Leukoaraiosis correlates with cerebral hypoperfusion in vascular dementia

Leukoaraiosis quantified by computerized densitometric measurements of reduced Hounsfield numbers was correlated with local cerebral blood flow on the same computed tomographic images of 35 patients with multi-infarct dementia and 16 age-matched elderly normal volunteers. The ratio for area of frontal leukoaraiosis to total area of parenchyma among the patients was significantly greater than that among the normal volunteers (5.8 +/- 2.3% compared with 3.1 +/- 1.3%, p less than 0.001). Severity of leukoaraiosis around the frontal horns of the lateral ventricles correlated significantly with severity of leukoaraiosis of the centrum semiovale adjacent to the bodies of the lateral ventricles. Cerebral blood flow values for all representative cerebral regions except the parietal white matter were reduced among the patients compared with the normal volunteers. Multivariate regression analysis revealed that reduced cerebral perfusion in the putamen and thalamus correlated significantly with the severity of leukoaraiosis. Cerebral hypoperfusion in territories supplied by deep penetrating arteries may contribute to the pathogenesis of leukoaraiosis.     

4,5-Dianilinophthalimide: a protein-tyrosine kinase inhibitor with selectivity for the epidermal growth factor receptor signal transduction pathway and potent in vivo antitumor activity.

Deregulated signal transduction via the epidermal growth factor receptor (EGF-R) family of protein-tyrosine kinase growth factor receptors is associated with proliferative diseases. We describe a class of compounds (4,5-dianilinophthalimides) that inhibit the EGF-R protein-tyrosine kinase in vitro with high selectivity. In cells, 4,5-dianilinophthalmide selectively inhibited both ligand-induced EGF-R and p185c-erbB2 autophosphorylation and c-fos mRNA induction. Antitumor activity could be demonstrated in vivo against xenografts of the A431 and SK-OV-3 tumors, which overexpress the EGF-R and p185c-erbB2, respectively. In contrast, a platelet-derived growth factor-driven tumor was not inhibited by 4,5-dianilinophthalimide, which is compatible with its cellular selectivity and hypothesized mechanism of action. No overt cumulative toxicity was observed during treatment even though high efficacy was observed, indicating a good therapeutic window. 4,5-Dianilinophthalimides may offer therapeutic agents for the treatment of hyperproliferative diseases that overexpress EGF-R family protein-tyrosine kinases or their ligands.     

Hugh Morriston Davies and lobectomy for cancer, 1912

The report of a lobectomy for bronchogenic carcinoma in 1912, by Hugh Morriston Davies of London, and without precedent, describes a surgical technique strikingly similar to that of today. Unfortunately, Davies' patient died because postoperative management of the pleural space was not yet well understood. The tumor had been identified by radiographic examination and the diagnosis confirmed by cytological examination of the sputum. The operative technique included individual ligation of hilar vessels and suture closure of the bronchus, neither of which was to be reported again for more than 20 years. More effective management of the pleural space was described, without special emphasis, by Harold Brunn of San Francisco 17 years later.     

Blood flow distribution and its temporal variability in stimulated dog gastrocnemius muscle

The distribution of blood flow in skeletal muscle stimulated to rhythmic isotonic contractions was studied by injections of radioactive microspheres into the arterial supply in 8 gastrocnemius muscles (mean weight 84 g) of 6 anesthetized dogs (20-25 kg body weight). The distribution of 10 micron microspheres in regions of about 0.5 g was very similar to that of the standard 15 micron microspheres, whereas that of 25 micron microspheres was more uneven. The coefficient of variation (CV = SD/mean) of the ratio of simultaneously injected 10 micron and 15 micron microspheres, 0.12, was taken as the inherent scatter of the method. The average spatial distribution inequality of 10-15 micron microspheres corresponded to a CV of 0.45 and the specific local blood flow inhomogeneity to a CV = 0.43 ( = square root 0.45(2) - 0.12(2], but there were marked differences between muscles. At equal blood flow levels, the inhomogeneity during reactive hyperemia was similar to that observed during stimulation. The temporal variability of blood flow in individual muscle pieces was obtained from the comparison of fractional trapping of 4 to 5 differently labeled microspheres injected at intervals of 2 min into steadily stimulated muscles. The mean CV for the variations in time was 0.23 and that corrected for methodological scatter, 0.19, but the differences in the extent of temporal blood flow changes among muscle pieces within a muscle and between different muscles were large. The presence of considerable spatial and temporal variations of blood flow in exercising muscle during apparent steady state may be important in limiting and/or modulating tissue O2 supply.     

Impfungen und Impfprogramme—aktuelle Aspekte des Impfwesens in Deutschland

Ohne Zusammenfassung     

A novel mutation (deletion of Aalpha-Asn 80) in an abnormal fibrinogen: fibrinogen Caracas VI. Consequences of disruption of the coiled coil for the polymerization of fibrin: peculiar clot structure and diminished stiffness of the clot.

An abnormal fibrinogen was identified in a 10-year-old male with a mild bleeding tendency; several years later, the patient developed a thrombotic event. Fibrin polymerization of plasma from the propositus and his mother, as measured by turbidity, was impaired. Plasmin digestion of fibrinogen and thrombin bound to the clot were both normal. The structure of clots from both plasma and purified fibrinogen was characterized by permeability, scanning electron microscopy and rheological measurements. Permeability of patients' clots was abnormal, although some measurements were not reliable because the clots were not mechanically stable. Consistent with these results, the stiffness of patients' clots was decreased approximately two-fold. Electron microscopy revealed that the patients' clots were very heterogeneous in structure. DNA sequencing of the propositus and his mother revealed a new unique point mutation that gives rise to a fibrinogen molecule with a missing amino acid residue at Aalpha-Asn 80. This new mutation, which would disrupt the alpha-helical coiled-coil structure, emphasizes the importance of this part of the molecule for fibrin polymerization and clot structure. This abnormal fibrinogen has been named fibrinogen Caracas VI.     

Neurotoxic effects of MDMA (“ecstasy”) administration to neonatal rats

3,4-Methylenedioxymethamphetamine damages fine serotonergic fibers and nerve terminals in adult organisms. Developing animals seem to be less susceptible to this effect, possibly due to a lack of drug-induced hyperthermia. We tested this hypothesis by producing hyperthermia in neonatal rats for 2 h after each of twice-daily MDMA (10 mg/kg s.c.) or saline injections administered from postnatal days 1–4. Other drug-treated and control litters were maintained at normothermic temperatures following injection. Changes in forebrain serotonergic innervation were assessed at postnatal day 25 (serotonin transporter binding and serotonin levels), postnatal day 60 (serotonin transporter binding), and 9 months of age (serotonin transporter immunohistochemistry). We also determined the influence of MDMA treatment on apoptotic activity by means of immunohistochemistry for cleaved caspase-3 at postnatal day 5. The hippocampus showed significant MDMA-related reductions in serotonergic markers at postnatal day 25 and postnatal day 60. At 9 months, there was no effect of prior MDMA exposure on serotonin transporter-immunoreactive fiber density in the hippocampus; however, significant reductions in fiber density were observed in two neocortical areas and a hyperinnervation was found in the caudate-putamen and nucleus accumbens shell. MDMA treatment also produced a two-fold increase in the number of cleaved caspase-3-immunoreactive cells in the rostral forebrain and hippocampus. All of these effects were completely independent of pup body temperature. These findings demonstrate that neonatal MDMA administration exposure stimulates apoptotic cell death in various forebrain areas and also leads to a long-term reorganization of the forebrain serotonergic innervation. Consequently, offspring of MDMA-using women may be at heightened risk for abnormal neural and behavioral development.     

CYP3A5 and ABCB1 Polymorphisms and Tacrolimus Pharmacokinetics in Renal Transplant Candidates: Guidelines from an Experimental Study

Genetic polymorphisms in biotransformation enzyme CYP3A5 (6986G > A, CYP3A5*3; 14690A > G, CYP3A5*6) and drug transporter ABCB1 (1236C > T; 2677G > T/A; 3435C > T) are known to influence tacrolimus (Tac) dose requirements and trough blood levels in stable transplant patients. In a group of 19 volunteers selected with relevant genotypes among a list of 221 adult renal transplant candidates, we evaluated whether consideration of CYP3A5 and ABCB1 genetic polymorphisms could explain the interindividual variability in Tac pharmacokinetics after the first administration of a standard dose (0.1 mg/kg body weight twice a day). Lower area under the time versus blood concentration curves (AUC) or lower trough concentrations were observed among CYP3A5 expressors (n = 9) than among nonexpressors (n = 10) using two different analytical methods for Tac determination (liquid chromatography with tandem mass spectrometry (LC-MS/MS) and immunoassay). The median AUC(0-infinity) was 2.6- and 2.1-fold higher in nonexpressors for LC-MS/MS and immunologic methods, respectively. No difference was observed in Tac pharmacokinetic parameters in relation to ABCB1 polymorphisms. In conclusion, our study confirms the very significant effect of CYP3A5 polymorphism early after the first administration of Tac. It also provides a strong argument for a doubling of the loading dose in patients early identified a priori on the transplantation list as possessing at least one CYP3A5*1 allele.     

Impaired in-vitro proliferation of hemopoietic precursors in HIV-1-infected subjects

Patients with acquired immunodeficiency syndrome (AIDS) and persistent lymphadenopathy syndrome (LAS) display significant hematological abnormalities of one or more cell lineages. In order to understand the pathophysiologic mechanisms leading to these abnormalities we studied the proliferation capacity of pluripotent and committed hemopoietic precursors using in-vitro colony assays. Anemia, leukopenia and thrombopenia were relatively frequent findings in HIV-infected subjects irrespectively of the patients' clinical status. The colony growth capacity of AIDS patients' GM-CFU and BFU-E was significantly decreased whereas no GEMM-CFU colonies could be obtained. There was no correlation between the number of BFU-E and GM-CFU colony number and the hemoglobin or the absolute number of polynuclear cells, respectively. The plating efficiency of both committed and pluripotent hematopoietic precursors from HIV infected patients could not be enhanced when additional exogenous recombinant GM-CSF, human interleukin 3 or erythropoietin were added in contrast to normal patients' cells. In addition, the impaired colony growth of these precursors could not be restored after adherent or T-cell depletion or the addition of normal allogenic irradiated adherent or/and T cells. Since this colony growth abnormality was also detected in HIV seropositive asymptomatic subjects our findings strongly suggest that the in-vitro growth of hematopoietic precursors is affected early after HIV-1 infection.