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Christina M Marra

Publications and source records attributed to Christina M Marra.

17 recordsLinked to original sources
PubMed2026

A new highly discriminatory typing scheme for Treponema pallidum reveals similar levels of genetic variability across lineages.

UNLABELLED: The global resurgence of treponematoses, particularly syphilis, poses a growing public health challenge. Despite advances in sequencing technologies, obtaining complete Treponema pallidum genome sequences for epidemiological studies remains challenging due to clinical sampling and methodological constraints. There is, therefore, a need for rapid, cost-effective, and accessible typing methods. Based on the analysis of 121 T. pallidum genomes spanning all three subspecies (TPA, TPE, and TEN) from diverse regions, we selected seven highly variable genes (tp0136, tp0326, tp0548, tp0705, tp0858, tp0865, and tp1031) to form a new typing system, combined with analysis of macrolide resistance mutations in the 23S rRNA gene. The scheme was validated on 542 global T. pallidum samples, using either Sanger reads or whole genome sequence data, obtaining 82 sequence types (STs) among the 415 fully typed samples. Macrolide resistance mutations were frequently detected, highlighting the need for ongoing epidemiological surveillance. Phylogenetic analyses based on concatenated multilocus typing (MLST) loci recovered the expected subspecies and lineage structure. Consistently, almost all sequence types formed monophyletic groups, indicating strong concordance between MLST-based classification and whole-genome phylogenies. In addition, population genetic analyses revealed comparable levels of within-lineage diversity across subspecies and lineages, despite pronounced differences in geographic distribution, and identified distinct regional genetic clusters consistent with localized transmission dynamics. Importantly, the scheme employs a single-step PCR for all seven targets, facilitating implementation in standard laboratories and is publicly accessible through PubMLST. Overall, our novel MLST scheme offers a rapid, cost-effective tool to advance molecular epidemiology of T. pallidum, facilitate transmission and resistance tracking, and support global surveillance to strengthen public health interventions for syphilis and endemic treponematoses control. IMPORTANCE: We have developed a new multilocus typing (MLST) scheme useful for all Treponema pallidum lineages after the analysis of 121 complete genome sequences of this species. The new scheme can be used directly with uncultured clinical samples, thus providing an excellent contribution to the molecular surveillance of syphilis and other treponematoses. The application of this MLST scheme to over 500 samples from all lineages and main geographical regions has revealed similar levels of genetic variation within them. Furthermore, the analyses show a complex pattern of spread, with global and local contributions to the observed distribution of genetic variation in the syphilis-producing sublineages. The new scheme represents a significant improvement over previous proposals and also reveals unsuspected levels of variability in T. pallidum lineages.

Treponema pallidum↗
PubMed2006

Antibiotic selection may contribute to increases in macrolide-resistant Treponema pallidum.

To determine whether the 23S rRNA mutation that confers macrolide resistance is present in >1 Treponema pallidum strain, 58 isolates collected between 2001 and 2005 were screened for this mutation and for an unrelated sequence that distinguishes between strains. The odds of identifying a macrolide-resistant strain increased over time (P=.006). In subjects who had received macrolides in the previous year, the relative risk of harboring a resistant strain was 2.2 (95% confidence interval, 1.1-4.4; P=.02). The macrolide-resistant strains were not identical. These findings suggest that macrolide resistance may be increasing in multiple strains in response to antibiotic pressure.

Drug Resistance, Bacterial↗
PubMed2006

A prospective study of hearing changes after beginning zidovudine or didanosine in HIV-1 treatment-naïve people.

BACKGROUND: While hearing loss in HIV-infected people after beginning nucleoside reverse transcriptase inhibitors (NRTIs) has been reported, there have been no prospective studies that measured hearing changes longitudinally in treatment-naïve HIV-infected subjects following initiation of regimens containing NRTIs. The goal of this study was to conduct a prospective assessment of the contribution of zidovudine (ZDV) and didanosine (ddI) to hearing loss. METHODS/DESIGN: A prospective observational pilot study to determine whether ZDV or ddI, alone or in combination, are associated with sensorineural hearing loss in HIV-infected persons. Changes in hearing levels at all frequencies and in low and high frequency pure tone averages were measured at baseline, 16, and 32 weeks after initiating antiretroviral therapy. DISCUSSION: Treatment with ZDV and ddI did not result in loss of hearing, even after taking into account noise exposure, immune status and age. The results of this prospective pilot study do not support the notion that treatment with nucleoside antiretrovirals damages hearing.

Adult↗
PubMed2006

Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis.

BACKGROUND: Treatment with natalizumab, a monoclonal antibody against the adhesion molecule very late activation antigen 4, an alpha4beta(1) integrin, was recently associated with the development of progressive multifocal leukoencephalopathy, a demyelinating disorder of the central nervous system caused by JC virus infection. OBJECTIVE: To test the effect of natalizumab treatment on the CD4(+)/CD8(+) T-cell ratios in cerebrospinal fluid (CSF) and peripheral blood. DESIGN: Prospective longitudinal study. SETTING: Academic and private multiple sclerosis centers. PATIENTS: Patients with multiple sclerosis (MS) treated with natalizumab, untreated patients with MS, patients with other neurologic diseases, and human immunodeficiency virus-infected patients. MAIN OUTCOME MEASURES: CD4(+) and CD8(+) T cells were enumerated in CSF and peripheral blood. The mean fluorescence intensity of unbound alpha4 integrin on peripheral blood CD4(+) and CD8(+) T cells was analyzed before and after natalizumab therapy. RESULTS: Natalizumab therapy decreased the CSF CD4(+)/CD8(+) ratio of patients with MS to levels similar to those of human immunodeficiency virus-infected patients. CD4(+)/CD8(+) ratios in peripheral blood in patients with MS progressively decreased with the number of natalizumab doses, but they remained within normal limits. Six months after the cessation of natalizumab therapy, CSF CD4(+)/CD8(+) ratios normalized. The expression of unbound alpha4 integrin on peripheral blood T cells decreases with natalizumab therapy and was significantly lower on CD4(+) vs CD8(+) T cells. CONCLUSIONS: Natalizumab treatment alters the CSF CD4(+)/CD8(+) ratio. Lower expression of unbound alpha4 integrin on CD4(+) T cells is one possible mechanism. These results may have implications for the observation that some natalizumab-treated patients with MS developed progressive multifocal leukoencephalopathy.

Adolescent↗
PubMed2006

Immune surveillance in multiple sclerosis patients treated with natalizumab.

OBJECTIVE: Our objective was to test whether natalizumab, an antibody against very late activating antigen (VLA)-4, interferes with central nervous system immune surveillance as assessed by leukocyte cell numbers and cellular phenotypes in cerebrospinal fluid (CSF) and peripheral blood. METHODS: Cell numbers and cellular phenotypes in CSF and peripheral blood were analyzed in multiple sclerosis (MS) patients treated with natalizumab, untreated MS patients, and patients with other neurological disease (OND). JC virus DNA in the CSF and peripheral blood was quantified by kinetic polymerase chain reaction. RESULTS: CSF leukocyte counts, CD4(+) and CD8(+) T cells, CD19(+) B cells, and CD138(+) plasma cells were significantly lower in natalizumab-treated MS patients compared with OND patients and untreated MS patients. JC virus DNA was not detected in CSF or peripheral blood from natalizumab-treated patients. Six months after cessation of natalizumab therapy, low lymphocyte counts in the CSF persisted. The patient with the highest total leukocyte and CD4(+) and CD8(+)T-cell counts in the CSF experienced a clinical relapse. INTERPRETATION: These data suggest that natalizumab treatment results in a prolonged decrease of lymphocytes in the CSF and are consistent with the hypothesis that natalizumab impairs immune surveillance of the central nervous system.

Adult↗
PubMed2006

A placebo-controlled study of memantine for the treatment of human immunodeficiency virus-associated sensory neuropathy.

Distal sensory polyneuropathy (DSP) is the most frequent neurological complication of HIV infection. Neuropathic symptoms vary from mild paresthesias to severe pain that respond only partially to symptomatic treatment. Forty-five subjects with human immunodeficiency virus (HIV)-associated symptomatic DSP (SDSP) were enrolled in a randomized, multicenter, 16-week placebo-controlled study of memantine, an N-methyl-D-aspartate (NMDA) uncompetitive antagonist. Although memantine was well tolerated, no trend toward clinical benefit was observed. Results were similar to those of other pilot studies of memantine for neuropathic pain unrelated to HIV, suggesting that memantine is ineffective for the symptomatic treatment of HIV-associated SDSP.

Adult↗
PubMed2004

Treponema pallidum strain-specific differences in neuroinvasion and clinical phenotype in a rabbit model.

BACKGROUND: The relationship between neuroinvasion and other manifestations of syphilis and the infecting strain of Treponema pallidum is not known. METHODS: Six groups of 8 rabbits were intravenously infected with 1 x 108 organisms from 1 of 6 strains of T. pallidum. Rabbits were examined 2-3 times/week; blood and cerebrospinal fluid (CSF) were collected weekly and every 2 weeks, respectively, for 10-12 weeks. Degree of CSF pleocytosis and skin-lesion severity were estimated by the area under the white blood cell-versus-time and lesion-versus-time curves. RESULTS: Maximum serum Venereal Disease Research Laboratory test titers, time to maximum titer, degree of CSF pleocytosis, and severity of skin lesions differed significantly among infecting strains. Overall, T. pallidum was identified, by reverse-transcriptase polymerase chain reaction, in CSF from 13 (27.7%) of 47 rabbits and was never identified in CSF from rabbits infected with 1 of the strains. The time course of detection varied by infecting strain. Severity of skin lesions and of CSF pleocytosis were inversely correlated (P=.005). CONCLUSIONS: There are particularly neuroinvasive T. pallidum strains, and the clinical phenotype of infection varies with infecting strain. This information could ultimately be used to identify patients at increased risk for neuroinvasion and, thus, at risk for neurosyphilis.

Animals↗
PubMed2004

Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter?

To identify factors that affect normalization of laboratory measures after treatment for neurosyphilis, 59 subjects with neurosyphilis underwent repeated lumbar punctures and venipunctures after completion of therapy. The median duration of follow-up was 6.9 months. Stepwise Cox regression models were used to determine the influence of clinical and laboratory features on normalization of cerebrospinal fluid (CSF), white blood cells (WBCs), CSF protein concentration, CSF Venereal Disease Research Laboratory (VDRL) reactivity, and serum rapid plasma reagin (RPR) titer. Human immunodeficiency virus (HIV)-infected subjects were 2.5 times less likely to normalize CSF-VDRL reactivity than were HIV-uninfected subjects. HIV-infected subjects with peripheral blood CD4+ T cell counts of < or =200 cells/ mu L were 3.7 times less likely to normalize CSF-VDRL reactivity than were those with CD4+ T cell counts of >200 cells/ mu L. CSF WBC count and serum RPR reactivity were more likely to normalize but CSF-VDRL reactivity was less likely to normalize with higher baseline values. Future studies should address whether more intensive therapy for neurosyphilis is warranted in HIV-infected individuals.

Anti-Bacterial Agents↗
PubMed2004

Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features.

OBJECTIVE: To define clinical and laboratory features that identify patients with neurosyphilis. METHODS: Subjects (n=326) with syphilis but no previous neurosyphilis who met 1993 Centers for Disease Control and Prevention criteria for lumbar puncture underwent standardized history, neurological examination, venipuncture, and lumbar puncture. Neurosyphilis was defined as a cerebrospinal fluid (CSF) white blood cell count >20 cells/ microL or reactive CSF Venereal Disease Research Laboratory (VDRL) test result. RESULTS: Sixty-five subjects (20.1%) had neurosyphilis. Early syphilis increased the odds of neurosyphilis in univariate but not multivariate analyses. In multivariate analyses, serum rapid plasma reagin (RPR) titer > or =1 : 32 increased the odds of neurosyphilis 10.85-fold in human immunodeficiency virus (HIV)-uninfected subjects and 5.98-fold in HIV-infected subjects. A peripheral blood CD4+ T cell count < or =350 cells/ microL conferred 3.10-fold increased odds of neurosyphilis in HIV-infected subjects. Similar results were obtained when neurosyphilis was more stringently defined as a reactive CSF VDRL test result. CONCLUSION: Serum RPR titer helps predict the likelihood of neurosyphilis. HIV-induced immune impairment may increase the risk of neurosyphilis.

Adolescent↗
PubMed2004

Neurosyphilis.

Treponema pallidum, the bacterium that causes syphilis, invades the central nervous system early in the course of disease but causes persistent infection in only a subset of infected persons. Individuals with persistent infection or asymptomatic meningitis are at risk for developing symptomatic neurosyphilis if they are not treated with a drug regimen that achieves sufficient drug levels in cerebrospinal fluid to kill the organism. In this article, recent studies that address the risk, diagnosis, and management of neurosyphilis are discussed within the context of a brief review. Particular attention is given to current controversies. In the developed world, these issues are particularly relevant to persons who are infected with HIV.

Animals↗
PubMed2004

Regional patterns of brain metabolites in AIDS dementia complex.

The relationship of the cellular changes in the HIV-infected brain to the onset and progression of AIDS dementia complex (ADC) remains uncertain. We undertook an in vivo proton magnetic resonance spectroscopy (MRS) study and used factor analysis to identify specific cellular and regional brain changes that may serve as metabolic markers of ADC. The ratio of N-acetyl aspartate (NAA), choline (Cho), and myoinositol (MI) over creatine (Cr), markers of neuronal and glial cell metabolism, were measured in the basal ganglia, centrum semiovale, and parietal cortex from 100 subjects with and without ADC. Three metabolic patterns were identified, which we termed "inflammatory" (mainly MI/Cr elevations in all three regions plus Cho/Cr increases in the centrum semiovale and parietal cortex), "basal ganglia" (mostly NAA/Cr and Cho/Cr elevations in the basal ganglia), and "neuronal" (primarily NAA/Cr reductions in the centrum semiovale and the parietal cortex). Logistic regression analysis revealed that, adjusted for age, basal ganglia and neuronal pattern scores were strongly associated with ADC but inflammatory levels were not. We conclude that by using factor analysis, we are able to combine multiple metabolites across brain regions in a biologically plausible manner and construct a predictive model of ADC adjusting for relevant factors such as age.

AIDS Dementia Complex↗
PubMed2004

Relapse of secondary syphilis after benzathine penicillin G: molecular analysis.

BACKGROUND AND OBJECTIVES: It is difficult to distinguish between relapse and reinfection in patients who develop a second episode of syphilis after treatment. GOAL: The goal of this study was to use molecular methods to distinguish between relapse and reinfection in a patient with recurrent secondary syphilis. STUDY DESIGN: Treponema pallidum tprK sequences were amplified from cerebrospinal fluid (CSF), skin, and blood from the initial presentation and from blood from the second presentation. Neighbor-joining clustering analysis was performed for deduced tprK sequences from the case patient and for sequences derived from blood and CSF of a different patient with secondary syphilis. RESULTS: The case patient's tprK sequences from both episodes of syphilis clustered together with a high degree of similarity. CONCLUSION: Our patient likely relapsed despite treatment.

Adult↗
PubMed2003

A multi-center 1H MRS study of the AIDS dementia complex: validation and preliminary analysis.

PURPOSE: To demonstrate the technical feasibility and reliability of a multi-center study characterizing regional levels of the brain metabolite ratios choline (Cho)/creatine (Cr) and myoinositol (MI)/Cr, markers of glial cell activity, and N-acetyl aspartate (NAA)/Cr, a marker of mature neurons, in subjects with AIDS dementia complex (ADC). MATERIALS AND METHODS: Using an automated protocol (GE PROBE-P), short echo time spectra (TE = 35 msec) were obtained at eight sites from uniformly prepared phantoms and from three brain regions (frontal white matter, basal ganglia, and parietal cortex) of normal volunteers and ADC and HIV-negative subjects. RESULTS: A random-effects model of the phantom and volunteer data showed no significant inter-site differences. Feasibility of a multi-center study was further validated by detection of significant differences between the metabolite ratios of ADC subjects and HIV-negative controls. ADC subjects exhibited significantly higher Cho/Cr and MI/Cr in the basal ganglia and significantly reduced NAA/Cr and significantly higher MI/Cr in the frontal white matter. These results are consistent with the predominantly subcortical distribution of the pathologic abnormalities associated with ADC. CONCLUSION: This is the first study to ascertain and validate the reliability and reproducibility of a short echo time (1)H-MRS acquisition sequence from multiple brain regions in a multi-center setting. It should now be possible to examine the regional effects of HIV infection in the brain in a large number of subjects and to study the metabolic effects of new therapies for the treatment of ADC in a clinical trial setting.

AIDS Dementia Complex↗
PubMed2002

A pilot study of cidofovir for progressive multifocal leukoencephalopathy in AIDS.

OBJECTIVE: To assess the safety, tolerability and effect of cidofovir for HIV-1 associated progressive multifocal leukoencephalopathy. DESIGN: Prospective, open-label study in nine AIDS Clinical Trials Units. PATIENTS AND METHODS: Twenty-four HIV-1-infected individuals, with neuroimaging and clinical findings consistent with PML, and symptoms for 90 days or less, whose diagnosis was confirmed by the detection of JC virus DNA in the cerebrospinal fluid or brain biopsy, received cidofovir 5 mg/kg intravenously at baseline and 1 week, followed by infusions every 2 weeks with the dose adjusted for renal function. Follow-up continued to 24 weeks. The safety of cidofovir and changes in neurological examination scores between baseline and week 8 were assessed. RESULTS: Seventeen subjects were receiving potent antiretroviral agents. Survival at 12 weeks was 54%. The CD4 cell count at entry was significantly associated with survival (P = 0.02). Five subjects discontinued treatment because of toxicity: a 50% or greater decrease in intraocular pressure in either eye in four, and proteinuria in one. Overall, magnetic resonance imaging abnormalities and neurological examination scores worsened. Only two subjects experienced a 25% or greater improvement in neurological examination scores at week 8, which were significantly better in subjects with HIV-1-RNA levels of 500 copies/ml or less at entry compared with those with HIV-1-RNA levels over 500 copies/ml (P = 0.05). CONCLUSION: Cidofovir did not improve neurological examination scores at week 8. However, such scores were significantly better in subjects who entered with suppressed plasma HIV-1-RNA levels, which could be the result of control of HIV-1 infection itself or cidofovir.

Adult↗