HLA-DPB1 gene polymorphism and multiple sclerosis: a large case-control study in the southwest of France

The polymorphism at the HLA-DPB1 locus has been characterized in a large number of patients with multiple sclerosis (n = 112) and in healthy controls (n = 115). Both patients and controls lived in the southwest of France (in the Pyrénées Atlantiques) and had similar ethnic background. The typing procedure involved the selective amplification of the second exon of the DPB1 locus by polymerase chain reaction, followed by hybridization of the amplified DNA with 14 sequence-specific oligonucleotide probes. Individual alleles were identified by the pattern of hybridization of the different probes. The distribution of the DPB1 alleles was not significantly different in multiple sclerosis patients and controls (p = 0.11). This does not corroborate the reported association of multiple sclerosis with the primed lymphocyte typing (PLT)-defined DPw4 specificity and is not in favour of a role played by polymorphic residues of the DP molecule in susceptibility to multiple sclerosis.     

Dopaminergic involvement in locomotion elicited from the ventral pallidum/substantia innominata

Microinjection of the indirect GABAA antagonist, picrotoxin, or the mu opioid agonist, Tyr-D-Ala-Gly-NMe-Phe-Gly-ol (DAGO), into the ventral pallidum and substantia innominata (VP/SI) increases locomotor activity in rats. The VP/SI has direct and indirect projections to the region of the ventral mesencephalon containing dopamine perikarya, and to certain dopamine terminal fields, including the nucleus accumbens. Thus, it is possible that modulation of the mesocorticolimbic dopamine system by pharmacological stimulation in the VP/SI may play a role in the locomotor stimulant response. It was shown that pretreatment with dopamine receptor antagonists, either peripherally or microinjected into the nucleus accumbens significantly attenuated the motor stimulant effect of DAGO or picrotoxin injection into the VP/SI. Injection of either picrotoxin or DAGO into the VP/SI increased the levels of dopamine metabolites in the nucleus accumbens and prefrontal cortex. Thus, the motor stimulant response following pharmacological stimulation of the VP/SI appears to be mediated by increased dopamine neurotransmission via feedback mechanisms to the mesocorticolimbic dopamine system.     

Olfactory Neuroblastoma and Neuroendocrine Carcinoma of the Anterior Skull Base: Treatment Results at the M.D. Anderson Cancer Center

Updated information on the pathologic characterization and treatment of olfactory neurobiastoma (ON) and neuroendocrine carcinoma (NEC) diseases is presented. A series of patients with ON or NEC was evaluated and retrospectively staged using the UCLA system. The parameters evaluated were symptoms, age, sex, risk factor assessment, stage of disease, treatment, and clinical outcome. The median follow-up was 3 years (range, 18 months to 23 years). The predominant therapy (63%) for ON was combined surgery and radiotherapy. Surgery alone or in combination with ancillary treatment was used in 58% of patients with NEC. For the most receat years of the study, patients with NEC have been treated successfully with combined chemotherapy and radiotherapy. Seventy percent of the patients with ON and 75% of the patients with NEC were clinically free of disease during the defined follow-up period. Surgical therapy consisting of a craniofacial resection combined with postoperative radiotherapy has resulted in good local and long-term control of ON. Our experience indicates that combined chemoradiation is an appropriate therapeutic approach for NEC.     

SI12Lymphocyte Subsets Following Autologous Transfer of CD25 Depleted Leukapheresis Products

The CXCL12/CXCR4 chemokine axis is a well characterized and important chemotactic stimulus/receptor unit that orchestrates the homing and migration of cells to the bone marrow and to ischemic tissues following tissue damage. Here, we demonstrate that the sialomucin, CD164, a regulator of haemopoietic precursor cell adhesion to stroma and entry of primitive CD34⁺CD38^lo/‐ precursor cells into cycle, modulates the migration of CD133⁺ cord blood cells to CXCL12 by associating with the CXCR4 receptor. This was demonstrated by a reduction in CD133⁺ cell migration on fibronectin to CXCL12 (i) by engaging the functional class II glycosylation‐dependent epitope on CD164 with the 103B2/9E10 class II but not the N6B6 class III antibody; and (ii) by RNAi knockdown of CD164 protein levels in CD133⁺ cells. The inhibition of migration was more pronounced in the more primitive CD34⁺CD38^lo/‐ cell subset. Similar studies using the Jurkat cell line confirmed these findings and led to further analyses using alternative chemokines. A direct association between CXCR4 and CD164 was demonstrated by the co‐localisation of CD164 with CXCR4 and VLA‐4 and VLA‐5 at the leading edge of CD133⁺ cells when CXCL12 was presented on fibronectin. This was further supported by immunoprecipitation studies that demonstrate in the absence of CXCL12, CXCR4 is associated only with VLA‐4 and VLA‐5 but on exposure to CXCL12, CD164 is rapidly recruited to the CXCR4 complex. Knock‐down of CD164 using siRNA revealed that signalling through CXCR4 via PKC‐ζ was significantly dampened. Our findings therefore support a novel association between three distinct families of cell surface receptors that regulate both cell migratory and proliferative responses and identify a CD164 as a key regulator of the CXCL12/CXCR4 axis.