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PubMed2003

Glitazones differentially regulate primary astrocyte and glioma cell survival. Involvement of reactive oxygen species and peroxisome proliferator-activated receptor-gamma.

The glitazones or thiazolidinediones are ligands of the peroxisome proliferator-activated receptor gamma (PPARgamma). The glitazones are used in the treatment of diabetes, regulate adipogenesis, inflammation, cell proliferation, and induce apoptosis in several cancer cell types. High grade astrocytomas are rapidly growing tumors derived from astrocytes, for which new treatments are needed. We determined the effects of two glitazones, ciglitazone and the therapeutic rosiglitazone, on the survival of serum-deprived primary rat astrocytes and glioma cell lines C6 and U251, which were assessed by the methylthiazolyl tetrazolium assay and lactate dehydrogenase release. Rosiglitazone (5-20 microM) decreased survival of glioma cells without affecting primary astrocytes, whereas ciglitazone at 20 microM was toxic for both cell types. Ciglitazone at 10 microM was cytoprotective for primary astrocytes but toxic to glioma cells. Cell death induced by ciglitazone, but not rosiglitazone, presented apoptotic features (Hoechst staining and externalization of phosphatidylserine). Two mechanisms to explain cytotoxicity were investigated: activation of PPARgamma and production of reactive oxygen species (ROS). PPARgamma does not seem to be the main mechanism involved, because the order of efficacy for cytotoxicity, ciglitazone > rosiglitazone, was inverse of their reported affinities for activating PPARgamma. In addition, GW9662, an inhibitor of PPARgamma, only slightly attenuated cytotoxicity. However, the rapid increase in ROS production and the marked reduction of cell death with the antioxidants ebselen and N-acetylcysteine, indicate that ROS have a key role in glitazone cytotoxicity. Ciglitazone caused a dose-dependent and rapid loss (in minutes) of mitochondrial membrane potential in glioma cells. Therefore, mitochondria are a likely source of ROS and early targets of glitazone cytotoxicity. Our results highlight the potential of rosiglitazone and related compounds for the treatment of astrogliomas.

Animals↗
PubMedDate not supplied

[Classification of the main kidney diseases in diabetes mellitus].

In the suggested classification of affections of the kidneys in diabetes mellitus the main attention is paid to the vascular genesis of the appearing disturbances. The terms used formerly ("diabetic glomerulosclerosis", "diabetic nephropathy") failed to reflect the primary affections of the vessels. The following new terms are suggested: "diabetic microangionephropathy" (affection of the small vessels), "macroangiography" (affection of the large vessels), "diabetic angionephropathy" (complex affection of the renal vessels). "Pyelonephritis" (acute and chronic) was also introduced into the classification due to its exceedingly frequent occurrence in diabetes. The term "diabetic nephropathy" is suggested for complex affection including diabetic angionephropathy and pyelonephritis. Diabetic microangionephropathy should be divided into four clinico-laboratory stages; their characteristics are presented. Particular attention was paid to the accessibility of their diagnosis in medical institutions.

Acute Disease↗
PubMed1982

The genetics of depression. A family study of unipolar and neurotic-reactive depressed patients.

Sixty unipolar (23 male and 37 female) patients and 67 patients (25 male and 42 female) suffering from a neurotic-reactive depressive disorder, consecutively admitted to the Department of Psychiatry of Umeå University have participated in a family study aimed at identifying morbidity risks for psychiatric illnesses among first degree relatives (n = 437). Besides the classification of affective disorders used in Umeå for research purposes the patients have been classified, according to the ICD-9, DSM-III, age at onset (below or above 40 years), and the Winokur's classification of primary affective disorders. However, only the findings regarding the Umeå classification and the Winokur's classification are given in the present article. Of the patients 90% fulfilled Kendell's criteria for depression at the time of the investigation whereas the others were in a phase of remission when studied. The diagnosis of secondary cases were made without knowledge of the diagnoses of the probands. Among relatives of unipolar probands only two secondary cases of bipolar affective disorder were found--one among parents, and one among siblings (MR% 1.1 and 0.6 respectively). The overall morbidity risk for affective disorders (MR% 22.8 among parents and 15.5 among siblings) proved to be higher than in previous studies. In the families of neurotic-reactive patients the morbidity risk for bipolar affective disorders was also very low (MR% 1.0 among parents and 0.7 among siblings), whereas the overall MR% for affective disorders proved to be surprisingly high (12.1 among parents and 6.7 among siblings). No increased risk for schizophrenia or alcoholism was found among the relatives of either group. When the relatives were divided according to their sex no clear-cut difference in morbidity risk emerged when fathers and brothers were compared with mothers and sisters but alcoholisms occurred more frequently in male relatives. Preliminary findings in second degree relatives suggest that secondary cases of affective disorders might occur among second degree relatives of patients classified as suffering from "sporadic depression" according to Winokur's classification.

Adjustment Disorders↗
PubMed2000

The control of Xenopus embryonic primary neurogenesis is mediated by retinoid signalling in the neurectoderm.

In Xenopus, the primary neurons form in three domains either side of the midline in the posterior neurectoderm. At the late neurula stage there are approximately 120 primary sensory neurons on each side of the embryo. Co-injecting synthetic mRNA encoding retinoic acid receptor alpha (NR1B1) and retinoid X receptor beta (NR2B2) results in an increase in the number of primary neurons and this is further enhanced by the addition of retinoic acid indicating that elevated retinoid signalling promotes an increase in the number of cells undergoing primary neurogenesis. However, primary neurogenesis remains confined to the three domains that normally give rise to primary neurons indicating that not all regions of the neurectoderm respond equivalently to elevated retinoid signalling. The inhibition of retinoid signalling with a dominant negative retinoid receptor or treatment with citral, an inhibitor of retinoid metabolism, inhibits the formation of primary neurons. However, the lateral extent of the neurectoderm does not differ following these experimental manipulations suggesting that changes in primary neuron cell number, in response to changes in retinoid signalling, cannot be accounted for by significant gains or losses of neurectoderm. In addition, two lines of evidence are presented to suggest that retinoid signalling affects primary neurogenesis by acting directly on the neurectoderm. First, animal caps neuralized by noggin undergo primary neurogenesis in response to retinoid signalling and second primary neurogenesis is elevated in neural conjugates in which the ectodermal, but not the mesodermal, component has been co-injected with RAR/RXR mRNA.

Acyclic Monoterpenes↗
PubMed2003

The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases.

Non-small cell lung cancer is characterized by a specific metastatic pattern. The mechanism for organ-specific metastasis is poorly understood, although evidence has suggested that the chemokine stromal derived factor-1 (CXCL12) and its cognate receptor CXCR4 may regulate breast cancer metastasis. We hypothesized that the CXCL12-CXCR4 biological axis is important in mediating non-small cell lung cancer metastases. Our results indicate that both non-small cell lung cancer tumor specimens resected from patients and non-small cell lung cancer cell lines express CXCR4, but not CXCL12. Non-small cell lung cancer cell lines undergo chemotaxis in response to CXCL12. CXCL12-CXCR4 activation of non-small cell lung cancer cell lines showed intracellular calcium mobilization and mitogen-activated protein kinase activation with enhanced extracellular signal-related kinase-1/2 phosphorylation without change in either proliferation or apoptosis. Target organs in a murine model that are the preferred destination of human non-small cell lung cancer metastases elaborate higher levels of CXCL12 than does the primary tumor, and suggest the generation of chemotactic gradients. The administration of specific neutralizing anti-CXCL12 antibodies to severe combined immunodeficient mice expressing human non-small cell lung cancer abrogated organ metastases, without affecting primary tumor-derived angiogenesis. These data suggest that the CXCL12-CXCR4 biological axis is involved in regulating the metastasis of non-small cell lung cancer.

Animals↗
PubMed1999

[The course of affective disorders--a registry study].

In recent years, studies of the risk of recurrence in affective disorder in relation to the number of prior episodes have given contradictory results. Survival analysis was used to calculate the rate of recurrence after successive episodes in a case register study including all hospital admissions with primary affective disorder in Denmark during 1971-1993. Totally, 20,350 first-admission patients were discharged with a diagnosis of affective disorder, depressive or manic/circular type. The rate of recurrence increased with the number of previous episodes in both unipolar and bipolar disorder. Initially, the two types of disorders followed markedly different courses, but later in the course of the illness the rate of recurrence was the same for the two disorders. The course of severe unipolar and bipolar disorder seems to be progressive in nature despite the effect of treatment.

Bipolar Disorder↗
PubMed2004

[Present ways of diagnosing and treatment of pulmonary hypertension in the Czech Republic].

Pulmonary hypertension is a condition characterized by elevation of the mean blood pressure in pulmonary artery above 25 mm Hg at rest or above 30 mm Hg during exercise. Pulmonary hypertension signs are not specific. They are frequently camouflaged by signs of a primary disease causing pulmonary hypertension. That causes difficulties with diagnosing and often doesn't lead to recognition of pulmonary hypertension till pressure in pulmonary artery is difficult to manage therapeutically. Treatment of secondary pulmonary hypertension tries to affect primary disease. In patients with pulmonary artery hypertension with preserved vasoreactivity so called conventional treatment is still recommended (vasodilatation treatment with calcium channels blockers, anticoagulation, oxygentherapy, treatment of heart failure). New ways of pharmacotherapy represent administration of prostacyclin, antagonists of endothelin receptors, and phosphodiesterase inhibitors. Nonpharmacology treatment of pulmonary hypertension includes balloon atrial septostomy, lung transplantation, and in chronic thromboembolic pulmonary hypertension pulmonary endarterectomy. Current recommendations for pulmonary hypertension treatment concentrate especially on patients in functional classes NYHA III and IV. In less symptomatic patients there is usually lack of unambiguous clinical data needed for treatment. Owning to seriousness of the disease, its difficult diagnosing and frequently difficult treatment the global trend is to concentrate care of patients with pulmonary hypertension in specialised centers. This problem systematically addresses a center at the 2nd Clinic of Internal Medicine of the 1st Medical Faculty of the Charles University and the General Teaching Hospital in Prague in close cooperation with the Clinic of Cardiovascular Surgery at the General Teaching Hospital in Prague, and the transplantation center at the 3rd Surgical Clinic of the Teaching Hospital Motol in Prague, the Czech Republic.

Czech Republic↗
PubMed2001

Common hereditary cancers and implications for primary care.

The identification of genes that place individuals at high risk of breast, ovarian, and colorectal cancer has greatly advanced our understanding of cancer predisposition over the past decade. This knowledge has received much attention from the media, and referrals to geneticists and surgeons, and requests for genetic testing, have risen. We review the published evidence for the management of people at increased risk of hereditary cancers, to draw attention to areas of uncertainty and to discuss implications for primary care. We focus on common inherited cancers, since they will have the greatest effect on clinical practice over the next decade. Cancer genetics offers a model of how information on the genetics of other common diseases could affect primary care in the future. Strategies to support the integration of genetic medicine in primary care are needed to enable primary-care practitioners to identify individuals at raised genetic risk and to reassure patients for whom genetic testing and increased surveillance offer little benefit.

Female↗
PubMed1993

Deoxyribonuclease treatment prevents blood-borne liver metastasis of cutaneously transplanted tumour cells in mice.

Murine L5178Y-ML cells, when transplanted subcutaneously into the flank of (BALB/c x DBA/2)F1 mice, grew locally and always formed spontaneous metastases in the liver. Even after surgical removal of the primary tumour mass 5 or 7 days after tumour cell inoculation, all mice died due to liver metastases within 18 days. Using this model of tumour metastasis, we examined whether serine protease or deoxyribonuclease I (DNase I) would affect metastasis. Spontaneous liver metastasis of L5178Y-ML cells was enhanced by systemic administration of alpha-chymotrypsin at 3, 4 and 5 days or at 5, 6 and 7 days after tumour cell inoculation. This result was consistent with a previous report on blood-borne lung metastasis. In contrast, systemic administration of DNase I at 3, 4 and 5 days or at 5, 6 and 7 days after tumour cell inoculation inhibited liver metastasis. Neither treatment affected primary tumour growth. An influence of DNase I on tumour cell arrest in the microvasculature of the liver was suggested by scanning electron microscopy. DNase I treatment resulted in a statistically significant prolongation of the survival period, however, the effect was not satisfactory. A more striking anti-metastatic treatment resulting in a greater prolongation of the survival period was achieved by combining surgical removal of the primary tumour mass with DNase I treatment. These results suggest that DNase I could be a potential therapeutic agent used in conjunction with surgery to prevent clinical blood-borne metastasis.

Animals↗
PubMed1980

Covariance of affective and schizophrenic symptoms in schizoaffective psychosis.

A case report of a patient with schizophrenic and affective symptoms in remarkable correlations (r = .94) is presented to highlight difficulties in documenting the diagnosis of schizoaffective disorder. Proposed solutions include the frequent use of appropriate rating scales, recognizing that postpsychotic depression is common and may mimic primary affective disorders, and employing statistical methods applicable to the individual case.

Adult↗
PubMed1998

Recurrence in affective disorder. I. Case register study.

BACKGROUND: In recent years, studies of the risk of recurrence in affective disorder in relation to the number of prior episodes have given contradictory results. METHOD: Survival analysis was used to calculate the rate of recurrence after successive episodes in a case register study including all hospital admissions with primary affective disorder in Denmark during 1971-1993. A total of 20,350 first-admission patients were discharged with a diagnosis of affective disorder, depressive or manic/cyclic type. RESULTS: The rate of recurrence increased with the number of previous episodes in both unipolar and bipolar disorder. Initially, the two types of disorders followed markedly different courses, but later in the course of the illness the rate of recurrence was the same for the two disorders. CONCLUSIONS: The course of severe unipolar and bipolar disorder seems to be progressive in nature despite the effect of treatment.

Adult↗
PubMed2005

Oncolytic adenovirus expressing a p53 variant resistant to degradation by HPV E6 protein exhibits potent and selective replication in cervical cancer.

Rationale in the development of novel treatment strategies for HPV-associated cancers is targeting on the basis of the presence of HPV in (pre)malignant cells. Here, we designed a new conditionally replicating adenovirus (CRAd) for selective and effective oncolytic replication in HPV-containing cells. As the backbone, we used the CRAd AdCB016, which replicates selectively in cells expressing HPV E6 and E7 proteins. To enhance its oncolytic potency, we armed AdCB016 with p53 variant mp53(268N), which is resistant to HPV E6-mediated degradation. The new CRAd AdCB016-mp53(268N) was analyzed for its lytic replication properties in cervical carcinoma cell lines, HPV-immortalized keratinocyte cell lines representing dysplastic cells, and primary human keratinocytes. AdCB016-mp53(268N) exhibited 10- to 1000-fold greater efficacy than AdCB016 on high-risk HPV-positive cervical carcinoma cells and HPV-immortalized keratinocytes. Importantly, infection with AdCB016-mp53(268N) did not affect primary nonmalignant human keratinocytes. This favorable efficacy and safety profile was confirmed in organotypic raft cultures. Our findings suggest that AdCB016-mp53(268N) is a promising new agent for treatment of HPV-associated human cancers.

Adenoviridae↗
PubMed2005

[Relationship between ABO histo-blood group type and an outbreak of norovirus gastroenteritis among primary and junior high school students: results of questionnaire-based study].

Noroviruses are common causative agents of epidemic gastroenteritis in humans. Recent studies showed that human susceptibility to noroviruses was associated with ABO histo-blood group type. It was also observed that various degrees of susceptibility were exhibited by different norovirus strains. In January 2003, an outbreak of acute gastroenteritis including 661 affected primary and junior high school students occurred through lunch bread contaminated with norovirus in Hokkaido, Japan. To clarify the relationship between ABO histo-blood group type and the norovirus infection, we performed a written questionnaire to schoolchildren about the consumption of the bread, onset of symptoms and person-to-person transmission in their household. Questionnaires were returned from 722 schoolchildren (response rate, 65.8%), of whom 55.3% suffered gastroenteritis. As a result of this survey, it was found that schoolchildren with blood group type A (71.1%, 133/187) were more susceptible to the norovirus infection, whereas, schoolchildren with blood group type AB (55.3%, 26/47) were less affected (P (Z0) < 0.025). In addition, the presumptive prevalence rate of person-to-person transmission in each household indicated that schoolchildren with blood group type AB (19.2%, 5/26) had a lower risk of infection than those with blood group type A or O [A : 41.4%, 55/133 O : 39.5%, 49/124 (unknown for one case) ] [P (Z0) < 0.025]. Our findings suggested that persons with blood group type AB were less affected by the norovirus infection in this outbreak.

ABO Blood-Group System↗
PubMed1997

Benign meningiomas: primary treatment selection affects survival.

PURPOSE: To examine the effect of primary treatment selection on outcomes for benign intracranial meningiomas at the University of Florida. METHODS AND MATERIALS: For 262 patients, the impact of age, Karnofsky performance status, pathologic features, tumor size, tumor location, and treatment modality on local control and cause-specific survival was analyzed (minimum potential follow-up, 2 years; median follow-up, 8.2 years). Extent of surgery was classified by Simpson grade. Treatment groups: surgery alone (n = 229), surgery and postoperative radiotherapy (RT) (n = 21), RT alone (n = 7), radiosurgery alone (n = 5). Survival analysis: Kaplan-Meier method with univariate and multivariate analysis. RESULTS: At 15 years, local control was 76% after total excision (TE) and 87% after subtotal excision plus RT (SE+RT), both significantly better (p = 0.0001) than after SE alone (30%). Cause-specific survival at 15 years was reduced after treatment with SE alone (51%), compared with TE (88%) or SE+RT (86%) (p = 0.0003). Recurrence after primary treatment portended decreased survival, independent of initial treatment group or salvage treatment selection (p = 0.001). Atypical pathologic features predicted reduced 15-year local control (54 vs. 71%) and cause-specific survival rates (57 vs. 86%). Multivariate analysis for cause-specific survival revealed treatment group (SE vs. others; p = 0.0001), pathologic features (atypical vs. typical;p = 0.0056), and Karnofsky performance status (> or = 80 vs. < 80; p = 0.0153) as significant variables. CONCLUSION: Benign meningiomas are well managed by TE or SE+RT. SE alone is inadequate therapy and adversely affects cause-specific survival. Atypical pathologic features predict a poorer outcome, suggesting possible benefit from more aggressive treatment. Because local recurrence portends lower survival rates, primary treatment choice is important.

Adolescent↗
PubMed1975

Sexual behavior and affective disorders.

One hundred and fifty four consecutively evaluated new and return psychiatric outpatients were examined by the same interviewer using a detailed, precoded questionaire based on the diagnostic criteria for psychiatric research proposed by Feighner, et al. Sexual behavior manifested as prostitution involvement, promiscuity and extramarital sexual experiences was studied for groups of patients with unipolar and bipolar primary affective disorders, secondary affective disorders and non affective disorders. Results and conclusions are reported.

Adult↗
PubMed2005

Preliminary findings of uncoupling of flow and metabolism in unipolar compared with bipolar affective illness and normal controls.

Cerebral metabolism (CMR for glucose or oxygen) and blood flow (CBF) have been reported to be closely correlated in healthy controls. Altered relationships between CMR and CBF have been reported in some brain disease states, but not others. This study examined relationships between global and regional CMRglu vs. CBF in controls and medication-free primary affective disorder patients. Nine bipolars, eight unipolars, and nine healthy controls had [15O]-water positron emission tomography (PET) scans at rest, and [18F]-fluorodeoxyglucose PET scans during an auditory continuous performance task. Patients had [15O]-water and FDG PET scans in tandem the same day; controls had an average of 45+/-27 days between scans. Maps of regional coupling were constructed for each subject group. In controls and bipolars, global and virtually all regional correlation coefficients for CMRglu and CBF were positive, albeit more robustly so in controls. However, correlative relationships in unipolars were qualitatively different, such that global and most regional measures of flow and metabolism were not positively related. Unipolars had significantly fewer positive regional correlation coefficients than healthy controls and bipolars. These were significantly different from controls in orbital cortex, anterior cingulate, posterior cingulate, and posterior temporal cortex, and different from bipolars in pregenual anterior cingulate. In unipolars, the degree of flow-metabolism uncoupling was inversely correlated with Hamilton depression scores, indicating the severity of uncoupling was directly related to the severity of depression. These preliminary data suggest abnormal relationships between cerebral metabolism and blood flow globally and regionally in patients with unipolar depression that warrant replication and extension to potential pathophysiological implications.

Adult↗
PubMed2005

Hysterical conversion and brain function.

Hysterical conversion disorders represent "functional" or unexplained neurological deficits such as paralysis or somatosensory losses that are not explained by organic lesions in the nervous system, but arise in the context of "psychogenic" stress or emotional conflicts. After more than a century of both clinical and theoretical interest, the exact nature of such emotional disorders responsible for hysterical symptoms, and their functional consequences on neural systems in the brain, still remain largely unknown. However, several recent studies have used functional brain imaging techniques (such as EEG, fMRI, PET, or SPECT) in the attempt to identify specific neural correlates associated with hysterical conversion symptoms. This article presents a general overview of these findings and of previous neuropsychologically based accounts of hysteria. Functional neuroimaging has revealed selective decreases in the activity of frontal and subcortical circuits involved in motor control during hysterical paralysis, decreases in somatosensory cortices during hysterical anesthesia, or decreases in visual cortex during hysterical blindness. Such changes are usually not accompanied by any significant changes in elementary stages of sensory or motor processing as measured by evoked potentials, although some changes in later stages of integration (such as P300 responses) have been reported. On the other hand, several neuroimaging results have shown increased activation in limbic regions, such as cingulate or orbitofrontal cortex during conversion symptoms affecting different sensory or motor modalities. Taken together, these data generally do not support previous proposals that hysteria might involve an exclusion of sensorimotor representations from awareness through attentional processes. They rather seem to point to a modulation of such representations by primary affective or stress-related factors, perhaps involving primitive reflexive mechanisms of protection and alertness that are partly independent of conscious control, and mediated by dynamic modulatory interactions between limbic and sensorimotor networks. A better understanding of the neuropsychobiological bases of hysterical conversion disorder might therefore be obtained by future imaging studies that compare different conversion symptoms and employ functional connectivity analyses. This should not only lead to improve clinical management of these patients, but also provide new insights on the brain mechanisms of self-awareness.

Brain↗
PubMed1998

Sonic hedgehog is required for survival of both myogenic and chondrogenic somitic lineages.

In vertebrates, the medial moieties of the somites give rise to the vertebrae and epaxial muscles, which develop in close relationship with the axial organs, neural tube and notochord. The lateral moieties contribute to the ribs and to limb and body wall muscles (hypaxial muscles) after a phase of lateral and ventral migration. Surgical ablation of the neural tube and notochord in the chick embryo during segmentation and early differentiation of the somites (day 2 of incubation) does not affect primary development of the hypaxial muscles, but leads to a complete absence of epaxial muscles, vertebrae and ribs, due to cell death in the somites. Here we demonstrate that cell death, which occurs within 24 hours of excision of the axial organs, affects both myogenic and chondrogenic cell lineages defined, respectively, by the expression of MyoD and Pax-1 genes. In contrast, Pax-3 transcripts, normally present in cells giving rise to hypaxial muscles, are preserved in the excised embryos. Backgrafting either the ventral neural tube or the notochord allows survival of MyoD- and Pax-1-expressing cells. Similarly, Sonic hedgehog-producing cells grafted in place of axial organs also rescue MyoD- and Pax-1-expressing cells from death and allow epaxial muscles, ribs and vertebrae to undergo organogenesis. These results demonstrate that the ventral neural tube and the notochord promote the survival of both myogenic and chondrogenic cell lineages in the somites and that this action is mediated by Sonic hedgehog.

Animals↗