From surnames to the history of Y chromosomes: the Sardinian population as a paradigm

A total of 202 Sardinian male subjects were examined for 13 biallelic stable markers, the complex 49a,f/TaqI system and three microsatellites of the Y chromosome in order to investigate, through surname analysis, on a possible territorial heterogeneity inside the island. The study of geographical distribution and linguistic derivation of Sardinian surnames allow us to discover their 'probable place of origin' and reconstruct ancient genetic isolates which borders are, today, no more recognizable. The molecular analysis revealed that about 90% of the Sardinian Y chromosomes fell into haplogroups E-M35, G-M201, I-M26, J-12f2 and R-M269. In contrast with the territorial homogeneity of these haplogroups, when the individuals were distributed according to their birthplace, a significant difference between the three historically and culturally distinct geographical areas into which Sardinia can be subdivided was observed when the individuals were distributed according to the ancestral location of surnames. In particular, the major contribution to this heterogeneity is due to the 'Sardinian-specific' haplogroup I-M26 (almost completely associated with the 49a,f-Ht12/12f2-10Kb/YCAIIa-21/YCAIIb-11 compound haplotype), which shows both a significantly higher incidence in the central-eastern (archaic) area and a significantly lower frequency in the northern area. The results of this study agree with the hypothesis that the ancestral homeland of this specific subset of haplogroup I is the mountainous central-eastern area of Sardinia, where the population underwent a long history of isolation since ancient times, and highlight the informative power of the surname analysis.     

Micronuclei containing whole chromosomes harbouring the selectable gene do not lead to mutagenesis

Loss of heterozygosity is one genetic change observed in manytumours. We do not know whether the loss of chromosomal materialthrough micronucleus formation is a viable mechanism associatedwith, and possibly leading to, genetic disease. Previously,we treated L5178Y mouse lymphoma cells with four aneugens. Althoughthese aneugens induced micronuclei containing predominantlywhole chromosomes, they did not induce mutations at Tk1, theselectable gene, under the same non-toxic conditions in whichthey induced micronuclei. This suggested that the inductionof micronuclei containing whole chromosomes was not an earlyevent leading to phenotypically expressed mutations in thesecells under the conditions used. However, it is possible thatchromosome 11, on which Tk1 resides, may be under-representedin the micronucleus population. To find out the frequency ofinduction of micronuclei containing chromosome 11, we appliedfluorescence in situ hybridization using a chromosome 11 paintto micronuclei induced by colcemid and vinblastine. We foundthat the numbers of micronuclei containing chromosome 11 aremore than sufficient to be detectable as mutations if thesemicronuclei lead to viable mutants. We conclude that the formationof micronuclei containing whole chromosomes does not lead toviable, dividing mutants in this system. ⁵To whom correspondence should be addressed     

An IFN-beta-albumin fusion protein that displays improved pharmacokinetic and pharmacodynamic properties in nonhuman primates.

The long half-life and stability of human serum albumin (HSA) make it an attractive candidate for fusion to short-lived therapeutic proteins. Albuferon (Human Genome Sciences [HGS], Inc., Rockville, MD) beta is a novel recombinant protein derived from a gene fusion of interferon-beta (IFN-beta ) and HSA. In vitro, Albuferon beta displays antiviral and antiproliferative activities and triggers the IFN-stimulated response element (ISRE) signal transduction pathway. Array analysis of 5694 independent genes in Daudi-treated cells revealed that Albuferon beta and IFN-beta induce the expression of an identical set of 30 genes, including 9 previously not identified. In rhesus monkeys administered a dose of 50 microg/kg intravenously (i.v.) or subcutaneously (s.c.) or 300 microg/kg s.c., Albuferon beta demonstrated favorable pharmacokinetic properties. Subcutaneous bioavailability was 87%, plasma clearance at 4.7-5.7 ml/h/kg was approximately 140-fold lower than that of IFN-beta, and the terminal half-life was 36-40 h compared with 8 h for IFN-beta. Importantly, Albuferon beta induced sustained increases in serum neopterin levels and 2',5' mRNA expression. At a molar dose equivalent to one-half the dose of IFN-beta, Albuferon beta elicited comparable neopterin responses and significantly higher 2',5'-OAS mRNA levels in rhesus monkeys. The enhanced in vivo pharmacologic properties of IFN-beta when fused to serum albumin suggest a clinical opportunity for improved IFN-beta therapy.     

Posttransplant CD30+ (Ki-1) anaplastic large cell lymphoma: a case report and review of the literature

Posttransplant CD30(+) (Ki-1) anaplastic large cell lymphoma (ALCL) is rare. A review of the literature revealed only 3 such cases. All 3 cases were developed after single-organ transplantation. We describe CD30(+) (Ki-1) ALCL in a dual-organ (liver and heart) transplantation recipient. The patient was a 68-year-old white female who underwent an orthotopic heart transplantation in 1999 and a liver transplantation in 2000. She presented with nausea and was found to have CD30(+) (Ki-1) ALCL by pathologic examination of the gastric antrum biopsy specimen. To our knowledge, this patient represents the first reported case of posttransplant CD30(+) ALCL following a dual-organ transplantation.     

Differential Effects of Left versus Right Monaural Biofeedback for Heart Rate Increase

Cerebral lateralization in the voluntary increase of heart rate was investigated in a biofeedback experiment involving 20 right-handed female subjects randomly assigned to one of two groups: right or left ear input of stimulus and biofeedback information. The stimulus was a 1000 Hz tone which signalled the start and duration of 30 20-sec training trials. Feedback was a click presented every time an interbeat interval was shorter than a criterion established through a shaping schedule. A monetary bonus provided additional reinforcement at the end of each trial. Subjects given right ear feedback increased their heart rate significantly more than subjects given left ear feedback. The largest difference between the group means (7 bpm) was recorded after the first 20 training trials. The results are discussed in terms of hemispheric perceptual and functional differences.     

The complexity of HLA class II (DRB1, DQB1, DM) associations with disseminated Mycobacterium avium complex infection among HIV-1-seropositive whites

Earlier associations of polymorphism in classic HLA class II (DRB1 and DQB1) genes have been extended to include the accessory genes DMA and DMB as determinants of disseminated Mycobacterium avium complex (DMAC) infection among HIV-1-seropositive whites. From the Multicenter AIDS Cohort study, 176 DMAC cases were matched with 176 controls in a nested case-control study. PCR-based HLA genotyping techniques were used to resolve variants of DRB1 and DQB1 to their four-digit or five-digit alleles, and single-strand conformation polymorphism was used to resolve sequences in exon 3 at each DM locus. The DMA*0102 allele occurred less frequently among DMAC cases than among controls (OR = 0.46, p =.02). Combinations of DRB1 alleles with or without specific DMA and DMB variants showed significant differences in distributions between the cases and controls, but both of the previously associated class II alleles (DRB1*1501 and DRB1*0701) showed stronger positive associations with DMAC in the absence than in the presence of DMA*0102. Apparent joint effects of DRB1 and DM allelic combinations on occurrence and timing of DMAC suggest that class II disease relationships may be better predicted by biologically plausible interactive combinations than by polymorphisms in individual genes.     

Repeated immunization with plasmid DNA formulated in poly(lactide-co-glycolide) microparticles is well tolerated and stimulates durable T cell responses to the tumor-associated antigen cytochrome P450 1B1

Injection of microparticle-encapsulated DNA elicits immune responses to plasmid-encoded antigens in mice and humans. Cytochrome P450 CYP1B1 (CYP1B1) is a member of the CYP1 P450 enzyme family that is overexpressed in a variety of solid tumors. The work described herein was performed to study the kinetics of stimulating T cell responsiveness with an encapsulated DNA encoding CYP1B1 and provides support for the clinical development of this formulation. Immunization of HLA-A2/Kb transgenic mice with human CYP1B1 encoding plasmid DNA formulated in poly(lactide-co-glycolide) (PLG) microparticles elicits CD8+ T cells that respond to human CYP1B1-positive target cells. The duration of the immune response, the effect on the immune response of multiple injections, and the safety of repeated injections were studied. These results show that the PLG-encapsulated DNA therapeutic elicits durable immune responses to CYP1B1, the responses are dependent on repeat immunization, and that the formulation is well tolerated.     

Randomized trial of cognitive behavior therapy versus supportive psychotherapy for HIV-related peripheral neuropathic pain

The feasibility and acceptability of cognitive behavior therapy for HIV-related peripheral neuropathic pain was examined and the potential efficacy of the intervention was compared with that of supportive psychotherapy in reducing pain, pain-related interference with functioning, and distress. Sixty-one patients were randomly assigned to receive six weekly sessions of cognitive behavior therapy or supportive psychotherapy. Thirty-three subjects completed the protocol. Both groups showed significant reductions in pain. The cognitive behavior group improved in most domains of pain-related functional interference and distress; the supportive psychotherapy group showed fewer gains. The high dropout rate suggests that psychotherapeutic treatments for HIV-related pain may have limited feasibility and acceptability.