Aberrant p53 expression in astrocytic neoplasms of the brain: association with proliferation.

Aberrant expression of the p53 suppressor gene was evaluated in 102 cases of astrocytic neoplasms. Immunohistochemical staining with a monoclonal antibody (DO-7) and a polyclonal antibody (CM-1) to p53 protein (both wild type and mutant) on formalin-fixed paraffin sections showed a strong correlation with malignancy grade. The staining was positive in 49% of malignant neoplasms (grades III and IV) and in 19 to 29% of grade II astrocytomas, whereas none of the grade I tumors were positive. p53 expression was significantly associated with proliferation rate determined by immunohistochemical proliferating cell nuclear antigen (PCNA)-staining (median PCNA-labeling index (%): 4.22 (DO-7-positive) versus 1.18 (DO-7-negative), P < 0.0001; 4.02 (CM-1-positive) versus 1.18 (CM-1-negative), P < 0.001). Interestingly, in the glioblastoma group (n = 44), p53-positive tumors had higher proliferation indices, suggesting that histologically similar tumors could be divided into prognostically different subgroups by immunohistochemical demonstration of aberrant p53 expression.     

Graft-versus-leukemia reactions after bone marrow transplantation

To determine whether graft-versus-leukemia (GVL) reactions are important in preventing leukemia recurrence after bone marrow transplantation, we studied 2,254 persons receiving HLA-identical sibling bone marrow transplants for acute myelogenous leukemia (AML) in first remission, acute lymphoblastic leukemia (ALL) in first remission, and chronic myelogenous leukemia (CML) in first chronic phase. Four groups were investigated in detail: recipients of non--T-cell depleted allografts without graft-versus-host disease (GVHD), recipients of non-- T-cell depleted allografts with GVHD, recipients of T-cell depleted allografts, and recipients of genetically identical twin transplants. Decreased relapse was observed in recipients of non--T-cell depleted allografts with acute (relative risk 0.68, P = .03), chronic (relative risk 0.43, P = .01), and both acute and chronic GVDH (relative risk 0.33, P = .0001) as compared with recipients of non--T-cell depleted allografts without GVHD. These data support an antileukemia effect of GVHD. AML patients who received identical twin transplants had an increased probability of relapse (relative risk 2.58, P = .008) compared with allograft recipients without GVHD. These data support an antileukemia effect of allogeneic grafts independent of GVHD. CML patients who received T-cell depleted transplants with or without GVHD had higher probabilities of relapse (relative risks 4.45 and 6.91, respectively, P = .0001) than recipients of non--T-cell depleted allografts without GVHD. These data support an antileukemia effect independent of GVHD that is altered by T-cell depletion. These results explain the efficacy of allogeneic bone marrow transplantation in eradicating leukemia, provide evidence for a role of the immune system in controlling human cancers, and suggest future directions to improve leukemia therapy.     

Diagnostic application of a polymerase chain reaction assay for the Whipple's disease bacterium to intestinal biopsies

BACKGROUND & AIMS: The uncultured Whipple's disease bacterium (Tropheryma whippelii) was characterized in 1991-1992 by polymerase chain reaction (PCR) and sequencing of the bacterial 16S ribosomal RNA gene. The aim of this study was to develop a PCR assay for diagnostic purposes. METHODS: Modified primers for PCR and a specific probe for hybridization were designed. The specificity of this PCR assay was tested using 37 bacterial control strains and intestinal biopsy samples from 16 patients without Whipple's disease. The sensitivity was tested in 88 intestinal biopsy samples from 35 patients with Whipple's disease. RESULTS: PCR and hybridization were negative in all 37 bacterial controls and in all 16 patients without Whipple's disease. Before therapy, DNA of T. whippelii was detected in all 30 patients with Whipple's disease from whom formalin-fixed biopsy material was available, whereas Bouin-fixed material was negative. During and after treatment, PCR was negative in 23 of the 24 patients who were followed up. Generally, conversion to negative occurred within 1 year. Despite negative intestinal PCR, symptomatic cerebral Whipple's disease appeared in 3 patients. CONCLUSIONS: This PCR assay is specific and sensitive and is applicable as a diagnostic test. However, PCR from intestinal biopsy samples seems less helpful for monitoring the effect of treatment. (Gastroenterology 1996 Jun;110(6):1735-43)     

Gender differences in homicide offenders' criminal career,substance abuse and mental health care. A nationwide register‐based study of Finnish homicide offenders 1995–2004

Background It is generally considered that women who kill are more likely to have a psychiatric disorder than their male counterparts, but as a relatively small group, women are much less often studied than men in this context. Aim To explore gender differences in the psychosocial history of homicide offenders. Method In this nationwide register‐based study, data were extracted from the forensic psychiatric examination and crime reports of all 91 women prosecuted for homicide in Finland between 1995 and 2004 and from those of the next adjacent man convicted of a separate homicide (n = 91). Results Both female and male homicide offenders had a troubled childhood, but more women had witnessed or experienced family violence; more women had failed to complete their primary education. Men, however, were more likely to have had an offending history. Although there were no differences between the men and women in the frequencies of psychiatric diagnoses or of substance abuse, the women had more often received prior mental health treatment. The women were also more likely to have had a history of suicidal behaviour. Conclusions Both female and male homicide offenders are a troubled group of people, with slightly different criminal careers. Many use mental health services and therefore prevention could be improved. The suggestion of a special sub‐group of women characterised by early educational and behavioural difficulties needs replication, as it may have implications for service development. Copyright © 2010 John Wiley & Sons, Ltd.     

Cognitive decline and amyloid accumulation in patients with mild cognitive impairment

Background/Aims: The relationship between baseline (11)C-Pittsburgh compound B ((11)C-PIB) uptake and cognitive decline during a 2-year follow-up was studied in 9 patients with mild cognitive impairment (MCI) who converted to Alzheimer's disease (AD) and 7 who remained with MCI. Methods: (11)C-PIB PET scan was conducted at baseline and cognitive assessment both at baseline and at follow-up. To obtain quantitative regional values of (11)C-PIB uptake, automated region of interest analysis was done using spatially normalized parametric ratio (region-to-cerebellar cortex) images. Results: At baseline, there were statistically significant differences in (11)C-PIB uptake, but not in cognitive test performances between the converters and nonconverters. Memory and executive function declined only in the converters during follow-up. In the converters, lower baseline frontal (11)C-PIB uptake was associated with faster decline in verbal learning. Higher baseline uptake in the caudate nucleus was related to faster decline in memory consolidation, and higher temporal uptake was associated with decline in executive function. Conclusion: Higher (11)C-PIB uptake in the caudate nucleus and temporal lobe was related to decline in memory and executive functions, whereas lower frontal uptake was related to decline in verbal learning. The results indicate that in prodromal AD, frontal amyloid accumulation reaches its maximum in the MCI stage, characterized by memory problems without full-blown dementia.     

Relaxation training combined with increased physical activity lowers the psychophysiological activation in community-home boys

Resting electrical activity (EMG) in the frontalis, temporalis, trapezius and erector trunci muscles, as well as systolic and diastolic blood pressure (BP), were measured in boys in a community home, and in controls of the same age in an ordinary school. EMG in the community-home boys was significantly higher than in controls, whereas BP did not yield any difference. The community-home boys participated in a programme consisting of relaxation training and increased physical activity for 4 months. After this intervention, EMG in all muscle groups was decreased, and the level of EMG was also lower than the values measured in controls. Systolic and diastolic BP in the community-home boys was also lowered, but the decrease was not significant as compared to the control group. In conclusion, relaxation training and/or increased physical activity is effective in decreasing the elevated activation observed in community-home boys.     

Mechanical properties of oxygenated red blood cells in sickle cell (HbSS) disease

Little data exist for the mechanical properties of individual irreversible or reversible sickle cells (ISC and RSC, respectively), nor is the process of ISC formation well understood. For oxygenated ISC and density-fractionated RSC, we have used micropipette techniques to measure cell surface area (SA) and volume (V), membrane shear elastic modulus (mu), time constant for viscoelastic shape recovery (tc), and hence to calculate membrane surface viscosity (eta = mu X tc). Volume loss associated with increasing cell density was accompanied by a proportionately smaller surface area decrease; SA/V ratio thus increased for denser cells, with ISC having the highest values. Membrane area loss by fragmentation must thus be accompanied by an accelerated decrease in cell volume. ISC had relatively rigid membranes (mu 130% above normal controls) and tc close to normal values, so that their effective membrane viscosity was more than double control. RSC had viscoelastic properties close to control, but showed wider variation between sickle cell donors and within samples. Measurements on density-separated RSC showed that, on average, mu was nearly constant, but that tc was longer for the densest cells, with their eta approaching ISC levels. A small subpopulation of RSC were found that had mu close to ISC values. Hypotonically swollen ISC (with internal hemoglobin concentration decreased to normal levels) retained their increased membrane stiffness but had markedly decreased tc, so that their eta approached normal values. The results show that elevated hemoglobin concentration influences the viscoelastic behavior of ISC and RSC, but that an irreversible change in membrane elasticity also occurs for ISC. These data suggest that ISC formation occurs via a two- stage process: (1) accelerated volume loss leading to increased cytoplasmic and effective membrane viscosity; (2) a sharp rise in membrane rigidity, presumably linked to membrane structural alteration.     

Platelet secretion defect associated with impaired liberation of arachidonic acid and normal myosin light chain phosphorylation

We describe four patients with impaired platelet aggregation and 14C- serotonin secretion during stimulation with adenosine diphosphate (ADP), epinephrine, collagen, and platelet-activating factor. The response to arachidonic acid was normal in all patients with regard to aggregation and in three of the four with regard to 14C-serotonin secretion. The total platelet adenosine triphosphate (ATP) and ADP content and the ATP to ADP ratio was normal in all patients, thereby excluding storage pool deficiency as the cause of the secretion defect. Studies with 3H-arachidonic acid-labeled platelets revealed that the thrombin-induced liberation of arachidonic acid from membrane-bound phospholipids was impaired in these patients. Further, platelet thromboxane B2 production, measured using a radioimmunoassay, was diminished during stimulation with ADP and thrombin, but was normal with arachidonic acid, indicating that the oxygenation of arachidonic acid was normal and that the diminished thromboxane production was due to a defect in the liberation of arachidonic acid. Release of arachidonic acid is mediated by phospholipases that are Ca++ dependent. To examine whether these patients may have a defect in making intracellular Ca++ available, another Ca++-dependent process, myosin light chain phosphorylation, was studied during thrombin stimulation. Platelets from three of the patients were found to behave the same as normal ones, suggesting that the deficiency in phospholipase activity may not be due to impaired Ca++ mobilization. Our studies demonstrate a novel group of patients with platelet secretion defects associated with impaired liberation of arachidonic acid from phospholipids. These patients exemplify a congenital defect, other than deficiencies of cyclooxygenase and thromboxane synthetase, by which thromboxane production may be impaired in platelets.     

Suicidal behavior among adolescents with conduct disorder--the role of alcohol dependence

Our aim was to investigate the association between alcohol dependence and suicidal behavior among adolescent girls and boys suffering from conduct disorder (CD). The original study sample consisted of 387 adolescents (age 12-17) admitted to psychiatric inpatient care between April 2001 and May 2005. DSM-IV-based psychiatric diagnoses and variables measuring suicidal behavior were obtained from the Schedule for Affective Disorders and Schizophrenia for School Aged Children--Present and Lifetime (K-SADS-PL). Of the total study population, 59 adolescent girls and 82 boys had CD according to DSM-IV criteria. Of all adolescents with CD, 24 (40.7%) girls and 24 (29.3%) boys were suffering from alcohol dependence. Among girls with CD, alcohol dependence increased the risk for suicide attempts up to 3.8-fold (95% CI 1.1-13.4). Among boys with CD, alcohol dependence increased the risk for life-threatening suicide attempt over nine-fold (95% CI 1.2-80.1). In addition, the risk for self-mutilative behavior was as high as 3.9-fold (95% CI 1.1-13.8) among girls and 5.3-fold (95% CI 1.1-26.5) among boys. The results indicate that, among adolescents suffering from CD, the risk of suicidal behavior is considerably increased by co-morbid alcohol dependence, which should therefore be carefully taken into account in clinical work.