Neuroprotection in acute brain injury: an up-to-date review

Neuroprotective strategies that limit secondary tissue loss and/or improve functional outcomes have been identified in multiple animal models of ischemic, hemorrhagic, traumatic and nontraumatic cerebral lesions. However, use of these potential interventions in human randomized controlled studies has generally given disappointing results. In this paper, we summarize the current status in terms of neuroprotective strategies, both in the immediate and later stages of acute brain injury in adults. We also review potential new strategies and highlight areas for future research.     

Agelasines J, K, and L from the Solomon Islands Marine Sponge Agelas cf. mauritiana

Three new diterpene alkaloids, agelasine J (3), agelasine K (4), and agelasine L (5), were isolated from the marine sponge Agelas cf. mauritiana collected in the Solomon Islands. The structures of these compounds were elucidated by physical data analyses. They displayed in vitro antimalarial activity against Plasmodium falciparum.     

Rearrangements of immunoglobulin and TCR genes in lymphoid blast crisis of Ph + chronic myeloid leukaemia

Clonal rearrangements of immunoglobulin heavy chain genes as well as both T cell receptor (TCR) delta and gamma genes were found in four cases of blast crisis of Ph+ chronic myeloid leukaemia with unequivocal B cell precursor (common) immunophenotype. In one case, the TCR beta chain gene was also rearranged. Although the developmental sequence of TCR delta, gamma and beta rearrangements in T lymphocytes appeared to be respected, a full phenotypic effect, characteristic of T cell was not observed in these otherwise typical 'common' blast cells. Cytogenetic analysis ruled out the occurrence of TCR rearrangement due to structural chromosome changes. A high incidence of unexpected TCR gene rearrangements has been previously reported in the de novo 'common' acute lymphoblastic leukaemias (ALL). Our cases of chronic myeloid leukaemia (CML) in lymphoid blast crisis show that genotypic similarities may exist between these two haematological entities.     

Antiangiogenic effect of erythromycin: an in vitro model of Bartonella quintana infection

BACKGROUND: Bartonella quintana, the etiological agent of bacillary angiomatosis (BA), causes endothelial cell proliferation. Erythromycin has dramatic effects on BA, and the effects are largely unexplained by the compound's bacteriostatic properties. Our aim here was to evaluate the possibility that erythromycin alters angiogenesis. METHODS: The effect of erythromycin on B. quintana-induced endothelial cell proliferation was studied using a wild-type strain and an erythromycin-resistant B. quintana mutant. The latter was generated by serial subcultures on blood agar plates. RESULTS: We show that erythromycin significantly inhibits the proliferation of dermal microvascular endothelial cells induced either by wild-type B. quintana or by our erythromycin-resistant mutant. Doxycycline and gentamycin failed to exert such an effect. Finally, we found that the resistant strain harbored a 27-bp insertion in the highly conserved region of the gene encoding the ribosomal protein L4; this insertion may explain the existence of the resistance to erythromycin. CONCLUSION: The data presented here indicate that erythromycin profoundly down-modulates endothelial cell proliferation irrespective of its bacteriostatic effects and suggest that this may be a key component of the efficacy of the compound in the treatment of patients with BA.     

A double-blind low dose-finding phase II study of granulocyte colony-stimulating factor combined with chemotherapy for stem cell mobilization in patients with non-Hodgkin's lymphoma

The aim of the study was to define the minimal effective dose (MED) of granulocyte colony-stimulating factor (G-CSF) among five daily doses following chemotherapy for peripheral blood stem cell (PBSC) collection. Twenty-five patients were included in this double-blind dose-finding phase II study conducted according to a two-stage Bayesian design. The estimated probabilities of success for PBSC collection for the G-CSF doses of 50, 75, 100, 125 and 150 microg/m2/day were 84%, 87.7%, 91%, 93.9 and 96.4%, respectively. Low G-CSF doses may be used with a similar probability of success as conventional doses and could allow significant savings.     

Impaired hair follicle morphogenesis and cycling with abnormal epidermal differentiation in nackt mice,a cathepsin L-deficient mutation

We previously described an autosomal-recessive mutation named nackt (nkt) exhibiting partial alopecia associated with CD4(+) T-cell deficiency. Also, we recently reported that nkt (now Ctsl(nkt)) comprises a deletion in the cathepsin L (Ctsl) gene. Another recent study reported that Ctsl knockout mice have CD4(+) T-cell deficiency and periodic shedding of hair, which recapitulate the nkt mutation and the old furless (fs) mutation. The current study focuses on the dermatological aspects of the nkt mutation. Careful histological analysis of skin development of homozygous nkt mice revealed a delayed hair follicle morphogenesis and late onset of the first catagen stage. The skin of Ctsl(nkt)/Ctsl(nkt) mice showed mild epidermal hyperplasia and hyperkeratosis, severe hyperplasia of the sebaceous glands, and structural alterations of hair follicles. Epidermal differentiation seems to be affected in nkt skin, with overexpression of involucrin and profilaggrin/filaggrin along with focal areas of keratin 6 expression in the interfollicular epidermis. Severe epidermal hyperplasia, acanthosis, orthokeratosis, and hyperkeratosis were only observed in mice maintained in nonpathogen-free environments. The analysis of Rag2-/- Ctsl(nkt)/Ctsl(nkt) double-mutant mice indicates that the skin defect remains under the absence of T and B cells. This animal model provides in vivo evidence that cysteine protease cathepsin L plays a critical role in hair follicle morphogenesis and cycling, as well as epidermal differentiation.     

22q11.2 duplication syndrome: two new familial cases with some overlapping features with DiGeorge/velocardiofacial syndromes

Twenty-one patients, including our two cases, with variable clinical phenotype, ranging from mild learning disability to severe congenital malformations or overlapping features with DiGeorge/velocardiofacial syndromes (DG/VCFS), have been shown to have a chromosome duplication 22q11 of the region that is deleted in patients with DG/VCFS. The reported cases have been identified primarily by interphase FISH and could have escaped identification and been missed by routine cytogenetic analysis. Here we report on two inherited cases, referred to us, to rule out 22q11 microdeletion diagnosis of VCFS. The first patient was a 2-month-old girl, who presented with cleft palate, minor dysmorphic features including short palpebral fissures, widely spaced eyes, long fingers, and hearing loss. Her affected mother had mild mental retardation and learning disabilities. The second patient was a 7(1/2)-year-old boy with velopharyngeal insufficiency and mild developmental delay. He had a left preauricular tag, bifida uvula, bilateral fifth finger clinodactyly, and bilateral cryptorchidism. His facial features appeared mildly dysmorphic with hypertelorism, large nose, and micro/retrognathia. The affected father had mild mental retardation and had similar facial features. FISH analysis of interphase cells showed three TUPLE1-probe signals with two chromosome-specific identification probes in each cell. FISH analysis did not show the duplication on the initial testing of metaphase chromosomes. On review, band q11.2 was brighter on one chromosome 22 in some metaphase spreads. The paucity of reported cases of 22q11.2 microduplication likely reflects a combination of phenotypic diversity and the difficulty of diagnosis by FISH analysis on metaphase spreads. These findings illustrate the importance of scanning interphase nuclei when performing FISH analysis for any of the genomic disorders.