Chronic treatment of female rhesus monkeys with low doses of the antiprogestin ZK 137 316: establishment of a regimen that permits normal menstrual cyclicity

Large doses of antiprogestin typically disrupt menstrual cyclicity. A chronic low-dose regimen of the potent new antiprogestin ZK 137 316, which permits continued menstrual cyclicity but alters gonadal- reproductive tract activity, was established. Rhesus monkeys received vehicle (n = 6) or 0.01 (n = 8), 0.03 (n = 8) or 0.1 (n = 5) mg ZK 137 316/kg body weight daily for five menstrual cycles (C-1 to C-5). Oestradiol, progesterone and gonadotrophin profiles were normal during cycles involving vehicle and 0.01 and 0.03 mg ZK 137 316/kg body weight. In the 0.1 mg/kg group, mid-cycle oestradiol and gonadotrophin surges, and subsequent progesterone production, were absent in C-3 and C-5. Ovarian cyclicity was accompanied by timely menstruation in the vehicle and 0.01 mg/kg groups. By C-3, half the animals in the 0.03 mg/kg group and all animals in the 0.1 mg/kg group were amenorrhoeic. A corpus luteum was noted during the mid-luteal phase of C-5 in the vehicle, 0.01 mg/kg and 0.03 mg/kg groups. Large antral and cystic follicles were evident in the 0.1 mg/kg group. Thus, a daily treatment with 0.01 mg/kg ZK 136317 permitted normal menstrual cyclicity in macaques. While the daily administration of 0.03 mg/kg ZK 136 317 allowed ovarian cyclicity, menstruation was disrupted in some animals. Increasing the dose to 0.1 mg/kg antagonized pituitary function and resulted in anovulation and amenorrhoea. A chronic low-dose regimen of the antiprogestin ZK 137 316, which permits normal ovarian/menstrual cyclicity, has potential as a contraceptive in women.      

Interchromosomal duplications of the adrenoleukodystrophy locus: a phenomenon of pericentromeric plasticity

A 9.7 kb segment encompassing exons 7-10 of the adrenoleukodystrophy (ALD) locus of the X chromosome has duplicated to specific locations near the pericentromeric regions of human chromosomes 2p11,10p11, 16p11 and 22q11. Comparative sequence analysis reveals 92-96% nucleotide identity, indicating that the autosomal ALD paralogs arose relatively recently during the course of higher primate evolution (5-10 million years ago). Analysis of sequences flanking the duplication region identifies the presence of an unusual GCTTTTTGC repeat which may be a sequence-specific integration site for the process of pericentromeric- directed transposition. The breakpoint sequence and phylogenetic analysis predict a two-step transposition model, in which a duplication from Xq28 to pericentromeric 2p11 occurred once, followed by a rapid distribution of a larger duplicon cassette among the pericentromeric regions. In addition to facilitating more effective mutation detection among ALD patients, these findings provide further insight into the molecular basis underlying a pericentromeric-directed mechanism for non- homologous interchromosomal exchange.      

Recognition of peptidyl epitopes by polymorphic epithelial mucin (PEM)-specific monoclonal antibodies.

Peptidyl epitope recognition by several murine monoclonal antibodies (MAbs E29, H23, HMFG-1, HMFG-2, MA5, MA6 and MA9) which react with the polymorphic epithelial mucins [PEM; epithelial membrane antigen (EMA)] was studied by using ten synthetic peptides representative of the 20 residue tandem repeat as test antigens. Antibody binding to 6-10 residue overlaps and to peptides having a common carboxy-terminus and staggered amino-termini (8-31 residues) was assessed by solid phase and competition ELISA techniques. From these analyses, all MAbs except MA9 were found to react predominantly with the carboxy-terminal half of the repeat motif. Polyclonal antibody responses in mice immunized with intact EMA/PEM-containing preparations also displayed significant reactivities against synthetic repeat peptide antigens and, conversely, synthetic peptides as carrier-conjugated immunogens induced antibodies recognizing intact antigens. These results are discussed vis-à-vis peptide conformation, the potential effects of O-glycosylation on secondary structure, and the possible effects of these parameters on immunogenicity and antigenicity.     

The salivary microbiota as a diagnostic indicator of oral cancer: A descriptive,non-randomized study of cancer-free and oral squamous cell carcinoma subjects

Background  

The purpose of the present investigation was to determine if the salivary counts of 40 common oral bacteria in subjects with an oral squamous cell carcinoma (OSCC) lesion would differ from those found in cancer-free (OSCC-free) controls.     

High co-prevalence of genogroup 1 TT virus and human papillomavirus is associated with poor clinical outcome of laryngeal carcinoma

BACKGROUND: The aetiology and factors leading to the progression of laryngeal cancer are still unclear. Although human papillomavirus (HPV) has been suggested to play a role, reports concerning the effect of HPV infection on tumour development are controversial. Recently, transfusion transmitted virus (TTV) was suggested to play a role in certain infections as a causative or coinfecting agent. AIMS: To investigate whether the development and progression of laryngeal squamous cell carcinoma is associated with coinfection with TTV and HPV. METHODS: The prevalence of TTV and HPV was investigated using the polymerase chain reaction in tissue samples from 40 healthy individuals, 10 patients with recurrent papillomatosis, five patients with papillomatosis with malignant transformation, and 25 patients with laryngeal carcinoma. The obtained prevalence data were compared and analysed statistically. RESULTS: In the 11 patients with carcinoma who had metastasis or relapse there was a high rate of coinfection with genogroup 1 TTV and HPV (eight of 11), whereas in the 14 without tumour progression no coinfection was found. Coinfection was associated with significantly lower tumour free survival in patients with carcinoma (p < 0.001). Furthermore, four of five patients who had papillomatosis with malignant transformation were coinfected with genogroup 1 TTV and HPV. CONCLUSIONS: Although the nature of cooperation between HPV and TTV needs to be investigated further, coinfection with genogroup 1 TTV and HPV appears to be associated with poor clinical outcome in laryngeal cancer.     

BK virus antibody titers and intensity of infections after renal transplantation

BACKGROUND: The mean urine BK viral load in kidney transplant recipients increases with the intensity of infection as the infection progresses from transient viruria to sustained viremia. OBJECTIVES: This study investigated whether the intensity of infection is associated with the humoral immune response. STUDY DESIGN: We measured BKV-specific IgG antibody titers in stored samples obtained serially over a 1-year period from 70 kidney transplant recipients with BKV infection and 17 control recipients without active BKV infection. RESULTS: The mean pre-transplant BKV antibody level was lower in recipients who developed viremia than the mean level in those who never developed viremia (p=0.004). Mean antibody titers in recipients who never showed evidence of active BKV infection rose slightly after transplant despite immunosuppression. The magnitude of the rise in the mean antibody titers in recipients who developed active BKV infection correlated with the intensity of infection (p<0.001). CONCLUSIONS: The mean antibody level increased in accordance with the intensity of the infection post-transplant. Pre-transplant seropositivity did not protect against sustained viremia and the antibody response was not associated with clearance of the virus.     

Mediation Analysis of a Theory-Based Culture and Age-Appropriate HIV/STI Prevention

Few studies have investigated mediator effects of HIV prevention interventions on adolescents in sub-Saharan Africa. Herein, we report on a secondary analysis of an intervention that increased intentions to use condoms, abstain from sexual intercourse, and seek safe male circumcision among adolescents in Botswana. In a study conducted in Botswana, 806 grade 9 students from 21 public Junior Secondary Schools were randomly assigned to either the OWN THE FUTURE: Pulling Together We Will” ( PTWW) intervention group or a health promotion control group. Both conditions consisted of 12 1-h modules, with two modules delivered during each of the six sessions on six consecutive school days. The students in both groups completed confidential computer-based surveys at several time points: pre-, immediately post-, 3, 6, and 12 months post-intervention. Mediation was assessed using the product-of-coefficients approach in a generalized estimating equations (GEE) framework. The analyses showed that condom use beliefs were significant mediators of the intervention effect on the intention to consistently use condoms over time. Also, negative socio-cultural beliefs, prevention beliefs, and HIV/STI knowledge were significant mediators of the intervention’s effects on the intention to abstain from sex. Additionally, normative beliefs, prevention beliefs, parental negotiation, and circumcision knowledge were significant mediators of the intervention’s effect on intention to seek safe male circumcision. The mediation analysis delineated a theoretical model and isolated activities that positively impact condom use, abstinence from sex, and circumcision intentions of Batswana middle school adolescents.

     

A host-cell-selected variant of influenza B virus with a single nucleotide substitution in HA affecting a potential glycosylation site was attentuated in virulence for volunteers

Summary An influenza B virus was passaged in man (virus A) and then in human embryo trachea (C) and into embryonated eggs (D) or directly into eggs (B). Virus A, B, and C had the same (cell-like) haemagglutinin phenotype on reaction with selected monoclonal antibodies while D had an egg-like phenotype. The viruses were administered at a dose of 1,000 TCD₅₀ (for MDCK cells) by intranasal inoculation to groups of 27 or 28 volunteers. Viruses A, B, and C all produced disease in six to eight volunteers, whereas D produced no illness and only four volunteers were infected. The viruses shed by the volunteers were indistinguishable from those with which they were inoculated. The haemagglutinin genes of the viruses were sequenced and changes were detected indicating amino acid substitutions at position 196–198 in the attenuated egg-grown virus D whereby a potential glycosylation site present in the other viruses was lost.