Perspectives for personalized therapy for patients with multidrug-resistant tuberculosis.

According to the World Health Organization (WHO), tuberculosis is the leading cause of death attributed to a single microbial pathogen worldwide. In addition to the large number of patients affected by tuberculosis, the emergence of Mycobacterium tuberculosis drug-resistance is complicating tuberculosis control in many high-burden countries. During the past 5 years, the global number of patients identified with multidrug-resistant tuberculosis (MDR-TB), defined as bacillary resistance at least against rifampicin and isoniazid, the two most active drugs in a treatment regimen, has increased by more than 20% annually. Today we experience a historical peak in the number of patients affected by MDR-TB. The management of MDR-TB is characterized by delayed diagnosis, uncertainty of the extent of bacillary drug-resistance, imprecise standardized drug regimens and dosages, very long duration of therapy and high frequency of adverse events which all translate into a poor prognosis for many of the affected patients. Major scientific and technological advances in recent years provide new perspectives through treatment regimens tailor-made to individual needs. Where available, such personalized treatment has major implications on the treatment outcomes of patients with MDR-TB. The challenge now is to bring these adances to those patients that need them most.

Polymorphism of X-linked CD40 ligand gene associated with pulmonary tuberculosis in the Han Chinese population.

Among those developing tuberculosis (TB) after exposure to Mycobacterium tuberculosis, approximately 70% are males. Host genetic variation, particularly immune-related genes on the X chromosome, may contribute to sex-specific differences in TB incidences. To study whether X-linked gene variation is associated with sex-specific presentation of pulmonary TB (pTB), three single-nucleotide polymorphisms (SNPs) of the TLR8, CD40LG and IRAK1 genes on the X chromosome were genotyped in 923 patients and 1033 healthy individuals of the Han Chinese population. Frequencies of the variants were analyzed independently as well as in their combinations. CD40LG rs3092923 and its combined effects with the other two SNPs were associated with an increased risk of pTB only in males. In males, the rs3092923 genotype C/(-) conferred relative protection (odds ratio (OR): 0.52, 95% confidence interval (CI): 0.35-0.78, Pcorr.=0.0045) and the combined effects of three SNPs increased gradually as the number of risk alleles increased (OR: 2.58, 2.83 and 2.96 for one, two and three risk alleles, respectively). For the remaining SNPs, significance was obtained only for the AA genotype of IRAK1 rs3027898 in the combined and female-only analysis. Our results indicate a role of a CD40LG variant and its combined effects with distinct TLR8 and IRAK1 variants in susceptibility to pTB in males.

Polymorphism in NFKBIA gene is associated with recurrent acute rejections in liver transplant recipients.

The nuclear factor of kappa light polypeptide gene enhancer B-cells inhibitor-alpha (NFKBIA) gene encodes a member of the nuclear factor-kappa-B inhibitor family. Polymorphisms in this gene might be associated with a susceptibility to acute rejection episodes following liver transplantation, as they may cause an increased activation level of the proinflammatory transcription factor nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB). The aim of this study was to evaluate whether the NFKBIA polymorphisms -297 C/T (rs2233409), -826 C/T (rs2233406) and 126 G/A (rs696) affect the incidence of acute liver graft rejection. A total of 199 liver transplant recipients was analyzed, 100 without (NAR) and 99 with early acute rejection (AR). Thirty-two individuals with multiple acute rejections (MAR) were analyzed as a subgroup of AR. Polymerase chain reaction-allele specific restriction enzyme analysis (PCR-ASRA) and allele-specific hybridization with fluorescence resonance energy transfer (FRET) were used for genotyping. We identified the genotype NFKBIA 126 AA (P = 0.002) as well as the haplotype NFKBIA-126A-297T-826T (P = 0.002) as a potential risk factor for the occurrence of recurrent acute rejections. Furthermore, we assessed an association between the 126 A allele and susceptibility to recurrent acute rejections (P = 0.027). Our data suggest that the NFKBIA 126 G/A polymorphism might be potentially helpful to identify liver transplant recipients with an increased susceptibility to develop recurrent acute rejections.

The dynamics of cortical and hippocampal atrophy in Alzheimer disease.

OBJECTIVE: To characterize rates of regional Alzheimer disease (AD)-specific brain atrophy across the presymptomatic, mild cognitive impairment, and dementia stages. DESIGN: Multicenter case-control study of neuroimaging, cerebrospinal fluid, and cognitive test score data from the Alzheimer's Disease Neuroimaging Initiative. SETTING: Research centers across the United States and Canada. PATIENTS: We examined a total of 317 participants with baseline cerebrospinal fluid biomarker measurements and 3 T1-weighted magnetic resonance images obtained within 1 year. MAIN OUTCOME MEASURES: We used automated tools to compute annual longitudinal atrophy in the hippocampus and cortical regions targeted in AD. We used Mini-Mental State Examination scores as a measure of cognitive performance. We performed a cross-subject analysis of atrophy rates and acceleration on individuals with an AD-like cerebrospinal fluid molecular profile. RESULTS: In presymptomatic individuals harboring indicators of AD, baseline thickness in AD-vulnerable cortical regions was significantly reduced compared with that of healthy control individuals, but baseline hippocampal volume was not. Across the clinical spectrum, rates of AD-specific cortical thinning increased with decreasing cognitive performance before peaking at approximately the Mini-Mental State Examination score of 21, beyond which rates of thinning started to decline. Annual rates of hippocampal volume loss showed a continuously increasing pattern with decreasing cognitive performance as low as the Mini-Mental State Examination score of 15. Analysis of the second derivative of imaging measurements revealed that AD-specific cortical thinning exhibited early acceleration followed by deceleration. Conversely, hippocampal volume loss exhibited positive acceleration across all study participants. CONCLUSIONS: Alzheimer disease-specific cortical thinning and hippocampal volume loss are consistent with a sigmoidal pattern, with an acceleration phase during the early stages of the disease. Clinical trials should carefully consider the nonlinear behavior of these AD biomarkers.

A structural variant of the human interferon-gamma gene.

The first structural IFNG variant, G54D (c.287G>A, ss105106770), located in the second exon, was identified.

No associations of human pulmonary tuberculosis with Sp110 variants.

BACKGROUND: After a recent report on the role of the Ipr1 gene in mediating innate immunity in a mouse model of Mycobacterium tuberculosis infection, the human Ipr1 homologue, Sp110, was considered a promising candidate for an association study in human tuberculosis. METHODS: In a sample of >1000 sputum positive, HIV negative West African patients with pulmonary tuberculosis and >1000 exposed, apparently healthy controls, we have genotyped 21 Sp110 gene variants that were either available from public databases, including HapMap data, or identified by DNA re-sequencing. RESULTS: No significant differences in the frequencies of any of the 21 variants were observed between patients and controls. This applied also for HapMap tagging variants and the corresponding haplotypes, when including sliding window analyses with three adjacent variants, and when stratifying controls for positivity and negativity according to the results of intradermal tuberculin (purified protein derivative, PPD) skin tests. DNA re-sequencing revealed 13 novel Sp110 variants in the 5'-UTR, exons, and adjacent intronic regions. CONCLUSIONS: Based on the results obtained in this case-control study, the hypothesis that Sp110 variants and haplotypes might be associated with distinct phenotypes of human M tuberculosis infection is doubtful.

Promoter haplotypes of the interleukin-10 gene influence proliferation of peripheral blood cells in response to helminth antigen.

Since interleukin (IL)-10 is a key mediator of immunosuppression, and immunosuppression is considered an important element of helminth infection, we studied variants of the putative IL-10 gene promoter in 337 individuals from 130 families heavily exposed to infection by the tissue nematode Onchocerca volvulus. As shown by transmission disequilibrium tests, variants of the IL-10 promoter at positions -1082(G/A), -819(C/T), and -592(C/A) in the haplotype of ATA were significantly associated with high peripheral blood cell (PBC) proliferative responses to O. volvulus antigen (OvAg). No associations were observed using phytohemagglutinin-induced PBC proliferation or with qualitative or quantitative phenotypes of onchocerciasis or onchocerciasis-related skin disease. The findings are compatible with the hypothesis that the ATA haplotype causes a decrease in IL-10 production by OvAg-reactive type-1 regulatory T-lymphocytes, thereby alleviating the suppression of other T cells. To our knowledge, this is the first time that an influence of IL-10 promoter variants is shown on the adaptive immune response.