Lead encephalo-myelopathy of the suckling rat and its implications on the porphyrinopathic nervous diseases

Summary Experimental lead encephalo-myelopathy of the suckling rat is the signpost on the tortuous road of uncovering prolonged metabolic dysoxidosis as the major pathogenetic principle in lead encephalopathy and in the other porphyrinopathic encephalopathies. This principle rests on the specific skill of the capillary endothelium of the nervous system to act as regulator of the blood-brain and blood-spinal cord barriers and on the extreme susceptability of this skill to chronic metabolic dysoxidosis. This same pathogenetic principle lies at the root of a group of neurological diseases for which we propose the name systembound dysoric encephalopathies. In contrast to lead encephalopathy of the suckling rat, human lead encephalopathy does not belong to this group because of added hemodynamic disorders. Such disorders prevent a pathoclitic distribution of the lesions.

---

Zusammenfassung Die experimentelle Bleiencephalomyelopathie der Saugratte ist der entscheidende Schritt auf dem verschlungenen Wege zur Aufdeckung der chronischen Wirkstoffmangeldysoxydose als pathogenetischer Faktor der porphyrinopathischen Encephalopathien und überhaupt als ein grundlegendes Prinzip der Neuropathologie. Dieses Prinzip brruht auf der den Capillarendothelien des Nervensystems eigenen Fähigkeit, die Bluthirn- bzw. die Blutrückenmarksscharanke zu regulieren, und andererseits auf der extremen Anfälligkeit dieser Fähigkeit gegenüber chronischer Wirkstoffmangeldysoxydose. Der Verlust dieser Fähigkeit reduziert die Capillaren auf die Stufe der weniger spezialisierten Capillaren der meisten übrigen Organe. Die Folge ist zunächst rein funktioneller Natur und äußert sich in psychischen Störungen mit oder ohne Krämpfe oder in motorischen Lähmungen. Diese Störungen sind in diesem Anfangsstadium reversibel, weil nach Beseitigung der Noxe die Capillaren ihre hoch-spezialisierte Fähigkeit wiedererlangen können. Bei längerer Dauer der Wirkstoffmangeldysoxydose jedoch kommt es zu einem breiten Spektrum von Strukturveränderungen dysorischer Art, an dessen äußerstem Ende Transudationen und Höhlenbildungen stehen.Die chronische Wirkstoffmangeldysoxydose ist die Grundursache einer großen Gruppe neurologischer Erkrankungen mit der Wernickeschen Encephalopathie als Protagonist, für welche die Bezeichnung systemgebundene dysorische Encephalopathien angebracht erscheint. Im Gegensatz zur Bleiencephalopathie der Saugratte gehört die menschliche Bleiencephalopathie nicht zu dieser Gruppe, weil sich bei ihr zum Versagen der Blutgehirnschranke Störungen der Durchblutung hinzugesellen. Die Anwesenheit solcher Störungen ist aber mit einer pathoklitischen Ausbreitung der Hirnschäden unvereinbar.

---

---

Julius Hallervorden (1882–1965) in memoriam.

---

This investigation was supported by a Research Grant NB-02275 from the National Institute of Neurological Diseases and Blindness, National Institutes of Health, Bethesda, Md.     

Loss of heterozygosity and microsatellite instability at the Xq28 and the A/G heterozygosity of the QM gene are associated with ovarian cancer

The QM gene is located at Xq28 of the X chromosome. QM may act as a tumor suppressor and may also participate in the 60S ribosomal subunit assembly. We studied loss of heterozygosity (LOH) and microsatellite instability (MSI) of microsatellite markers DXS15A, DXS1107, WI12360 and WI9327 for the Xq28 region in 29 ovarian cancer biopsies. The results showed that the LOH frequencies were 18.2%, 30%, 26.3% and 20.8% for WI12360, WI9327, DXS1107 and DXS15A, respectively, whereas the MSI rates were 18.2%, 50.0%, 31.6% and 12.5%, respectively. All tumors showed LOH or MSI for at least one of these markers. Sequencing the QM cDNA did not identify any mutation other than the adenine (A)/guanine (G) replacement at the 605th nucleotide which changes the coding from serine to asparagine. In 17 (58.6%) of the 29 tumors, both A and G types of QM mRNA were detected, indicating that the QM was A/G heterozygous and escaped X-inactivation. However, cDNA and genomic DNA sequencing revealed that the adjacent normal tissues showed the A/G heterozygosity in only 3 of the 17 cases, while in the remaining 14 cases, four had no more adjacent tissue available and ten revealed either G or A at the 605th nt, indicating an A/G point mutation in these tumors. The allele distribution was 32.8% for the A and 67.2% for the G type QM gene. The frequencies of A/A, G/G and A/G homo- or hetero-zygosity were 3.5%, 37.9% and 58.6%, respectively in cancer tissues but they were 26.1%, 52.2% and 21.7%, respectively in the adjacent tissues, indicating a higher heterozygous rate in cancer (58.6% vs 21.7%, p < 0.01). These results suggest that high frequencies of LOH and MSI at the Xq28 and of the A/G heterozygosity at the 605th nt of the QM gene may be associated with ovarian cancer.     

C-type lectins on macrophages participate in the immunomodulatory response to Fasciola hepatica products

Fasciola hepatica releases excretory-secretory products (FhESP), and immunomodulatory properties have been described for the carbohydrates present in these parasite products. The interaction of FhESP with the innate immune cells, such as macrophages, is crucial in the early stage of infection. In this work we observed that peritoneal macrophages from naive BALB/c mice stimulated in vitro with FhESP presented: an increased arginase activity as well as Arginase I expression, and high levels of transforming growth factor-β and interleukin-10. A similar macrophage population was also observed in the peritoneum of infected mice. A partial inhibition of the immunomodulatory effects described above was observed when macrophages were pre-incubated with Mannan, anti-mannose receptor, Laminarin or anti-Dectin-1, and then stimulated with FhESP. In addition, we observed a partial inhibition of these effects in macrophages obtained from mice that were intraperitoneally injected with Mannan or Laminarin before being infected. Taken together, these results suggest the participation of at least two C-type lectin receptors, mannose receptor and Dectin-1, in the interaction of FhESP with macrophages, which allows this parasite to induce immunoregulatory effects on these important innate immune cells and may constitute a crucial event for extending its survival in the host.     

Rat eosinophils stimulate the expansion of Cryptococcus neoformans-specific CD4(+) and CD8(+) T cells with a T-helper 1 profile

Experimental Cryptococcus neoformans infection in rats has been shown to have similarities with human cryptococcosis, revealing a strong granulomatous response and a low susceptibility to dissemination. Moreover, it has been shown that eosinophils are components of the inflammatory response to C. neoformans infections. In this in vitro study, we demonstrated that rat peritoneal eosinophils phagocytose opsonized live yeasts of C. neoformans, and that the phenomenon involves the engagement of FcγRII and CD18. Moreover, our results showed that the phagocytosis of opsonized C. neoformans triggers eosinophil activation, as indicated by (i) the up‐regulation of major histocompatibility complex (MHC) class I, MHC class II and costimulatory molecules, and (ii) an increase in interleukin (IL)‐12, tumour necrosis factor‐α (TNF‐α) and interferon‐γ (IFN‐γ) production. However, nitric oxide (NO) and hydrogen peroxide (H₂O₂) synthesis by eosinophils was down‐regulated after interaction with C. neoformans. Furthermore, this work demonstrated that CD4⁺ and CD8⁺ T lymphocytes isolated from spleens of infected rats and cultured with C. neoformans‐pulsed eosinophils proliferate in an MHC class II‐ and class I‐dependent manner, respectively, and produce important amounts of T‐helper 1 (Th1) type cytokines, such as TNF‐α and IFN‐γ, in the absence of T‐helper 2 (Th2) cytokine synthesis. In summary, the present study demonstrates that eosinophils act as fungal antigen‐presenting cells and suggests that C. neoformans‐loaded eosinophils might participate in the adaptive immune response.     

Studies of pilocarpine:carbomer intermolecular interactions

The interactions between pilocarpine (PIL) and the anionic polyelectrolyte carbomer (CBR) were investigated. The effects of the chemical interactions on the chemical stability of the drug also were evaluated. The binary system was characterized by nuclear magnetic resonance techniques, Fourier-transform infrared spectroscopy (FT-IR), X-ray powder diffraction, scanning electron microscopy (SEM) and thermal analysis. The experiments showed that the complex, prepared by freeze-drying, is a solid amorphous form different from its precursors, thereby offering an interesting alternative for the preparation of extended release matrices. The solution stability of PIL was studied at pH 7 and 8, at 70 °C. The PIL solution stability was evaluated alone and in the presence of CBR. Results indicated that the drug in the presence of the polymer is 3.3 and 3.5 times more stable, at pH 7 and pH 8, respectively, than the drug without CBR. The activation energy and the frequency factor, according to Arrhenius plot, were estimated to be 13.9 ± 0.4 and 14.8 ± 0.5 kcalmol(-1), and 6.1 ± 0.3 and 7.6 ± 0.3, with and without the polymer, respectively.     

Prevalence of Lyme meningitis in children with aseptic meningitis in a Lyme disease-endemic region

This study determined the prevalence of Lyme meningitis in children with undifferentiated aseptic meningitis from April to December in a Lyme disease-endemic region. Of the 60 children, 8 were seropositive (prevalence 13.3%; 95% confidence interval: 6.3-25.1%), with another probable case having high cerebrospinal fluid antibody titers. Clinicians in endemic regions should evaluate children with undifferentiated aseptic meningitis for Lyme meningitis in appropriate seasons.     

Molecular typing of epithelial ovarian carcinomas using inflammatory markers

BACKGROUND:

Ovarian epithelial carcinomas have recently been classified as slow growing type I tumors and rapidly growing highly aggressive type II tumors. The present study sought to molecularly characterize type I and II tumors using known molecular markers.

METHODS:

Specimens from 213 patients with ovarian carcinoma were categorized as type I or type II, and evaluated by immunohistochemistry for the inflammatory markers glucose transporter protein‐1 (Glut‐1), inducible nitric oxide synthase (iNOS), cyclooxygenase‐1 (COX‐1), cyclooxygenase‐2 (COX‐2), and nuclear factor kappa B. Statistical analysis was performed to investigate whether these molecular markers could distinguish between type I and type II tumors. Kaplan‐Meier survival curves and COX regression analysis were used to determine the prognostic effect of these markers on survival in the 2 types of tumors.

RESULTS:

Overexpression of COX‐1, COX‐2, iNOS, and Glut‐1 was significantly higher in type II tumors (P < .05). Women with type II tumors had a poorer median survival (60 months) as compared with those with type I tumors (141 months) (P = .0001). Multivariate analysis revealed type II tumors, late stage, and age >60 years as significant predictors of poor survival. For type II tumors, median survival of patients with tumors overexpressing COX‐2 was 44 compared with 85 months for those with tumors with low COX‐2 expression (P = .029). Looking at both type I and II tumors, the number of markers simultaneously overexpressed in each tumor was a significant predictor of poor patient survival (P = .005).

CONCLUSIONS:

The present study demonstrates that the new proposed histologic classification of ovarian epithelial carcinomas correlates with a distinct expression of inflammatory pathway proteins. High expression of these markers may explain the different biologic behavior of these 2 tumor types and provide targets for therapy. Cancer 2011. © 2010 American Cancer Society.