Pathogenesis of visna. IV. Spinal fluid studies.

Visna is a persistent retrovirus infection of sheep which produces a chronic progressive paralytic disease after an incubation period lasting from months to years. The cerebrospinal fluid (CSF) was repeatedly sampled in a group of Icelandic sheep which were infected intracerebrally and followed up to 42 months. Minimal levels of infectious virus were isolated from the cerebrospinal fluid (CSF) up to 4 months after infection after which CSF neutralizing antibodies appeared in many sheep. These antibodies varied in titer and in some animals exceeded serum antibody levels which were moderate to high. CSF antibody is apparently produced within the CNS by local proliferation of B cell clones, and is accompanied by the appearance of considerable numbers of plasma cells in the neural parenchyma. Some sheep raised serum antibody to a second serotype of visna virus and in a number of these animals heterotypic antibody was also found in the CSF. An increase in CSF leukocytes often occurs within 1 to 3 months following infection and may then persist or wane. A persistent high level of CSF cells is an indicator of progressive CNS disease and such animals are more likely to yield virus, have higher CSF antibody levels, more severe CNS lesions, and an enhanced risk of clinical illness (progressive paralysis). CSF cells are predominantly macrophages and lymphocytes, with a consistent minority of plasma cells.

Pathogenesis of central nervous system lesions in visna: cell-mediated immunity and lymphocyte subsets in blood, brain and cerebrospinal fluid.

There are several indications that central nervous system (CNS) lesions in visna are immune-mediated and that cell-mediated immunity (CMI) may be of importance in the initiation of the lesions. To study the role of CMI in the pathogenesis of CNS lesions, five sheep were infected by intracerebral inoculation with visna virus and observed for 1 year. The following parameters were monitored at regular intervals: (1) neutralizing and ELISA antibodies; (2) visna virus-specific stimulation of lymphocytes from peripheral blood; (3) lymphocyte subpopulations in peripheral blood, cerebrospinal fluid (CSF) and brain at sacrifice. The CNS lesions were graded and compared with other parameters. The time course and titers of antibodies did not correlate with the severity of CNS lesions whereas the CMI did, indicating that CMI may play an important role in lesion development. The correlation of the number of CD8-positive cells in the CSF with the severity of lesions and the reversed ratio of CD4/CD8-positive cells in the diffusely infiltrated neuroparenchyma indicates that the CD8-positive T lymphocyte may be an important effector cell in the induction of CNS lesions.

Cerebrospinal fluid immunoglobulins in sheep with visna, a slow virus infection of the central nervous system.

Icelandic sheep were injected intracerebrally with visna virus, which produces a persistent infection of the CNS accompanied by encephalomyelitis and focal demyelinating lesions. Studies were conducted on two groups of sheep, with short-term infections (25 sheep sampled 1-3 months after infection) and long-term infections (14 sheep sampled 5-6 years after infection). Quantitative determination of CSF immunoglobulin levels 5 years after infection indicated that IgM concentration was usually elevated, IgG2 was occasionally elevated and IgG1 was rarely elevated. CSF oligoclonal bands were seen in about half the sheep examined 5 years after infection. There was a correlation between high titers of CSF antiviral antibody and both elevated CSF IgM concentration and CSF oligoclonal bands. Serum/CSF IgG1 ratios indicated that the blood-brain barrier was apparently intact in long-term visna infection, consistent with intrathecal synthesis of IgM and of antiviral antibody. The alterations in CSF immunoglobulins in visna resemble those found in other persistent CNS virus infections and in multiple sclerosis.

Herpes zoster in children and adolescents.

OBJECTIVES: To follow the clinical course of herpes zoster and to determine the incidence, frequency of complications and association with malignancy in children and adolescents. DESIGN: Prospective cohort study in a primary health care setting in Iceland. The main outcome measures were age and sex distribution of patients and discomfort or pain 1, 3 and 12 months after the rash and general health before and 3 to 6 years after the zoster episode. RESULTS: During observation of the target population for a period of 75750 person years, 121 episodes of acute zoster developed (incidence 1.6/1000/year) in 118 patients. End points were gained for all 118 patients after 554 person years of follow-up. Systemic acyclovir was never used. No patient developed postherpetic neuralgia, moderate or severe pain or any pain lasting longer than 1 month from start of the rash (95% confidence interval, 0 to 0.03). Potential immunomodulating conditions were diagnosed in 3 patients (2.5%) within 3 months of contracting zoster. Only 5 (4%) had a history of severe diseases. CONCLUSIONS: The probability of postherpetic neuralgia in children and adolescents is extremely low. Zoster is seldom associated with undiagnosed malignancy in the primary care setting.

Treatment of glaucoma using minidrops of clonidine.

A single regular (70 microL) or mini (15 microL) eyedrop of 0% (placebo), 0.25%, and 0.50% strengths of clonidine hydrochloride was administered to 16 patients with open-angle glaucoma in a double-masked crossover study. Both the regular drops and minidrops of 0.25% and 0.50% concentrations of the drug substantially lowered the intraocular pressure over a five-hour period as compared with the placebo. Only the regular drops of 0.50% clonidine substantially lowered the systemic BP. These results indicate the value of using a smaller volume of clonidine drop as an ocular hypotensive agent to avoid systemic effects.

Repair of an inadvertent buttonhole or leaking filtering bleb.

Buttonholing of conjunctival flaps at the time of filtering glaucoma surgery or a leak in the flap postoperatively can cause serious problems and may be most difficult to repair. A new delicate atraumatic needle has been used successfully in five cases to close conjunctiva to conjunctiva or conjunctiva to cornea defects.

Evaluation of superoxide dismutase (orgotein) in medical treatment of canine cataract.

Orgotein (Palosein) is a veterinary product with marked superoxide dismutase activity that has been used intracamerally to treat senile cataracts in the dog. Fourteen old dogs with bilateral senile cataracts were injected twice in one eye with orgotein and twice in the other eye with isotonic saline under masked conditions. Observations were made over an average of a 12-week period. No clearing of lenses could be detected and there was no observed subjective improvement in the dogs' visual behavior.

Pathogenesis of central nervous system lesions in visna cell-mediated immunity and lymphocyte subsets in blood, brain, and cerebrospinal fluid.

The time course and titers of antibodies did not correlate with the severity of CNS lesions whereas the CMI did, indicating that CMI may play an important role in lesion development. The correlation of the number of CD8 positive cells in the CSF with the severity of lesions and the reversed ratio of CD4/CD8 positive cells in the diffusely infiltrated neuroparenchyma indicates that the CD8 positive T cells may be an important effector cell in the induction of CNS lesions.

Human and ovine lentiviral infections compared.

Maedi-visna virus (MVV) of sheep was the first lentivirus to be isolated. The genomic organization of MVV is very similar to that of human immunodeficiency virus (HIV) with several genes regulating the expression of the viral genome. Viral replication is severely restricted in the host and some cells apparently contain the genetic information in a DNA provirus form with little or no expression of viral antigens. This seems to be a major factor in causing the "slowness" of lentiviral infections and the persistence of the virus in the host since the immune system may not recognize the provirus-containing cells. The target cells for HIV and MVV are similar although T4 lymphocytes are not specifically destroyed in maedi-visna. There are also certain similarities in the pathological changes in both diseases, both in the central nervous system, the lungs and the lymphatic system. Although the severe final immunodeficiency state characteristic of AIDS has not been observed in maedi-visna, the basic biological features of the MVV and its interaction with host cells are so similar to HIV infection, that we consider ovine maedi-visna useful animal model for the human lentivirus infections.

Intratracheal inoculation as an efficient route of experimental infection with maedi-visna virus.

Maedi-visna virus (MVV) spreads horizontally via the respiratory route. In order to establish an experimental mucosal infection route, we compared intranasal and intratracheal inoculation using the infectious MVV molecular clone KV1772-kv72/67. For intranasal infection 0.5 x 10(3)-0.5 x 10(7) TCID50 of virus was sprayed into the nostrils of the sheep. For the intratracheal infection 10(0)-10(6) TCID50 of virus was injected into the trachea. Successful infection was indicated by development of MVV specific antibodies and virus isolation over a period of 6 months. In the intranasal infection, only the sheep receiving the highest dose i.e., 0.5 x 10(7) TCID50, became infected, suggesting that intranasal application was not an efficient mode of infection. In the intratracheal infection, the sheep infectious dose 50% was 10(1) TCID50 and virus could be isolated from the central nervous system 4 months post infection with 10(4) TCID50. Therefore it is concluded that intratracheal infection is a very efficient route for experimental inoculation with MVV.

Precipitating antibodies in experimental visna and natural progressive pneumonia of sheep.

Serological responses of Icelandic sheep experimentally infected with visna virus (vv) were contrasted with responses in American Targhee sheep naturally infected with progressive pneumonia virus (PPV). Precipitating antibodies assayed by immunodiffusion were compared with the neutralising and complementing fixing antibody response. In experimental infections with vv, complement fixing and neutralising antibodies appeared early after infection and rose to high levels in all sheep, while precipitating antibodies were detected only at minimal titre. In natural infections with PPV, immune responses were less consistent and precipitating antibodies were detected more frequently than complement fixing or neutralising antibodies against PPV. These results may suggest important biological differences between the lytic fibroblast-tropic virus strains used for experimental infection of Icelandic sheep and the nonlytic macrophage-tropic strains of PPV circulating in nature. Lytic strains evoke a brisk response against the viral glycoprotein with high titre neutralising antibody while nonlytic strains induce a less consistent response to the glycoprotein.

Prevalence of postherpetic neuralgia after a first episode of herpes zoster: prospective study with long term follow up.

OBJECTIVE: To estimate the frequency, duration, and clinical importance of postherpetic neuralgia after a single episode of herpes zoster. DESIGN: Prospective cohort study with long term follow up. SETTING: Primary health care in Iceland. PARTICIPANTS: 421 patients with a single episode of herpes zoster. MAIN OUTCOME MEASURES: Age and sex distribution of patients with herpes zoster, point prevalence of postherpetic neuralgia, and severity of pain at 1, 3, 6, and 12 months and up to 7.6 years after the outbreak of zoster. RESULTS: Among patients younger than 60 years, the risk of postherpetic neuralgia three months after the start of the zoster rash was 1.8% (95% confidence interval 0.59% to 4.18%) and pain was mild in all cases. In patients 60 years and older, the risk of postherpetic neuralgia increased but the pain was usually mild or moderate. After three months severe pain was recorded in two patients older than 60 years (1.7%, 2.14% to 6.15%). After 12 months no patient reported severe pain and 14 patients (3.3%) had mild or moderate pain. Seven of these became pain free within two to seven years, and five reported mild pain and one moderate pain after 7.6 years of follow up. Sex was not a predictor of postherpetic neuralgia. Possible immunomodulating comorbidity (such as malignancy, systemic steroid use, diabetes) was present in 17 patients. CONCLUSIONS: The probability of longstanding pain of clinical importance after herpes zoster is low in an unselected population of primary care patients essentially untreated with antiviral drugs.

Functional outcome and alignment in computer-assisted and conventionally operated total knee replacements: a multicentre parallel-group randomised controlled trial.

We performed a randomised controlled trial comparing computer-assisted surgery (CAS) with conventional surgery (CONV) in total knee replacement (TKR). Between 2009 and 2011 a total of 192 patients with a mean age of 68 years (55 to 85) with osteoarthritis or arthritic disease of the knee were recruited from four Norwegian hospitals. At three months follow-up, functional results were marginally better for the CAS group. Mean differences (MD) in favour of CAS were found for the Knee Society function score (MD: 5.9, 95% confidence interval (CI) 0.3 to 11.4, p = 0.039), the Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales for 'pain' (MD: 7.7, 95% CI 1.7 to 13.6, p = 0.012), 'sports' (MD: 13.5, 95% CI 5.6 to 21.4, p = 0.001) and 'quality of life' (MD: 7.2, 95% CI 0.1 to 14.3, p = 0.046). At one-year follow-up, differences favouring CAS were found for KOOS 'sports' (MD: 11.0, 95% CI 3.0 to 19.0, p = 0.007) and KOOS 'symptoms' (MD: 6.7, 95% CI 0.5 to 13.0, p = 0.035). The use of CAS resulted in fewer outliers in frontal alignment (> 3° malalignment), both for the entire TKR (37.9% vs. 17.9%, p = 0.042) and for the tibial component separately (28.4% vs 6.3%, p = 0.002). Tibial slope was better achieved with CAS (58.9% vs. 26.3%, p < 0.001). Operation time was 20 minutes longer with CAS. In conclusion, functional results were, statistically, marginally in favour of CAS. Also, CAS was more predictable than CONV for mechanical alignment and positioning of the prosthesis. However, the long-term outcomes must be further investigated.

Survival rates and causes of revision in cemented primary total knee replacement: a report from the Norwegian Arthroplasty Register 1994-2009.

We evaluated the rates of survival and cause of revision of seven different brands of cemented primary total knee replacement (TKR) in the Norwegian Arthroplasty Register during the years 1994 to 2009. Revision for any cause, including resurfacing of the patella, was the primary endpoint. Specific causes of revision were secondary outcomes. Three posterior cruciate-retaining (PCR) fixed modular-bearing TKRs, two fixed non-modular bearing PCR TKRs and two mobile-bearing posterior cruciate-sacrificing TKRs were investigated in a total of 17 782 primary TKRs. The median follow-up for the implants ranged from 1.8 to 6.9 years. Kaplan-Meier 10-year survival ranged from 89.5% to 95.3%. Cox's relative risk (RR) was calculated relative to the fixed modular-bearing Profix knee (the most frequently used TKR in Norway), and ranged from 1.1 to 2.6. The risk of revision for aseptic tibial loosening was higher in the mobile-bearing LCS Classic (RR 6.8 (95% confidence interval (CI) 3.8 to 12.1)), the LCS Complete (RR 7.7 (95% CI 4.1 to 14.4)), the fixed modular-bearing Duracon (RR 4.5 (95% CI 1.8 to 11.1)) and the fixed non-modular bearing AGC Universal TKR (RR 2.5 (95% CI 1.3 to 5.1)), compared with the Profix. These implants (except AGC Universal) also had an increased risk of revision for femoral loosening (RR 2.3 (95% CI 1.1 to 4.8), RR 3.7 (95% CI 1.6 to 8.9), and RR 3.4 (95% CI 1.1 to 11.0), respectively). These results suggest that aseptic loosening is related to design in TKR.