ORIGINAL ARTICLE: AIDS and optic neuritis in a rhesus monkey infected with the R5 clade C SHIV‐1157ipd3N4

A Chinese rhesus macaque infected with the pathogenic CCR5‐tropic clade C simian‐human immunodeficiency virus, SHIV‐1157ipd3N4, had persistent viremia, depletion of CD4⁺ T cells to <200 cells/μl, opportunistic infections, coagulopathy, and gradual development of bilateral blindness. MRI revealed marked thickening of both optic nerves. Histopathological evaluation showed diffuse cellular infiltration at necropsy and a focus of SHIV‐infected cells. This is the first report of CNS pathology following chronic infection with an obligate R5 SHIV.     

Specific dynamic action of ambystomatid salamanders and the effects of meal size, meal type, and body temperature

The past decade has witnessed a dramatic increase in studies of amphibian and reptile specific dynamic action (SDA). These studies have demonstrated that SDA, the summed energy expended on meal digestion and assimilation, is affected significantly by meal size, meal type, and body size and to some extent by body temperature. While much of this attention has been directed at anuran and reptile SDA, we investigated the effects of meal size, meal type, and body temperature on the postprandial metabolic responses and the SDA of the tiger salamander (Ambystoma tigrinum tigrinum). We also compared the SDA responses among six species of Ambystoma salamanders representing the breadth of Ambystoma phylogeny. Postprandial peaks in VO(2) and VO(2), duration of elevated metabolism, and SDA of tiger salamanders increased with the size of cricket meals (2.5%-12.5% of body mass). For A. tigrinum, as for other ectotherms, a doubling of meal size results in an approximate doubling of SDA, a function of equal increases in peak VO(2) and duration. For nine meal types of equivalent size (5% of body mass), the digestion of hard-bodied prey (crickets, superworms, mealworms, beetles) generated larger SDA responses than the digestion of soft-bodied prey (redworms, beetle larvae). Body temperature affected the profile of postprandial metabolism, increasing the peak and shortening the duration of the profile as body temperature increased. SDA was equivalent among three body temperatures (20 degrees, 25 degrees, and 30 degrees C) but decreased significantly at 15 degrees C. Comparatively, the postprandial metabolic responses and SDA of Ambystoma jeffersonianum, Ambystoma maculatum, Ambystoma opacum, Ambystoma talpoideum, Ambystoma texanum, and the conspecific Ambystoma tigrinum mavortium digesting cricket meals that were 5% of their body mass were similar (independent of body mass) to those of A. t. tigrinum. Among the six species, standard metabolic rate, peak postprandial VO(2), and SDA scaled with body mass with mass exponents of 0.72, 0.78, and 1.05, respectively.     

Use of Trichomonas vaginalis clinical isolates to evaluate correlation of gene expression and metronidazole resistance

We investigated whether variations in gene expression of enzymes associated with anaerobic resistance of laboratory-derived strains of Trichomonas vaginalis could be detected in a group of 28 clinical isolates with variations in metronidazole sensitivity. We compared isolates by real-time PCR because this method allows for highly sensitive quantification of mRNA and for evaluation of several genes simultaneously. We found that PFOR gene A mRNA levels were highly correlated with PFOR gene B levels, as well as the D subunit of malic enzyme and ferrodoxin. Ferrodoxin mRNA expression was also significantly correlated with that of malic enzyme and hydrogenase. However, when we evaluated relationships between these enzymes and resistance to metronidazole, we found no significant correlations between aerobic or anaerobic in vitro sensitivity to drug and mRNA levels of any of the enzymes tested. Similarly, using a Student's t-test, no significant differences in enzyme mRNA levels were observed between isolates separated by metronidazole resistance or susceptibility. The lack of correlation between gene expression and resistance or susceptibility could be the result of differences in expression at the protein level or because other biochemical pathways or genes are involved in the resistance observed in clinical settings.     

Multiplex analysis of circulating cytokines in the sera of patients with different clinical forms of visceral leishmaniasis.

BACKGROUND: The clinical spectrum of visceral leishmaniasis (VL), a chronic intracellular parasitic disease, ranges from a subclinical, asymptomatic infection to severe clinical disease (kala-azar). In experimental leishmaniasis, mice that have a Th1 response to infection tend to have limited disease while a Th2 response is associated with disease progression. Humans with VL most often have mixed rather than polarized responses. However, most clinical studies have used methods that require a relatively large sample volume, thus limiting their scope. Measuring multiple cytokine levels in blood samples using a multiplexed microsphere assay (MMA) may be useful to further evaluate the Th1/Th2 paradigm in humans. METHODS: Bangladeshi individuals (n=120) living in an area endemic for VL were categorized into one of the five clinical categories. Sera from these individuals were measured for levels of IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IFN-gamma, and TNF-alpha by multiplexed microsphere cytokine immunoassay. RESULTS: Circulating IL-8, IL-10, and IL-12 differed significantly among the clinical groups. Persons with kala-azar demonstrated the highest median levels of IL-8 and IL-10 but lower median levels of IL-12. CONCLUSIONS: The MMA for cytokines is an extremely time-and sample-efficient method for characterizing circulating cytokine levels in visceral leishmaniasis patients.     

Evaluation of an Online Platform for Multiple Sclerosis Research: Patient Description,Validation of Severity Scale,and Exploration of BMI Effects on Disease Course

Objectives

To assess the potential of an online platform, PatientsLikeMe.com (PLM), for research in multiple sclerosis (MS). An investigation of the role of body mass index (BMI) on MS disease course was conducted to illustrate the utility of the platform.

Methods

First, we compared the demographic characteristics of subjects from PLM and from a regional MS center. Second, we validated PLM’s patient-reported outcome measure (MS Rating Scale, MSRS) against standard physician-rated tools. Finally, we analyzed the relation of BMI to the MSRS measure.

Results

Compared with 4,039 MS Center patients, the 10,255 PLM members were younger, more educated, and less often male and white. Disease course was more often relapsing remitting, with younger symptom onset and shorter disease duration. Differences were significant because of large sample sizes but small in absolute terms. MSRS scores for 121 MS Center patients revealed acceptable agreement between patient-derived and physician-derived composite scores (weighted kappa = 0.46). The Walking domain showed the highest weighted kappa (0.73) and correlation (rs = 0.86) between patient and physician scores. Additionally, there were good correlations between the patient-reported MSRS composite and walking scores and physician-derived measures: Expanded Disability Status Scale (composite rs = 0.61, walking rs = 0.74), Timed 25 Foot Walk (composite rs = 0.70, walking rs = 0.69), and Ambulation Index (composite rs = 0.81, walking rs = 0.84). Finally, using PLM data, we found a modest correlation between BMI and cross-sectional MSRS (rho = 0.17) and no association between BMI and disease course.

Conclusions

The PLM population is comparable to a clinic population, and its patient-reported MSRS is correlated with existing clinical instruments. Thus, this online platform may provide a venue for MS investigations with unique strengths (frequent data collection, large sample sizes). To illustrate its applicability, we assessed the role of BMI in MS disease course but did not find a clinically meaningful role for BMI in this setting.     

Irrigation and infection: the immunoepidemiology of schistosomiasis in ancient Nubia

Schistosomiasis has been deemed "the most important water-based disease from a global public-health perspective" in modern populations. To better understand the burden of schistosomiasis in ancient populations, we conducted immunologic examinations of desiccated tissue samples from two ancient Nubian populations, Wadi Halfa (N = 46) and Kulubnarti (N = 191). Saqia irrigated agriculture increases the available habitat for the aquatic vector snails and the risk of exposure. On the basis of evidence regarding the impact of saqia irrigation on schistosomiasis prevalence and transmission in modern populations, we predicted that the prevalence of Schistosoma mansoni infection would be higher in Wadi Halfa (saqia irrigation) than Kulubnarti (annual flooding). We also predicted that peak infection prevalence would occur at an earlier age within the Wadi Halfa population than the Kulubnarti population and that in both populations the prevalence of schistosomiasis would be higher in males than females due to differential water contact. The prevalence of S. mansoni was greater in the Wadi Halfa population (26.1%) than at Kulubnarti (9.4%) (P = 0.002). However, peak prevalence of infection did not occur in a younger age category within the Wadi Halfa population; prevalence of infection peaked at 66.7% in the mature adult age group (46+ years) in the Wadi Halfa population and at 16% in the later child age group (6-10 years) in the Kulubnarti population. There were no statistically significant differences in prevalence between males and females of either population. The impact of human alteration of the environment on the transmission of schistosomiasis is clearly shown in these populations.     

Recent advances in the immunogenetics of idiopathic inflammatory myopathy

This review summarizes the previous and current literature on the immunogenetics of idiopathic inflammatory myopathy (IIM) and updates the research progress that has been made over the past decade. A substantial part of the genetic risk for developing adult- and juvenile-onset IIM lies within the major histocompatibility complex (MHC), and a tight relationship exists between individual human leukocyte antigen alleles and specific serological subtypes, which in turn dictate clinical disease phenotypes. Multiple genetic regions outside of the MHC are increasingly being identified in conferring IIM disease susceptibility. We are still challenged with the task of studying a serologically and clinically heterogeneous disorder that is rarer by orders of magnitude than the likes of rheumatoid arthritis. An ongoing and internationally coordinated IIM genome-wide association study may provide further insights into IIM immunogenetics.     

Schistosoma mansoni enhances host susceptibility to mucosal but not intravenous challenge by R5 Clade C SHIV

Background

The high prevalence of HIV-1/AIDS in areas endemic for schistosomiasis and other helminthic infections has led to the hypothesis that parasites increase host susceptibility to immunodeficiency virus infection. We previously showed that rhesus macaques (RM) with active schistosomiasis were significantly more likely to become systemically infected after intrarectal (i.r.) exposure to an R5-tropic clade C simian-human immunodeficiency virus (SHIV-C) than were parasite-free controls. However, we could not address whether this was due to systemic or mucosal effects. If systemic immunoactivation resulted in increased susceptibility to SHIV-C acquisition, a similarly large difference in host susceptibility would be seen after intravenous (i.v.) SHIV-C challenge. Conversely, if increased host susceptibility was due to parasite-induced immunoactivation at the mucosal level, i.v. SHIV-C challenge would not result in significant differences between parasitized and parasite-free monkeys.

Methods and Findings

We enrolled two groups of RM and infected one group with Schistosoma mansoni; the other group was left parasite-free. Both groups were challenged i.v. with decreasing doses of SHIV-C. No statistically significant differences in 50% animal infectious doses (AID₅₀) or peak viremia were seen between the two groups. These data strongly contrast the earlier i.r. SHIV-C challenge (using the same virus stock) in the presence/absence of parasites, where we noted a 17-fold difference in AID₅₀ and one log higher peak viremia in parasitized monkeys (P<0.001 for both). The lack of significant differences after the i.v. challenge implies that the increased host susceptibility is predominantly due to parasite-mediated mucosal upregulation of virus replication and spread, rather than systemic effects.

Conclusions

The major impact of schistosome-induced increased host susceptibility is at the mucosal level. Given that >90% of all new HIV-1 infections worldwide are acquired through mucosal contact, parasitic infections that inflame mucosae may play an important role in the spread of HIV-1.