Identification of an antagonist that selectively blocks the activity of prostamides (prostaglandin-ethanolamides) in the feline iris

BACKGROUND AND PURPOSE: The prostamides (prostaglandin-ethanolamides) and prostaglandin (PG) glyceryl esters are biosynthesized by COX-2 from the respective endocannabinoids anandamide and 2-arachidonyl glycerol. Agonist studies suggest that their pharmacologies are unique and unrelated to prostanoid receptors. This concept was further investigated using antagonists. EXPERIMENTAL APPROACH: The isolated feline iris was used as a key preparation, where prostanoid FP receptors and prostamide activity co-exist. Activity at human recombinant FP and other prostanoid receptors was determined using stable transfectants. KEY RESULTS: In the feline iris, AGN 204396 produced a rightward shift of the dose-response curves for prostamide F2alpha and the prostamide F2alpha analog bimatoprost but did not block the effects of PGF2alpha and synthetic FP receptor agonists. Studies on human recombinant prostanoid receptors confirmed that AGN 204396 did not behave as a prostanoid FP receptor antagonist. AGN 204396 exhibited no antagonism at DP and EP1-4, but was a highly effective TP receptor antagonist. Contrary to expectation, the FP receptor antagonist AL-8810 efficaciously contracted the cat iris. AGN 204396 did not affect AL-8810 induced contractions, demonstrating that AL-8810 and AGN 204396 are pharmacologically distinct. Unlike AL-8810, the ethylamide derivate of AL-8810 was not an agonist. Al-8810 did not block prostamide F2alpha activity. Finally, AGN 204396 did not block PGE2-glyceryl ester activity. CONCLUSIONS AND IMPLICATIONS:The ability of AGN 204396 to selectively block prostamide responses suggests the existence of prostamide sensitive receptors as entities distinct from receptors recognizing PGF2alpha and PGE2-glyceryl ester.     

A prospective pilot study of antibodies against human papillomaviruses and cutaneous squamous cell carcinoma nested in the Oxford component of the European Prospective Investigation into Cancer and Nutrition

In a prospective pilot study nested in the EPIC-Oxford cohort, we examined the seroprevalence of antibodies against the L1 antigen of 38 human papilloma virus (HPV) types among 39 cases of cutaneous squamous cell carcinoma (SCC) for whom plasma was collected prior to diagnosis (incident) and 80 controls. Fifteen cases having already developed SCC at blood collection (prevalent) were also tested. There were no statistically significant differences in the seroprevalence of antibodies against any of the HPV types examined between incident cases and controls, nor was there a difference in the seroprevalence of multiple infections. However, consistent with results from published case-control studies, the seroprevalence of many beta-HPV types was higher among prevalent cases than among either incident cases or controls. For example the seroprevalence of antibodies against HPV-8 was 20% (16/80) in controls, 23% (9/39) among incident cases and 40% (6/15) among prevalent cases. Among the incident cases only, the seroprevalence was 16% (5/32) among those for whom blood was collected 18+ months prior to diagnosis, but 57% (4/7) among those for whom diagnosis was within 18 months of blood collection, a pattern seen for many of the HPV types. This might suggest that if HPV is involved in the aetiology of SCC, the process occurs close to the time of diagnosis, or that the antibody response observed in people with SCC is a consequence of tumor formation. Further and larger prospective studies are needed to clarify the role of HPV in the aetiology of cutaneous SCC.     

Sexual behavior, human papillomavirus type 16 (HPV 16) infection, and HPV 16 seropositivity

BACKGROUND: Sexual behaviors have been linked to seropositivity for human papillomavirus (HPV) but not with the magnitude of the seroreactivity. GOALS: The objective of this analysis was to examine the association of sexual behavior, cervical HPV 16 DNA positivity at enrollment (past) and at diagnosis (current), and other potential determinants with the likelihood and magnitude of HPV 16 seropositivity at diagnosis. STUDY DESIGN: With use of stored specimens from an incidence case-control study at Kaiser Permanente (Portland, OR), women were tested for seroreactivity to HPV 16 by enzyme-linked immunosorbent assay with virus-like particles at diagnosis and were tested for past and concurrent cervical HPV 16 DNA positivity with MY09/MY11 L1 consensus primer PCR. Questionnaire data were used to ascertain past sexual behavior. RESULTS: Increased lifetime number of sex partners (P(Trend) < 0.001), past HPV 16 DNA positivity (odds ratio = 6.9; 95% confidence interval = 1.5-31), and a current cytologic diagnosis (P(Trend) < 0.03) were independently associated with HPV 16 seropositivity. Among the seropositive, only lifetime number of sex partners (P(Trend) < 0.001) and past HPV 16 DNA positivity (P = 0.003) were independently associated with mean signal strength (optical density) in an age-adjusted analysis. Women negative for past and concurrent HPV 16 DNA had a significant trend of increasing optical densities associated with greater numbers of lifetime partners (P(Trend) < 0.001). Conversely, the mean signal strength for those women who were ever HPV 16 DNA-positive during the study did not depend on lifetime numbers of sex partners (P(Trend) = 0.36). CONCLUSIONS: HPV 16 seropositivity is a surrogate for past HPV 16 infection. Circulating levels of antibodies to HPV 16 may reflect recent HPV 16 infection or the frequency of past HPV 16 infection.     

Infectious Myelitis

Infections are an uncommon but very important etiology of myelitis as a correct diagnosis would allow for timely treatment and recovery. The term ??myelitis?? is generally used to describe an inflammatory pathologic process affecting the spinal cord and causing an interruption of the ascending and descending pathways, and, therefore, partial or complete loss of function. The onset may be acute or subacute, and the etiology may be cumbersome to determine. This article will review the most recently published literature regarding the infectious agents causing myelitis with an emphasis on diagnosis and treatment.     

Advanced Airway Type and Its Association with Chest Compression Interruptions During Out-of-Hospital Cardiac Arrest Resuscitation Attempts

Objective: To assess interruptions in chest compressions associated with advanced airway placement during cardiopulmonary resuscitation (CPR) of out-of-hospital cardiac arrest (OHCA) victims. Methods: The method used was observational analysis of prospectively collected clinical and defibrillator data from 339 adult OHCA victims, excluding victims with <5 minutes of CPR. Interruptions in CPR, summarized by chest compression fraction (CCF), longest pause, and the number of pauses greater than 10 seconds, were compared between patients receiving bag valve mask (BVM), supraglottic airway (SGA), endotracheal intubation (ETI) via direct laryngoscopy (DL), and ETI via video laryngoscopy (VL). Secondary outcomes included first pass success and the effect of multiple airway attempts on CPR interruptions. Results: During the study period, paramedics managed 23 cases with BVM, 43 cases with SGA, 148 with DL, and 125 with VL. There were no statistically significant differences between the airway groups with regard to longest compression pause (BVM 18 sec [IQR 11–33], SGA 29 sec [IQR 15–65], DL 26 sec [IQR 12–59], VL 22 sec [IQR 14–41]), median number of pauses greater than 10 seconds (BVM 2 [IQR 1–3], SGA 2 [IQR 1–3], DL 2 [IQR 1–4], VL 2 [IQR 1–3]), or CCF (0.92 for all groups). However, each additional attempt following failed initial DL was associated with an increase in the risk of additional chest compression pauses (relative risk 1.29, 95% confidence interval 1.02–1.64). Such an association was not observed with additional attempts using VL or SGA. First pass success was highest with SGA (77%), followed by between DL (68%) and VL (67%); these differences were not statistically significant. Conclusions: While summary measures of chest compression delivery did not differ significantly between airway classes in this observational study, repeated attempts following failed initial DL during cardiopulmonary resuscitation were associated with an increase in the number of pauses in chest compression delivery observed     

Codetection of a mixed population of candHPV62 containing wild-type and disrupted E1 open-reading frame in a 45-year-old woman with normal cytology

We have cloned, sequenced, and characterized the complete genome of a novel human papillomavirus (HPV), candHPV62. During cloning, 2 candHPV62 viral isolates were recovered from a single cervical sample; 1 had all anticipated HPV open-reading frames (ORFs) intact, whereas the other exhibited an E1 frame-shift mutation. Further experiments indicated that the 2 strains were equivalent in abundance. It appears that an early mutation occurred within the E1 ORF, which was transcomplemented by an intact E1 protein. A search of the HPV database identified disruption of the E1 ORF in the cloned reference isolates of HPV16, HPV53, HPV56, and HPV72. These data suggest that disruption of the E1 ORF in genital HPVs is not uncommon.