Long-term effects of intermittent interleukin-2 therapy in chronic HIV-infected patients (ANRS 048-079 Trials)

OBJECTIVE: Interleukin (IL)-2 therapy leads to significant CD4 cell increases in HIV-infected patients. Since phase III trials are ongoing, studies supporting the long-term feasibility of this strategy are needed. METHODS: We studied the long-term outcomes of 131 patients treated with IL-2 in two studies initiated either before (ANRS 048) or following (ANRS 079) the advent of HAART. RESULTS: At the last assessment (median follow-up 3.4 years), these patients experienced a gain of 428 cells/microl and a decrease in plasma HIV RNA to 1.70 log10 copies/ml. In both studies, high CD4 cell counts were maintained with a median of ten 5-day cycles of subcutaneous IL-2. Median time since the last cycle was 2 years. At last assessment, 59% of 048 patients maintained a non-HAART regimen. Detailed analysis at week 170 showed that median CD4 cell counts were 856 (048) and 964 (079) cells/microl. This corresponded to a gain from baseline of 515 (048) and 627 (079) cells/microl. The median viral load decreases from baseline and corresponded to 1.70 (048) and 1.88 (079) log10 copies/ml. Comparisons across the studies showed that CD4 gains and viral load changes were similar whether HAART or non-HAART was used. The frequency of cycling, but not CD4 cell counts, viral loads or antiviral regimen at baseline, was predictive of long-term CD4 gain (P = 0.03). CONCLUSION: Altogether, these observations support IL-2 as a long-term therapeutic strategy in HIV infection.     

Neurobiological effects of repeated radiofrequency exposures in male senescent rats

The increasing use of mobile phones by aging people raises issues about the effects of radiofrequency electromagnetic fields (RF-EMF) on the aging central nervous system. Here, we tested if mobile phone RF-EMF exposures could exacerbate senescence-typical neurobiological deficits. Thus, aged (22–24 months) and young (4–6 months) adult male rats were subjected to head RF-EMF exposures (900 MHz, specific absorption rate (SAR) of 6 W/kg, 45 min/day for 1 month in restraint rockets). To assess senescence-typical neurobiological deficits, spatial memory, emotional memory, anxiety-related behavior, locomotor activity, interleukins (IL)-1β and 6, glial fibrillary acidic protein and corticosterone were measured. Aged rats presented deficits in spatial learning, exploration, anxiety-related behaviors, and increased hippocampal ILs and cortical IL-1β. Results showed that senescence-typical neurobiological deficits were not modified by RF-EMF exposures. RF-EMF-exposed rats (young and aged adults pooled) had decreased anxiety-related behaviors in the elevated plus maze. This study which is the first to assess RF-EMF exposures during late aging did not support the hypothesis of a specific cerebral vulnerability to RF-EMF during senescence. More investigations using longer RF-EMF exposures should be performed to conclude regarding the inoffensiveness of RF-EMF exposures.     

Diagnostic approach to neurotransmitter monoamine disorders: experience from clinical,biochemical, and genetic profiles

Background and aim

To improve the diagnostic work-up of patients with diverse neurological diseases, we have elaborated specific clinical and CSF neurotransmitter patterns.

Methods

Neurotransmitter determinations in CSF from 1200 patients revealed abnormal values in 228 (19%) cases. In 54/228 (24%) patients, a final diagnosis was identified.

Results

We have reported primary (30/54, 56%) and secondary (24/54, 44%) monoamine neurotransmitter disorders. For primary deficiencies, the most frequently mutated gene was DDC (n = 9), and the others included PAH with neuropsychiatric features (n = 4), PTS (n = 5), QDPR (n = 3), SR (n = 1), and TH (n = 1). We have also identified mutations in SLC6A3, FOXG1 (n = 1 of each), MTHFR (n = 3), FOLR1, and MTHFD (n = 1 of each), for dopamine transporter, neuronal development, and folate metabolism disorders, respectively. For secondary deficiencies, we have identified POLG (n = 3), ACSF3 (n = 1), NFU1, and SDHD (n = 1 of each), playing a role in mitochondrial function. Other mutated genes included: ADAR, RNASEH2B, RNASET2, SLC7A2-IT1 A/B lncRNA, and EXOSC3 involved in nuclear and cytoplasmic metabolism; RanBP2 and CASK implicated in post-traductional and scaffolding modifications; SLC6A19 regulating amino acid transport; MTM1, KCNQ2 (n = 2), and ATP1A3 playing a role in nerve cell electrophysiological state. Chromosome abnormalities, del(8)(p23)/dup(12) (p23) (n = 1), del(6)(q21) (n = 1), dup(17)(p13.3) (n = 1), and non-genetic etiologies (n = 3) were also identified.

Conclusion

We have classified the final 54 diagnoses in 11 distinctive biochemical profiles and described them through 20 clinical features. To identify the specific molecular cause of abnormal NT profiles, (targeted) genomics might be used, to improve diagnosis and allow early treatment of complex and rare neurological genetic diseases.

     

Subcutaneous emphysema, pneumomediastinum, pneumoperitoneum and retropneumoperitoneum following a colonoscopy with mucosectomy

The occurrence of associated intraperitoneal and retroperitoneal colonic perforation is uncommon after colonoscopy. We report a case of this complication revealed by subcutaneous emphysema, pneumomediastinum, pneumoperitoneum and retro-pneumoperitoneum after colonic mucosectomy.     

Pseudomonas aeruginosa otochondritis complicating localized cutaneous leishmaniasis: prevention of mutilation by early antibiotic therapy

A patient with an ulcerated cutaneous leishmaniasis of the pinna had suppurative otochondritis after a first unsuccessful course of treatment with meglumine antimoniate. Although the Leishmania ulceration healed after a second course of meglumine antimoniate, and despite three oral dicloxacillin or pristinamycin courses, the otochondritis extended and an abscess developed. Pus from the abscess revealed a pure culture of Pseudomonas aeruginosa. Five days of oral ciprofloxacin plus rifampin led to a marked improvement. The P. aeruginosa isolate was sensitive to ciprofloxacin but fully resistant to rifampin. Healing with minimal mutilation was obtained at the end of a six-week course of multiple antibiotic therapy. Pseudomonas aeruginosa otochondritis was a co-factor of cartilage mutilation in this patient. Thus, infection with P. aeruginosa should be promptly treated when present in tender cutaneous or mucosal leishmaniasis lesions near cartilaginous areas.     

Apolipoprotein E epsilon4 allele frequency in elderly depressed patients with and without cerebrovascular disease

Late-onset depression (LOD) could be a very early manifestation of Alzheimer's disease (AD), although contradictory results have been reported. Cerebrovascular disease (CVD) may favor the development of LOD, and that the particular forms of vascular depression should be individualized. The Apolipoprotein E (ApoE) epsilon4 allele was shown to be a risk factor for AD. Its role in LOD is controversial, while it is still unknown in vascular depression. Our objective was to clarify the relationship between ApoE epsilon4 allele and LOD in patients with and without CVD. We examined the ApoE phenotypes in a sample of 311 subjects: 50 with vascular LOD, 24 with LOD without CVD, 115 with AD and 122 normal controls (NC). The study of the ApoE epsilon4 allele frequency showed significant differences between: AD group and the vascular LOD and NC groups; LOD group without CVD compared with NC group (p<0.05 to 0.001). The frequency of the epsilon4 allele in the LOD group without CVD did not differ significantly from the AD group, similarly the frequency of the epsilon4 allele in the vascular LOD group was not different from that in NC. The study suggests an association between the ApoE epsilon4 allele and the LOD without CVD. These patients could be at risk of developing AD by an epsilon4-dependent pathway. In contrast, the results show no association between the presence of ApoE epsilon4 allele and vascular depression and provide further evidence in support of the concept that ApoE epsilon4 allele is not associated with clinical CVD.     

Myocardial Ischemia Induced by 5-Fluorouracil: A Prospective Electrocardiographic and Cardiac Biomarker Study

BackgroundCardiotoxicity induced by 5‐fluorouracil (5‐FU) is well known but poorly understood. In this study, we undertook ECG recording (Holter) and analyses of the biomarkers troponin and copeptin in patients receiving 5‐FU to increase our understanding of the cardiotoxicity.Subjects, Materials, and MethodsPatients with colorectal or anal cancer that received first‐time treatment with 5‐FU‐based chemotherapy were prospectively included. Holter recording, clinical evaluation, 12‐lead electrocardiogram, and assessment of plasma concentrations of troponin I and copeptin were performed before (control) and during 5‐FU treatment (intervention).ResultsA total of 108 patients were included, 82 with colorectal and 26 with anal cancer. The proportion of patients with myocardial ischemia on Holter recording was significantly higher during the first 5‐FU infusion (14.1%) than before (3.7%; p = .001). The ischemic burden per day (p = .001), the number of ST depression episodes per day (p = .003), and the total duration of ischemic episodes per day (p = .003) were higher during the first 5‐FU infusion than before, as was plasma copeptin (p < .001), whereas plasma troponin I was similar (p > 0.999). Six patients (5.6%) developed acute coronary syndromes and two (1.8%) developed symptomatic arrhythmias during 5‐FU treatment.Conclusion5‐FU infusion is associated with an increase in the number of patients with myocardial ischemia on Holter recording. According to biomarker analyses, 5‐FU is associated with an increase in copeptin, but rarely with increases in cardiac troponin I. However, 5%–6% of the patients developed acute coronary syndromes during treatment with 5‐FU.Implications for PracticeSymptomatic 5‐fluorouracil (5‐FU) cardiotoxicity occurs in 0.6%–19% of patients treated with this drug, but a small electrocardiographic (Holter) study has revealed silent myocardial ischemia in asymptomatic patients, suggesting a more prevalent subclinical cardiac influence. This study demonstrated a significant increase in the number of patients with myocardial ischemia on Holter recording during 5‐FU treatment and an increase in ischemic burden. Cardiac biomarker analyses suggested that 5‐FU infusion results in endogenous stress (increased copeptin) but rarely induces myocyte injury (no change in troponin). These findings suggest a more prevalent cardiac influence from 5‐FU and that Holter recording is an important tool in the evaluation of patients with suspected cardiotoxicity from 5‐FU.     

Evaluation of methods to assess transmission potential of Venezuelan equine encephalitis virus by mosquitoes and estimation of mosquito saliva titers

Determining the dose of an arbovirus transmitted by a mosquito is important to design transmission and pathogenesis studies simulating natural infection. Several different artificial infection and transmission methods used to assess vector competence and to estimate the dose injected during mosquito feeding have not been fully evaluated to determine whether they accurately reflect natural transmission. Additionally, it is not known whether different mosquito vectors transmit similar amounts of a given virus. Therefore, we compared three traditional artificial transmission methods using Venezuelan equine encephalitis virus (VEEV) and Aedes albopictus and Ochlerotatus taeniorhynchus mosquitoes. Both the mosquito species and the infection route used affected the amount of virus detected in the saliva after a 10-day extrinsic incubation period. Median titers of virus detected in saliva of Ae. albopictus and Oc. taeniorhynchus mosquitoes ranged from 0.2 to 1.1 log(10) (mean 0.7-1.4 log(10)) and 0.2 to 3.2 log(10) (mean 1.0-3.6 log(10)) plaque-forming units, respectively. The results of this study will aid in the design of transmission and pathogenesis studies involving arboviruses.