Local gene therapy with indoleamine 2,3-dioxygenase protects against development of transplant vasculopathy in chronic kidney transplant dysfunction.

Chronic transplant dysfunction (CTD) is the primary cause of late allograft loss in kidney transplantation. Indoleamine 2,3-dioxygenase (IDO) is involved in fetomaternal tolerance and IDO gene therapy inhibits acute rejection following kidney transplantation. The aim of this study is to investigate whether gene therapy with IDO is able to attenuate CTD. Transplantation was performed in a rat Dark-Agouti to Wistar-Furth CTD model. Donor kidneys were incubated either with an adenovirus carrying IDO gene, a control adenovirus or saline. During the first 10 days recipients received low-dose cyclosporine. Body weight, blood pressure, serum creatinine and proteinuria were measured every 2 weeks. Rats were killed after 12 weeks. IDO had a striking beneficial effect on transplant vasculopathy at week 12. It also significantly improved body weight gain; it reduced blood pressure and decreased proteinuria during the follow-up. However, it did not affect the kidney function. In addition, IDO therapy significantly decreased the number of graft-infiltrating macrophages at week 12. The messenger RNA levels of forkhead box p3 and transforming grow factor-ß were elevated in the IDO treated group at week 12. Here we show for first time a clear beneficial effect of local IDO gene therapy especially on transplant vasculopathy in a rat model of renal CTD.

Mitochondrial DNA phylogeny in Eastern and Western Slavs.

To resolve the phylogeny of certain mitochondrial DNA (mtDNA) haplogroups in eastern Europe and estimate their evolutionary age, a total of 73 samples representing mitochondrial haplogroups U4, HV*, and R1 were selected for complete mitochondrial genome sequencing from a collection of about 2,000 control region sequences sampled in eastern (Russians, Belorussians, and Ukrainians) and western (Poles, Czechs, and Slovaks) Slavs. On the basis of whole-genome resolution, we fully characterized a number of haplogroups (HV3, HV4, U4a1, U4a2, U4a3, U4b, U4c, U4d, and R1a) that were previously described only partially. Our findings demonstrate that haplogroups HV3, HV4, and U4a1 could be traced back to the pre-Neolithic times ( approximately 12,000-19,000 years before present [YBP]) in eastern Europe. In addition, an ancient connection between the Caucasus/Europe and India has been revealed by analysis of haplogroup R1 diversity, with a split between the Indian and Caucasus/European R1a lineages occurring about 16,500 years ago. Meanwhile, some mtDNA subgroups detected in Slavs (such as U4a2a, U4a2*, HV3a, and R1a1) are definitely younger being dated between 6,400 and 8,200 YBP. However, robust age estimations appear to be problematic due to the high ratios of nonsynonymous to synonymous substitutions found in young mtDNA subclusters.

Mitochondrial DNA variability in Slovaks, with application to the Roma origin.

To gain insight into the mitochondrial gene pool diversity of European populations, we studied mitochondrial DNA (mtDNA) variability in 207 subjects from western and eastern areas of Slovakia. Sequencing of two hypervariable segments, HVS I and HVS II, in combination with screening of coding region haplogroup-specific RFLP-markers, revealed that the majority of Slovak mtDNAs belong to the common West Eurasian mitochondrial haplogroups (HV, J, T, U, N1, W, and X). However, a few sub-Saharan African (L2a) mtDNAs were detected in a population from eastern part of Slovakia. In addition, about 3% of mtDNAs from eastern Slovakia encompass Roma-specific lineages. By means of complete mtDNA sequencing we demonstrate here that the Roma-specific M-lineages observed in gene pools of different Slavonic populations (Slovaks, Poles and Russians), belong to Indian-specific haplogroups M5a1 and M35. Moreover, we show that haplogroup J lineages found in gene pools of the Roma and some Slavonic populations (Czechs and Slovaks) belong to new subhaplogroup J1a, which is defined by coding region mutation at position 8460.

[Collagenofibrotic glomerulopathy--rare glomerulonephritis]. / Kolagenofibrotická glomerulopatia--raritná glomerulonefritída.

Glomerulopathies with fibrillary deposits form a heterogeneous group of renal diseases that can be identified only by means of electron microscopy. A case of a rare type of such a nephropathy, the collagenofibrotic glomerulopathy with focus on differential diagnostics is presented and current knowledge relating to this renal disease is reviewed.

[Can serologic markers be indicators of dietary errors in patients with celiac disease?]. / Môzu byt' sérologické markery ukazovatelom diétnych chýb u pacientov s celiakiou?

Coeliac disease is a disease of small intestine requiring life-long strict gluten free diet to avoid acute and chronic complications. To reach maximum adherence to the diet is in some of coeliac patients, especially adults, difficult because it requires distinct changes in eating habits. To diagnose coeliac disease tests of antigliadin and anti-endomysial antibodies in serum are used. Authors monitored levels of antibodies in 32 adults 3, 6, and 12 month after histology validation of coeliac disease and after recommendation of a gluten free diet. The results were compared with data from nutritional history. Maximum adherence to the diet indicated 24 patients (75%), occasional consummation of gluten indicated 6 patients (19%) and more frequent breaking a diet indicated 2 patients (6%). In a group which adhered to the diet the most rapid was a decline in levels of anti-endomysial antibodies, less rapid was a decline in levels of IgA-class antigliadin antibodies, and the least rapid was a decline in levels of IgG-class antigliadin antibodies. In the group with occasional intake of gluten was the decline slower and in the group with frequent dietary mistakes levels of antibodies have not declined at all. Adherence to the diet positively correlated with level of accomplished education of patients. Monitoring of titter kinetics proved to be a good indicator of discipline and cooperation of patients during treatment with gluten free diet.

Coxsackievirus infection of mice. I. Viral kinetics and histopathological changes in mice experimentally infected with coxsackieviruses B3 and B4 by oral route.

We followed the viral kinetics and histopathological changes in different organs of immunocompetent mice infected orally with coxsackieviruses B3 (CVB3) Nancy strain and B4 (CVB4) JVB strain separately. The viruses used were not adapted to mouse organs. In the acute phase of infection, the viral kinetics indicated virus replication in the heart, spleen, thymus, pancreas, and small and large intestines. This was accompanied by histopathological changes, mild infiltration of mononuclear cells and fibrosis in the heart. The necrotic changes with mononuclear infiltration and fibrosis in the myocard was observed on days 56 and 71 p.i. in the CVB4-infected animals only. In the mice infected with CVB3 and CVB4 a prolonged presence of infectious virus was shown in the spleen and small intestine; in the latter viral antigen was localized in smooth muscles of the muscular wall immunohistochemically. This is the first report on prolonged replication of coxsackieviruses (CV) in the spleen and small intestine in orally infected mice.

Composite multicystic mesothelioma and adenomatoid tumor of the ovary: additional observation suggesting common histogenesis of both lesions.

An unusual case of composite multicystic mesothelioma and adenomatoid tumor of the ovary is reported. The gradual transitions between both tumor components were well apparent. This observation indicates a histogenetic relationship between adenomatoid tumor and benign multicystic mesothelioma.

Renal angiomyolipoma resembling gastrointestinal stromal tumor with skenoid fibers.

We report an unusual case of renal angiomyolipoma occurring in 68-year-old man. The tumor lacked well-developed vascular and adipose components and was composed almost exclusively of smooth muscle cells. Numerous skenoid-like periodic acid-Schiff-positive globules were interspersed between the tumor cells; the lesion therefore closely resembled a low-grade stromal tumor of the gastrointestinal tract. The HMB45-positive/CD34-negative immunophenotype was essential for the diagnosis of angiomyolipoma. Neither gastrointestinal tumor nor any signs of tuberous sclerosis were found. This lesion should be included in the list of morphologic variations of angiomyolipoma, which may cause diagnostic difficulties.

[Extraskeletal myxoid chondrosarcoma with neuroendocrine differentiation]. / Extraskeletálny myxoidný chondrosarkóm s neuroendokrinou diferenciáciou.

We describe a case of extraskeletal myxoid chondrosarcoma with neuroendocrine differentiation. The tumor occurred in subcutaneous tissue of the right popliteal region in a 50-year-old man. It measured 5 cm in diameter, was well circumscribed, lobular and gelatinous, and lacked any necrosis or hemorrhage. Histologically, the tumor structure was a typical of extraskeletal myxoid chondrosarcoma. The lesion was lobulated and contained small to medium-sized chondroblast-like cells with ovoid hyperchromatic nuclei and without prominent nucleoli. The cells created cords and nests and showed focally a perivascular rosette-like arrangement. A few of the tumor cells were spindle shaped. The myxoid matrix was stained with alcian blue and this reaction was resistant to prior treatment with hyaluronidase. PAS-positive glycogen was found in the cytoplasm of some tumor cells. Immunohistochemically, the tumor cells were diffusely positive for neuron specific enolase, monoclonal synaptophysin and vimentin. Following antibodies gave negative results: desmin, actins, S-100 protein, pancytokeratin, epithelial membrane antigen, chromogranin A, neurofilament protein, myelinic basic protein, glial fibrillary acidic protein. The patient is well four years after the wide excision of tumor and radiotherapy. Neuroendocrine differentiation in extraskeletal myxoid chondrosarcoma was described at first by Chhieng et al. in 1998 (1). Our observation confirms this interesting finding.

[Perineurioma]. / Perineurióm.

Perineurioma (storiform perineurial fibroma) is a rarely diagnosed benign tumour of perineurial cells. Presented tumour occurred subcutaneously in the right thigh of a 53-year-old man. It was well limited and consisted of whirl like and concentric laminar bundles of spindle and oval cells in variable local density. A storiform pattern was not present. Cells with richer cytoplasm, bland nuclei and solitary intranuclear pseudoinclusions formed focal meningioma like structures. Differential diagnosis had to distinguish benign neuronal tumours, myxoid variant of dermatofibrosarcoma protuberans and especially a "low grade" fibromyxoid sarcoma. A relevant immunohistochemical marker of perineurioma (for differential diagnosis) was the expression of epithelial membrane antigen (EMA) with negativity of S-100 protein.

Yolk sac carcinoma of the stomach with gastrin positivity.

A gastric antral tumor histologically classified as a yolk sac carcinoma was studied immunohistochemically. The tumor contained immunoreactive alpha-fetoprotein and gastrin. This is the first yolk sac carcinoma in which neuroendocrine differentiation was demonstrated immunohistochemically.

[Heterogeneous carcinoma of the gallbladder with neuroendocrine differentiation]. / Heterogénny karcinóm zlcníka s prevazujúcou neuroendokrinnou diferenciáciou.

A heterogenous mostly neuroendocrine small cell carcinoma was found in a gallbladder resected from a 75-year-old man suffering from CLL. It progressed along bile ducts into choledochus, into omentum and liver. Its histology was characterized by solid alveoli and small cell trabeculae with a high mitotic activity, dissociated infiltration in some parts and desmoplasia. Sometimes a typical adenocarcinomatous differentiation could be found out. Tumour cells produced immunohistological expression of EMA, CEA, NSE and CHG and had Grimelius silver impregnation positivity. Neuroendocrine gallbladder carcinomas used to be more aggressive than carcinomas of another type, can cause an endocrine syndrome and claim a special treatment.