Clinical predictive factors of histological chorioamnionitis: case-control study.

INTRODUCTION: Histological chorioamnionitis or "intrauterine inflammation or infection" (Triple I) it is an acute inflammation of amniotic membrane, chorionic plate and umbilical cord. SUBJECT: To assess in the event of the clinical predictive factors associated to histological chorioamnionitis. METHODS: Prospective examination of 50 placentas from aberrant pregnancies, and 50 placentas from 'normal' deliveries. The Placentas analyzed by the conventional histopathology method, and the severity of chorioamnionitis was classified histologically according to the intensity and the topography of placental inflammation.The clinical and histopathological features of the study groups were introduced into the SPSS 13 database (License University Mohammed V-Rabat). RESULTS: 36/50 placentas of aberrant pregnancies showed a histological chorioamnionitis often associated to a funisitis, and 11/50 normal placentas have shown some lesions of histological chorioamnionitis mainly grade one without funisitis.On the other hand we noted a statistically significant association between histological chorioamnionitis and premature rupture of the membranes (PROM) over than 12h (p < 0.001). CONCLUSIONS: Our study confirmed the predominance of histological chorioamnionitis lesions in clinically suspected cases of chorioamnionitis with 72% versus 22% in the controls group.Among the clinical parameters studied, only the premature rupture of the Membranes was shown a statistically significant association with the appearance of histological signs of chorioamnionitis.In conclusion, chorioamnionitis is sometimes clinically silent. Morphological placental study could be a confirmation of this pathology, which is predominantly associated to PROM over than 12 h.

Prevalence of congenital malformations at the "les Orangers" maternity and reproductive health Hospital of Rabat: descriptive study of 470 anomalies.

BACKGROUND: Congenital malformations are described in about 3% of live births and 20% of stillbirths in the industrialized countries. The prevalence of congenital anomalies in developing countries, including Morocco, is not well known at the national level. The aim of our study is to conduct a descriptive exploratory analysis of congenital malformations cases diagnosed at the "Les Orangers" Maternity and Reproductive Health Hospital in Rabat. METHODS: We collected all the cases of congenital malformations diagnosed at the "Les Orangers" Maternity and Reproductive Health Hospital in Rabat, from January 1st, 2011 to June 31st, 2016. Data were reported on pre-established sheets and on a registry of malformations. Total and specific prevalences were calculated for each malformation. A principal component analysis (PCA) was then conducted followed by a Varimax rotation in order to identify the different associations of malformations in our series. RESULTS: We registred 245 cases of congenital malformations out of a total of 43,923 recorded births; a prevalence of 5.58 per thousand births of which 19.2% were FDIU (fetal deaths in utero). A polymalformative syndrome was found in 26.5% of cases which makes a total number of 470 anomalies. The musculoskeletal anomalies predominate with a rate of 33%, followed by neurological abnormalities 18%, of whom 31% were hydrocephalus, 26.2% anencephaly, and 20.24% spina bifida. Malformations of the eye, ear, face and neck were described in 12% of the cases, while genetic abnormalities were observed in 8,5% of which 87.5% represented Down syndrome. The antenatal diagnosis of congenital malformations was performed in 28.6% of cases. CONCLUSIONS: Our study provides a general overview of the epidemiological situation related to different types of congenital anomalies for a specific area in Morocco. It represents a database that should be complemented by other multicenter studies and the implementation of a national registry to determine the prevalence of congenital malformations at a national level.

[Puerperal uterine inversion]. / Inversion utérine puerpérale.

The uterine inversion defines itself anatomically as the invagination of the uterine bottom "finger of glove" until be able to at most express itself in the vulva. It is a dramatic accident of the delivery and a sporadic occurrence in countries with low medical entity, this rarity which can mislead the practitioner, the delay of the diagnosis ends in redoubtable complications even the maternal death. Through a retrospective study concerning six case reports brought together within CHU Hassan II of Fez spreading out over eight years and review of literature, we try to describe different aspects epidemiological, etiologic, therapeutic and prognosis of this rather particular entity.

Discordance between biochemical markers of liver activity and fibrosis (Actitest-Fibrotest) and liver biopsy in patients with chronic hepatitis C.

INTRODUCTION: The purpose of this clinical trial was to determine in routine practice and in comparison with liver biopsy the limitations of two blood tests, Actitest and Fibrotest, for the evaluation of hepatic activity and fibrosis in patients with chronic hepatitis C. METHODS: Routine blood tests, Actitest and Fibrotest, and liver biopsy were performed in 96 patients with chronic hepatitis C attending routine outpatient clinics. Receiver operating characteristics (ROC) curves were used to assess the diagnostic value of the biochemical tests in comparison with the METAVIR classification. RESULTS: The study population was predominantly male (63.5%) with a mean age of 48 years; 83.3% of the patients had genotype 1 hepatitis C virus infection. Treatment status was naive (62.5%), nonresponders (17.7%), relapsers (7.3%), or unknown (12.5%). The comparison of F0-F2 versus F3-F4 estimated the negative predictive value at 92% and the positive predictive value at 52% for a cut-off of 0.455. Discrepancies in activity score were more frequently due to a higher score of the biochemical test compared to biopsy (18 cases out of 19). Discrepancies for fibrosis were observed in 18 patients with a higher score for biochemical test in eight and a higher score for liver biopsy in 10 cases. A significant increase of gamma-glutamyl-transferase (GGT) (p=0.0001) and alanine aminotransferase (ALT) (p<0.0001) was observed in case of biochemical test overestimation of activity, and a significant increase of alpha2-macroglobulin (p=0.006) and GGT (p=0.018) in case of biochemical test overestimation of fibrosis. CONCLUSION: This prospective study confirms the good diagnostic value of biochemical tests for necrotico-inflammatory activity and fibrosis as compared with the histological analysis of liver biopsy. Clinicians must interpret Actitest and Fibrotest results with caution in patients with a significant elevation of ALT, and/or GGT and/or alpha2-macroglobulin which could overestimate hepatic injury.

Factor VIII (FVIII) gene mutations in 120 patients with hemophilia A: detection of 26 novel mutations and correlation with FVIII inhibitor development.

BACKGROUND: As the publication of the sequence of the factor VIII gene (FVIII) in 1984, a large number of mutations that cause hemophilia A (HA) have been identified. Thanks to the advances in the detection of mutations, it is now possible to identify a putative FVIII sequence alteration in the vast majority of patients with HA. OBJECTIVES: Our main objective was to report on the spectrum of FVIII mutations and their distribution throughout the gene in 120 patients with HA. METHODS: Screening of FVIII mutations was performed using direct sequencing. Newly described missense mutations were further studied by molecular modeling. RESULTS: A total of 47 different HA causative FVIII mutations have been identified, 26 of which are described for the first time. These novel mutations include 14 missense and six nonsense mutations, two small deletions, one large deletion and three splice-site mutations. We further investigated the development of FVIII-specific inhibitors in all patients with HA. We found that four novel mutations (Ser882X, Tyr1786Ser, Ala2218Thr and a splice-site defect in intron 22) were associated with inhibitor development. CONCLUSION: These data extend our insight into the mechanisms by which novel amino acid substitutions may lead to HA, and how HA patient genotypes influence the risk of FVIII inhibitor development.

The potential epidemiological impact of a genital herpes vaccine for women.

BACKGROUND: In two phase III vaccine trials immunisation of women previously uninfected by herpes simplex virus provided protection against genital herpes disease. In deciding policy, an evaluation of the epidemiological impact of the partial protection provided by the vaccine should be considered. METHODS: A sex and sexual activity stratified deterministic differential and partial differential equation model of the natural history of herpes simplex virus type 2 (HSV-2) and the impact of vaccination is developed and analysed. To explore the role of vaccination, the pattern of viral shedding and the transmission of infection during sexual acts within sexual partnerships are described. RESULTS: Using literature derived estimates of parameter values and assuming efficacy in only 40% of women the impact of the vaccine depends on assumptions made about its action. The vaccine has a limited impact if it only prevents disease but a more substantial impact if it reduces asymptomatic viral shedding, which it could do indirectly by preventing infection or directly by modifying the biology of the infection. Concern over the implications of a vaccine that prevents disease but has no impact on viral shedding was addressed in a worst case scenario. Here there is a modest increase in the incidence of infection in both men and women but an increase in disease prevalence in men alone, since the virus directly protects some women from disease. CONCLUSIONS: Results suggest that a herpes vaccine should be used universally and that a vaccine that only protects HSV-1-/2- women can paradoxically have a significant epidemiological impact, the scale of which depends upon changes in patterns of viral shedding.

Monophosphoryl lipid A adjuvant reverses a principal histologic parameter of formalin-inactivated respiratory syncytial virus vaccine-induced disease.

The mechanisms by which administration of a formalin-inactivated respiratory syncytial virus vaccine resulted in enhanced disease among children after they later became naturally infected with the virus remains largely undefined. After immunization and live virus challenge, the cotton rat demonstrated the histopathologic marker of the enhanced disease, polymorphonuclear leukocyte infiltration of lung alveolar spaces. We now report that immunization with formalin-inactivated vaccine formulated with the adjuvant, 3-deacylated monophosphoryl lipid A, dramatically reduces or eliminates the polymorphonuclear leukocyte infiltration within the alveoli of cotton rats post-challenge. We suggest, that this or similar adjuvants may be beneficial components of candidate non-replicating respiratory syncytial virus vaccines, whose development has been hampered by safety concerns.

A hepatitis B vaccine formulated with a novel adjuvant system.

Although more than 95% of the vaccinated population responds to the currently licensed vaccines against hepatitis B, some groups were found to be low responders. Lipid A as adjuvant, through its ability to activate macrophages, might improve humoral as well as cellular immune response. Therefore we evaluated the profile of a hepatitis B vaccine with the new adjuvant system SBAS4. 150 young adults were enrolled and randomized into three groups: one received the SBAS4 hepatitis B vaccine, the second Engerix-B(TM) and the third a hepatitis B vaccine with an alternative formulation on alum. Vaccinations were at 0 and 6 months. The vaccine was well tolerated. At month 7 all vaccinees were protected but with significant differences in GMTs between groups: 13,271 mIU/ml for the SBAS4 group versus 1203 and 1823 mIU/ml. Hence the hepatitis B vaccine with the new adjuvant system is more immunogenic compared to the other vaccines containing the same antigen and could be suitable for a two dose schedule.

Pulmonary lesions in primary respiratory syncytial virus infection, reinfection, and vaccine-enhanced disease in the cotton rat (Sigmodon hispidus).

Infection of the cotton rat lung with a human strain of respiratory syncytial virus results in substantial virus replication and is associated with mild-to-moderate peribronchiolitis, perivasculitis, and bronchitis. Reinfection after 49 days did not result in detectable virus replication, but surprisingly, was associated with an earlier appearance and accentuation of the three types of lesions seen in cotton rats undergoing primary infection. Animals primed with formalin-inactivated virus and challenged after 49 days had pulmonary viral titers 1/10 to 1/100 of that seen in naive animals, but developed markedly accentuated lesions of the same type as in animals undergoing primary or secondary infection. In addition, the animals with the vaccine-enhanced disease developed alveolitis and interstitial pneumonitis, which seem to be specific markers for the vaccine enhancement. These latter markers may be useful in determining the safety of nonreplicating vaccines.

Potent induction of focused Th1-type cellular and humoral immune responses by RTS,S/SBAS2, a recombinant Plasmodium falciparum malaria vaccine.

The RTS,S/SBAS2 vaccine confers sterile protection against Plasmodium falciparum sporozoite challenge. The mechanisms underlying this are of great interest, yet little is known about the immune effector mechanisms induced by this vaccine. The immune responses induced by RTS,S/SBAS2 were characterized in 10 malaria-naive volunteers. Several epitopes in the circumsporozoite protein (CSP) were identified as targets of cultured interferon (IFN)-gamma-secreting CD4+ T cells. RTS,S-specific IFN-gamma-secreting effector T cells were induced in 8 subjects; this ex vivo response mapped to a single peptide in Th2R. CSP-specific CD8+ cytotoxic T lymphocytes were not detected. RTS, S-specific IFN-gamma production was universal, whereas interleukin-4 and -5 production was rare. RTS,S-specific lymphoproliferative responses and antibodies to CSP were strongly induced in all volunteers. Responses waned with time but were boostable. Thus, RTS, S/SBAS2 is a potent inducer of Th1-type cellular and humoral immunity. These results highlight possible immune mechanisms of protection and have important implications for vaccine design in general.

Cellular immune response of a varicella vaccine following simultaneous DTaP and VZV vaccination.

BACKGROUND: Chickenpox and zoster are an important cause of morbidity among children and adults. The ability of a new, thermostable vaccine to induce varicella-zoster-virus (VZV)-specific humoral and cell mediated immunity when given simultaneously with diphtheria-tetanus-acellular pertussis vaccine (DTaP) as a booster dose in the second year of life was investigated. METHODS: A new, temperature stable varicella vaccine (OKA-strain, SB-Biologicals, Rixensart, Belgium) was given simultaneously with a booster dose of DTaP vaccine. VZV-specific humoral and cell-mediated immunity was studied in the first 27 out of 232 vaccinated children at 16-28 months of age, from blood samples drawn just before and six weeks after vaccination. VZV-specific antibody response, T-cell proliferation, cytokine production and expression of activation markers (CD25, HLADR) on T-cells were analyzed. RESULTS: Vaccination resulted in a significant rise of VZV-specific serum IgG titers and in a strong VZV-specific T-cell response in all vaccinated infants. Analysis of the expression of activation marker revealed activation of both CD4+-T-helper- and CD8+-T-cells. CONCLUSIONS: The varicella vaccine given simultaneously with DTaP produced strong B- and T-cell responses alike. This is the first report to show that CMI to VZV is conferred to young children by vaccination with a temperature stable VZV vaccine.

Development and efficacy assessment of combination vaccines, with emphasis on acellular pertussis.

The number of vaccines suitable for infant immunization is increasing, leading to a need to co-administer them in combination or combos. The recent demonstration of high efficacy against whooping cough using DTPa vaccines makes it desirable to administer combos such as DTPaHBIPVHib. For all vaccines included, surrogate markers for protection exist, except for pertussis. The field efficacy studies performed with DTPa vaccines did not allow the establishment of a correlate for protection. We propose to use detailed serology and cell-mediated immunity markers obtained from infant immunization studies, as well as a mouse intranasal challenge model, to monitor the immune responses induced by DTPa-combos.

Long-term efficacy and immune responses following immunization with the RTS,S malaria vaccine.

The malaria sporozoite vaccine candidate RTS,S, formulated with an oil-in-water emulsion plus the immunostimulants monophosphoryl lipid A and the saponin derivative QS21 (vaccine 3), recently showed superior efficacy over two other experimental formulations. Immunized volunteers were followed to determine the duration of protective immune responses. Antibody levels decreased to between one-third and one-half of peak values 6 months after the last dose of vaccine. T cell proliferation and interferon-gamma production in vitro were observed in response to RTS,S or hepatitis B surface antigen. Seven previously protected volunteers received sporozoite challenge, and 2 remained protected (1/1 for vaccine 1, 0/1 for vaccine 2, and 1/5 for vaccine 3). The prepatent period was 10.8 days for the control group and 13.2 days for the vaccinees (P < .01). Immune responses did not correlate with protection. Further optimization in vaccine composition and/or immunization schedule will be required to induce longer-lasting protective immunity.

Safety and immunogenicity of a hepatitis B vaccine formulated with a novel adjuvant system.

A formulation of recombinant hepatitis B surface antigen (HBsAg) combined with a novel adjuvant system, SBAS4--a combination of aluminium salt and monophosphoryl lipid A (MPL), was assessed in 27 healthy adult volunteers with a commercial vaccine (Engerix-B) as control. After three doses (0, 1, 6 months schedule), reactogenicity profiles were similar. Local reactions were essentially mild, the most frequent being soreness at the injection site. Seroprotection was achieved after two doses in all subjects given the candidate vaccine, all Engerix-B vaccines being seroprotected after the third dose. After the second and third doses, higher anti-HBs Geometric Mean Titres (GMTs) were observed in the group which received the formulation with the novel adjuvant system, and cellular immunity, measured as HBsAg-specific lymphoproliferation was stronger than with Engerix-B. These results indicate that the new formulation is safe, well-tolerated and immunogenic and may promote more rapid protection against hepatitis B infection.

Efficacy of a recombinant glycoprotein D subunit vaccine on the development of primary and recurrent ocular infection with herpes simplex virus type 1 in mice.

The protective efficacy of a glycoprotein D subunit vaccine (gD2 SB AS4) was evaluated in a mouse model of human recurrent herpetic stromal keratitis (HSK). When administered before primary infection, gD2 SB AS4 protected mice against corneal pathology, mortality, and latency resulting from ocular viral challenge with herpes simplex virus type 1 (HSV-1) McKrae strain. In addition, gD2 SB AS4 significantly decreased postreactivation corneal disease. A control vaccine, gD2 alum, protected against acute ocular infection only. When administered after primary infection, gD2 SB AS4 vaccination decreased postreactivation ocular shedding but had no other significant effects. Vaccination with gD2 SB AS4 was associated with high anti-gD antibody responses and low delayed-type hypersensitivity responses. These results have identified a prophylactic vaccine, gD2 SB AS4, with activity against acute and recurrent HSK in mice and emphasize the need for vaccine evaluation in both primary and recurrent ocular herpetic disease models.

Adjuvants influence the quantitative and qualitative immune response in BALB/c mice immunized with respiratory syncytial virus FG subunit vaccine.

The ability of monophosphoryl lipid A (MPL), QS-21 and alum to alter the immunologic response to immunization with respiratory syncytial virus a chimeric FG construct (FG) subunit vaccine was examined in BALB/c mice. FG/MPL, FG/alum, and FG/MPL/QS-21 combinations increased non-neutralizing antibody response, while FG/QS-21 did not. FG subunit vaccine with MPL, QS-21, or both had cytokine responses more closely resembling primary infection than FG/alum, with decreased interleukin-4 mRNA levels and increased IgG2a isotype antibody. The lungs of the mice immunized with FG subunit vaccines showed a heightened inflammatory response to respiratory syncytial virus challenge as compared to live virus immunization. Adjuvants can be used to alter the humoral and cellular responses to RSV subunit immunization.

Seroprevalence of herpes simplex virus types 1 and 2 and cytomegalovirus in adolescents.

We determined the prevalence of herpes simplex virus (HSV) and cytomegalovirus (CMV) antibodies in a cohort of adolescents 12 to 22 years of age in anticipation of the development of vaccines to control HSV and CMV infections. For the overall study population, we found that 62% were seropositive for HSV type 1 (HSV-1), 12% were seropositive for HSV type 2 (HSV-2), and 65% were seropositive for CMV. Race was not related to HSV-1 seropositivity, but African-American adolescents were more likely than Caucasian adolescents to be seropositive for HSV-2 and CMV. Girls also were more likely than boys to be seropositive for HSV-2 and CMV. For boys, history of a sexually transmitted disease was identified as a risk factor for HSV-2 seropositivity; for girls, a greater number of sexual partners increased the risk of being seropositive for HSV-2. Our data demonstrating a high prevalence of infection during adolescence suggest that immunization for HSV-1, HSV-2, and CMV may need to occur in childhood.