Multiple mechanisms of telomere maintenance exist and differentially affect clinical outcome in diffuse malignant peritoneal mesothelioma

PURPOSE: This study aims to investigate the prevalence of the two known telomere maintenance mechanisms, telomerase activity (TA) and alternative lengthening of telomeres (ALT), and to assess their prognostic relevance in diffuse malignant peritoneal mesothelioma (DMPM). EXPERIMENTAL DESIGN: In 44 DMPM specimens obtained from 38 patients, TA was determined using the telomeric repeat amplification protocol and ALT was detected by assaying ALT-associated promyelocytic leukemia nuclear bodies. The prognostic significance of telomere maintenance mechanisms was analyzed by Cox regression in the overall series and in a subset of 29 patients who underwent a uniform treatment regimen consisting of cytoreductive surgery and hyperthermic i.p. chemotherapy. RESULTS: Telomere maintenance mechanisms were detectable in 86.4% of DMPM: ALT or TA alone was found in 18.2% or 63.6% of lesions, respectively, whereas two cases (4.6%) were ALT+/TA+. TA and ALT proved to be inversely associated (P = 0.002). In the overall series, TA was prognostic for 4-year relapse (TA+ versus TA-, hazard ratio, 3.30; 95% confidence interval, 1.23-8.86; P = 0.018) and cancer-related death (TA+ versus TA-, hazard ratio, 3.56; 95% confidence interval, 1.03-12.51; P = 0.045), whereas ALT failed to significantly affect clinical outcome. These results held true also in the subset of patients submitted to uniform treatment with cytoreductive surgery and hyperthermic i.p. chemotherapy. CONCLUSIONS: Our results indicate that both known telomere maintenance mechanisms, TA and ALT, are present in DMPM and differentially affect patient prognosis.     

Chlamydia infection and lymphomas: association beyond ocular adnexal lymphomas highlighted by multiple detection methods

PURPOSE: Chlamydia psittaci (Cp) has been associated to ocular adnexal lymphomas (OAL) with variable geographic distribution. Herein, we used multiple Chlamydia detection tools to identify Cp elementary bodies-containing cell and to assess Cp prevalence in both nodal and extranodal lymphomas. EXPERIMENTAL DESIGN: TETR-PCR, immunohistochemistry, immunofluorescence, electron microscopy, and laser-capture microdissection were done in 35 OALs to define their effect in Chlamydia detection and, moreover, to identify the Cp cellular carrier. Cp prevalence was screened by TETR-PCR in 205 extraorbital lymphomas and 135 nonneoplastic controls. RESULTS: Twenty-six (74%) OALs were associated with Cp infection: immunohistochemistry, immunofluorescence, and laser-capture microdissection-assisted PCR showed that monocytes/macrophages were the Cp carriers; electron microscopy showed the presence of intact Cp elementary bodies into these cells. Immunohistochemistry and TETR-PCR showed a 70% concordance rate (P = 0.001). Cp DNA was equally prevalent in non-OAL, nodal, and extranodal lymphomas: among the latter, it was more common in diffuse large B-cell lymphomas of the skin (P = 0.03) and Waldeyer's ring. CONCLUSIONS: This multiparametric approach shows, for the first time, that monocytes/macrophages are the carriers of Cp, Cp seems preferentially associated with lymphomas arising in organs primarily exposed to antigens. The clinical implications of these findings deserve to be prospectively investigated.     

The effect of social network on burden and pessimism in relatives of patients with schizophrenia

The authors explored the social network of caregivers of patients with schizophrenia in relation to relatives' sociodemographic characteristics, patients' clinical variables, family burden, and pessimism about the consequences of the disease. They evaluated 709 key relatives of patients with schizophrenia concerning the above-mentioned variables by means of well-validated questionnaires. A more supportive social network was found in relatives who reported lower levels of burden and pessimism about schizophrenia. The effect of social network on relatives' burden and opinions about schizophrenia was significantly different in relation to relatives' gender. Strengthening the relatives' social network may represent a useful strategy to alleviate their burden and pessimism about schizophrenia.     

Agitated depression in bipolar I disorder: prevalence, phenomenology, and outcome

OBJECTIVE: The study aimed to explore how prevalent agitated depression is in bipolar I disorder, whether it represents a mixed state, and whether it differs from nonagitated depression with respect to course and outcome. METHOD: From 313 bipolar I patients with an index episode of major depression, the authors selected those fulfilling Research Diagnostic Criteria for agitated depression. These 61 patients were compared to 61 randomly recruited bipolar I patients with an index episode of nonagitated depression and 61 randomly recruited bipolar I patients with an index episode of mania regarding demographic, historical, and clinical features. The two depressive groups were also compared regarding time to recovery from the index episode, treatment received for that episode, percentage of time spent in an affective episode during a prospective observation period, and 5-year outcome. RESULTS: Patients with agitated depression were consistently not elated or grandiose, but one-fourth had the cluster of symptoms with racing thoughts, pressured speech, and increased motor activity, and one-fourth had the paranoia-aggression-irritability cluster. Compared to patients with nonagitated depression, they had a longer time to 50% probability of recovery from the index episode, were more likely to receive standard antipsychotic drugs during that episode, and spent more time in an affective episode during the observation period. CONCLUSIONS: The occurrence of agitated depression in bipolar I disorder is not rare and has significant prognostic and therapeutic implications. Whether the co-occurrence of a major depressive syndrome with one or two of these symptomatic clusters makes up a "mixed state" remains unclear.     

The prognostic significance of "switching" in patients with bipolar disorder: a 10-year prospective follow-up study

OBJECTIVE: This study explored whether "switching" (i.e., the direct transition from one mood polarity to the other) has significant prognostic implications in patients with bipolar disorder. METHOD: Bipolar disorder patients (N=97) whose first prospectively observed episode included at least one mood polarity switch and 97 bipolar disorder patients whose index episode was monophasic were compared with respect to several demographic and historical variables, symptomatic features of the index episode, time to recovery from the index episode, time spent in an affective episode during a prospective observation period, and psychopathological and psychosocial outcome at a 10-year follow-up interview. RESULTS: Patients whose index episode included at least two mood polarity switches spent significantly more time in an affective episode during the observation period and had a significantly worse psychopathological and psychosocial outcome 10 years after recruitment than those whose index episode included only one mood polarity switch or was monophasic. Patients whose polyphasic index episode started with depression spent a significantly higher proportion of time in an affective episode and had a significantly worse 10-year outcome than those whose polyphasic index episode started with mania or hypomania. Retention of the switching pattern throughout the observation period was seen in 42.4% of patients whose index episode started with mania and in 65.2% of those whose index episode started with depression. CONCLUSIONS: An index episode including at least two mood polarity switches, especially if starting with depression, is associated with a poor long-term outcome in patients with bipolar disorder. This pattern represents a significant target for new pharmacological and psychosocial treatment strategies.     

Presence of claudins mRNA in the brain. Selective modulation of expression by kindling epilepsy

In the central nervous system, the junctional types that establish and maintain tissue architecture include gap junctions, for cytoplasmic connectivity, and tight junctions, for paracellular and/or cell polarity barriers. Connexins are the integral membrane proteins of gap junctions, whereas occludin and members of the multigene family of claudins form tight junctions. In the brain, there are no transendothelial pathways, as continuous tight junctions are present between the endothelial cells. Thus, they provide a continuous cellular barrier between the blood and the insterstitial fluid. However, several brain pathologies, including epilepsy, are known to alter the permeability of the blood-brain barrier and to cause edema. Therefore, since claudins, as constitutive proteins of tight junctions are likely candidates for modulation under pathological states, we explored their normal pattern of expression in the brain and its modulation by seizures. We found that several members of this family are normally expressed in the hippocampus and cortex. Interestingly, claudin-7 is expressed in the hippocampus but not in the cortex. On the other hand, the expression of claudin-8 is selectively down-regulated in the hippocampus as kindling evolves. These results link for the first time the modulation of expression of a tight junction protein to abnormal neuronal synchronization that could probably be reflected in permeability changes of the blood-brain barrier or edema.     

Long-term outcome of patients with monostotic Ewing's sarcoma treated with combined modality

One hundred and twenty-one consecutive patients with monostotic Ewing's sarcoma (ES) were treated according to three consecutive combined modality programs from 1974 to 1986. Their 3-year progression free survival (PFS) rate from diagnosis of 59% was identical to the event free survival (EFS) rate, since all the 50 events occurring within 3 years from diagnosis were tumor recurrences. Primary tumor was treated with radiotherapy in 75 cases, surgical resection plus radiotherapy in 38, and radical surgery in 8. Chemotherapy was given to all patients and each program included adriamycin, vincristine, and cyclophosphamide ± dactinomycin. Median follow-up was 12 years, ranging from 6 to 19 years. The PFS rate decreased to 49% at 6 years and plateaued at 46% after the 7th year from diagnosis, even though some relapses were observed as late as 14 years from diagnosis. Second malignancies developed in 7 patients free from progressive ES and were represented by osteogenic sarcoma in previously irradiated bone in 4 cases and by breast carcinoma in 3. No other event but tumor relapse or second malignancy occurred in this series. EFS rate was 47% at 6 years and 39% at 12 years, further decreasing in the following years because of a number of late events. A continuous PFS longer than 7 years may be consistent with cure in the majority of patients with monostotic ES. However, these patients should be followed indefinitely because of risk of second malignancies. © 1994 Wiley-Liss, Inc.     

Study of subcellular localization of membrane‐bound choline acetyltransferase in Drosophila central nervous system and its association with membranes

Choline acetyltransferase (ChAT), the enzyme which catalyses the biosynthesis of the neurotransmitter acetylcholine, exists in a soluble and membrane-bound form in cholinergic nerve terminals of different animal species. This study was performed on the enzyme present in Drosophila central nervous system. We show that the two forms of the enzyme have the same apparent molecular weight (75 kDa) when analysed by immunoblotting using an antibody we raised against the recombinant enzyme. According to different authors, membrane-bound enzyme might be associated with synaptic vesicles or plasma membrane. Subfractionation of Drosophila head homogenates in linear glycerol gradients showed that ChAT does not associate with synaptic vesicles. Analysis of ChAT activity and immunoreactivity showed that two peaks of ChAT were produced. One peak was present in fractions containing soluble components and the other was associated with rapidly sedimenting membranes containing plasma membranes. ChAT in the first peak was mainly hydrophilic. A large proportion of ChAT associated with rapidly sedimenting membranes was amphiphilic. Further fractionation of these membranes by flotation in sucrose gradients showed that membrane-associated ChAT sedimented in fractions containing plasma membrane marker. Membrane-bound ChAT was neither solubilized nor converted to hydrophilic enzyme after membrane treatment with 1 m hydroxylamine, suggesting that the enzyme is not palmitoylated and therefore not anchored to membrane through thioester-linked long chain fatty acid. Partial solubilization of ChAT present on membranes with urea and carbonate suggests that this form of ChAT is a peripheral membrane protein. Carbonate solubilization of membrane-bound ChAT converted the enzyme from hydrophobic to hydrophilic protein.     

Survival of adults treated for medulloblastoma using paediatric protocols

We retrospectively studied 26 consecutive adults treated for medulloblastoma using paediatric protocols. Between 1987 and 2003, patients 18 years old were given adjuvant chemotherapy consisting of one of two 'paediatric' regimens (depending on the time of presentation) and craniospinal local-boost radiotherapy: regimen A (n = 12), vincristine (VCR), intrathecal and/or intravenous methotrexate and conventional radiotherapy; or regimen B (n = 11) sequencing intensive doses of multiple agents followed by hyperfractionated accelerated radiotherapy (HART). A VCR-lomustine-based maintenance followed both regimens. Three additional patients received a tailored treatment due to their impaired neurological status after surgery. The median age at diagnosis was 26 years (range 18-41 years). With a median follow-up of 46 months, 5-year disease-free and overall survival rates were 65+/-11% and 73+/-10%, respectively, for the series as a whole. All patients who received regimen B (5 of whom had metastatic Chang M2-M3 disease) are alive with no evidence of disease at 39 months. Although the number of patients is limited, our data suggest that the sandwich sequential, moderately intensive chemotherapy in combination with HART is an effective treatment for medulloblastoma in adults, and this approach seems to overcome previously-recognised risk factors.