (GEN), bisphenol A (BPA) and p-tert-octylphenol (OCT) in DA/Han (DA), Sprague-Dawley (SD) and Wistar (WIS) rats after repeated oral application. Rats were treated per os for 3 days with different doses of these weakly estrogenic compounds and the potent reference estrogen ethinylestradiol (EE). Then uterine wet weight, thickness of the uterine epithelium, uterine gene expression of clusterin (CLU), and thickness of the vaginal epithelium were examined as parameters for estrogenic potency of the test compounds in the three strains of rats. The uterotrophic response to treatment with BPA, OCT and GEN was similar in the three strains, and allowed us to rank them as GEN being more potent than OCT, and BPA being the weakest estrogen. This was confirmed by analysis of other biological endpoints, despite some differences in the magnitude of their response among strains and to distinct compounds. For instance, the uterus wet weight response to EE treatment indicated lower sensitivity of SD rats than that of DA and WIS rats, but this was not observed for responses of the uterine or vaginal epithelium. Moreover, blood concentrations were assessed at the time of killing and related to biological responses: plasma levels of total and unconjugated BPA and GEN depended upon the dose administered and varied to some extent within treatment groups and among the three rat strains. However, there was no good correlation in the three strains between individual compound concentrations analysed 24 h after the last dose and the uterotrophic wet weights. Summarising our results, we conclude that the sensitivity of various biological endpoints can differ slightly between strains of rats. On the other hand, our data demonstrate that the choice of the rat strain does not lead to pronounced differences in the evaluation of estrogenic activities of chemicals, especially when different biological endpoints are included in the analysis.     

Nasal Administration of Cationic Nanoemulsions as Nucleic Acids Delivery Systems Aiming at Mucopolysaccharidosis Type I Gene Therapy

Purpose

This study demonstrates the nasal administration (NA) of nanoemulsions complexed with the plasmid encoding for IDUA protein (pIDUA) as an attempt to reach the brain aiming at MPS I gene therapy.

Methods

Formulations composed of DOPE, DOTAP, MCT (NE), and DSPE-PEG (NE-PEG) were prepared by high-pressure homogenization, and assessed in vitro on human fibroblasts from MPS I patients and in vivo on MPS I mice for IDUA production and gene expression.

Results

The physicochemical results showed that the presence of DSPE-PEG in the formulations led to smaller and more stable droplets even when submitted to dilution in simulated nasal medium (SNM). In vitro assays showed that pIDUA/NE-PEG complexes were internalized by cells, and led to a 5% significant increase in IDUA activity, besides promoting a two-fold increase in IDUA expression. The NA of pIDUA/NE-PEG complexes to MPS I mice demonstrated the ability to reach the brain, promoting increased IDUA activity and expression in this tissue, as well as in kidney and spleen tissues after treatment. An increase in serum IL-6 was observed after treatment, although with no signs of tissue inflammatory infiltrate according to histopathology and CD68 assessments.

Conclusions

These findings demonstrated that pIDUA/NE-PEG complexes could efficiently increase IDUA activity in vitro and in vivo after NA, and represent a potential treatment for the neurological impairment present in MPS I patients.

     

SARS-CoV-2 B.1.1.7 Variant Infection in Malayan Tigers,Virginia, USA

We report infection of 3 Malayan tigers with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.7 (Alpha) variant at a zoologic park in Virginia, USA. All tigers exhibited respiratory signs consistent with SARS-CoV-2 infection. These findings show that tigers are susceptible to infection with the SARS-CoV-2 B.1.1.7 variant.     

In utero and postnatal exposure to a phytoestrogen-enriched diet increases parameters of acute inflammation in a rat model of TNBS-induced colitis

Inflammatory bowel disease (IBD) is very common in Europe and USA. Its incidence in East Asia has been traditionally low, albeit the risk of IBD increases in Asian immigrants adopting western lifestyles, suggesting a strong role of environmental/dietary factors in IBD. A lifelong exposure to phytoestrogen-rich diets has been associated with a decreased risk of developing breast cancer and might also be protective against IBD. We studied the influence of in utero and postnatal exposure to a phytoestrogen (PE)-rich diet on acute inflammation in an animal model of TNBS-induced colitis. Wistar rats were exposed in utero and postnatally to high (genistein: 240 μg/g feed; daidzein: 232 μg/g feed) or very low levels (genistein and daidzein <10 μg/g feed) of phytoestrogen isoflavones fed to pregnant dams with the diet and throughout nursing. After weaning, the offspring had free access to these diets. At the age of 11 weeks, colitis was induced with an enema of TNBS. After 3 days, animals were sacrificed and tissues were collected for histological evaluation and analysis of molecular markers of inflammation. Animals kept on a PE-rich diet (PRD) had higher colon weights than animals on low PE-levels (PDD), suggesting enhanced acute inflammation by phytoestrogens. This result was supported by histological findings and by analysis of myeloperoxidase activity. Interestingly, relative mRNA and protein expression of cyclooxygenase-2 (COX-2) were modulated in rats on PRD, providing evidence that COX-2, the inducible isoform of the enzyme, is involved in the management of colonic inflammation. Our results suggest that early-in-life exposure to PE might not protect against the development of IBD but enhances the extent of acute inflammation.