Vascular permeability in cerebral cavernous malformations

Patients with the familial form of cerebral cavernous malformations (CCMs) are haploinsufficient for the CCM1, CCM2, or CCM3 gene. Loss of corresponding CCM proteins increases RhoA kinase-mediated endothelial permeability in vitro, and in mouse brains in vivo. A prospective case-controlled observational study investigated whether the brains of human subjects with familial CCM show vascular hyperpermeability by dynamic contrast-enhanced quantitative perfusion magnetic resonance imaging, in comparison with CCM cases without familial disease, and whether lesional or brain vascular permeability correlates with CCM disease activity. Permeability in white matter far (WMF) from lesions was significantly greater in familial than in sporadic cases, but was similar in CCM lesions. Permeability in WMF increased with age in sporadic patients, but not in familial cases. Patients with more aggressive familial CCM disease had greater WMF permeability compared to those with milder disease phenotype, but similar lesion permeability. Subjects receiving statin medications for routine cardiovascular indications had a trend of lower WMF, but not lesion, permeability. This is the first demonstration of brain vascular hyperpermeability in humans with an autosomal dominant disease, as predicted mechanistically. Brain permeability, more than lesion permeability, may serve as a biomarker of CCM disease activity, and help calibrate potential drug therapy.     

Mitochondrial function in the brain links anxiety with social subordination

Dominance hierarchies are integral aspects of social groups, yet whether personality traits may predispose individuals to a particular rank remains unclear. Here we show that trait anxiety directly influences social dominance in male outbred rats and identify an important mediating role for mitochondrial function in the nucleus accumbens. High-anxious animals that are prone to become subordinate during a social encounter with a low-anxious rat exhibit reduced mitochondrial complex I and II proteins and respiratory capacity as well as decreased ATP and increased ROS production in the nucleus accumbens. A causal link for these findings is indicated by pharmacological approaches. In a dyadic contest between anxiety-matched animals, microinfusion of specific mitochondrial complex I or II inhibitors into the nucleus accumbens reduced social rank, mimicking the low probability to become dominant observed in high-anxious animals. Conversely, intraaccumbal infusion of nicotinamide, an amide form of vitamin B3 known to enhance brain energy metabolism, prevented the development of a subordinate status in high-anxious individuals. We conclude that mitochondrial function in the nucleus accumbens is crucial for social hierarchy establishment and is critically involved in the low social competitiveness associated with high anxiety. Our findings highlight a key role for brain energy metabolism in social behavior and point to mitochondrial function in the nucleus accumbens as a potential marker and avenue of treatment for anxiety-related social disorders.In most socially living species, the social rank of an individual is established during competitive encounters with conspecifics. The outcome of these encounters determines the allocation of territory, resources and access to reproduction (1), and greatly influences physiology and health (2). Winning a social competition is rewarding, enhances rank in social hierarchies, and increases the probability of winning future contests (3, 4). In contrast, losing a social encounter typically undermines one’s social rank. In humans, a low social status predicts morbidity and survival (5) and has also been linked to the development of psychopathologies (6). Despite the important consequences of social rank on health, little is known regarding the mechanisms underlying the establishment of social hierarchies.One of the main reasons for the paucity of neurobiological mechanisms determining social hierarchies may be that social competition involves interacting subjects that both need to be taken into account. The competitors may exhibit different features such as size, age, gender, as well as previous social experience, all known to influence social competitiveness. However, when subjects are matched for these characteristics, the impact of innate personality traits on social competitiveness may be investigated. One such personality trait, anxiety, may have important consequences for the outcome of social competitions. In humans, high-anxious individuals often display a subordinate status and report feelings of being overlooked and rejected (7), and their competitive self-confidence becomes undermined under stress (8). Thus, interindividual differences in anxiety could predetermine the outcome of a competitive encounter and, as such, trait anxiety may have important consequences for social status. However, the neural mechanisms whereby anxiety might affect social hierarchy formation are largely unknown.We addressed this question by examining social competitiveness between male rats characterized for trait anxiety. Recent work has highlighted the potential for individual differences in mitochondrial function and, more broadly, energy metabolism to influence vulnerability to develop psychopathological disorders, such as anxiety and depression (9–14). Here, we demonstrate that trait anxiety is a determining factor of social rank that is mediated by brain region-specific mitochondrial function. We show that manipulation of mitochondrial function in the nucleus accumbens (NAc) is sufficient to influence social rank, highlighting a key role for brain mitochondrial function in social behavior.     

Renin inhibition

Summary Modification of the renin-angiotensin-aldosterone system by renin inhibitors may be an alternative to angiotensin-converting enzyme inhibitors in the treatment of cardio-vascular disease. The development of clinically useful renin inhibitors has been hampered by a variety of pharmacologic problems, most notably the poor oral bioavailability of these peptide-related compounds. Peptidomimetic renin inhibitors that have been stabilized to enzymatic degradation in conjunction with optimizing physical characteristics amenable to intestinal absorption offer the greatest promise to date. Studies in animal models demonstrate that renin inhibitors are capable of reducing both systolic and diastolic blood pressures without causing reflex tachycardia. The response appears to be sustained with chronic administration. The beneficial cardiovascular effects of these compounds have been confirmed in the few studies conducted in patients with hypertension and in those with congestive heart failure. Further development of renin inhibitors is warranted.     

Diabetic ketoacidosis due to insulin resistance treated by haemodialysis

A 14-year-old female patient with insulin resistance is reported in whom it appeared that initially insulin breakdown was unusually rapid. Subsequently there was in addition evidence of reduced insulin sensitivity. The rapidly increasing requirement of insulin (1600 units daily), given by continuous IV infusion, was dramatically reduced by haemodialysis, and was maintained subsequently. We suggest that insulin aggregates which may have blocked insulin receptor sites, causing insulin resistance, were removed by haemodialysis.     

Tightly spiral shaped bacteria in the human stomach: another cause of active chronic gastritis?

Tightly spiral shaped Gram negative bacteria were seen in the gastric biopsies obtained from two patients undergoing gastroscopy. Active chronic gastritis was present in both patients and one patient also had gastric ulceration. Attempts to culture the organism by a number of methods were unsuccessful but positive urease results were obtained in both patients. Both patients were treated with colloidal bismuth subcitrate. Biopsies taken after treatment showed resolution of infection and histological gastritis. These results suggest that Helicobacter pylori is not the only organism associated with chronic active gastritis in man.     

Concomitant administration of granulocyte transfusions and amphotericin B in neutropenic patients: absence of significant pulmonary toxicity

One hundred and ninety-five series of granulocyte transfusions in 144 patients were evaluated with respect to possible severe pulmonary toxicity from concomitant administration of granulocytes and amphotericin B. Dyspnea as a side effect of granulocyte transfusion was equally common among patients receiving amphotericin B and those in a matched control group not receiving amphotericin B. Granulocyte transfusions and amphotericin B were given simultaneously in 35 transfusion series, involving 32 patients. Respiratory deterioration, defined as the appearance of new pulmonary infiltrates on chest x-ray, occurred in 11 of these 35 episodes. Patients developing respiratory deterioration were similar to those not developing respiratory deterioration in age, diagnosis, disease status, duration of concomitant therapy, and outcome, but more often had positive fungal cultures as an indication for treatment (91% versus 58%; p = 0.1). In 8 patients, the episodes of respiratory deterioration were readily explained by congestive heart failure, by simultaneous bacteremia or fungemia, or by fungal pneumonia discovered at autopsy. One patient had a leukoagglutinin reaction (responsive to steroids) and the other 2 had unexplained, but reversible respiratory deterioration. We concluded that concomitant administration of granulocyte transfusions and amphotericin B is not associated with unexpected or rapidly fatal pulmonary toxicity and when appropriate, can be safely accomplished.     

An investigation of LH pulsatility in burned men by bioassay and radioimmunoassay.

LH pulsatility studies were performed in six burned patients by removing blood samples at 10 min intervals over a 6 h period. All samples were assayed for LH by bioassay (B-LH), LH by radioimmunoassay (I-LH) and testosterone. Mean serum testosterone concentrations of the burned patients were low (6.7 +/- 1.6 nmol/l). I-LH levels were lower than B-LH in all samples. Frequency of bioactive or immunoreactive pulses as well as mean B-LH and I-LH concentrations were similar to previously published data from normal men examined in the same laboratory. The mean biological activity of LH (expressed as the ratio of B-LH to I-LH, the B:I ratio) was lower in burned subjects (1.9 +/- 0.1) than previously reported in normal men. The B:I ratios of burned men were lower (p less than 0.01) at pulse peaks than at nadirs (1.8 +/- 0.1 vs 2.0 +/- 0.1) and an increase in serum testosterone concentration did not follow an LH peak. Serum testosterone concentrations did not cross-correlate with B-LH or I-LH. This contrasts with the findings in normal subjects where the B:I ratios have been found to be higher at pulse peaks than at nadirs and an increase in serum testosterone concentration follows a pulse peak and serum testosterone cross-correlates with B-LH and I-LH. LH secreted in a pulse peak in normal men may contain a particularly biologically potent form of the molecule but this may not be the case in burned men.     

Anticardiolipin, anticentromere and anti-Scl-70 antibodies in patients with systemic sclerosis and severe digital ischaemia.

OBJECTIVE--Following observation of weakly positive anticardiolipin (aCL) antibodies in four of eight patients with systemic sclerosis (SSc) and severe digital ischaemia requiring amputation, the association between the presence of these and other antibodies and severe peripheral ischaemia in patients with SSc was examined. METHODS--ACL antibodies (IgG and IgM), anticentromere and anti-Scl-70 antibodies were measured in a further 60 patients with SSc over a one year period. Thirty one of the 68 patients in whom aCL antibodies were assayed had 'severe ischaemia', having suffered digital ischaemia severe enough to warrant amputation (13 patients), surgical debridement or admission for intravenous vasodilator therapy. RESULTS--There was no difference in aCL positivity between those with severe ischaemia and those without, nor between those who had amputations and those who had not. Three of the 31 patients (10%) with severe ischaemia had IgG and eight (26%) IgM aCL antibodies in weak to moderate titre compared to 10 (27%) and 6 (16%) respectively of the remaining patients (p = 0.06 for IgG and p = 0.25 for IgM, Fisher's exact test). Seventeen of the 31 patients (55%) with severe ischaemia were anticentromere antibody positive compared with nine of 37 (24%) without ischaemia (p = 0.01). Six patients with severe ischaemia had anti-Scl-70 antibodies compared with two of the 37 without ischaemia (p = 0.08). CONCLUSIONS--The findings do not support an association between aCL antibodies and severe ischaemia in SSc, but confirm the previously reported association between anticentromere antibodies and severe peripheral ischaemia. Although anti-Scl-70 antibodies were present only in a small number of patients, there was also a tendency for these to be associated with severe ischaemia, suggesting that patients with either anticentromere or anti-Scl-70 antibodies should be considered at risk of digital loss.     

Metabolism of ara-C by blast cells from patients with ANLL

The dose-response relationship between extracellular concentration of cytosine arabinoside (ara-C) and intracellular formation of the putative active metabolites of ara-C [ara-C incorporation into DNA and intracellular pools of ara-C in triphosphate form (ara-CTP)] was investigated in blast cells obtained from patients with acute nonlymphocytic leukemia (ANLL) by exposing these cells in vitro to 10, 100, or 1,000 nmol/L of ara-C. We studied 23 untreated patients who subsequently achieved complete remission (CR) with a regimen using daunorubicin and conventional doses of ara-C (ara-C-sensitive group), and 30 patients judged to be ara-C-resistant either by failing initial induction therapy (16 patients) or by having relapsed on an ara-C- containing maintenance regimen (14 patients). In both patient groups, ara-C incorporation into DNA and intracellular ara-CTP both displayed statistically significant increases in response to increasing extracellular concentrations of ara-C (P = .0001 in both cases), with the rate of increase of ara-CTP greater than that of ara-C incorporation. Moreover, blast cells from all patients, even those who were most clinically resistant to ara-C, were able to form ara-CTP and to incorporate ara-C into DNA. Each tenfold increment in extracellular ara-C concentration caused an 8.5-fold increase in ara-CTP, but only a 3.6-fold increase in ara-C incorporation into DNA. Thus, the efficiency of incorporation of ara-C into DNA (defined as the ratio of ara-C incorporation to ara-CTP pools) decreased by 58% with each tenfold increment in the extracellular concentration of ara-C (P less than .0001), presumably as a result of the inhibitory effect of ara-CTP on DNA polymerase. Using an analysis of covariance, modest differences were found in the levels of the ara-C metabolite variables in the ara-C- sensitive group as compared with the resistant group. However, because there was considerable overlap in ara-C metabolite formation among the patient groups, it was not possible to predict clinical outcome by these in vitro assessments of ara-C metabolism.