A rare RET gene exon 8 mutation is found in two Greek kindreds with familial medullary thyroid carcinoma: implications for screening

OBJECTIVE: Familial medullary thyroid carcinoma (FMTC) is caused by germ-line mutations in the RET proto-oncogene. These mutations concern mainly cysteine residues in exons 10 and 11, whereas noncysteine mutations in exons 13-16 are rare. Mutations in other exons have been reported only in isolated families. In this study we have analysed the RET gene in two FMTC families negative for mutations in the above exons. DESIGN: We have analysed exons 7-19 and 21 in one index patient from each family using DNA sequencing. PATIENTS: Twenty-eight subjects from both families were clinically assessed and subsequently molecularly analysed for the presence of RET gene mutations. RESULTS: We have found the mutation c.1597G-->T (Gly533Cys) in two Greek families with FMTC. The mutation was detected in all seven MTC patients of both families as well as in 13 asymptomatic relatives in the heterozygote state, although one of the patients was also a homozygote due to consanguinity. The mutation shows a wide clinical heterogeneity, as there are carrier patients with age of diagnosis ranging from 23 to 88 years. CONCLUSIONS: It is likely that this mutation causes FMTC, as no other mutation was found in the RET gene, the mutation co-segregates with FMTC, and family members without the mutation are clinically unaffected. As the same point mutation was previously found in a large Brazilian family, it may be present in other populations as well. Therefore, exon 8 of RET should be screened in FMTC families with no identified common RET mutations.     

Polyclonal hypergammaglobulinemia in a case of B-cell chronic lymphocytic leukaemia: the result of IL-2 production by the proliferating monoclonal B cells?

Summary. CLL is typically characterized by acquired hypogammaglobulinemia. We report the case of a female patient suffering from B-CLL who developed polyclonal hypergammaglobulinaemia: 38-3 g/I polyclonal IgG, 0.97g/1 IgA and 0.33 g/1 IgM. Immunophenotyping showed a monoclonal lymphocytic population CD19⁺ CD5⁺ CD40⁺ CD23+, low slg⁺ (95%), K type in the great majority (96%). RT-PCR of immunoglobulin genes gave evidence of monoclonal rearrangement of the IgM type. Our tests showed that IL-2 was produced when leukaemic B cells were stimulated with phorbol myristate acetate, ionomycin and lipopoly-saccharide. In addition, transfections with the full IL-2 promoter or elements thereof revealed that IL-2 expression is inducible and mediated through the NF-kB-promoter element. Finally, the amount of IL-2 secreted by these cells is about 39ng/ml/10⁶ cells, which is remarkably high for non-T cells. These results suggest that the large amounts of polyclonal IgG seen in this case of B-CLL are secreted by normal B cells which are in turn stimulated by IL-2 produced by proliferating monoclonal (leukaemic) B cells. Under cyclosporin A treatment, immunoglobulin secretion and B cell count remained low.     

Regulation of lymphangiogenesis in the diaphragm by macrophages and VEGFR-3 signaling

Lymphatic vessels play important roles in fluid drainage and in immune responses, as well as in pathological processes including cancer progression and inflammation. While the molecular regulation of the earliest lymphatic vessel differentiation and development has been investigated in much detail, less is known about the control and timing of lymphatic vessel maturation in different organs, which often occurs postnatally. We investigated the time course of lymphatic vessel development on the pleural side of the diaphragmatic muscle in mice, the so-called submesothelial initial diaphragmatic lymphatic plexus. We found that this lymphatic network develops largely after birth and that it can serve as a reliable and easily quantifiable model to study physiological lymphangiogenesis in vivo. Lymphangiogenic growth in this tissue was highly dependent on vascular endothelial growth factor receptor (VEGFR)-3 signaling, whereas VEGFR-1 and -2 signaling was dispensable. During diaphragm development, macrophages appeared first in a linearly arranged pattern, followed by ingrowth of lymphatic vessels along these patterned lines. Surprisingly, ablation of macrophages in colony-stimulating factor-1 receptor (Csf1r)-deficient mice and by treatment with a CSF-1R-blocking antibody did not inhibit the general lymphatic vessel development in the diaphragm but specifically promoted branch formation of lymphatic sprouts. In agreement with these findings, incubation of cultured lymphatic endothelial cells with conditioned medium from P7 diaphragmatic macrophages significantly reduced LEC sprouting. These results indicate that the postnatal diaphragm provides a suitable model for studies of physiological lymphangiogenic growth and maturation, and for the identification of modulators of lymphatic vessel growth.     

Adefovir plus lamivudine are more effective than adefovir alone in lamivudine-resistant HBeAg- chronic hepatitis B patients: A 4-year study

Background and Aim:  Adefovir dipivoxil (ADV) is effective in lamivudine (LAM)-resistant hepatitis B e antigen-negative (HBeAg^-) chronic hepatitis B (CHB). However, it is unclear whether LAM treatment should be continued in these patients. We aimed to compare the long-term efficacy of adding ADV to ongoing LAM treatment versus switching to ADV monotherapy in LAM-resistant HBeAg^- CHB.
Methods:  Sixty LAM-resistant patients with HBeAg^- CHB were randomly assigned (3:1) to combination therapy (10 mg ADV once daily plus ongoing LAM at 100 mg once daily [ n  = 45]) or 10 mg ADV monotherapy once daily ( n  = 15). Virological and biochemical responses were defined as hepatitis B virus (HBV)–DNA <400 copies/mL and as normalization of alanine aminotransferase levels, respectively.
Results:  The median follow-up time was 53 months (range 20–60 months). A virological response was observed in 38/45 (84.4%) and 11/15 (73.3%) patients in the ADV/LAM and ADV monotherapy groups, respectively ( P  = 0.56). Biochemical response rates were higher in the ADV/LAM group than in the ADV monotherapy group (90.9% vs 57.1%, respectively; P  = 0.01). In the ADV/LAM group, serum HBV–DNA remained undetectable in all patients who achieved a virological response ( n  = 38). In the ADV monotherapy group, virological breakthrough occurred in four of the 11 patients who achieved a virological response (36.4%; P  < 0.001 vs the ADV/LAM group, log–rank test). In addition, two patients in each group who did not achieve a virological response eventually developed ADV resistance.
Conclusions:  Adding ADV to LAM is more effective than switching to ADV monotherapy in LAM-resistant patients with HBeAg^- CHB.     

Addressing hepatic metastases in ovarian cancer: Recent advances in treatment algorithms and the need for a multidisciplinary approach

The lifetime risk for ovarian cancer incidence is 1.39% and the lifetime risk of death is 1.04%. Most ovarian cancer patients are diagnosed at advanced stages(Ⅲ, Ⅳ) because there were no specific symptoms or existing screening tests. Liver metastases have been found in up to 50% of patients dying of advanced ovarian cancer. Recent studies indicate the need for a multidisciplinary approach from initial diagnosis to oncologic surgery and chemotherapy treatment, mandating the involvement of gynecologic oncologists, surgical oncologist, medical oncologists, hepatobiliary surgeons, and interventional radiologists.     

Fourteen-year seroepidemiological study of zoonoses in a Greek village

A seroepidemiological study carried out in a high-risk village in Crete in 1985-1987 and 1998 showed that although the awareness of the people concerning zoonoses had increased during this period, the situation did not improve: there was a significant increase of the spread of seroprevalence in time and space of Coxiella burnetii, Rickettsia typhi, Brucella sp., and Entamoeba histolytica. Toxoplasma gondii, Rickettsia conorii, Borrelia burgdorferi, Echinococcus granulosus, Leishmania sp., and Fasciola hepatica stayed at the same levels. This first study of Bartonella henselae in Crete showed that 15.9% of the children tested were seropositive. The results indicate that reservoirs and vectors of the pathogens studied are widespread in the environment, and the way of life of the people favors contact with them. Seven of 30 milk samples were positive for Brucella sp. by seminested polymerase chain reaction.     

The Relationship between Hopelessness and Clinical Characteristics of Hospitalized Patients with Recent Suicide Attempt

This study aimed to assess hopelessness in 170 hospitalized individuals with recent suicide attempt and examine its association with patients’ characteristics, with a view to improving awareness in health professionals and especially nurses, who are among the first to take care of these patients. Participants completed Beck Hopelessness Scale and Beck Depression Inventory. More than half (51.18%) experienced moderate-to-severe hopelessness. A multiple linear regression analysis showed that age, attempted suicide method, past suicide attempt, and psychiatric diagnosis contributed statistically significantly to hopelessness prediction. Hopelessness assessment could efficiently help health professionals to minimize both inpatient suicide and suicidal acts after discharge.