M C Lobo

To further understand the role of cytokine responses in symptom formation and host defenses in influenza infection, we determined the levels of IL-1beta, IL-2, IL-6, IL-8, IFN-alpha, TGF-beta, and TNF-alpha in nasal lavage fluid, plasma, and serum obtained serially from 19 volunteers experimentally infected with influenza A/Texas/36/91 (H1N1) and correlated these levels with various measures of infection and illness severity. We found that IL-6 and IFN-alpha levels in nasal lavage fluids peaked early (day 2) and correlated directly with viral titers, temperature, mucus production, and symptom scores. IL-6 elevations were also found in the circulation at this time point. In contrast, TNF-alpha responses peaked later (day 3 in plasma, day 4 in nasal fluids), when viral shedding and symptoms were subsiding. Similarly, IL-8 peaked late in the illness course (days 4-6) and correlated only with lower respiratory symptoms, which also occurred late. None of IL-1beta, IL-2, or TGF-beta levels increased significantly. These data implicate IL-6 and IFN-alpha as key factors both in symptom formation and host defense in influenza.

The isolation rates of strains of group C beta-hemolytic streptococci from throat swab cultures of patients with exudative pharyngitis, the common cold, and healthy controls were compared. By using a cohort study design in a college health service, patients with exudative pharyngitis were retrospectively identified by description of tonsillar exudate on chart review. Patients with rhinoviral infection were prospectively identified during a common cold study. Healthy controls were prospectively recruited from patients presenting with noninfectious conditions. Isolation of Lancefield group A and C beta-hemolytic streptococci from throat cultures was used as an outcome measurement. A total of 265 students (62% female; average age 20.2 years) with exudative pharyngitis were identified. A total of 75 students (60% female; average age, 21.7 years) from a common cold study with rhinoviral infection were identified. A total of 162 students (53% female; average age, 22.6 years) were recruited as healthy controls. Group A beta-hemolytic streptococci were isolated from 5% of patients with pharyngitis but none of those with rhinovirus (P = 0.045) and none of the controls (P = 0.007). Group C Streptococcus dysglactiae subsp. equisimilis was isolated from 11% of patients with pharyngitis but none of those with rhinovirus (P = 0.006) and 2% of controls (P = 0.001). Lancefield group C Streptococcus anginosus was isolated from 8% of patients with pharyngitis but 3% of those with rhinovirus (P = 0.18) and 1% of controls (P = 0.006). Heavier growth of colonies on the primary culture plate was observed for patients from whom S. equisimilis and group A beta-hemolytic streptococci were isolated. Lancefield group C beta-hemolytic streptococci appear to be associated with exudative pharyngitis in college students.

Bacteria surviving within leukocytes are protected from the lethal action of high concentrations of most antibiotics, which may explain, in part, the failure of bactericidal antibiotics to eradicate staphylococci from abscesses. Since rifampin is unique in its ability to kill intraleukocytic bacteria, the efficacy of this drug was tested in the treatment of staphylococcal infections in mice. Groups of mice infected intravenously with Staphylococcus aureus were treated with rifampin (20 mg/kg), procaine penicillin (937.5 mg/kg), or methicillin (200 mg/kg). All untreated mice died with disseminated visceral abscesses. After 10 days of therapy, survival in groups treated with penicillin and methicillin was 16 and 20%, respectively, whereas with rifampin it was 80% (P < 0.0005). Antibiotic concentrations in the serum of mice treated with penicillin, methicillin, or rifampin were bactericidal for the strain of S. aureus used. Serial bacterial counts of kidney, lung, and spleen homogenates showed that neither penicillin nor methicillin was able to eradicate staphylococci, whereas rifampin completely sterilized those organs in many mice. When abscess contents and infected peritoneal washings were incubated with high concentrations of penicillin, methicillin, or rifampin, only rifampin killed all of the bacteria. The capacity of rifampin to eradicate staphylococci from pus in vitro and from abscesses in mice appears to be related to the ability of rifampin to kill intraleukocytic bacteria.

Abstract Background Microglial activation is implicated in the pathophysiology of schizophrenia. The monoclonal antibody natalizumab antagonizes α4β1-integrins, and is known to suppress activation of microglia in neuroinflammatory disorders. Aims &amp; Objectives To pharmacologically reduce microglial activation, we investigated the effects of a 3-month treatment with natalizumab on [18F]DPA-714 distribution volume ratio (DVR) and symptom measures in patients with first-episode psychosis (FEP). We hypothesized that natalizumab would decrease [18F]DPA-714 DVR at follow-up, and this change would correlate with symptom improvement. Method A baseline case-control comparison of patients with FEP and healthy volunteers was performed, as well as a nested longitudinal study where patients were assessed following a 3-month treatment with natalizumab 300mg or placebo. All patients were symptomatic despite receiving dopamine blockers (median chlorpromazine equivalent dose 287mg/day). Baseline and follow-up brain imaging was carried out using [18F]DPA-714, a positron emission tomography (PET) radiotracer for the translocator protein (TSPO), which is upregulated in activated microglia. Participants with the low affinity binder TSPO genotype were excluded. Total gray matter (GM), frontal lobe GM, and temporal lobe GM were defined as a priori regions of interest (ROI). We used DVR as our outcome measure to quantify TSPO binding, while using a supervised clustering approach to define a pseudo-reference region. For the case-control comparison, we used ANCOVA with age and TSPO genotype included as covariates. Paired t-tests were used to analyze changes in DVR at follow-up. We used repeated-measures ANOVA to test if effects of natalizumab on symptom measures differed from placebo. Spearman’s correlation was used for correlations. All analyses were two-tailed with p&amp;lt;0.05 considered statistically significant. Results 62 patients with FEP (median duration of illness 22 months, median PANSS total score 55) and 41 healthy volunteers received baseline PET imaging. Demographics including age, sex, and TSPO genotype were not statistically different between groups. 47 patients completed follow-up PET imaging after receiving natalizumab (n=31) or placebo (n=16). At baseline, DVR was higher in patients relative to controls in total GM (η2=0.043, p=0.038) and temporal lobe GM (η2=0.057, p=0.016), but not in frontal lobe GM (p=0.406). Contrary to our expectation, there was no significant change in DVR across these ROIs following natalizumab treatment (all p&amp;gt;0.05). The magnitude of improvement in PANSS total scores was similar between natalizumab and placebo-treated groups, with a significant effect of time (p&amp;lt;0.001) but not a time*group interaction (p=0.768). There was no significant correlation between percent change in PANSS total scores and change in DVR from baseline to follow-up in all three ROIs (all p&amp;gt;0.05). Discussion &amp; Conclusions To our knowledge, this is the largest PET TSPO study to date in FEP, and the first study to test the effects of natalizumab in patients with schizophrenia. Our findings indicate higher TSPO levels in temporal and total GM in patients with FEP compared to healthy controls, with a small to medium effect size. Natalizumab treatment did not normalize this signal or improve symptom measures relative to placebo, indicating this is unlikely to be an efficacious therapeutic approach for schizophrenia. ClinicalTrials.gov: NCT03093064.