Cerebral blood flow disturbances after anterior choroidal artery infarcts. Anatomical and functional correlates

We have investigated the cortical and subcortical regional cerebral blood flow (rCBF) disorders resulting from infarcts of the anterior choroidal artery (AChA), and correlations with the severity of lesions, the physical and cognitive deficits, and the functional impairment. Eighteen patients presenting with recent anterior choroidal artery infarct without any other brain injury were examined at the secondary phase post-stroke using the single photon emission computed tomography technique and 133 Xenon inhalation. The rCBF and asymmetry indexes (AI) were calculated for 12 symmetrical hemispheric areas, and the cerebellum. The AI values were compared with those of 24 control subjects. The severity of the lesions was evaluated from CT scans or MRI. The neurological status (Orgogozo scale, walking disorders, MMSE, attention impairment, aphasia) and disability (functional independance measure: FIM) were assessed for each patient at the same time period. The relationships between rCBF disorders and brain lesions, and between the results of clinical investigations and rCBF disorders and brain lesions were assessed by linear regression analyses (stepwise variable selections, p=0.05). The AI values were significantly increased in the cerebral hemispheres, and this was most severe in the internal capsule (direct effect of the lesion) and the dorsolateral hemispheric cortex (diaschisis). Individual evaluations showed that AI were significantly increased in 13 patients in at least one ROI of the cerebral hemispheres, and in 3 patients in the internal capsule. Stepwise variable selections revealed that AI were best explained by the severity of the lesions in the internal capsule and the internal temporal area. The AI of the external temporal area and the internal capsule also helped explain the clinical (physical and cognitive) deficits. Thus, AChA infarcts may have relatively large effects on the central part of the lateral and dorsal cortex of the ipsilateral hemisphere. Subcortical and cortical consequences both contribute to explain the motor and cognitive deficits and disability.     

Acroosteolysis

Four cases of idiopathic acroosteolysis are reported. The first is a common phalangeal type, the second, the Hozay variety. The third case was diagnosed after a mumps infection, and marked regress of the changes was noted in the following years. The fourth case shows skin changes, periostitis, mild osteosclerosis, and skull changes as well as acroosteolysis.     

Early osseous abnormalities in Menkes' Kinky Hair Syndrome

Bone changes in a 4m.o. infant with Menkes' Kinky Hair Syndrome, who also had a skeletal survey as a newborn, are reported. Whereas the late bone changes were diagnostic, the neonatal ones were similar to congenital rubella and cytomegalic virus infection. However the distribution of the metaphyseal changes was different.     

Endoscopic retrograde cholangiopancreatography in children

Gastroduodenoscopy and retrograde cholangiopancreatography has been performed on 25 occasions in 20 children aged between 7 and 16. Radiographs of the clinically relevant duct or ducts were achieved in 96% of attempts, with no complications. The diagnostic information proved useful clinically; in particular it provided a precise map if biliary or pancreatic surgery was being contemplated. Several unexpected congenital duct anomalies were found. This and other recent reports, particularly from Germany, indicate that endoscopic retrograde cholangiopancreatography deserves greater application in children, and can also be used in babies.     

Suppressive Roles of Calreticulin in Prostate Cancer Growth and Metastasis

Calreticulin is an essential, multifunctional Ca²⁺-binding protein that participates in the regulation of intracellular Ca²⁺ homeostasis, cell adhesion, and chaperoning. Calreticulin is abundantly expressed and regulated by androgens in prostate epithelial cells. Given the importance of both calreticulin in multiple essential cellular activities and androgens in prostate cancer, we investigated the possibility of a role for calreticulin in prostate cancer progression. Immunohistochemistry revealed the down-regulation of calreticulin in a subset of human prostate cancer specimens. Prostate cancer cells overexpressing exogenous calreticulin produced fewer colonies in both monolayer culture and soft agar. Furthermore, calreticulin overexpression also inhibited tumor growth in the orthotopic PC3 xenograft tumor model and macroscopic lung metastasis in the rat Dunning AT3.1 prostate tumor model. To address the potential mechanism of calreticulin suppression of prostate cancer, we generated calreticulin mutants with different functional domains deleted. The calreticulin mutants containing the P-domain, which binds to other endoplasmic reticulum chaperone proteins, were sufficient for the suppression of PC3 growth in colony formation assays. Overall, our data support the hypothesis that calreticulin inhibits growth and/or metastasis of prostate cancer cells and that this suppression requires the P-domain.Prostate cancer was the most frequently diagnosed non-skin cancer and the third leading cause of cancer death among American men in 2008.¹ Androgens are intimately associated with prostate cancer progression and as such, androgen ablation remains the standard therapy for patients with metastatic prostate cancer.² However, hormone therapy is not curative and the vast majority of treated patients eventually experience disease progression. Elucidating the mechanism of androgen influence on prostate cancer is important as it may facilitate the development of more effective therapies and methods of disease prevention.Androgen action is mediated through the androgen receptor, which controls the expression of androgen-responsive genes.³ As androgen-responsive genes likely play important roles in prostate cancer progression, the characterization of their expression patterns and functions should provide insight into the roles of androgen in disease development. Calreticulin is one of the androgen-responsive genes in the prostate.^4,5 Androgen ablation by castration rapidly down-regulates calreticulin at both the mRNA and protein levels by more than tenfold. In contrast, androgen replacement rapidly restores the expression of calreticulin in the regrowth of the castrated prostate. Northern blot analysis of the tissue-specificity of calreticulin expression in the rat model shows that the most abundant levels occur in the prostate, as compared with the liver, kidney, brain, heart, muscle, and seminal vesicles. In situ hybridization and immunohistochemistry studies demonstrate that prostatic epithelial cells specifically express calreticulin.^5,6 The expression profile and androgen-responsiveness of calreticulin in the prostate indicate that calreticulin may play a key role in androgen action in prostate epithelial cells.Calreticulin performs a variety of functions within the cell. This evolutionarily conserved protein localizes to the endoplasmic reticulum (ER),^7,8,9 but possibly may also be found at the cell surface.^10,11 Within the ER, calreticulin serves as a molecular chaperone to ensure proper folding of glycoproteins.^12,13,14,15 In addition, calreticulin modulates intracellular Ca ²⁺ homeostasis by its ability to bind Ca²⁺ with high affinity.^6,16,17,18 Other possible activities include integrin α-binding and cell adhesion,^19,20,21,22 major histocompatibility class I assembly,²³ steroid-mediated gene regulation,^24,25,26 as well as Zn²⁺ binding and storage.²⁷ Gene knockout experiments further underscore the importance of this protein, as loss of calreticulin results in embryonic death from defective cardiac development.²⁸ Calreticulin consists of three distinctive domains. The N-domain (residues 1 to 180) is thought to bind heavy metals (Zn²⁺) and interact with other ER chaperones, nuclear receptors, and nucleic acids.²⁹ The P-domain (residues 181 to 290) contains a proline-rich region that forms an extended arm structure and interacts with other chaperones in the lumen of the ER. Lastly, the C-domain (residues 291 to 400) is a highly acidic region that binds Ca²⁺ and is involved in Ca²⁺ storage.³⁰Although the role of calreticulin in normal cellular functions and during embryogenesis is well-established, its role in human carcinogenesis remains poorly understood.³¹ In the current study, we demonstrate the down-regulation of calreticulin protein in a subset of human prostate cancer specimens. Furthermore, we show that calreticulin overexpression in prostate cancer cells inhibits prostate tumor growth and metastasis and that its growth inhibitory role requires the P-domain. Overall, our present study provides evidence, for the first time, that calreticulin is capable of suppressing prostate cancer progression.     

Biology and therapeutic potential of cannabinoid CB2 receptor inverse agonists

Evidence has emerged suggesting a role for the cannabinoid CB2 receptor in immune cell motility. This provides a rationale for a novel and generalized immunoregulatory role for cannabinoid CB2 receptor-specific compounds. In support of this possibility, we will review the biology of a class of cannabinoid CB2 receptor-specific inverse agonist, the triaryl bis-sulfones. We will show that one candidate, Sch.414319, is potent and selective for the cannabinoid CB2 receptor, based on profiling studies using biochemical assays for 45 enzymes and 80 G-protein coupled receptors and ion channels. We will describe initial mechanistic studies using this optimized triaryl bis-sulfone, showing that the compound exerts a broad effect on cellular protein phosphorylations in human monocytes. This profile includes the down regulation of a required phosphorylation of the monocyte-specific actin bundling protein L-plastin. We suggest that this observation may provide a mechanism for the observed activity of Sch.414319 in vivo. Our continued analysis of the in vivo efficacy of this compound in diverse disease models shows that Sch.414319 is a potent modulator of immune cell mobility in vivo, can modulate bone damage in antigen-induced mono-articular arthritis in the rat, and is uniquely potent at blocking experimental autoimmune encephalomyelitis in the rat.     

Immunogenicity of viral vector,prime-boost SIV vaccine regimens in infant rhesus macaques: Attenuated vesicular stomatitis virus (VSV) and modified vaccinia Ankara (MVA) recombinant SIV vaccines compared to live-attenuated SIV

In a previously developed infant macaque model mimicking HIV infection by breast-feeding, we demonstrated that intramuscular immunization with recombinant poxvirus vaccines expressing simian immunodeficiency virus (SIV) structural proteins provided partial protection against infection following oral inoculation with virulent SIV. In an attempt to further increase systemic but also local antiviral immune responses at the site of viral entry, we tested the immunogenicity of different orally administered, replicating vaccines. One group of newborn macaques received an oral prime immunization with a recombinant vesicular stomatitis virus expressing SIVmac239 gag, pol and env (VSV-SIVgpe), followed 2 weeks later by an intramuscular boost immunization with MVA-SIV. Another group received two immunizations with live-attenuated SIVmac1A11, administered each time both orally and intravenously. Control animals received mock immunizations or non-SIV VSV and MVA control vectors. Analysis of SIV-specific immune responses in blood and lymphoid tissues at 4 weeks of age demonstrated that both vaccine regimens induced systemic antibody responses and both systemic and local cell-mediated immune responses. The safety and immunogenicity of the VSV-SIVgpe + MVA-SIV immunization regimen described in this report provide the scientific incentive to explore the efficacy of this vaccine regimen against virulent SIV exposure in the infant macaque model.