Immunogenicity of an AAV-Based COVID-19 Vaccine in Murine Models of Obesity and Aging

The SARS-CoV-2 pandemic has had a disastrous impact on global health. Although some vaccine candidates have been effective in combating SARS-CoV-2, logistical, economical, and sociological aspects still limit vaccine access globally. Recently, we reported on two room-temperature stable AAV-based COVID-19 vaccines that induced potent and protective immunogenicity following a single injection in murine and primate models. Obesity and old age are associated with increased mortality in COVID-19, as well as reduced immunogenicity and efficacy of vaccines. Here, we investigated the effectiveness of the AAVCOVID vaccine candidates in murine models of obesity and aging. Results demonstrate that obesity did not significantly alter the immunogenicity of either vaccine candidate. In aged mice, vaccine immunogenicity was impaired. These results suggest that AAV-based vaccines may have limitations in older populations and may be equally applicable in obese and non-obese populations.     

Treatment of rheumatoid polyarthritis with methotrexate in Dakar: efficacy, tolerance and cost

Methotrexate (MTX), which has been used for years in cancer treatment, is now being proposed as a first-line treatment for rheumatoid arthritis (RA), despite its potential side effects. The aim of this study was to investigate the short-term efficacy, safety and relative cost of low-dose MTX for the treatment of RA. We carried out an open, nonrandomized trial in which patients received a 7 mg injection of MTX once per week, with clinical and biological follow up. A single physician performed the weekly assessments, which involved evaluation of the duration of morning stiffness, the number of night awakenings, the number of painful and swollen joints and Ritchie's index. Blood cell count and erythrocyte sedimentation rate were determined monthly. Twelve RA patients were enrolled in the trial, over a mean treatment period of 356 +/- 175 days. A significant improvement was observed in all variables except the number of swollen joints. Ritchie's index decreased from a mean of 31.8 +/- 11.85 to 6.5 +/- 8.98 (p<1.6 x 10- 4). Minor adverse reactions were observed but none indicated treatment withdrawal: 6 cases of nausea, 2 of a moderate increase in transaminase activity, 1 of bronchitis, in which the responsibility of MTX was not definitely established and 3 cases in which hemoglobin levels decreased. The monthly cost of the treatment, including the drug itself and laboratory tests, is lower than that of gold salt injection. Three issues of key importance in our region were investigated in this study: 1) the possible desire to become pregnant of female patients undergoing MTX treatment. In addition, some of the young and unmarried patients did not understand or appreciate the contraceptive effects of the treatment; 2) poor compliance with the treatment due to limited financial resources. Many patients did not regularly attend for their follow-up appointments and many stopped taking the medication. One third of the patients were lost to follow-up during this study; 3) the prevalence of chronic hepatitis, which may limit the use of MTX in our region. Serological tests should be performed before the treatment is started and a liver biopsy is recommended for patients with chronic hepatitis B or C.     

Alteration of pulmonary cytochrome p-450 system: effects of asphalt fume condensate exposure

Exposure to asphalt fumes is a health concern due to the presence of polycyclic aromatic compounds (PACs) in asphalt. Bioactivation of many PACs requires metabolism by the cytochrome P-450 (P-450) system. The objective of this study was to evaluate the effects of exposure of rats to asphalt fume condensate (AFC), collected at the top of a paving asphalt storage tank, on the pulmonary microsomal P-450 system and to determine the genotoxic effects of such exposure. Male Sprague-Dawley rats were intratracheally instilled with saline or with 0.45, 2.22, or 8.88 mg/kg AFC for 3 consecutive days and sacrificed the following day. Lung microsomes were isolated by differential centrifugation of lung homogenates. Microsomal protein level, NADPH cytochrome c reductase activity, and the activities and protein levels of cytochrome P-450 isozymes CYP1A1 and CYP2B1 were monitored to assess the effects of AFC exposure on pulmonary P-450. The activities of CYP2B1 and CYP1A1 were determined by monitoring xenobiotic metabolism of 7-pentoxyresorufin and 7-ethoxyresorufin, respectively. CYP2B1 and CYP1A1 levels were determined by immunochemical analysis. Micronucleus (MN) formation in bone-marrow polychromatic erythrocytes (PCEs) was determined to assess the genotoxic effects of AFC exposure. The results showed that exposure of rats to AFC did not significantly affect total cytochrome P-450 content or cytochrome c reductase activity in the lung. CYP2B1 levels and enzyme activity were not significantly affected by AFC exposure. In contrast, CYP1A1 levels and activity were significantly increased in microsomes isolated from AFC-exposed lungs. Increased MN formation was observed only in high-dose AFC-exposed bone marrow PCEs. These results demonstrate that AFC exposure induced CYP1A1 activity and increased the enzyme levels of CYP1A1 in lung microsomes, suggesting that AFC exposure may alter metabolism of PACs by the cytochrome P-450 system in the lung. Alteration of cytochrome P-450 metabolism of PACs may contribute to the AFC-induced genotoxic effects demonstrated as MN formation.     

Mapping geographic zones of cancer risk with epigenetic biomarkers in normal breast tissue.

PURPOSE: Genetic alterations were previously identified in normal epithelia adjacent to invasive cancers. The aim of this study was to determine DNA methylation in histologically normal tissues from multiple geographic zones adjacent to primary breast tumors. EXPERIMENTAL DESIGN: First, methylation status of a 4-kb region of RASSF1A promoter was interrogated using oligonucleotide-based microarray in 144 samples (primary tumors, 47; adjacent normals, 69; reduction mammoplasty tissues, 28). Second, allelic imbalance (AI)/loss of heterozygosity (LOH) surrounding RASSF1A promoter were analyzed in 30 samples (tumors, 8; adjacent normals, 22). Third, global methylation screening of 49 samples (tumors, 12; adjacent normals, 25; reduction mammoplasty, 12) was done by differential methylation hybridization. Real-time quantitative methylation-specific PCR was used to validate the microarray findings. RESULTS: DNA methylation in the core RASSF1A promoter was low in reduction mammoplasty tissues (P=0.0001) when compared with primary tumors. The adjacent normals had an intermediate level of methylation. The regions surrounding the core were highly methylated in all sample types. Microsatellite markers showed AI/LOH in tumors and some of the adjacent normals. Concurrent AI/LOH and DNA methylation in RASSF1A promoter occurred in two of six tumors. Global methylation screening uncovered genes more methylated in adjacent normals than in reduction mammoplasty tissues. The methylation status of four genes was confirmed by quantitative methylation-specific PCR. CONCLUSIONS: Our findings suggest a field of methylation changes extending as far as 4 cm from primary tumors. These frequent alterations may explain why normal tissues are at risk for local recurrence and are useful in disease prognostication.     

Aspects of genital tuberculosis in women

Thirteen cases of genital tuberculosis are reported to make emphasis onto the difficulties of diagnosis, management and prognosis of the disease. The average age of the patients is 31 years. Most of them were under 30. The circumstances of diagnosis were variable. The diagnosis was essentially made thanks to histology. The evolution was favorable under antibiotics. But clinical sequels as amenorrhea and infertility are frequent.     

Escherichia coli meningitis during bacteremia in the Ibrahima-Diop-Mar infectious diseases clinic, Dakar Fann National Hospital Center (Senegal)

OBJECTIVES: The aim of this study was to describe epidemiological, clinical, and bacteriological aspects of Escherichia coli bacteremia and meningitis in the Ibrahima-Diop-Mar infectious diseases clinic, Dakar Fann National Hospital Center (Senegal). MATERIALS AND METHODS: Data was collected from the bacteriology laboratory and hospitalization files. RESULTS: 57 cases of E. coli bacteremia were reported. Among them, 10 were associated with meningitis. AIDS was diagnosed in 74% of the cases. The global lethality rate was 47% but this rate was higher in cases of associated meningitis (80 vs 37%) and in AIDS patients (50 vs 27%). Ceftriaxone, aztreonam, gentamicin, and ciprofloxacin were active on more than 95% of strains but cotrimoxazole was active on only 49% of the strains. Resistance to cotrimoxazole was higher among E. coli strains isolated from AIDS patients (62 vs 13%). CONCLUSION: The low susceptibility to cotrimoxazole might increase the incidence of E. coli infections among patients with AIDS. It is therefore important to find an alternative to cotrimoxazole chemoprophylaxis.     

Current aspects of pediatric and adult tetanus in Dakar

OBJECTIVE: This retrospective study was undertaken to assess epidemiological and clinical aspects as well as outcome of tetanus cases in patients over 28 days of age, so as to issue recommendations. PATIENTS AND METHODS: This study included patients admitted to the Fann teaching hospital in Dakar from 2001 to 2003. Age, sex, portal of entry, clinical signs, delay from onset to admission, stage and outcome of the tetanus were recorded. RESULTS: 410 cases of tetanus were observed. The sex-ratio was 2.41. The mean age was 20 years [range 2 months-89 years]. Sixty-two percent of the patients were between six and 30 years of age. Most of the patients were workers and craftsmen (58%) or pupils (19%). A wound was the most frequent portal of entry (73%). Tetanus was localized in four out of 406 cases. The global mortality rate was 22%; but it was higher when tetanus was stage III and in case of complications. CONCLUSION: According to these results, it seems necessary to include booster doses in the Expanded Immunization Program, and to implement better prevention strategies targeting people not taken into account in this program. In addition, health care providers should check out the immunization status of their patients and accordingly offer an update or a full course of active immunization.