Molecular analysis of relapse in chronic myeloid leukemia after allogeneic bone marrow transplantation

Four patients with Philadelphia (Ph') positive chronic myeloid leukemia (CML) were studied before, after, and on relapse following allogeneic bone marrow transplantation (BMT). Southern analysis of DNA from cells collected before and at relapse after BMT was performed in order to investigate the origin of the leukemia at relapse. Using minisatellite probes we showed that the relapse occurred in cells of host origin in all four patients and this was confirmed with a Y chromosome specific probe in two male patients who had a female donor. Furthermore, using two probes for the breakpoint cluster region (bcr) on chromosome 22, we showed that leukemic cells at relapse bore identical rearrangements to those in the disease at time of presentation of each patient. We conclude that relapse in all four patients is due to re-emergence of the original leukemic clone.     

Traumatic brain injury and schizophrenia in members of schizophrenia and bipolar disorder pedigrees

OBJECTIVE: Schizophrenia following a traumatic brain injury could be a phenocopy of genetic schizophrenia or the consequence of a gene-environment interaction. Alternatively, traumatic brain injury and schizophrenia could be spuriously associated if those who are predisposed to develop schizophrenia have greater amounts of trauma for other reasons. The authors investigated the relationship between traumatic brain injury and psychiatric diagnoses in a large group of subjects from families with at least two biologically related first-degree relatives with schizophrenia, schizoaffective disorder, or bipolar disorder. METHOD: The Diagnostic Interview for Genetic Studies was used to determine history of traumatic brain injury and diagnosis for 1,275 members of multiplex bipolar disorder pedigrees and 565 members of multiplex schizophrenia pedigrees. RESULTS: Rates of traumatic brain injury were significantly higher for those with a diagnosis of schizophrenia, bipolar disorder, and depression than for those with no mental illness. However, multivariate analysis of within-pedigree data showed that mental illness was related to traumatic brain injury only in the schizophrenia pedigrees. Independent of diagnoses, family members of those with schizophrenia were more likely to have had traumatic brain injury than were members of the bipolar disorder pedigrees. The members of the schizophrenia pedigrees also failed to show the gender difference for traumatic brain injury (more common in men than in women) that was expected and was present in the bipolar disorder pedigrees. Subjects with a schizophrenia diagnosis who were members of the bipolar disorder pedigrees (and thus had less genetic vulnerability to schizophrenia) were less likely to have had traumatic brain injury (4.5%) than were subjects with schizophrenia who were members of the schizophrenia pedigrees (and who had greater genetic vulnerability to schizophrenia) (19.6%). CONCLUSIONS: Members of the schizophrenia pedigrees, even those without a schizophrenia diagnosis, had greater exposure to traumatic brain injury compared to members of the bipolar disorder pedigrees. Within the schizophrenia pedigrees, traumatic brain injury was associated with a greater risk of schizophrenia, consistent with synergistic effects between genetic vulnerability for schizophrenia and traumatic brain injury. Posttraumatic-brain-injury schizophrenia in multiplex schizophrenia pedigrees does not appear to be a phenocopy of the genetic disorder.     

From the Cover: Feature Article: Identification of an essential endogenous regulator of blood–brain barrier integrity,and its pathological and therapeutic implications

The blood–brain barrier (BBB), a critical guardian of communication between the periphery and the brain, is frequently compromised in neurological diseases such as multiple sclerosis (MS), resulting in the inappropriate passage of molecules and leukocytes into the brain. Here we show that the glucocorticoid anti-inflammatory messenger annexin A1 (ANXA1) is expressed in brain microvascular endothelial cells, where it regulates BBB integrity. In particular, ANXA1^−/− mice exhibit significantly increased BBB permeability as a result of disrupted interendothelial cell tight junctions, essentially related to changes in the actin cytoskeleton, which stabilizes tight and adherens junctions. This situation is reminiscent of early MS pathology, a relationship confirmed by our detection of a selective loss of ANXA1 in the plasma and cerebrovascular endothelium of patients with MS. Importantly, this loss is swiftly restored by i.v. administration of human recombinant ANXA1. Analysis in vitro confirms that treatment of cerebrovascular endothelial cells with recombinant ANXA1 restores cell polarity, cytoskeleton integrity, and paracellular permeability through inhibition of the small G protein RhoA. We thus propose ANXA1 as a critical physiological regulator of BBB integrity and suggest it may have utility in the treatment of MS, correcting BBB function and hence ameliorating disease.The presence of narrow and dense tight junctions between adjacent endothelial cells is peculiar to the cerebral vasculature, and their integrity is essential for the maintenance of correct blood–brain barrier (BBB) function as the primary regulator of cross-talk between the brain and the rest of the body (1). Increasing evidence indicates that the integrity of this structural and functional barrier is compromised in neurological conditions such as multiple sclerosis (MS), Alzheimer’s, and Parkinson diseases, leading to the failure of the normal mechanisms controlling passage of substances into the brain (2) and to the sensitization and/or worsening of pathologic conditions. Pharmacological intervention to prevent or correct BBB alteration in such diseases is a difficult task, but potential therapeutic leads can be gained from the study of endogenous mediators regulating barrier integrity.Annexin A1 (ANXA1) is an important anti-inflammatory protein, principally known as a regulator of peripheral leukocyte migration and a promoter of macrophage phagocytosis (3). ANXA1 is expressed in several cell types within the brain, including ependyma and microglia, but in particular in the endothelium of the brain microvasculature (4), although its role in these cells remains obscure. We have previously shown glucocorticoids to up-regulate expression of ANXA1 in the cerebral endothelium (5), and, given that glucocorticoids enhance BBB tightness (6), we hypothesized that ANXA1 may play a role in the regulation of BBB permeability. Through combined in vitro and in vivo approaches, we have identified a dual role for ANXA1 in organizing the interendothelial cell tight and adherens junctions: (i) endogenously through its interactions with the actin cytoskeleton, and (ii) exogenously in an autocrine/paracrine via formyl peptide receptor 2 (FPR2), leading to the down-regulation of RhoA GTPase activity. Together, these two actions of ANXA1 regulate paracellular permeability in the BBB, and provide a major contribution to BBB integrity and function. Moreover, we describe a selective down-regulation of ANXA1 expression in the plasma and cerebral microvascular endothelia of patients with MS, strongly suggesting an explanation for the BBB dysfunction that is a typical early sign of this disease. All these findings pinpoint ANXA1 as a critical component of the BBB endothelium contributing to barrier integrity. Its autoparacrine role and the loss in patients with MS highlight the potential utility of the protein or its peptidomimetics as a therapeutic target for pathologic processes characterized by compromised BBB function, such as MS.     

Negative socio-emotional resonance in schizophrenia: a functional magnetic resonance imaging hypothesis

The aim of the present study is to use neuroscience theories about brain function (mirror-neurons MN) to draw inferences about the mechanisms supporting emotional resonance in two different groups of schizophrenia patients (with flat affect FA+ n = 13 and without flat affect FA- n = 11). We hypothesize that FA+ will not activate key brain areas involved in emotional processing. Conversely, FA- will have a functional mirror system for emotional resonance confirmed by activation of the prefrontal cortex and behavioral results. To test this hypothesis, we compared the two groups using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) displaying a passive visual task (44 negative IAPS pictures and 44 neutral pictures). A random-effects analysis, for schizophrenia patients FA-, revealed significant loci of activation in the left mesial prefrontal (MPFC), right orbitofrontal (OFC) and left anterior cingulate cortices (ACC). Correlational analyses carried out between self-report ratings of negative feelings and BOLD signal changes revealed the existence of positive correlation in the LACC, LMPFC and ROFC. Conversely, FA+ did not show significant activation in the prefrontal cortex. We propose that negative emotional resonance induced by passively viewing negative pictures may be a form of "mirroring" that grounds negative feelings via an experiential mechanism. Hence, it could be argued that FA- were able to 'feel' emotions through this resonance behavior. Conversely, we suggest that the dysfunction seen in the FA+ group is a failure or distortion in the development of the MN system. This could be due to genetic or other endogenous causes, which affected prefrontal cortex MN involved in emotional resonance.     

Paternal age and sporadic schizophrenia: evidence for de novo mutations

Schizophrenia is an etiologically heterogeneous syndrome. It has a strong genetic component and exists in clinically indistinguishable familial and nonfamilial (sporadic) forms. A significant role for de novo genetic mutations in genetic schizophrenia vulnerability is suggested by a strong monotonic increase in schizophrenia risk with advancing paternal age. However, an alternative explanation for the paternal age effect in schizophrenia is that childbearing is delayed in fathers who themselves have genetic schizophrenia vulnerability. In this study, we compared paternal birth ages between patient groups with familial (n = 35) and sporadic (n = 68) patients with DSM-IV schizophrenia from an inpatient schizophrenia research unit. If later age of fathering children is related to having some genetic schizophrenia vulnerability, then paternal birth age should be later in familial schizophrenia cases than in sporadic cases, and any association of father's age and schizophrenia risk in offspring would be a spurious finding, unrelated to etiology. However, if de novo mutations cause sporadic schizophrenia, then patients without a family history of schizophrenia would have older fathers than familial patients. We found that patients without a family history of schizophrenia had significantly older fathers (4.7 years) than familial patients; so later childbirth was not attributable to parental psychiatric illness. These findings support the hypothesis that de novo mutations contribute to the risk for sporadic schizophrenia.     

Pulmonary arterio-venous fistulae in hepatic cirrhosis

Cyanosis, clubbing, and arterial oxygen desaturation may occur in patients with liver disease, and are attributed to the presence of pulmonary or peripheral arterio-venous shunting. Cardiac catheterisation and angiocardiography in a patient with a normal heart did not demonstrate the presence of abnormal arterio-venous anastomoses. Pulmonary shunting was proved when intravenous technetium-labelled macroaggregated albumin, normally held up in capillary networks, was passed quickly through the lungs and immediately detected in high systemic blood flow organs. The opening of peripheral and pulmonary anastomoses in patients with liver disease may be owing to the presence of a vasodilatory substance such as ferritin, which was found to be abnormally increased in the patient's blood.     

Migraine with aura and white matter abnormalities: Notch3 mutation

The authors report on an Italian family with eight affected members who show autosomal dominant migraine with prolonged visual, sensory, motor, and aphasic aura. These symptoms are associated with white matter abnormalities on brain MRI. All living affected members carry a Notch3 mutation (Arg153Cys) previously reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). White matter abnormalities occur in a variable percentage of the general migraine population; CADASIL should be suspected in migraineurs with prolonged atypical aura and white matter abnormalities.