Overt and incomplete (silent) cerebral infarction in sickle cell anemia: diagnosis and management

Regional complete infarctions in children with sickle cell anemia (HbSS) are often associated with stenosis of the large intracranial arteries and result in lifetime disability. Incomplete infarction occurs more frequently than previously recognized and has far-reaching effects on neurocognitive development and the risk for overt secondary strokes into adulthood. Clinical and neuroimaging modalities have been highlighted in an algorithmic approach, with the studies giving the highest yield in results and most likely to be available listed in sequential order. The recognition of an emerging "second peak" incidence in the third decade of life is worrisome and warrants more intense scrutiny and diagnosis of subtle findings of stroke in this young adult population.     

Late magnetic resonance imaging features of leukoencephalopathy in children with central nervous system tumours following high-dose methotrexate and neuraxis radiation therapy

High-dose methotrexate (HDMTX) is used increasingly to treat children with central nervous system (CNS) tumours. Although the neuro-imaging features of leukoencephalopathy associated with systemic or intrathecal methotrexate administered after cranial radiation have been well described, the extent to which the sequencing of HDMTX prior to cranial radiation in infants and children predisposes to late neuroradiological features of leukoencephalopathy is unknown. This report describes the National Cancer Institute (NCI) toxicity grade of leukoencephalopathy based on magnetic resonance imaging (MRI) findings in all patients who survived 4 or more years after treatment on an earlier phase II study. These patients, with newly diagnosed CNS embryonal tumours, were in the age range 3.5-14.2 years (median 6.9 years) at diagnosis, and received four courses of pre-irradiation combination chemotherapy, including HDMTX 8 g/m(2). Following completion of the 'up-front' phase II study, all patients received conventionally fractionated whole brain doses of 36-50.4 Gy. The radiation dose and treatment volumes were determined individually according to the primary tumour location and results of extent of disease evaluations. The most recent MRI brain scans, obtained 4.0-10.5 years (median 6.5 years) after radiation therapy and comprising a minimum of T1, T1 following gadolinium and T2 sequences, were reviewed centrally to assess the neuroradiological grade of leukoencephalopathy, based on the NCI Common Terminology Criteria for Adverse Events, v3.0. Grade I changes (mild increase in subarachnoid space, and/or mild ventriculomegaly, and/or small/focal T2 hyperintensities) were evident in 8 of the 12 patients and grade II changes (moderate increase in subarachnoid space and/or moderate ventriculomegaly, and/or focal T2 hyperintensities extending to the centrum ovale) were found in the remaining 4. In conclusion, treatment with multiple courses of HDMTX prior to 36-50.4 Gy cranial radiation did not result in moderate to severe MRI features of leukoencephalopathy. Future studies in paediatric neuro-oncology patients, involving HDMTX combined with prospective neuropsychological evaluations appear justified.     

Enhanced induction of prostatic dysplasia and carcinoma in Noble rat model by combination of neonatal estrogen exposure and hormonal treatments at adulthood

Estrogens have been implicated to play certain but yet undefined roles in the normal and neoplastic growth of prostate gland. Studies of perinatal exposure in rodents demonstrate that effects of perinatal estrogenization are permanent and carcinogenic in prostate gland. In the Noble (Nb) rat model, prostatic dysplasia and neoplastic lesions can be induced by a chronic treatment with both testosterone and estrogen at adulthood. However, by this conventional protocol, neoplastic lesions are mostly confined to the lateral (LP) and ventral (VP) prostates, while gross prostatic tumors are rarely induced. Based on these two experimental models, we developed a modified treatment protocol for the enhancement of prostate cancer induction in Nb rat model by combining neonatal estrogen exposure of male offspring followed by the hormonal treatment at adulthood (NeoE + T-E2). Using this modified protocol, we were able to induce more extensive development of neoplastic lesions in all three prostatic lobes and also gross tumors at relatively high incidence within 6-9 months. Western blottings and immunohistochemistry showed that ERalpha expression was increased in the hypertrophic peri-acinar and -ductal smooth muscle cells while ERbeta and AR expressions are markedly decreased in dysplastic and neoplastic lesions in NeoE + T-E2-treated prostates. Immunohistochemistry showed that expression of three tumor suppressors (BRCA2, PTEN, and Rap1) and tubulin-alpha are markedly decreased in dysplastic and neoplastic lesions. In addition, loss of expression of smooth muscle differentiation markers (desmin, alpha-actin, and vinculin) and defects of basement membranes were also seen in the reactive stroma. These results suggest that exposure to high levels of estrogens, either endogenous or exogenous, in early life could play a role in the development of prostate cancer in later life.     

Genetic dissection of theta rhythm heterogeneity in mice

Rhythmic oscillatory activities at the theta frequency (4-12 Hz) in the hippocampus have long-attracted attention because they have been implicated in diverse brain functions, including spatial cognition. Although studies based on pharmacology and lesion experiments suggested heterogeneity of these rhythms and their behavioral correlates, controversies are abundant on these issues. Here we show that mice harboring a phospholipase C (PLC)-beta1(-/-) mutation (PLC-beta1(-/-) mice) lack one subset of theta rhythms normally observed during urethane anesthesia, alert immobility, and passive whole-body rotation. In contrast, the other subset of theta rhythms observed during walking or running was intact in these mutant mice. PLC-beta1(-/-) mice also have somewhat disrupted theta activity during paradoxical sleep but do have an atropine-resistant component of theta rhythm. In addition, carbachol-induced oscillations were obliterated in hippocampal slices of PLC-beta1(-/-) mice. Interestingly, PLC-beta1(-/-) mice showed deficits in a hidden platform version of the Morris water maze yet performed well in motor coordination tests and a visual platform version of the Morris water maze. The results genetically define the existence of at least two subtypes of theta rhythms and reveal their association with different behaviors.     

Anatomic distribution of myocardial ischemia as a determinant of exercise-induced ST-segment depression

Cardiac single-photon emission computed tomographic correlates of ST depression were examined in 129 subjects who had inducible ST depression of > or =0.1 mV and reversible perfusion defects. Patients were separated on the basis of single-photon emission computed tomographic defect distribution into a group with anatomically contiguous ischemia (anterior or posterior/inferior defects, n = 68) and a group with anatomically opposed ischemia (anterior and posterior/inferior defects, n = 61). ST depression in the contiguous ischemia group correlated with defect size (r = 0.40, p = 0.001) and severity (r = 0.38, p = 0.002); multivariate regression demonstrated each to be independent determinants of ST-depression magnitude (r = 0.51, p <0.001). In the opposed ischemia group, ST depression did not significantly correlate with defect extent or severity. After adjusting for differences in perfusion indexes, ST depression was paradoxically greater in the contiguous than in the opposed group (2.82 +/- 1.15 vs 2.44 +/- 1.15 mm, p <0.001). In conclusion, these findings demonstrate that the anatomic distribution of ischemia can alter the relation between ST depression and functional indexes of ischemia and may confound the accuracy of assessments of coronary artery disease based on ST-depression magnitude alone.     

Synthetic peptides outside the spike protein heptad repeat regions as potent inhibitors of SARS-associated coronavirus

A novel severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV) has been identified as the aetiological agent of SARS. We previously isolated and characterized SARS-CoV and SARS-CoV-like viruses from human and animals, respectively, suggesting that SARS could be transmitted from wild/farmed animals to humans. Comparison of the viral genomes indicated that sequence variation between animal and human isolates existed mainly in the spike (S) gene. We hypothesized that these variations may underlie a change of binding specificity of the S protein to the host cells, permitting viral transmission from animals to humans. Here we report that four 20-mer synthetic peptides (S protein fragments), designed to span these sequence variation hotspots, exhibited significant antiviral activities in a cell line. SARS-CoV infectivity was reduced over 10 000-fold through pre-incubation with two of these peptides, while it was completely inhibited in the presence of three peptides. Molecular modelling of the SARS-CoV peplomer suggests that three of these antiviral peptides map to the interfaces between the three monomers of the trimeric peplomer rather than the heptad repeat region from which short peptides are known to inhibit viral entry. Our results revealed novel regions in the spike protein that can be targeted to inhibit viral infection. The peptides identified in this study could be further developed into antiviral drugs.