Rubella Virus Infection, the Congenital Rubella Syndrome, and the Link to Autism.

Rubella is a systemic virus infection that is usually mild. It can, however, cause severe birth defects known as the congenital rubella syndrome (CRS) when infection occurs early in pregnancy. As many as 8%-13% of children with CRS developed autism during the rubella epidemic of the 1960s compared to the background rate of about 1 new case per 5000 children. Rubella infection and CRS are now rare in the U.S. and in Europe due to widespread vaccination. However, autism rates have risen dramatically in recent decades to about 3% of children today, with many cases appearing after a period of normal development ('regressive autism'). Evidence is reviewed here suggesting that the signs and symptoms of rubella may be due to alterations in the hepatic metabolism of vitamin A (retinoids), precipitated by the acute phase of the infection. The infection causes mild liver dysfunction and the spillage of stored vitamin A compounds into the circulation, resulting in an endogenous form of hypervitaminosis A. Given that vitamin A is a known teratogen, it is suggested that rubella infection occurring in the early weeks of pregnancy causes CRS through maternal liver dysfunction and exposure of the developing fetus to excessive vitamin A. On this view, the multiple manifestations of CRS and associated autism represent endogenous forms of hypervitaminosis A. It is further proposed that regressive autism results primarily from post-natal influences of a liver-damaging nature and exposure to excess vitamin A, inducing CRS-like features as a function of vitamin A toxicity, but without the associated dysmorphogenesis. A number of environmental factors are discussed that may plausibly be candidates for this role, and suggestions are offered for testing the model. The model also suggests a number of measures that may be effective both in reducing the risk of fetal CRS in women who acquire rubella in their first trimester and in reversing or minimizing regressive autism among children in whom the diagnosis is suspected or confirmed.

Predictive Factors of Intraocular Pressure Level Evolution Over Time and Glaucoma Severity in Fuchs' Heterochromic Iridocyclitis.

Purpose: To investigate the clinical and virologic-associated and predictive factors of intraocular pressure (IOP) evolution over time and its severity in Fuchs' heterochromic iridocyclitis (FHC). Methods: Consecutive patients with both clinical FHC and intraocular synthesis of rubella virus (RV)-specific antibodies were included in this study. Specific ocular production of RV antibodies was confirmed using the quotient of serum/aqueous humor ratio of RV IgGs (Crv) and control antiviral IgGs (Cctl), using quantitative serology methods. Epidemiologic, clinical, biological, and virologic data at referral were collected and correlated with IOP values over time, occurrence, and severity of glaucoma. Results: Sixty-eight eyes of 68 patients were included. Mean age at diagnosis was 40.7 ± 11.1 years. Mean follow-up was 4.3 ± 4.3 years. Mean baseline Crv and Cctl values were 12.34 ± 14.67 and 216.70 ± 98.4, respectively. Mean baseline IOP was 17.2 ± 7.2 mm Hg (range, 9-40) and 15.6 ± 5.6 (range, 3-30) 5 years after referral. The predictive factors for pejorative IOP evolution over time and glaucoma severity were male sex (P = 0.03) and decreased Crv (P = 0.04) and presence of iris nodules (P < 0.001) and decreased Cctl (P = 0.02), respectively. Diagnostic delay was associated with increased likelihood of undergoing glaucoma surgery (P = 0.02). Conclusions: Time to diagnosis, male sex, presence of iris nodules at baseline, and decreased Crv and Cctl ratios were associated with increased likelihood of pejorative IOP evolution over time. Given the aggressiveness of glaucoma in FHC, these results provide interesting insight into what category of patients should need the closest screening.

Impact of Maternal BMI on Rubella Nonimmunity at Antenatal Screening.

OBJECTIVE: The aim of this study was to examine the relationship between BMI and the incidence of rubella nonimmunity among pregnant women with regard to the World Health Organization categories. METHODS: This was a retrospective cohort study of 117,063 eligible gravidas, managed between 1998 and 2015 in a university hospital of Hong Kong, China. BMI at antenatal booking was banded using the following World Health Organization definitions: < 18.5 kg/m2 , 18.5 to 24.9 kg/m2 , 25.0 to 29.9 kg/m2 , and ≥30.0 kg/m2 . Maternal rubella nonimmunity status by BMI was assessed. Incidence rates were also assessed after adjusting for maternal advanced age, short stature < 151 cm, mothers' birthplace, and postobstetric history covariates. RESULTS: Rubella nonimmunity incidence increased as the BMI increased (P < 0.001). Gravidas with high BMI were more likely to be nonimmune if born in Hong Kong (odds ratio [OR], 1.234; 95% CI: 1.159-1.315; P < 0.001) compared with those born outside of Hong Kong (OR, 1.066; 95% CI: 0.997-1.141; P = 0.063). After adjusting for covariates, women with BMI ≥ 25 kg/m2 had 1.127 (P < 0.001; 95% CI: 1.074-1.182) greater odds of being nonimmune. CONCLUSIONS: High maternal BMI (≥ 25.0 kg/m2 ) is associated with reduced rubella immunity, an effect confined to gravidas with almost complete vaccine coverage in childhood.

[Progress on mechanism of cell apoptosis induced by rubella virus].

Rubella virus (RV), a member of the family Togaviridae, can induce apoptosis of host cells in vitro. Protein kinases of the Ras-Raf-MEK-ERK pathway and PI3K-Akt pathway play essential roles in virus multiplication, cell survival and apoptosis. Proteins p53 and TAp63 that bind to specific DNA sequences stimulate Bax in a manner to produce functional pores that facilitate release of mitochondrial cytochrome c and downstream caspase activation. In this review, the molecular mechanisms of RV-induced cell apoptosis, including RV-infected cell lines, pathological changes in cell components and apoptosis signaling pathways are summarized.

[Detection of rubella virus RNA in clinical material by real time polymerase chain reaction method].

AIM: Development of a reagent kit for detection of rubella virus RNA in clinical material by PCR-RT. MATERIALS AND METHODS: During development and determination of analytical specificity and sensitivity DNA and RNA of 33 different microorganisms including 4 rubella strains were used. Comparison of analytical sensitivity of virological and molecular-biological methods was performed by using rubella virus strains Wistar RA 27/3, M-33, "Orlov", Judith. Evaluation of diagnostic informativity of rubella virus RNAisolation in various clinical material by PCR-RT method was performed in comparison with determination of virus specific serum antibodies by enzyme immunoassay. RESULTS: A reagent kit for the detection of rubella virus RNA in clinical material by PCR-RT was developed. Analytical specificity was 100%, analytical sensitivity - 400 virus RNA copies per ml. Analytical sensitivity of the developed technique exceeds analytical sensitivity of the Vero E6 cell culture infection method in studies of rubella virus strains Wistar RA 27/3 and "Orlov" by 11g and 31g, and for M-33 and Judith strains is analogous. Diagnostic specificity is 100%. Diagnostic specificity for testing samples obtained within 5 days of rash onset: for peripheral blood sera - 20.9%, saliva - 92.5%, nasopharyngeal swabs - 70.1%, saliva and nasopharyngeal swabs - 97%. Positive and negative predictive values of the results were shown depending on the type of clinical material tested. CONCLUSION: Application of reagent kit will allow to increase rubella diagnostics effectiveness at the early stages of infectious process development, timely and qualitatively perform differential diagnostics of exanthema diseases, support tactics of anti-epidemic regime.

Comparison of rubella virus- and herpes virus-associated anterior uveitis: clinical manifestations and visual prognosis.

PURPOSE: To compare the clinical characteristics and visual prognosis of patients with anterior uveitis (AU) and intraocular fluid analysis positive for rubella virus (RV), herpes simplex virus (HSV), or varicella zoster virus (VZV). DESIGN: Retrospective, observational study. PARTICIPANTS: The study included 106 patients with AU and positive polymerase chain reaction (PCR) results, Goldmann-Witmer coefficients (GWCs), or both, for RV (n = 57), HSV (n = 39), or VZV (n = 10). METHODS: Clinical records of the included patients were analyzed retrospectively; demographic constitution, ophthalmologic characteristics, and visual prognosis were compared. MAIN OUTCOME MEASURES: Age, gender, and diverse clinical and laboratory characteristics, including course and laterality of AU; prevalence of positive results for PCR, GWC, or both; conjunctival redness; corneal edema; history of keratitis; presence of keratic precipitates; synechiae; heterochromia; and grade of inflammation. In addition, complications and visual acuity at 1 and 3 years of follow-up were recorded. RESULTS: All 3 types of viral AU were characterized by unilateral involvement (80%-97%). Rubella virus AU was characterized by younger age at onset and chronic course and typically was associated with cataract at presentation. Heterochromia was present in 23% of RV AU patients. Anterior uveitis associated with HSV or VZV occurred characteristically in older patients and frequently followed an acute course. Clinical features associated with herpetic AU included conjunctival redness, corneal edema, history of keratitis, and development of posterior synechiae. Herpes simplex virus AU often had severe anterior chamber inflammation, whereas the presence of vitritis was more common in RV AU and VZV AU. The prevalence of documented intraocular pressure (IOP) of more than 30 mmHg (25%-50%; P = 0.06) and development of glaucoma (18%-30%; P = 0.686) were similar in all 3 groups. Focal chorioretinal scars were seen in 22% of RV AU eyes, in 0% of HSV AU eyes, and in 11% of VZV AU eyes (P = 0.003). Visual prognosis was favorable for all 3 groups. CONCLUSIONS: These observations identify clinical differences between RV AU, HSV AU, and VZV AU and may be of particular value to ophthalmologists who are unable to carry out intraocular fluid analysis to discriminate between these types of viral AU. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

[Influence of TORCH-infections on the spermatogenesis of men].

The purpose of the given study was to reveal causal relations between infection of the urino-genital tract by intracellular parasites, the so-called TORCH-infections, and the decrease of spermatogenesis. For observation 182 men of reproductive age (from 22 to 38 years) with oligozoospermia and aspermia, without any complaints or clinical symptoms indicating existence of infections of urino-genital tracts, were selected. Out of those, 131 revealed oligozoospermia, i.e. the quantity of spermatozoons was no higher than 20 mln in 1 ml of ejaculate, and 51 revealed - aspermia. For examination of some TORCH infections, medical doctors in charge directed 44 oligozoospermia patients and 15 aspermia patients, who respectively constituted group I and group II. Examinations were carried out for Chlamydia trachomatis--(Ch.t), Herpes simplex virus--(HSV), Ureaplasma urealiticum--(U.u.), Cytomegalovirus--(CMV), and Mycoplasma hominis--(M.h.). In the group with oligozoospermia, cases of infections by Chlamydias (41.5%) and Herpes virus (51.3%) were frequent, but Ureaplasma (56,5%) was more frequent than any infections. Cytomegalovirus occurred in the least number of cases. Making any conclusions on the frequency of infections by M.h. is difficult due to the low number of examinations. Similar picture was observed in Group II as well. Following successful treatment of infections in Group I, 8 patients with Ch.t. and 8 patients with U.u. showed an improved spermogram after several months. Treatment of other infections did not yield tangible results. In Group II spermatogenesis remained without any changes.

The effect of infliximab on antiviral antibody profiles in patients with rheumatoid arthritis.

The duration of humoral immunity in patients treated with immunosuppressive drugs is poorly defined. The objective of the study was to investigate the effect of infliximab on the levels of antiviral antibodies against poliomyelitis, rubella and measles in rheumatoid arthritis (RA) patients. Fifty-two consecutive RA patients being treated with 3 mg/kg infliximab were prospectively studied. The antiviral antibody profiles for measles, rubella and three serotypes of poliomyelitis were tested on the day of the first infusion of infliximab and 6 months later. The study group comprised 36 women and 16 men (mean age 54 years, range 33-81) with a mean disease duration of 15 +/- 9 years. Forty-two (81%) patients were being treated with methotrexate and 22 (42%) were receiving prednisone. All patients had baseline protective levels of antibodies against measles and the three strains of polio, while 48 (92%) patients had protective antibodies against rubella. No significant change in the levels of antiviral antibodies was observed after 6 months of treatment with infliximab: from 3.67 at baseline to 3.87 IU/ml for measles, 169.50-197.0 IU/ml for rubella. No change was noticed for the geometric mean concentrations of antibodies against strains of poliomyelitis: 366-478 IU/ml for the Mahoney polio strain, 906-845 IU/ml for the MEF strain and 175-196 IU/ml for the Sauket strain. Patients with longstanding RA conserve long-term immunity to common viruses despite the use of immunosuppressive drugs. Levels of antiviral antibodies against measles, rubella and polio remain stable under treatment with infliximab.

Encephalitis in a child during atypical course of rubella.

Rubella is usually encountered as a mild viral illness in children and complications are not common. We reported rubella encephalitis in the atypical course of rubella without rash in a 9-year-old boy. He was admitted with a headache, fever, loss of consciousness and bilateral retroauricular lymphadenopathy. The cerebrospinal fluid (CSF) examination showed lymphocytic pleocytosis, increased protein levels and a normal glucose value. Immunoglobulin (Ig) M antibodies against rubella virus were positive in CSF and serum. IgG antibody also became positive in his serum 3 weeks after his admittance. We emphasized that rubella may appear without any rash and cause encephalitis. In unvaccinated children, rubella should be considered in the differential diagnosis of encephalitis.

The usual childhood diseases: forgotten but not gone.

With the advent of vaccine protection for many diseases, many of today's practitioners have never seen cases of what were the common childhood diseases. If any of these diseases returns, there is a risk that the practitioner will not recognize it. This article tries to establish why the diseases may return and to describe the diseases with photographs.

Rubella virus and birth defects: molecular insights into the viral teratogenesis at the cellular level.

BACKGROUND: In utero rubella virus (RV) infection of a fetus can result in birth defects that are often collectively referred to as congenital rubella syndrome (CRS). In extreme cases, fetal death can occur. In spite of the availability of a safe and effective vaccine against rubella, recent worldwide estimates are that more than 100,000 infants are born with CRS annually. RECENT PROGRESS: Recently, several significant findings in the field of cell biology, as well as in the RV replication and virus-cell interactions, have originated from the authors' laboratory, and other researchers have provided insights into RV teratogenesis. It has been shown that 1) an RV protein induces cell-cycle arrest by generating a subpopulation of tetraploid nuclei (i.e., 4N DNA) cells, perhaps representative of the tetraploid state following S phase in the cell cycle, due to its interaction with citron-K kinase (CK); 2) RV infection induces apoptosis in cell culture, and 3) CK functional perturbations lead to tetraploidy, followed by apoptosis, in specific cell types. CONCLUSIONS: Based on several similarities between known RV-associated fetal and cellular manifestations and CK deficiency-associated phenotypes, it is reasonable to postulate that P90-CK interaction in RV-infected cells interferes with CK function and induces cell-cycle arrest following S phase in a subpopulation, perhaps representative of tetraploid stage, which could lead to subsequent apoptosis in RV infection. Taking all these observations to the fetal organogenesis level, it is plausible that P90-CK interaction could perhaps be one of the initial steps in RV infection-induced apoptosis-associated fetal birth defects in utero.

In utero infection and adult schizophrenia.

We review emerging evidence indicating that in utero exposure to infection is a risk factor for schizophrenia. It is hypothesized that a prenatal infection increases the liability to schizophrenia in adulthood by adversely affecting the maturation of critical brain structural and functional components implicated in the pathogenesis and pathophysiology of the disorder. Early evidence for a role of in utero infection includes investigations linking schizophrenia with birth during the winter and in urban regions, and ecologic studies demonstrating associations between influenza epidemics and births of pre-schizophrenic patients. The findings of the latter studies are, however, equivocal. To more rigorously address this question, our group has used increasingly sophisticated research designs that incorporate more refined measures of exposure and outcome, and continuous follow-up of treated cases. This work has already yielded several intriguing findings, including associations between schizophrenia and two in utero infections--rubella and respiratory infection. We also describe our ongoing birth cohort investigations that are expected to advance this work further, including studies that utilize maternal serum samples drawn during pregnancy of offspring who were later diagnosed with schizophrenia.

Estudio descriptivo sobre el nivel de conocimiento acerca de la rubeola en el embarazo que poseen los ingresantes a la Facultad de Ciencias Medicas de la Universidad Nacional de Rosario, en la ciudad de Rosario, en el año 2002 / Description study about he level of knowledge about of the measles in the pregnancy that posses the ingresants to the Faculty of Medical Sciences of the Univedrsity of Rosario, in the city of Rosario, in the year 2002

El tema de este trabajo se sitúa en tomo a la rubéola y trata de establecer el nivel de conocimiento que poseen las ingresantes de la Facultad de Ciencias Médicas de la Universidad Nacional de Rosario acerca de la rubéola durante la gestación. Además se trató de conocer la proporción de mujeres que padecieron rubéola, la proporción que ha sido vacunada y las que están dispuestas a vacunarse. Como la población era muy grande se tomó una muestra de 300 ingresantes de las diferentes Escuelas: 100 ingresantes a Medicina, 100 a Licenciatura en Fonoaudiologia y 100 a Licenciatura en Enfermería. La muestra es homogénea en cuanto a sexo (femenino), edad (todas se encuentran en edad fértil, lo que hace interesante este trabajo) y nivel de instrucción (todas tienen secundario completo)- Para conocer el nivel de conocimiento que poseen se indagó acerca de la forma de contagio de la rubéola, los síntomas del que padece rubéola, la forma en que se trasmite la enfermedad al bebé durante el embarazo, las secuelas que puede dejar en el bebé el padecimiento de la enfermedad durante el embarazo, las medidas preventivas que conocen. El instrumento utilizado fue un formulario de entrevista con preguntas abiertas y cerradas. A cada una de las respuestas se les otorgó un puntaje determinado según el criterio de valoración considerado en este trabajo. La entrevista se confeccionó a partir de la información bibliográfica consultada, En la mayoría de las entrevistadas (62) se evaluó un nivel de conocimiento bueno, el 38 (114 mujeres) tienen un nivel de conocimiento escaso. No se observo un nivel muy bueno. La mayoría de las mujeres entrevistadas tienen la vacuna aplicada (66,7). En las restantes la disposición a vacunarse se manifestó en un 92 de las mismas. El total de las entrevistadas, la mayoría no tiene hijos (92,3). De éstas, más de la mitad, tienen la vacuna aplicada (65), el resto no lo sabe o dice no tenerla. En aquellas que tienen hijos se obtuvo un porcentaje mayor de mujeres que dicen tener la vacuna aplicada (87). El 9,7 (29) padeció rubéola, 74 (222) no la padeció y 16,3 (49) no saben. De las que no padecieron rubéola 65,3 tienen la vacuna aplicada, 7,7 no y 27 no saben. De las que no saben si padecieron rubéola: el 59 tienen la vacuna aplicada, el 2 no y el 39 no sabe.

Estudio descriptivo sobre el nivel de conocimiento acerca de la rubeola en el embarazo que poseen los ingresantes a la Facultad de Ciencias Medicas de la Universidad Nacional de Rosario, en la ciudad de Rosario, en el año 2002 / Description study about he level of knowledge about of the measles in the pregnancy that posses the ingresants to the Faculty of Medical Sciences of the Univedrsity of Rosario, in the city of Rosario, in the year 2002

El tema de este trabajo se sitúa en tomo a la rubéola y trata de establecer el nivel de conocimiento que poseen las ingresantes de la Facultad de Ciencias Médicas de la Universidad Nacional de Rosario acerca de la rubéola durante la gestación. Además se trató de conocer la proporción de mujeres que padecieron rubéola, la proporción que ha sido vacunada y las que están dispuestas a vacunarse. Como la población era muy grande se tomó una muestra de 300 ingresantes de las diferentes Escuelas: 100 ingresantes a Medicina, 100 a Licenciatura en Fonoaudiologia y 100 a Licenciatura en Enfermería. La muestra es homogénea en cuanto a sexo (femenino), edad (todas se encuentran en edad fértil, lo que hace interesante este trabajo) y nivel de instrucción (todas tienen secundario completo)- Para conocer el nivel de conocimiento que poseen se indagó acerca de la forma de contagio de la rubéola, los síntomas del que padece rubéola, la forma en que se trasmite la enfermedad al bebé durante el embarazo, las secuelas que puede dejar en el bebé el padecimiento de la enfermedad durante el embarazo, las medidas preventivas que conocen. El instrumento utilizado fue un formulario de entrevista con preguntas abiertas y cerradas. A cada una de las respuestas se les otorgó un puntaje determinado según el criterio de valoración considerado en este trabajo. La entrevista se confeccionó a partir de la información bibliográfica consultada, En la mayoría de las entrevistadas (62) se evaluó un nivel de conocimiento bueno, el 38 (114 mujeres) tienen un nivel de conocimiento escaso. No se observo un nivel muy bueno. La mayoría de las mujeres entrevistadas tienen la vacuna aplicada (66,7). En las restantes la disposición a vacunarse se manifestó en un 92 de las mismas. El total de las entrevistadas, la mayoría no tiene hijos (92,3). De éstas, más de la mitad, tienen la vacuna aplicada (65), el resto no lo sabe o dice no tenerla. En aquellas que tienen hijos se obtuvo un porcentaje mayor de mujeres que dicen tener la vacuna aplicada (87). El 9,7 (29) padeció rubéola, 74 (222) no la padeció y 16,3 (49) no saben. De las que no padecieron rubéola 65,3 tienen la vacuna aplicada, 7,7 no y 27 no saben. De las que no saben si padecieron rubéola: el 59 tienen la vacuna aplicada, el 2 no y el 39 no sabe. (AU)

Syndromes with salivary dysfunction predispose to tooth wear: Case reports of congenital dysfunction of major salivary glands, Prader-Willi, congenital rubella, and Sjögren's syndromes.

Four cases-of congenital dysfunction of the major salivary glands as well as of Prader-Willi, congenital rubella, and Sjögren's syndromes-were identified in a series of 500 patients referred for excessive tooth wear. Although there was evidence of consumption of highly acidic drinks, some occlusal parafunction, and unacceptable toothbrushing habits, salivary dysfunction was the salient factor predisposing a patient to tooth wear in these syndromal cases. The 500 subjects have been characterized either as having medical conditions and medications that predispose them to xerostomia or lifestyles in which workplace- and sports-related dehydration lead to reduced salivary flow. Normal salivation, by buffering capacity, clearance by swallowing, pellicle formation, and capacity for remineralization of demineralized enamel, protects the teeth from extrinsic and intrinsic acids that initiate dental erosion. Thus, the syndromes, unrelated in many respects, underline the importance of normal salivation in the protection of teeth against tooth wear by erosion, attrition, and abrasion.