Dysregulation of apoptosis genes in hematopoietic malignancies

Ever since the discovery of Bcl-2 and the elucidation of its role in apoptosis, tremendous interest has arisen in prospects for triggering suicide of malignant cells by exploiting knowledge emerging from apoptosis research. In this review, we summarize information about the multiple genetic lesions which have been identified in apoptosis-regulatory genes of hematopoietic and lymphoid neoplasms. Emerging data about the structural and biochemical details of apoptosis proteins and their upstream regulators have reveal novel strategies for therapeutic intervention, some of which are under interrogation in clinical trials currently.     

Inter-individual variation,seasonal variation and close correlation of OGG1 and ERCC1 mRNA levels in full blood from healthy volunteers

The mRNA levels of the nucleotide excision DNA repair gene ERCC1 and the base excision DNA repair gene OGG1 were quantified in 43 healthy volunteers in a dietary intervention trial as markers for the DNA repair capacity. Nine samples were collected from each subject over a period of 52 days. Sampling took place from January to May. The mRNA levels of OGG1 and ERCC1 correlated closely (r = 0.86, P < 0.0001) after normalization to either 18S ribosomal RNA or to beta-actin mRNA. The levels of OGG1 and ERCC1 mRNA were relatively constant within an individual with intra-individual correlation (R(2) = 0.45-0.46) in a General Linear Model. The amounts of ERCC1 and OGG1 relative to 18S RNA were doubled in May compared with January. This coincided with an increase in the monthly influx of sunlight from 18 MJ/m(2) in January to 242 MJ/m(2) in May. The mRNA levels of both ERCC1 and OGG1 were positively correlated to the average daily influx of sunlight in the previous 30 and 5 days (r = 0.49; r = 0.37, respectively, P < 0.001). There were no significant effects of the dietary interventions. The inter-individual variation was 5-10-fold, which is more than the observed 2-3-fold seasonal variation. Thus, despite seasonal variation of the individual mRNA levels, the inter-person variation is still far larger than the intra-person variation, supporting the use as biomarkers.     

Risk factors for suicide in epilepsy: a case control study

PURPOSE: Suicide is considered to be one of the most important causes of death contributing to the increased mortality of persons with epilepsy. We investigated the association between the risk of suicide in persons with epilepsy and clinical factors that might increase or have been suggested to increase the risk of suicide. METHODS: A case-control study was nested within a cohort of 6,880 patients registered in the Stockholm County In-Patient Register with a diagnosis of epilepsy. The study population was followed up through the National Cause of Death Register. Twenty-six cases of suicide, 23 cases of suspected but not proven suicide, and 171 controls, living epilepsy patients, were selected from the cohort. Clinical data were collected through medical record review. RESULTS: There was a ninefold increase in risk of suicide with mental illness and a 10-fold increase in relative risk (RR) with the use of antipsychotic drugs. The estimated RR of suicide was 16.0 [95% confidence interval (CI), 4.4-58.3] for onset of epilepsy at younger than 18 years, compared with onset after 29 years. The risk of suicide seemed to increase with high seizure frequency and antiepileptic drug (AED) polytherapy, although the estimates were imprecise and the associations not statistically significant. Insufficient data on seizure frequency and changes in AED dosage due to incomplete case records were associated with high RRs. We found no association between risk of suicide and any particular AED, with type of epilepsy, or localization or lateralization of epileptogenic focus on EEG [RR = 0.3 (95% CI, 0.1-1.7)]. CONCLUSIONS: The profile of the epilepsy patient who commits suicide that emerges from our study is a patient with early onset (particularly onset during adolescence) but not necessarily severe epilepsy, psychiatric illness, and perhaps inadequate neurologic follow-up. Previous reports of an association with temporal lobe epilepsy could not be confirmed.     

Aberrant sprouting and downregulation of tyrosine hydroxylase in lesioned nigrostriatal dopamine neurons induced by long-lasting overexpression of glial cell line derived neurotrophic factor in the striatum by lentiviral gene transfer

The effects of sustained (up to 9 months) striatal overexpression of glial cell line derived neurotrophic factor (GDNF) on lesioned nigrostriatal dopamine (DA) neurons was studied using a recombinant lentiviral (rLV) vector to deliver GDNF into the striatum 4 weeks prior to the creation of an intrastriatal 6-hydroxydopamine lesion. The results of the amphetamine-induced rotation suggested an initial partial protection followed by a complete recovery, whereas the spontaneous motor behaviors remained impaired. There was a clear protection of the nigral tyrosine hydroxylase (TH)-positive neurons in the rLV-GDNF group compared to rats injected with the control vector encoding green fluorescent protein (GFP) (70 and 20% of the intact side, respectively). However, the striatal TH+ fiber density was equally reduced (to 20% of the intact side) in both groups. Further morphological analyses indicated that the nigrostriatal projections of the DA neurons were indeed preserved in the GDNF group. The axonal projections were visualized using two independent methods: First, retrograde labeling of the nigral cell bodies by intrastriatal Fluoro-Gold injections showed that the majority of rescued cells in the GDNF group had preserved axonal projections to striatum. Second, injections of a recombinant adeno-associated viral vector expressing GFP into the nigra was used to anterogradely fill the DA neurons and their projections with GFP protein. GFP immunostaining clearly demonstrated that the fibers of the nigral DA cells were preserved along the nigrostriatal pathway and innervated large parts of the striatum, but did not express TH at detectable levels. In addition, fiber sprouting was observed in the globus pallidus, entopeduncular nucleus, and substantia nigra, corresponding to areas where GDNF protein was released. The lack of functional recovery in the spontaneous motor behaviors may, at least in part, be explained by this extensive aberrant fiber sprouting in the downstream striatal target nuclei and/or decreased synthesis of dopamine in the striatum.     

Sleep-disordered breathing,psychiatric distress,and quality of life impairment in sexual assault survivors

Using American Academy of Sleep Medicine research criteria, sleep-disordered breathing (SDB) was assessed in a pilot study of 187 sexual assault survivors with posttraumatic stress symptoms. Nightmares, sleep quality, distress, and quality of life were also assessed along with historical accounts of prior treatments for sleep complaints. Presumptive SDB diagnoses were established for 168 patients. Twenty-one of 168 underwent sleep testing, and all met objective SDB diagnostic criteria. There were no clinically meaningful differences in age, body-mass index, sleep quality, distress, or quality of life measures between 21 confirmed SDB cases and 147 suspected cases not tested. Compared with 19 women without SDB, 168 women with diagnosed or suspected SDB reported significantly worse nightmares, sleep quality, anxiety, depression, posttraumatic stress, and impaired quality of life. Despite suffering from sleep problems for an average of 20 years, which had not responded to repeated use of psychotropic medications or psychotherapy, few of these women had been referred to sleep specialists. SDB appears widespread among sexual assault survivors seeking help for nightmares. Research is needed to clarify the associations among SDB, distress, and physical and mental health impairment in trauma patients.     

Altered tubulin and neurofilament expression and impaired axonal growth in diabetic nerve regeneration

Cytoskeletal protein expression in sensory neurons and sciatic nerve axonal growth were examined in type 1 diabetic BB/Wor rats after sciatic nerve crush injury. Diabetic male rats were subjected to sciatic nerve crush at 6 wk of diabetes. L4 and L5 dorsal root ganglia (DRG) mRNA expression of low and medium molecular weight neurofilaments (NF-L, NF-M), betaII- and betaIII-tubulin as well as protein expression of NF-L, NF-M, and beta-tubulin were examined at various time points following crush injury and compared with age- and sex-matched non-diabetic BB/Wor rats. Steady state mRNA expression of NF-L, NF-M, betaII- and betaIII-tubulin were decreased in diabetic DRG. NF-L and NF-M proteins were also decreased in DRG of uncrushed diabetic animals. After crush injury, betaII- and betaIII-tubulin mRNA were upregulated in control animals at day 2 and day 6, respectively, and beta-tubulin protein showed similarly increased expression after crush injury, while such upregulations did not occur in diabetic animals. Conversely, mRNA and protein expressions of NF-L, NF-M were downregulated to a lesser extent in diabetic animals compared to control rats. These changes were associated with impaired axonal elongation and caliber growth of regenerating fibers in diabetic rats. We propose that upregulation of tubulin has a negative feedback on NF expression in response to nerve injury, as seen in control rats. The absence of this upregulation in diabetic animals may impair its regulatory effect on NF expression and contribute to perturbed nerve regeneration seen in diabetic nerve.     

The role of personality variables and social support in distress and perceived health in patients following myocardial infarction

Objectives: (1) To investigate whether patients with low versus high social support and satisfaction with support report less distress and health complaints following a first myocardial infarction (MI). (2) To examine whether personality traits mediate social support and its effect on distress and health complaints. Methods: A questionnaire was distributed to 112 consecutive patients with a first MI 4–6 weeks postinfarction. Objective clinical measures were obtained from the patients' medical records. Results: Patients with low social support were at increased risk of depression and posttraumatic stress disorder (PTSD). Patients less satisfied with support were at increased risk of anxiety, depression, PTSD, and reported more health complaints. Generally, larger effect sizes were found for satisfaction with support compared with social support per se in relation to distress and health complaints. Neuroticism was identified as an independent predictor of all types of distress and health complaints when including both traits and social support variables in multivariable analyses, adjusted for demographic and clinical variables. Satisfaction with support only remained an independent predictor of depression. Conclusion: These results suggest that personality traits may mediate social support and its effect on distress and health complaints. Hence, it may be important to include personality variables when investigating social support in relation to distress and health. In clinical practice, screening for particular personality traits could identify patients at risk of distress and recurrent cardiac events.     

Influence on coagulation activity by subcutaneous LMW heparin as an adjuvant treatment to fibrinolysis in acute myocardial infarction

In this study, which includes 101 patients with acute ST segment-elevated myocardial infarction, we investigated the influence on the increased coagulation activity after streptokinase treatment by adding low-molecular-weight (LMW) heparin or placebo and the relation between the coagulation activity and ischemic episodes, coronary patency, and mortality. The expected increase of prothrombin fragment 1+2 (F1+2), thrombin-antithrombin (TAT), and D-dimer were significantly attenuated at 2, 6, and 18 h (D-dimer only at 18 h) in the dalteparin group compared to placebo. Ischemic episodes during the first 24 h appeared significantly more often in patients with F1+2 levels above the median at 18 h. There was a tendency to a lower frequency of Thrombolysis In Myocardial Infarction Trial (TIMI) grade 3 flow in the infarct-related artery in patients with TAT and D-dimer levels above the median at 18 h. F1+2, TAT, and D-dimer were significantly higher after 18, 6, and 18 h, respectively, in the deceased compared to surviving patients. Also, the lack of reduction of the levels of F1+2 between 6 and 18 h was related to a raised mortality. In conclusion, adjuvant treatment with LMW heparin to streptokinase attenuates increased coagulation activity. This might be of importance as remaining high coagulation activity is associated with signs of early reocclusion and raised mortality.