Mild Clinical Disease Research Articles

Animal models of Duchenne and Becker muscular dystrophy.

Two animal models have been shown to be related to Duchenne and Becker muscular dystrophy at the molecular level. The mdx mouse is characterized by early onset of muscle degeneration and very mild clinical disease. The disease is minimally progressive and fibrosis of muscle is absent. Linkage studies, absence of dystrophin, and reduced levels of message indicate that the mutation in mdx lies in the gene for dystrophin, the gene that is defective in Duchenne and Becker muscular dystrophy. The xmd dog develops lesions that are essentially indistinguishable from those of Duchenne dystrophy, and there is progressive fibrosis and destruction of muscle tissue. Affected dogs develop severe clinical disease. The absence of dystrophin and its message in muscle, and the linkage of RFLPs recognized by Duchenne cDNA probes, indicate that the mutation in the xmd dog lies in the gene for dystrophin. Exploitation of these models should lead to a greater understanding of molecular and cellular events involved in the pathogenesis of Duchenne and Becker muscular dystrophies.

Experimental chlamydial keratitis in rabbits. Correlation with chlamydia infected McCoy tissue culture cells.

Rabbit corneas were inoculated three times at weekly intervals with the agent of chlamydia trachomatis using the scratch method. Specimens of the corneal epithelium were obtained using the replica technique on the 1st, 2nd, 3rd and 4th day after each inoculation and at two weeks after the last inoculation. The development of chlamydial inclusions and the inflammatory cell response were monitored using Giemsa stain, acridine orange stain and direct immunofluorescent technique. Primary inoculation produced mild clinical disease associated cytologically with polymorphonuclear leucocytic cellular inflammatory response. Repeated inoculations produced more severe disease associated clinically with pannus formation and cytologically with the presence of lymphocytes and Leber cells in addition to polymorphonuclear leucocytes. Halberstaedter Prowazek inclusion bodies were detected in all the specimens. Additional intracytoplasmic and intranuclear inclusions of different morphological appearances were present. The cytological findings detected in the corneal epithelium of rabbits were correlated with the findings in McCoy tissue culture cells inoculated with chlamydia trachomatis.

Experimental pneumonia in conventionally reared and gnotobiotic calves by dual infection with Mycoplasma bovis and Pasteurella haemolytica

Mild clinical disease was produced in conventionally reared calves by the intranasal inoculation of 18-hour cultures of Pasteurella haemolytica simultaneously with Mycoplasma bovis; at necropsy seven days later moderate pneumonic consolidation was observed in two of four calves. Additional intratracheal injection of these organisms did not increase the severity of disease. In contrast, inoculation of six-hour cultures of P haemolytica with M bovis produced more severe disease and more extensive pneumonic consolidation. The most severe disease and greatest degree of pneumonic consolidation was induced by intranasal and intratracheal inoculation of six-hour cultures of P haemolytica one day after the intranasal inoculation of M bovis. Omitting the intranasal injection of P haemolytica reduced the severity and consolidation only slightly. Studies in gnotobiotic calves revealed that more severe disease and more extensive pneumonic consolidation resulted when M bovis was inoculated before P haemolytic rather than vice versa.

Immunity in the female genital tract after intravaginal vaccination of mice with an attenuated strain of herpes simplex virus type 2.

Herpes simplex virus type 2 is a common human venereal pathogen which causes lethal neurological illness after intravaginal inoculation into BALB/cJ mice. To investigate whether an attenuated, nonlethal strain of this virus would confer immunity after inoculation of mice, we constructed a strain containing a partial deletion of the thymidine kinase gene, which is necessary for viral replication and spread in sensory ganglia. Unlike its wild-type counterpart, this deletion-containing strain of herpes simplex virus type 2 caused mild clinical disease and was not lethal when studied in an age-dependent murine model of intravaginal infection. Furthermore, after intravaginal infection, the deletion-containing strain could not be isolated from sensory ganglia at a time when wild-type virus was abundant. Of greater significance, intravaginal inoculation with the deletion-containing strain rendered mice completely resistant to rechallenge with a 10-fold 50% lethal dose of wild-type virus. These results suggest that a strain of herpes simplex virus type 2 containing a deletion of the thymidine kinase gene will be useful in studying the cellular basis of mucosal immunity in the genital tract.

Comparative studies of United Kingdom isolates of swine vesicular disease virus

The characteristics of four United Kingdom isolates of swine vesicular disease (SVD) virus from 1981 to 1982 have been compared with those of an isolate obtained from the first outbreak of swine vesicular disease diagnosed in the United Kingdom in 1972. When the virus structural proteins were examined by polyacrylamide gel electrophoresis the four isolates from 1981-82 all had the same polypeptide pattern, which was different from that of the 1972 isolate. Immunodiffusion tests with the 1972 isolate and one 1982 isolate did not reveal any antigenic difference between the viruses but minor antigenic differences were shown by cross-neutralisation tests between the 1972 isolate and the four isolates from 1981-82. In experimentally infected pigs the 1972 isolate produced typical SVD lesions whereas the four more recent SVD viruses produced only very mild clinical disease. Clinical lesions scored numerically were four- to 10- and five- to 11-fold higher at seven and 14 days after infection for pigs infected with the 1972 isolate than with the four isolates from 1981-82. The serum of pigs infected with the 1972 isolate contained significantly higher levels of neutralising antibody than those of pigs infected with more recent isolates. The antibody titres of pigs with only primary lesions ranged from log10 1.9 to 2.8 and one clinically normal pig had a titre of log10 2.4 at 14 days after infection. Attention is drawn to the implication of these findings for SVD control policies based only on the recognition and reporting of clinical disease.

Adoptive transfer of EAE-like lesions from rats with coronavirus-induced demyelinating encephalomyelitis.

Viruses have been found to induce inflammatory demyelinating lesions in central nervous system (CNS) tissue of both animal and man, either by natural infections or after vaccination1,2. At least two different pathogenic mechanisms have been proposed for these changes, a cytopathic viral infection of oligodendroglia cells with subsequent cell death, and a host immune reaction against virus and brain antigens. We now report the occurrence of cell-mediated immune reactions against basic myelin proteins in the course of coronavirus infections in Lewis rats. Infection of rats with the murine coronavirus JHM leads to demyelinating encephalomyelitis developing several weeks to months post-infection3–7. Lymphocytes from these diseased Lewis rats can be restimulated with basic myelin protein (BMP) and adoptive transfer of these cells leads to lesions resembling those of experimental allergic encephalomyelitis (EAE) in recipients, which can be accompanied by a mild clinical disease. This model demonstrates that a virus infection in CNS tissue is capable of initiating an autoimmune response which may be of pathogenic importance.

Lassa virus infection of rhesus monkeys: pathogenesis and treatment with ribavirin.

Rhesus monkeys were experimentally infected with Lassa virus to establish their suitability as a nonhuman primate model for the human disease and to test the protective efficacy of ribavirin, an antiviral drug. Six of 10 untreated control monkeys died after subcutaneous inoculation of 10(6.1) plaque-forming units of Lassa virus (strain Josiah). Infectivity titrations of tissue homogenates from the six dead monkeys indicated significant replication in all tissues tested except the central nervous system. This distribution of virus was confirmed by direct immunofluorescence examination of cryostat-sectioned tissues. Ribavirin was beneficial in the treatment of two groups of infected monkeys. Four monkeys first treated on the day of viral inoculation experienced only mild clinical disease; four monkeys first treated five days later experienced a more severe illness. None of the eight monkeys treated with ribavirin died. Viremia titers and elevations of levels of serum transaminases in treated monkeys were significantly lower than in controls. Ribavirin may be beneficial in the treatment of humans exposed to this life-threatening virus.

Hepatobiliary complications of ulcerative colitis

The records of 202 patients with chronic ulcerative colitis seen over a 12 year period were reviewed. Over one half (55 percent) were found to have liver function test abnormalities. These abnormalities correlated with the extent and severity of ulcerative colitis but not with the duration of the disease. Eight patients (4 percent) developed cirrhosis and four required portasystemic decompression for bleeding varices. Four patients (2 percent) developed biliary tract complications. Two patients were diagnosed as having sclerosing cholangitis, and two patients developed carcinoma of the extrahepatic biliary tree. Three of these four patients had whole colon involvement, but all four had mild clinical disease. It is concluded that the hepatobiliary complications of ulcerative colitis are the most frequent and serious extracolonic manifestations of the disease.

The pathogenesis of foot-and-mouth disease in the African buffalo ( Syncerus caffer) and the role of this species in the epidemiology of the disease in Kenya

Exposure of African buffalo to a measured dose of virus of serotypes SAT 1 and SAT 2 by intranasal instillation resulted in mild clinical disease with no mouth lesions and a single interdigital ulcer following exposure with the SAT 2 type. Exposure by tongue inoculation with type A did not result in overt disease. Viraemia was present for up to 6 days and virus was isolated from the nose for up to 15 dae. Virus was repeatedly isolated from the throat. Prolonged contact between carrier buffalo and susceptible cattle did not result in transmission of disease. A field survey showed that SAT 1 and SAT 2 carrier buffalo were present in the south of the country while there was also serological evidence that types O and A had cycled in the buffalo population. No strain differences were found between isolates from buffalo and cattle.

Epidemiologic, clinical, and virologic observations on dengue in the Kingdom of Tonga.

An outbreak of dengue type 2 infection occurred in the Pacific island Kingdom of Tonga in 1974 and an outbreak of dengue type 1 occurred there in 1975. The 1974 outbreak was characterized by relatively mild clinical disease with few hemorrhagic manifestations, a low attack rate, and relatively low viremia levels. The 1975 outbreak was characterized by relatively severe disease with frequent hemorrhagic manifestations and a high attack rate. The differences between the outbreaks could not be attributed to differences in abudance of, or susceptibility to infection of, mosquito vectors or to the prior immune status or other characteristics of the human population. It appeared that a difference in viral virulence was the most likely explanation.

EQUINE HERPESVIRUSES: Experimental Infecton of a Foetus with Type 2

SummaryIntrauterine infection of pregnant mare with equine herpesvirus type 2 (EHV 2) did not result in foetal abortion, stillbirth or recognisable disease. Collection of uterine fluid by allantocentesis or amniocentesis 107 days after inoculation confirmed that intrauterine infection was established. EHV 2 was isolated from both allantoic and amniotic fluid separately collected at the time of elective Caesarean section 156 days after inoculation and virus neutralising antibody to EHV 2 was present in the foal's presuckle serum at birth. A very mild clinical disease, characterised by a scant, mucous oculo‐nasal discharge was observed between 4 and 11 days after birth. EHV 2 was isolated from 22 nasal swabs taken between birth and 65 days of age, on which day the foal was infected with equine adenovirus. EHV 2 was not isolated from 6 nasal swabs collected from 66 to 71 days of age.

Animal health.

The problems of animal health in the Britain of the 1980s must be visualized in terms of increased intensivism, larger units, and a further diminished labour force. This will demand the increased application of professional services and more highly skilled planning in unit economics, disease control, nutrition, genetics, and in a pasture management integrated with extensive animal production systems. Steadily increasing production will depend upon: (i) Maintenance of freedom from the major animal plagues by effective import examination of animals and their products, continuing and developing international disease surveillance and supporting international disease control schemes. (ii) Systematic application of known preventive and remedial agents for specific diseases. (iii) In all animal enterprises the evaluation, diagnosis and treatment of inapparent or mild clinical disease by examination of strategically directed records of animal performance, for example, in breeding or in yield of final product. (iv) The development in pigs, and possibly in poultry, of breeding nuclei free of specific disease. The aim for the 1980s should be not only to increase production in quantitative terms, but to improve its efficiency and the quality of the product. All are dependent upon a high animal health status.

Beta-thalassemia in the American Negro.

In Italian patients with high hemoglobin A(2) beta-thalassemia trait, the synthesis of beta-chains of adult hemoglobin in the peripheral blood is approximately one-half that of alpha-chains. In this study the relative rates of beta- and alpha-chain synthesis were determined in 26 Negro heterozygotes and five homozygotes for beta-thalassemia in six families. The beta/alpha ratio of globin synthesis was decreased in only 15 heterozygotes, whereas in the other 11, beta/alpha globin synthesis was in the normal range or was slightly increased. These unusual findings did not appear to be due to the presence of alpha-thalassemia or a hyperactive "normal" beta-allele. This study demonstrates that the beta/alpha ratio of globin synthesis in the peripheral blood is normal in some patients with beta-thalassemia trait. In five Negro homozygotes with relatively mild clinical disease the beta/alpha ratios were similar to those of Caucasians with Cooley's anemia. Further studies are needed to explore the relationship between normal synthesis ratios in many Negro heterozygotes and milder clinical disease in homozygotes in the same families.

The Histopathology of Pneumonia Produced by Aerosol Infection of Pigs with a Strain of Aujeszky’s Disease Virus

Summary Pathogen-free and conventionally reared pigs were exposed to an aerosol cloud of Aujeszky’s disease virus. Mild clinical respiratory disease resulted, and from the third day at necropsy all lobes of the lungs contained numerous small areas of consolidation. Histologically these lesions consisted of necrotising bronchiolitis and alveolitis. From the fifth day a lympho-retiadar reaction developed at the periphery of the lesions and by the tenth day repair had been effected by fibrosis.

Identification and Treatment of Group A Beta-Hemolytic Streptococcal Infections: Role of the Pediatrician and the Nurse-Practitioner

The risk of rheumatic fever in childhood continues to be high in the United States, especially where crowded living conditions promote epidemic spread of streptococcal pharyngitis. Early identification and appropriate penicillin therapy shorten the acute streptococcal illness and greatly reduce the occurrence of sequelae. Florid disease usually presents no therapeutic dilemma, but a firm scientific basis for definitive diagnosis and treatment of the carrier state, inapparent infection, mild clinical disease, or relapse is lacking. Appreciation of these unresolved issues is helpful in developing practical therapeutic guidelines for physicians and assistants. Public health throat culture programs may provide the initiative for effective community streptococcal control, but centralization of facilities on a large scale may delay institution of therapy because of slow reporting of culture results. Although delay in treatment may engender increased risk of rheumatic fever, institution of appropriate penicillin therapy may prevent rheumatic fever even if started after an untreated streptococcal tonsillitis has run its usual 5 day symptomatic course. Throat cultures are necessary in diagnosis, but clinical judgment must be exercised in initiating penicillin therapy before the culture is reported. The relative morbidity and ultimate mortality of the sequelae to streptococcal disease suggest assignment of national health priority to the development of preventive programs. Utilization of nurse-practitioners or similarly trained medical assistants seems necessary to effective delivery of care in the crowded areas of highest rheumatic fever incidence.

Experimental trachoma in owl monkeys.

Experimental trachoma in nonhuman primates has been handicapped because trachoma (as opposed to inclusion conjunctivitis) produces very mild clinical disease and minimal microbiologic changes. In a direct comparison between the Old World Taiwan monkey, Macaca cyclopis, and the New World owl monkey, Aotus trivirgatus, the latter was found to be much more susceptible. Owl monkeys manifested severe disease for a period of 2 or more weeks, while none was observed in Taiwan monkeys during the same period of time. Given identical inoculations of 2,000 EID50 in the left eye and 20 EID50 in the right eye, six Taiwan monkeys on the 7th day averaged 21 inclusions in the left eye and one in the right. Comparable figures for six owl monkeys were 641 and 1,396, respectively.

CONGENITAL DISORDERS OF THE MECHANISM FOR COAGULATION OF BLOOD

Ninety-two new cases of hemophilia A and 16 of hemophilia B are reported. The data, together with those from other reported series, suggest that hemophilia A and B comprise over 90% of all congenital hemorrhagic diseases due to defective formation of a fibrin clot. Of those with deficiencies of AHF or PTC, the incidence of PTC deficiency is about 16%. The rise in age at death of patients with hemophilia from 14.5 to 29 years since 1940 is largely attributed to the wide use and availability of fresh blood and its derivatives. The usefulness of various coagulation tests in the differential diagnosis of the congenital abnormalities of the clotting mechanism is demonstrated. With the development of more sensitive diagnostic techniques, the concept of hemophilia has broadened to include many cases of very mild clinical disease in patients with essentially normal life expectancy. Specific assay procedures are necessary for diagnosis.