Measuring disease activity and functional status in patients with scleroderma and Raynaud's phenomenon

OBJECTIVE: To document disease activity and functional status in patients with scleroderma (systemic sclerosis [SSc]) and Raynaud's phenomenon (RP) and to determine the sensitivity to change, reliability, ease of use, and validity of various outcome measures in these patients. METHODS: Patients with SSc and moderate-to-severe RP participating in a multicenter RP treatment trial completed daily diaries documenting the frequency and duration of RP attacks and recorded a daily Raynaud's Condition Score (RCS). Mean scores for the 2-week periods prior to baseline (week 0), end of trial (week 6), and posttrial followup (week 12) were calculated. At weeks 0, 6, and 12, physicians completed 3 global assessment scales and performed clinical assessments of digital ulcers and infarcts; patients completed the Health Assessment Questionnaire (HAQ), the Arthritis Impact Measurement Scales 2 (AIMS2) mood and tension subscales, 5 specific SSc/RP-related visual analog scales (VAS), and 3 other VAS global assessments. We used these measures to document baseline disease activity and to assess their construct validity, sensitivity to change, and reliability in trial data. RESULTS: Two hundred eighty-one patients (248 women, 33 men; mean age 50.4 years [range 18-82 years]) from 14 centers participated. Forty-eight percent had limited cutaneous SSc; 52% had diffuse cutaneous SSc. Fifty-nine patients (21%) had digital ulcers at baseline. Patients had 3.89 +/- 2.33 (mean +/- SD) daily RP attacks (range 0.8-14.6), with a duration of 82.1 +/- 91.6 minutes/attack. RCS for RP activity (possible range 0-10) was 4.30 +/- 1.92. HAQ scores (0-3 scale) indicated substantial disability at baseline (total disability 0.86, pain 1.19), especially among the subscales pertaining to hand function (grip, eating, dressing). AIMS2 mood and tension scores were fairly high, as were many of the VAS scores. Patients with digital ulcers had worse RCS, pain, HAQ disability (overall, grip, eating, and dressing), physician's global assessment, and tension, but no significant difference in the frequency of RP, duration of RP, patient's global assessment, or mood, compared with patients without digital ulcers. VAS scores for digital ulcers as rated by the patients were not consistent with the physician's ratings. Factor analysis of the 18 measures showed strong associations among variables in 4 distinct domains: disease activity, RP measures, digital ulcer measures, and mood/tension. Reliability of the RCS, HAQ pain and disability scales, and AIMS2 mood and tension subscales was high. The RP measures demonstrated good sensitivity to change (effect sizes 0.33-0.76). CONCLUSION: Our findings demonstrate that the significant activity, disability, pain, and psychological impact of RP and digital ulcers in SSc can be measured by a small set of valid and reliable outcome measures. These outcome measures provide information beyond the quantitative metrics of RP attacks. We propose a core set of measures for use in clinical trials of RP in SSc patients that includes the RCS, patient and physician VAS ratings of RP activity, a digital ulcer/infarct measure, measures of disability and pain (HAQ), and measures of psychological function (AIMS2).     

Increased efficiency of retroviral-mediated gene transfer and expression in primate bone marrow progenitors after 5-fluorouracil-induced hematopoietic suppression and recovery.

To define conditions for improved efficiency of retroviral-mediated gene transfer and expression in primate progenitor cells, four rhesus monkeys were treated with a 200 mg/kg intravenous bolus of 5-fluorouracil (5-FU). The kinetics of hematopoietic suppression and recovery were assessed in peripheral blood, bone marrow mononuclear cells, and bone marrow cells fractionated in an albumin density gradient. Bone marrow mononuclear cells were transduced with N2, a retroviral vector carrying the bacterial neomycin phosphotransferase gene (NPT), which confers resistance to the otherwise toxic neomycin analogue, G418. Circulating colony-forming units-granulocyte-macrophage (CFU-GM) disappeared at 2 days. CFU-GM, transducible CFU-GM, CD34+ cells, and the percent of cells in cycle decreased at 3 days in unfractionated bone marrow cells and in a light density population known to be enriched for these progenitors and for stem cells. NPT activity in the light-density fraction, marginally detectable before treatment, disappeared at 3 days as well. At day 7 the CFU-GM plating efficiency, the CD34+ cell content, and the percentage of cells in cell cycle began to increase in the light-density fraction. The NPT assay became faintly positive again but the CFU-GM were not yet transducible, implying that it was an earlier progenitor population that was dividing and differentiating. By day 15, there was a marked rebound in all of the progenitors measured, and transduction efficiency assessed by G418R CFU-GM and NPT assay rebounded to several times pretreatment levels. The data suggest that CFU-GM are optimally transduced at 15 days but that earlier progenitors are more likely cycling and transducible before 5 days, a time when a gene transfer experiment would probably have the best chance to succeed.     

Preferential coronary arterial drug delivery

A transcatheter technique for administering drugs preferentially to the canine left coronary circulation is described. The method involves pulsed, diastolic, small-volume (0.2 ml) injections through a specially designed aortic cusp catheter. In order to evaluate preferential delivery to the coronary circulation, papaverine was administered using this technique and compared to intravenous delivery. Left circumflex and carotid arterial blood flow, as well as systemic arterial pressure, were simultaneously measured. In eight of ten animals studied, diastolic aortic cusp administration of the drug for periods of up to 30 minutes increased circumflex flow an average of 136%, increased carotid arterial flow 22%, and decreased systemic arterial pressure 18%. Intravenous delivery increased circumflex flow an average of 34%, increased carotid flow 41%, and decreased systemic arterial pressure 13%. The technique has immediate research and potential clinical application as a means of preferentially delivering diagnostic or therapeutic agents, such as thrombolytics, to the coronary circulation.     

Prolonged CD4+ lymphocytopenia and thrombocytopenia in a chimpanzee persistently infected with human immunodeficiency virus type 1.

The immunologic and virologic status of a chimpanzee inoculated with multiple isolates of the human immunodeficiency virus type 1 (HIV-1) were assessed over 57 months to determine whether prolonged thrombocytopenia and CD4+ lymphocytopenia observed in the animal might be associated with long-term HIV infection. Although the chimpanzee showed no signs of disease, it lost both CD4+ (as low as 134 cells/microliter) and CD8+ lymphocytes approximately 30 months after initial infection, followed by thrombocytopenia that has persisted for greater than 2 years. Lymphopenia and thrombocytopenia were preceded by or coincided with the appearance of antibodies cross-reactive with histone H2B and decreased levels of complement component C4; an eightfold decrease in HIV-specific antibody titers; the inability of CD8+ lymphocytes to suppress virus replication; impaired proliferative responses to T cell mitogens; and the isolation of cell-free HIV from plasma. These data suggest that, given sufficient time, HIV-infected chimpanzees may develop disease.     

Incidence of gastric parietal cell antibody in families of patients with iron deficiency anaemia

There is an association of pernicious anaemia with iron deficiency anaemia (Faber and Gram, 1924). There is also a high incidence (85 per cent) of gastric parietal cell antibody in the sera of patients with pernicious anaemia (Taylor, Roitt, Doniach, Couchman and Shapland, 1962) and a less marked, but significantly increased incidence (33 per cent) in patients with iron deficiency anaemia who have a histamine fast achlorhydria (Dagg, Goldberg, Anderson, Beck and Gray, 1964). Pernicious anaemia has a familial incidence (Askey, 1940; Callender and Denborough, 1957) and there is also an increased frequency of achlorhydria in relatives of patients with pernicious anaemia (Askey, 1940; Neel, 1947). In addition te Velde, Abels, Anders, Arends, Hoedemaeker and Nieweg (1964) have found the gastric parietal cell antibody in 20 per cent of relatives of patients with pernicious anaemia, compared with 6 per cent in a control series. Because of the association of iron deficiency anaemia with pernicious anaemia and the increased incidence of histamine fast achlorhydria and parietal cell antibody in both diseases, the occurrence of the antibody has been assessed in the families of patients with iron deficiency anaemia, histamine fast achlorhydria and gastric parietal cell antibody. In a group of 22 patients with iron deficiency anaemia, histamine fast achlorhydria and gastric parietal cell antibody, Dagg, Goldberg, Gibbs and Anderson (1966) found that seven had a ⁵⁸Co vitamin B₁₂ absorption test (Schilling, 1953) characteristic of pernicious anaemia, and six of these had reduced serum vitamin B₁₂ levels; that is these patients had latent pernicious anaemia. In 10 of the 22 patients the serum vitamin B₁₂ levels and the Schilling test were normal, and in the remaining five patients the serum vitamin B₁₂ was low but the Schilling test was normal. Since it appeared possible that the familial incidence of gastric parietal cell antibody would be higher in relatives of the patients with latent pernicious anaemia than in relatives of those without latent pernicious anaemia, 11 families from these 22 patients were investigated, six of which had propositi with latent pernicious anaemia and five of which had propositi without latent pernicious anaemia (Table I). The relatives of the remaining 11 patients were unwilling to co-operate in these investigations.     

Knockout mice lacking steroidogenic factor 1 are a novel genetic model of hypothalamic obesity.

Knockout (KO) mice lacking steroidogenic factor 1 (SF-1) exhibit a phenotype that includes adrenal and gonadal agenesis, impaired gonadotropin expression, and abnormalities of the ventromedial hypothalamic nucleus (VMH). Studies in rodents with lesions of the ventromedial hypothalamus have implicated the VMH in body weight regulation, suggesting that SF-1 KO mice may provide a genetic model of obesity. To prevent death, SF-1 KO mice were rescued with corticosteroid injections, followed by syngeneic adrenal transplants from wild-type (WT) littermates. Corticosterone and ACTH levels in WT and SF-1 KO mice were indistinguishable, documenting restoration of hypothalamic-pituitary-adrenal function. Although weights at earlier ages did not differ significantly from WT littermates, SF-1 KO mice were significantly heavier by 8 wk of age and eventually weighed almost twice as much as WT controls. Obesity in SF-1 KO mice predominantly resulted from decreased activity rather than increased food intake. Leptin was increased markedly, insulin was modestly elevated, and glucose was indistinguishable from WT mice. Although sex steroids in rodents affect weight, ovariectomy did not abolish the weight difference between WT and SF-1 KO mice. These SF-1 KO mice are a genetic model of late-onset obesity that may help elucidate the role of the VMH in weight regulation.