Experimental Chlamydia pneumoniae infection in NIH/S mice: effect of reinoculation with chlamydial or cell preparation on culture,PCR and histological findings of lung tissue

The cellular components present in chlamydial preparations may contribute to the course of the experimental infection. NIH/S mice were inoculated and reinoculated intranasally with Chlamydia pneumoniae or a cellular preparation. The mock inoculation induced only mild histological changes in the lungs, which possibly induced partial protection against subsequent C. pneumoniae infection and, when given as reinoculation, possibly reactivated the culture-negative infection as culture-positive. In addition, serum antibodies against mouse heat shock protein 60 (Hsp60) were found in a few mice. In conclusion, the main immunopathogenic factors in a C. pneumoniae mouse model are chlamydial components. However, a cellular preparation may participate in an inflammatory reaction. Autoimmunity against Hsp60 may also play a role in the pathogenesis of C. pneumoniae infection.     

Involvement of the first transmembrane segment of human α(2) -adrenoceptors in the subtype-selective binding of chlorpromazine, spiperone and spiroxatrine

BACKGROUND AND PURPOSE

Some large antagonist ligands (ARC239, chlorpromazine, prazosin, spiperone, spiroxatrine) bind to the human α_2A-adrenoceptor with 10- to 100-fold lower affinity than to the α_2B- and α_2C-adrenoceptor subtypes. Previous mutagenesis studies have not explained this subtype selectivity.

EXPERIMENTAL APPROACH

The possible involvement of the extracellular amino terminus and transmembrane domain 1 (TM1) in subtype selectivity was elucidated with eight chimaeric receptors: six where TM1 and the N-terminus were exchanged between the α₂-adrenoceptor subtypes and two where only TM1 was exchanged. Receptors were expressed in CHO cells and tested for ligand binding with nine chemically diverse antagonist ligands. For purposes of interpretation, molecular models of the three human α₂-adrenoceptors were constructed based on the β₂-adrenoceptor crystal structure.

KEY RESULTS

The affinities of three antagonists (spiperone, spiroxatrine and chlorpromazine) were significantly improved by TM1 substitutions of the α_2A-adrenoceptor, but reciprocal effects were not seen for chimaeric receptors based on α_2B- and α_2C-adrenoceptors. Molecular docking of these ligands suggested that binding occurs in the orthosteric ligand binding pocket.

CONCLUSIONS AND IMPLICATIONS

TM1 is involved in determining the low affinity of some antagonist ligands at the human α_2A-adrenoceptor. The exact mechanism is not known, but the position of TM1 at a large distance from the binding pocket indicates that TM1 does not participate in specific side-chain interactions with amino acids within the binding pocket of the receptor or with ligands bound therein. Instead, molecular models suggest that TM1 has indirect conformational effects related to the charge distribution or overall shape of the binding pocket.     

Effects of Preoperative Atorvastatin Treatment On Erectile Function After Radical Prostatectomy: Results From a Subgroup of ESTO1, a Randomized,Double-Blind,Placebo-Controlled Study

IntroductionErectile dysfunction is common after radical prostatectomy because of damage to the cavernous nerves. Thus, it is important to identify new ways to avoid this problem. For example, statins have shown positive effects on erectile function and may have anti-inflammatory effects that improve recovery after surgery.AimThe aim of this exploratory analysis of a subgroup from ESTO1, a randomized, double-blind, placebo-controlled study, was to evaluate the preoperative use of atorvastatin on erectile function after radical prostatectomy.MethodPatients were randomized to either 80 mg atorvastatin or placebo daily before undergoing radical prostatectomy from study inclusion to the day of surgery. Altogether 118 men with prostate cancer and scheduled for radical prostatectomy were asked to fill out the 5-item version of the International Index of Erectile Function (IIEF-5) questionnaire before surgery and at 3, 6, 9, and 12 months after surgery.Main Outcome MeasurementsThe study was exploratory, with the main outcome being the overall difference between IIEF-5 scores in the 2 groups at 12 months. Several hypotheses generating sub-analyses were conducted.ResultsOverall, 85% filled out the IIEF-5 questionnaire before their operation and 85%, 81%, 78%, and 78% completed it at 3, 6, 9, and 12 months follow-up, respectively. 52% of men had information available at all time points. There were no statistically significant differences between the groups at baseline in either erectile function, comorbidities, or tumor characteristics. The median duration of use of atorvastatin and placebo before surgery was 27 and 25 days, respectively. Preoperative atorvastatin treatment had no statistically significant effect on erectile function after prostatectomy as compared with placebo, although IIEF-5 scores were higher at all time points in the statin arm. Furthermore, atorvastatin treatment compared with placebo improved IIEF-5 scores at 12 months after surgery when the cavernous nerves were at least partially intact bilaterally (P < .04, n = 65); however, after full bilateral or unilateral nerve-sparing, the difference was not statistically significant.Clinical ImplicationShort-term statin treatment did not improve recovery of erectile function after prostatectomy; however, further studies are needed before final conclusions.Strengths & LimitationsThis was a randomized placebo-controlled study. Original ESTO1 study was designed to detect a difference in prostate cancer biomarkers.ConclusionShort-term atorvastatin treatment before radical prostatectomy had no statistically significant effect on the recovery of erectile functions in a non-selected cohort of patients undergoing radical prostatectomy. Further studies will be needed to clarify the role of long-term atorvastatin use before and after prostatectomy.Siltari A, Riikonen J, Fode M, et al. Effects of Preoperative Atorvastatin Treatment On Erectile Function After Radical Prostatectomy: Results From a Subgroup of ESTO1, a Randomized, Double-Blind, Placebo-Controlled Study. J Sex Med 2019;16:1597–1605.     

Results from a randomized clinical trial of coadministration of RotaTeq, a pentavalent rotavirus vaccine, and NeisVac-C, a meningococcal serogroup C conjugate vaccine

RotaTeq (Merck & Co. Inc./Sanofi Pasteur MSD) is a three-dose, oral pentavalent rotavirus vaccine for the immunization of infants from 6 weeks of age for the prevention of rotavirus gastroenteritis. The primary objective of the present trial was to demonstrate that RotaTeq can be coadministered with meningococcal serogroup C conjugate vaccine (MenCC; NeisVac-C; Baxter Healthcare) to healthy infants without impairing the protective immune responses to MenCC. This was an open-label, randomized, comparative study conducted in Finland. The study was designed to assess concomitant versus sequential administration of RotaTeq and MenCC on the immune response to both vaccines. Healthy infants (n = 247), aged 6 to 7 weeks, were recruited. Coadministration of MenCC with RotaTeq was noninferior to sequential administration for the seroprotection rate against meningococcal serogroup C (the proportion of infants with a serum bactericidal antibody titer using baby rabbit complement of ≥ 8 was 100% in both groups). The other responses to MenCC (titer of ≥ 1:128, ≥ 4-fold increase in titer, and geometric mean titers [GMTs]) and the responses to RotaTeq (IgA and SNA response to G1 to G4 and P1A[8], GMTs, and ≥ 3-fold increase in titer) were comparable between groups, including a ≥ 3-fold IgA increase in >96% of the infants in both groups. Concomitant administration of the first doses of MenCC, diphtheria and tetanus toxoids and acellular pertussis vaccine, inactivated poliovirus vaccine, and Haemophilus influenzae type b conjugate vaccine (DTaP-IPV-Hib), and RotaTeq was associated with a higher rate of vomiting and diarrhea than concomitant administration of MenCC and DTaP-IPV-Hib, but that was not observed after the second concomitant administration. The convenience of concomitant administration of RotaTeq and MenCC may, however, outweigh the additive effect of mostly mild adverse events reported after the individual administration of each vaccine. These results support the coadministration of RotaTeq and MenCC.     

Risk factors for prolonged intensive care unit stay and hospital mortality in acute drug-poisoned patients: an evaluation of the physiologic and laboratory parameters on admission

Background

The share of patients receiving intensive care treatment because of acute drug poisoning is 2% to 14% of all patients receiving intensive care. The outcome is mainly good and the length of intensive care is usually less than 2 days. Our aim was to recognize the risks for prolonged intensive care and hospital mortality using admission Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scoring in acute drug-poisoned patients.

Methods

A national, prospectively collected intensive care unit (ICU) data registry was used for analysis. Data from 28 ICUs in university and secondary nonteaching hospitals from 1998 to 2004 were available.

Results

There were 255 admissions because of acute drug poisoning, which represented 4.5% of all admissions. The mean length of the ICU stay was 32.1 hours. Of the patients, 11.5% had a prolonged ICU stay (>48 hours). Hospital mortality was 2.3%. The mean Acute Physiology and Chronic Health Evaluation II score was 14.4 (SD, 8.1) and the mean Sequential Organ Failure Assessment score was 4.8 (SD, 3.0). The mean Glasgow Coma Scale score on admission was 9.7 (SD, 4.7). In the multivariate analysis, the highest odds ratios for prolonged ICU stay were respiratory failure, lowered platelet count, and renal dysfunction. In the multivariate analysis, the highest odds ratios for hospital mortality were respiratory failure, renal failure, and hypotension.

Conclusions

In acute intoxication, respiratory and renal dysfunction and failure are risk factors for poor outcome.     

Immunogenicity and safety of the human rotavirus vaccine Rotarix™ co-administered with routine infant vaccines following the vaccination schedules in Europe

This study assessed the immunogenicity and safety of a human rotavirus vaccine RIX4414; the effect of co-administration of childhood vaccines on the immune responses was also assessed.     

Biological aggressiveness of prostate cancer in the Finnish screening trial

Prostate cancer aggressiveness was evaluated based on pathologic characterization of cases detected in the Finnish prostate cancer screening trial. The trial population consists of 80,458 men aged 55–67 years. A total of 32,000 men were randomized to the screening arm. The remaining 48,000 men formed the control arm. The interval cases and cancers among nonparticipants and in the control arm were identified from the Finnish Cancer Registry. Random samples were selected from screen‐detected cases (126 of 543 in the first and 133 of 508 in the second round) and control arm cancers (133 out of 863), in addition to all 92 interval cancers and 106 cases among nonparticipants. All the biopsies were regraded according to the Gleason system. The expression of the proliferation antigen Ki‐67 was determined in 479 cases (72%). More than half of the tumors diagnosed in the first round of screening were high‐grade cancers (Gleason 7 or higher). In the second round, the proportion of low‐grade cancers increased from 47% to 70%. Cancers in the screening arm were more commonly focal and fewer bilateral cancers were detected. The cancers among nonparticipants were the most aggressive group. The aggressiveness of the interval cancers was between the cancers detected in the first and the second round. Our results indicate that prostate cancers detected through screening are less biologically aggressive. This was most notable after the first screening round. Nonparticipants had more aggressive cancers. © 2008 Wiley‐Liss, Inc.