The effect of PTH(1-84) or strontium ranelate on bone formation markers in postmenopausal women with primary osteoporosis: results of a randomized, open-label clinical trial.

UNLABELLED: We explored the effects of PTH(1-84) compared with strontium ranelate on bone remodeling as measured by bone remodeling markers in postmenopausal women with osteoporosis. Biochemical markers of bone formation were significantly increased after treatment with PTH(1-84) but not strontium ranelate, indicating a different mechanism of action between these agents. INTRODUCTION: PTH(1-84) and strontium ranelate (SR) are both known to reduce fracture risk in osteoporosis. Measuring changes in biochemical markers of bone turnover induced by these agents can help in characterizing the action of PTH(1-84) and SR on bone remodeling. METHODS: A 24-week, randomized, open-label, parallel group, phase IV trial was conducted in 81 postmenopausal women with primary osteoporosis (≥50 years of age, lumbar spine, or total hip T-score ≤-2.5 SD) to assess the effect of SR as compared to PTH(1-84) on bone formation markers P1NP and BSAP. The bone resorption marker CTX was also measured. Subjects were randomly assigned to receive daily either 100 µg PTH(1-84) (n = 41) (subcutaneous injection) or oral 2 g SR (n = 40) for 24 weeks with daily supplements of 800 IU vitamin D(3) and 1,000 mg calcium. Patient-reported outcomes were collected to investigate the effect of treatment on quality of life (QoL). RESULTS: Percentage changes from baseline in P1NP and BSAP were significantly increased for PTH(1-84) by week 24 compared with SR (p < 0.0001). Significant changes from baseline in P1NP and BSAP were noted for PTH(1-84) from week 4 onwards; no significant changes were noted for SR. A trend towards a positive impact on QoL was seen with PTH(1-84) treatment. Safety profiles concur with previous analyses. CONCLUSIONS: PTH(1-84) had a more rapid and higher effect on bone formation markers compared to SR, indicating that SR has a different mode of action on bone remodeling than the bone building agent PTH(1-84) in postmenopausal women with osteoporosis.

Canine distemper and experimental allergic encephalomyelitis in the dog: comparative patterns of demyelination.

The pattern of virus-induced and allergic demyelinating encephalomyelitis in the dog were compared. The predominant pattern of myelin loss in canine distemper (CD) infection was focal, periventricular and was initially noninflammatory. In contrast, sensitization to myelin produced a uniform pattern of central nervous system (CNS) myelinolysis which was disseminated, inflammatory and perivascular. Ultrastructurally, virus-infected neuroglia participated in the demyelination in CD, whereas infiltrating haematogenous mononuclear cells predominated in the lesions of experimental allergic encephalomyelitis (EAE). Areas of predilection within the CNS differed, being influenced by viral spread in CD and by vascular factors in EAE. In CD, the paramyxovirus appears to play a central role in the process of demyelination. In contrast to EAE, however, these studies do not support the view that autoreactivity to myelin contributes to the pathogenesis of CD demyelinating encephalomyelitis.

Canine distemper encephalomyelitis: variation with virus strain.

Disease induced by 3 virulent strains of Canine Distemper Virus (CDV) was compared in specific pathogen-free Beagle dogs. All strains produced an encephalomyelitis but variation was observed in the severity, clinical course and resulting neuropathology. Infection with Snyder Hill strain of CDV was consistently acute; dogs either succumbed 14 to 19 days post-inoculation (PI) or recovered. Lesions in the neuraxis were those of a polioencephalomyelitis. In contrast, CDV strain A75-17 produced subacute to chronic disease in which demyelination was the predominant finding. Some dogs succumbed, generally around 28 to 42 days PI. Total recovery was again recorded for some members of the group. Others developed persistent central nervous system (CNS) infection but remained clinically stable until electively killed with barbiturate, up to 62 days PI. CDV strain R252 also induced delayed, predominantly white matter disease with a mixed pattern of mortalities, persistent infections and recoveries, similar to A75-17. Neutralizing antibody responses correlated with the disease course. Dogs which died had low serum titres or lacked serum antibody. Recovering dogs had the earliest and highest titres. A few dogs with persistent CNS infection had antibody in the cerebrospinal fluid also. Current concepts of the pathogenesis of canine distemper encephalomyelitis (CDE) are discussed and a basis for the strain-dependent clinical and pathological expression of CDE is proposed. Viral strain appears to be an important factor in this common disease of the canine CNS.

Does virus persist in the uvea in multiple sclerosis, as in canine distemper encephalomyelitis?

Epidemiological studies suggest that multiple sclerosis (MS) might be triggered by an infectious agent. Uveitis has been observed in a small percentage of MS patients. Dogs with canine distemper encephalomyelitis, another demyelinating disease of the central nervous system, have an anterior uveitis which is usually mild and asymptomatic, and dogs with persistent CNS infection and chronic distemper encephalomyelitis harbour virus persistently in the uvea. These observations in dogs suggest that pathological and virological studies of the uveitis associated with MS would be worth while.

Ultrastructure of the articular cartilage and synovium in the early stages of degenerative joint disease in canine hip joints.

A combined light and electron microscopic study recorded the developing degenerative changes in the hip joints of dogs with spontaneous joint disease. Synovium from joints with normal articular cartilage contained 33% type A and 64% type B cells. The 1st evidence of articular cartilage degeneration was loss of the surface amorphous layer and disruption of collagen fibrils. In the face of the earliest focal cartilage defects, the number of type A cells decreased (P less than 0.01) and remained low. Necrotic synoviocytes and synoviocytes of uncertain type increased as articular cartilage lesions progressed. The earliest pathologic changes in the synovium and the articular cartilage surface were evident only on ultrastructural examination.

Reduced deposition of collagen in the degenerated articular cartilage of dogs with degenerative joint disease.

Collagen metabolism in the focal degenerated cartilage from immature dogs with degenerative joint disease was compared with that in the adjacent 'normal' cartilage of the same joint surface. The deposition of collagen into the cartilage in vitro as measured by accumulation of hydroxy[14C]proline was decreased in the early and in advanced stages of cartilage degeneration. The deposition of collagen into cartilage in vivo as measured by the accumulation of hydroxy[3H]proline (intravenously injected [3H]proline) also was reduced in the degenerated cartilages of a dog with degenerative joint disease. Gel electrophoretic analysis revealed that degenerated cartilage contained less alpha 1 II collagen chains, but increased amounts of larger proteins. Degenerated cartilage contained more water, increased amounts of unidentified, non-collagenous protein, increased collagenolytic enzyme activity and fewer chondrocytes. Decreased deposition of collagen would result in collagen depletion in the foci of degenerated cartilage in joints of dogs with degenerative joint disease.

Sensitivity of bovid herpesvirus 2 replication to temperatures found in the natural host.

Two isolates of bovid herpesvirus 2 replicated poorly in bovine testicular cells and fetal kidney cells at 39--40 degrees C, temperatures commonly observed in virus-infected cattle. High viral titers occurred in replicate cultures at 30--37 degrees C. Persistent viral infections were noted in cultures maintained at 40 degrees C. Interferon-like activity was not responsible for the high-temperature restriction since the level was not significantly different between virus-infected cultures incubated at 35 degrees or 40 degrees C. Spontaneous viral inactivation was only three times as rapid at 41 degrees as at 35 degrees C. Analysis of temperature shift experiments with respect to results of growth studies and electron microscopy indicated a temperature sensitive event late in replication. The sensitivity of bovid herpesvirus 2 replication to elevated temperature provides a possible explanation for the extensive viral growth and occasionally severe lesions which are limited exclusively to the skin of infected cattle.

Studies on viral leukoencephalomyelitis and swayback in goats.

Six kid goats with CNS disease were studied by a variety of techniques. All had morphological evidence of Viral Leukoencephalomyelitis of Goats. (VLG) characterized by demyelinating encephalomyelitis and pneumonitis. Attempts were made to isolate a virus from 5 of these goats by direct culture of CNS and visceral tissues. Syncytial formation was found in some lung, spleen and bone marrow cultures but syncytia were found to be free of complete virus by electron microscopy. When newborn goats were inoculated with syncytia forming cells, a visna-like virus was found in bone marrow cultures of 1 goat 8 days post inoculation. Bone marrow cells from a twin goat 3 months after inoculation produced syncytia without complete virus. it is suggested that complete virus might be present in goats shortly after infection, while persisting in an incomplete form. Three of the 6 goats studied also had lesions of swayback with diffuse encephalomyelopathy and low liver copper levels. Control copper levels in kids with non-neurological disease were variable, occasionally being as low as swayback animals. The experience of others that swayback in the goat and low copper status are poorly correlated is confirmed. Discrepancies inherent in assaying formalin preserved tissues for copper are described.

Canine viral enteritis. I. Status report on corona- and parvo-like viral enteritides.

This report attempts to provide the most recent information on salient features of two newly recognized viral enteritides of dogs. The viruses, a corona-like virus and canine parvo-like virus, are distinct but the disease manifestations in a particular outbreak often are similar. Laboratory study is therefore required. The parvoviral infection generally is more severe, with leukopenia (relative lymphopenia) a most prominent feature. Knowledge of the pathogenesis, epizootiology and the host's immune response is fragmentary at the present time, but research now in progress will doubtless expand knowledge of both diseases and of the viruses that cause them.

Early events in canine distemper demyelinating encephalomyelitis.

The early neuropathological development of demyelinating Canine Distemper Encephalomyelitis (CDE) was studied in SPF dogs. Neural tissues were examined up to 30 days post infection (PI). Three phases of activity were observed. The primary event (first observed 8 days PI) was a nonsuppurative encephalomyelitis associated with the initiation of central nervous system (CNS) infection by virus-laden lymphocytes. At 24 days PI noninflammatory demyelination occurred in well defined, subependymal foci. Cell fusion and syncytia formation accompanied this early demyelination. The third phase, found at day 30 PI in one dog showing signs of recovery, was a second wave of nonsuppurative inflammation. The initial encephalomyelitis was widely disseminated throughout the CNS but subsequent demyelination appeared to be initiated from within the ventricular system. Myelin was phagocytosed by endogeneous CNS macrophages often infected with Canine Distemper Virus (CDV). The possible importance of viral induced cell fusion as well as immune factors in the mechanism of demyelination are discussed.

Canine viral enteritis. II. Morphologic lesions in naturally occurring parvovirus infection.

The morphologic lesions associated with naturally occurring canine parvovirus infection are described. The disease is characterized by necrosis of crypt epithelium in the small intestine and of lymphoid tissue in Peyers patches, lymph nodes, spleen and thymus.

Possible initiation of viral encephalomyelitis in dogs by migrating lymphocytes infected with distemper virus.

The principal pathways by which viruses spread to the central nervous system (C.N.S.) are considered to be direct invasion along peripheral nerves or the haematogenous route. The latter is thought to involve passive transfer or active replication of virus in C.N.S. endothelial cells. In this study histological evidence of mild perivascular encephalomyelitis was found 8-10 days after infection of dogs with canine distemper virus (C.D.V.). C.D.V. antigen and viral nucleocapsids were detectable in the mononuclear cells infiltrating nervous tissue and C.D.V. was isolated from lymphoid tissue and buffy-coat cells. C.N.S. infection may thus be initiated by migrating virus-infected lymphocytes and this pathway may operate in other viral disorders of the C.N.S.

Pathogenesis of canine bordetellosis.

Bordetella bronchiseptica produced tracheobronchitis when administered in aerosol to specific pathogen-free dogs. Clinical signs appeared to be directly related to numbers of bacteria in the trachea. Electron microscopic examination revealed that each bacterium was close to one or more tracheal cilia and that a fibrillar material was radiating from the bacterial cell wall. B. bronchiseptica required 14 weeks to be cleared from the tracheas of infected dogs; in contrast, other organisms commonly isolated from the respiratory tracts of dogs were cleared within one to three days. Strains of high and low in vitro passage and strains representing three different morphotypes were of equal pathogenicity. Local immunity was observed after infection and appeared to be of primary importance in recovery from the infection. Presumably this response involves prevention of bacterial attachment and reattachment to cilia.

Bacteriological variation among Bordetella bronchiseptica isolates from dogs and other species.

Bacteriological properties of 50 isolates of Bordetella bronchiseptica were compared. Phase variation, which involved colonial morphology and its associated characters of hemagglutination, hemolysis, acriflavine agglutination; crystal violet staining, flagellation, and fimbriation, occurred among these isolates. Organisms representing the three observed morphotypes did not have different growth rates, nor were any differences in their bacteriological characteristics observed after repeated subculture on agar. There were also variations in antimicrobial drug susceptibility, especially to sulfonamide-trimethoprim, and in nitrate reduction. The relationships among these variable parameters were not apparent. None of the observed variations could be attributed to differences in the species of origin.