Autoantibodies in juvenile arthritis

Sera from 104 children with JA with different onset-types of disease were evaluated for 19S IgM RF by the LFT , hidden 19S IgM RF by the hemolytic assay, ANA by HEp-2 cell substrate, and levels of IC by the C1qSPA . Their relationship to active disease was determined. Classical 19S IgM RF were detected by the LFT in only seven patients. All were late-onset polyarticular females. Hidden 19S IgM RF were detected by the hemolytic assay in the separated IgM-containing fraction in 55 patients of all onset-types. Clinical activity correlated with the presence of hidden 19S IgM RF in 82% of cases. ANA, using the HEp-2 cell substrate, were found in 61 patients, the majority showing a speckled, immunofluorescent pattern. ANA were noted in all RF positive patients and in nine of 10 patients with iridocyclitis. IC were found in 39 patients, and correlation with clinical activity occurred in 54% of cases. A search for positive associations among the four parameters showed no statistically significant correlations except for the concordance of ANA positivity in all seven RF positive patients. The presence of hidden RF correlated more closely with disease activity (P less than 0.001) than did that of ANA or IC. The significance of these data and previous studies remains to be determined. We have demonstrated that in the average JA population 7% have 19S IgM RF and about 60% have hidden RF, ANA, or elevated levels of IC. The present findings of 98 of 104 patients with at least one of the abnormal immunoproteins , the association of ANA in patients with iridocyclitis or with RF positivity, of hidden RF with disease activity, and the presence of 19S IgM RF in isolated IC suggest a possible immunologic etiology for JA.     

Extractable nuclear antigens

ENAs are acidic macromolecules extracted from the saline soluble fractions of cells. Twenty different ENAs have been described to date. The antigens are derived from several different sources, and antibodies to these antigens can be detected by a number of different techniques.Antibodies to ENAs usually produce a speckled ANA pattern. The clinician, seeing such a result, will often pursue this by ordering an “ENA” to clarify which antigen-antibody system is responsible for the speckled ANA. Most often, clinical laboratories report results of hemagglutination assays giving the titers of agglutination with and without prior RNase digestion. Antibodies sensitive to RNase have been taken to be the equivalent of anti-RNP, the antibody associated with MCTD. Antibody not sensitive to RNase has often been equated with antibody to the Sm antigen associated with SLE. The failures and abuses of this nomenclature have been discussed in detail.Defining ENAs and the particular anti-ENA antibodies seen in individual patients is of value. From a clinical standpoint, defining these antigen-antibody systems may be helpful for diagnostic and prognostic purposes. From a more basic standpoint, understanding these antigenantibody systems may provide insights into the etiology and pathogenesis of CTDs. To date, only a few of the anti-ENA antibodies discussed above are available for routine clinical use. The extensive review of present information is briefly summarized below.The presence of antibody to RNP correlates with an overlap syndrome, MCTD,^3,12 though long-range studies have shown a progression of PSS-like features.^19,20 These patients, however, seem to have a favorable response to steroids.^3,12,19 Antibodies to Sm and MA are highly specific for SLE.^6–11 While antibodies to Sm may connote a more benign disease with less renal involvement,^8–10 antibodies to MA seem to point to more severe disease.¹¹ The presence of antibodies to PM-1, Mi, and Jo-1 are found mainly in patients with clinical findings of myositis.^24–28 However, they do not correlate with disease activity or severity. Antibodies to Scl-70 are highly specific for PSS.²⁹ Antibodies to SS-A (Ro) are found mainly in patients with SLE and/or the sicca complex,^39–43 and antibodies to SS-B (La or Ha) are present in patients with the sicca complex alone or in association with SLE.^{37–39,41–43} Antibodies to Ro and/or La are directed to cytoplasmic constituents and would account for the presence of clinical SLE in patients with a negative ANA.^37,38,40 They may also be found in a more benign form of SLE.³⁹ Antibodies to RANA (SS-C) are found mainly in patients with RA or RA in combination with SS.^42,44 Thus, the patient with clinical symptoms of a CTD and a speckled ANA pattern or, in limited cases other ANA patterns or a negative ANA, should be evaluated for antibodies to ENA by the HA and ID. Such information can be useful in determining diagnosis and prognosis and expand our understanding of CTDs.     

Inhibition of creatine and phosphocreatine accumulation in skeletal muscle and heart

A series of creatine analogues was tested for ability to inhibit ¹⁴C-creatine accumulation in vivo and for ability to serve as substrates for creatine kinase in vitro. The most potent inhibitors of accumulation were 1-carboxymethyl-2-imino-hexahydropyrimidine, N-methylamidino-N-methylglycine, β-guanidinopropionate, and DL-β-guanidinobutyrate. The first two compounds are known to be inactive as substrates for creatine kinase, and DL-β-guanidinobutyrate was shown to be inactive in the present experiments, producing a V_max less than 0.01% of that produced by creatine. The latter compound and β-guanidinopropionate were also found to be ineffective as inhibitors of creatine kinase in vitro. The best substrates for creatine kinase were N-ethyl-N-amidinoglycine and guanidinoacetate; these two compounds were inefficient as inhibitors of ¹⁴C-creatine accumulation. Moreover, adding a methyl group to β-guanidinopropionate to form N-methyl-N-amidino-β-alanine eliminated the compound's ability to inhibit ¹⁴C-creatine accumulation but had little effect on its ability to serve as a substrate for creatine kinase. Thus, we found no evidence that creatine kinase mediates creatine transport. In feeding trials with rats given DL-β-guanidinobutyric acid as 2% or 6% of their diet for 1 mo, this compound accumulated to concentrations of 14 μmole/g wet weight in skeletal muscle and of 4 μmole/g wet weight in heart. Simultaneously, in skeletal muscle there was a depletion of phosphocreatine to 50%, and of ATP to 80%, of control values. The total creatine content (creatine + phosphocreatine) of the heart also decreased, going from 12.8 to 2.8 μmole/g wet weight. Animals fed DL-β-guanidinobutyric acid should be suitable for studies of the long-term effects of creatine and phosphocreatine depletion in skeletal muscle and heart.     

Biochemical and ultrastructural changes in skeletal muscle induced by a creatine antagonist

To evaluate the essentiality of creatine and phosphocreatine for the maintenance of the ultrastructure of skeletal muscle, chicks were fed a creatine antagonist, β-guanidinobutyric acid (β-GBA), as 2% of a Chow diet. Chicks fed β-GBA exhibited growth retardation and weakness, and they accumulated large amounts of a monosubstituted guanidino compound, presumably β-GBA, in their skeletal muscles. After 2 wk, there was a 74% decrease in the uptake of [¹⁴C]-1-creatine into pectoralis muscles of chicks fed β-GBA. After 3 wk there was a significant decrease in phosphocreatine concentrations in pectoralis muscles from 20.1 ± 2.8 μmoles per g wet weight (mean ± S.D.) for 8 control chicks to 16.5 ± 2.5 for 7 chicks fed β-GBA. Selected fibers of the pectoralis and gastrocnemius muscles of chicks fed β-GBA exhibited ultrastructural abnormalities including loss of thick and thin filaments, disruption of the Z band, dilated mitochondria, and dilated and displaced sarcoplasmic reticulum. The pectoralis muscles of chicks given 6% creatine in addition to 2% β-GBA in the diet accumulated little β-GBA, maintained normal phosphocreatine concentrations, and exhibited no significant ultrastructural abnormalities. These findings are the first experimental evidence that high concentrations of phosphocreatine are essential for the maintenance of the ultrastructural integrity of skeletal muscle.     

Shell gland responsiveness to prostaglandins F2α and E1 and to arginine vasotocin during the laying cycle of the domestic hen (Gallus domesticus)

Contractile responses of isolated shell gland (SG) strips from laying hens displayed no significant differences 6 hrs before oviposition, at oviposition, and 6 hrs after oviposition when stimulated with arginine vasotocin (AVT), prostaglandin E₁ (PGE₁), or prostaglandin F_2α (PGF_2α). Dose-response curves show that the sensitivity of the SG to these agents, in vitro, is: AVT > PGF₂ > PGE₁. PGF_2α, however, produces the largest contractile response, while PGE₁ appears to be a poor agonist of contractile activity in vitro. These results are discussed in relation to the known hormonal patterns during the ovulatory cycle of the hen and the physiological roles attributed to these oxytocics in the control of oviposition.     

The effects of exercise and weight loss on plasma lipids in young obese men

We studied the independent and combined effects of exercise training and weight loss on blood lipids under fixed diet and exercise conditions. Twenty-one obese sedentary men were randomly allocated to one of four treatment groups: (1) inactive and constant weight (control), (2) exercise training and constant weight, (3) inactive and weight loss, and (4) exercise training and weight loss. There were three study periods: a 3 week baseline period inactive and on an isocaloric diet, a 12 week treatment period, and a 3 week weight stabilization period. Exercise consisted of treadmill walking at an energy cost of 3500 kcal/wk for groups 2 and 4 with replacement caloric intake only in group 2. Group 3 reduced caloric intake by 3500 kcal/wk during the treatment period. Weight loss for groups 3 and 4 were 13.4 pounds and 13.7 pounds, respectively. Maximal oxygen uptake (mL/min) increased 6% in both exercise groups (2 and 4), and percent body fat decreased only in these groups. Regression analysis by group assignment on HDL cholesterol (HDL-C) showed that the inactivity-weight loss modality (group 3) and the exercise-constant weight modality (group 2) each significantly increased HDL-C, with an additive effect of exercise and weight loss (group 4). The rate of HDL-C change differed significantly between groups (P = 0.01). HDL-C increased 0.63, 0.61, and 1.89 mg/dL per 3 weeks or 2%, 2.4%, and 5.5% above baseline levels in groups 2, 3, and 4, respectively, while the control group decreased 0.11 mg/dL. Plasma triglycerides and very low-density lipoprotein (VLDL) cholesterol increased with exercise at constant weight (group 2) and decreased with exercise associated with weight loss (group 4). In conclusion, exercise and weight loss separately and independently increase HDL-C, and their effects are additive.     

Effects of mammalian gonadotropins on progesterone release and cyclic nucleotide production by isolated avian granulosa cells

Cyclic AMP and, to a lesser extent, cyclic GMP have been implicated as mediators of gonadotropin-induced steroidogenesis in ovarian tissue and cells of mammals The functional role of these cyclic nucleotides in steroidogenesis in avian granulosa cells has not yet been investigated. In the present study the release of progesterone and levels of cyclic nucleotides were measured in granulosa cells isolated by a nonenzymatic procedure from the largest preovulatory follicle of laying hens 22–24 hr prior to ovulation. Bovine LH(NIH-B10) promoted progesterone production in a dose-related manner. Although steroidogenesis was maximally stimulated by 0.1–0.2 μg/ml bLH, cyclic nucleotide levels remained unaffected even at 5 μg/ml bLH at which concentration progesterone release was significantly inhibited when compared to maximal responses. Similarly, oFSH while stimulating steroidogenesis, although less effectively than bLH, failed to significantly increase cyclic AMP production. Theophylline potentiated the steroidogenic effect of gonadotropins and raised basal levels of the cyclic nucleotides. Dibutyryl cyclic AMP (BU₂cAMP) induced a dose-dependent release of progesterone while dibutyryl cyclic GMP (BU₂cGMP) had an inhibitory effect. Agonists of adenylate cyclase such as isoproterenol and cholera toxin in combination with theophylline stimulated progesterone production while heparin, an inhibitor of adenylate cyclase, completely blocked the steroidogenic effect of bLH. Moreover, imidazole, a phosphodiesterase activator, suppressed both progesterone and cyclic AMP production. It is suggested therefore that a small fraction of intracellular cyclic AMP, but not cyclic GMP, which cannot be accurately detected by the RIA method employed, plays an important role in LH-promoted steroidogenesis in chicken granulosa cells.     

Skin lesions in viral hepatitis: histologic and immunofluorescent findings.

A variety of skin rashes are knowned to occur as a part of the serum sickness-like prodrome of acute viral hepatitis which is thought to be due to immune complex deposition. We report the histologic and immunofluorescent findings in the skin and the seroloigc abnormalities in a patient with both erythematous maculopapular and purpuric rashes. We found circulating hepatitis B surface antigen (HBsAg), hypocomplementemia and cultaneous vasculitis associated with deposition of immunoglobulin and complement in the skin. We could not demonstrate intradermal deposition of HBsAg, but the findings are consistent with the immune complex hypothesis.     

Immediate and short-term benefit of multilesion coronary angioplasty: influence of degree of revascularization

The safety and short-term therapeutic benefit of multilesion percutaneous transluminal coronary angioplasty was assessed in 135 patients, 66 of whom had a minimum of 6 months of follow-up study. Primary success, defined as successful dilation of the most critical lesion or all lesions attempted without major in-hospital complications was obtained in 117 (87%) of the 135 patients. Cardiac complications associated with the procedure were uncommon; prolonged angina occurred in 5% and myocardial infarction in 3%; emergency coronary bypass surgery was performed in 4% of the patients. There were no deaths. Complete revascularization was achieved in 46% of the 117 patients with a primary success. Of the 66 patients eligible for 6 month follow-up, 80% had an uncomplicated course and required no further procedures. Clinical improvement by at least one angina functional class was observed in 90% of the patients. Cardiac events such as the need for a second revascularization procedure were significantly more common in patients who had incomplete versus complete revascularization (35 versus 9%; p = 0.018). Repeat coronary angiography performed an average of 5 months after angioplasty revealed restenosis in 18 of 22 symptomatic patients and 3 of 9 asymptomatic patients. Restenosis occurred at the site of a single dilation in 12 patients, at two sites in 8 patients and at three sites in 1 patient. Thus, multilesion coronary angioplasty is an important therapeutic option for selected patients with multivessel disease and can be performed with relatively low risk. Improvement in angina status can be expected even in patients who have incomplete revascularization.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin infusion responses in diabetic ketoacidosis alone and with a mixed hypochloremic alkalosis

AimsAlthough diabetic ketoacidosis (DKA) commonly presents as a pure diabetic ketoacidosis (PDKA), up to 30% of cases may be associated with a mixed hypochloremic metabolic alkalosis (HMA). It is unknown whether there is a difference in treatment outcomes between these two entities. We evaluated an insulin infusion protocol (IIP), previously validated for hyperglycemia management in ICU's, for the management of PDKA and HMA.Materials and methodsA retrospective case series/cohort study of 41 DKA admissions was further characterized as having PDKA or HMA. HMA was defined in those having an elevated delta-delta gradient (ΔAG-ΔHCO3) ≥ 5 mmol/L and base excess chloride (BE_Cl) > 2.7 mmol/L. The main outcome measures were times to recovery of glucose levels to ≤250 mg/dL and of anion gap to ≤12 mmol/L.ResultsThe initial serum glucose was 553 ± 265 mg/dL, serum bicarbonate of 8.8 ± 5.1 mmol/L, and venous pH 7.13 ± 0.2). Recovery of glucose occurred in 5 h: 25 min (±3 h:39min), and for anion gap in 11 h:25 min (±6 h:56min). HMA compared with PDKA had a delayed recovery of serum glucose (7 h: 23min ± 3 h: 35min vs. 4 h: 31min ± 3:h:21min, p = 0.017), which was due to the higher initial level of glucose (p = 0.02) rather than level of BE_Cl (p = 0.17). There was no difference in time to anion gap closure between the PDKA and HMA.ConclusionsCorrection of hyperglycemia and acidosis in PDKA as well as in HMA was managed through the IIP. The simultaneous fluid and electrolyte management corrected the hypochloremic alkalosis.     

The occurrence of angiographically detected intracoronary thrombus in patients with unstable angina pectoris

To examine the role of intracoronary thrombus (ICT) in unstable angina, we reviewed the coronary arteriograms of 83 patients with unstable angina (group I) and 37 patients with stable angina (group II) for angiographic evidence of ICT. Group I and group II patients were similar with respect to mean age, presence of single and multiple vessel disease, and past history of myocardial infarction. Group I patients had no ECG or creatine kinase enzyme evidence of acute myocardial infarction. The angiographic criteria for ICT included an intracoronary filling defect, intraluminal staining, and total coronary artery occlusion with convex dye outline. ICT was found in 10 of 83 patients in group I (12.0%) vs 0 of 37 patients in group II (p less than 0.05). These findings suggest that in some patients coronary artery thrombosis plays an important role in the pathogenesis of unstable angina.     

Prostaglandins and steroid hormones in plasma and ovarian follicles during the ovulation cycle of the domestic hen (Gallus domesticus)

The concentrations of prostaglandins E and F (PGE, PGF), estradiol (E₂), estrone (E₁), and progesterone (P) were determined by sensitive and specific RIAs in the plasma and ovarian follicular tissue collected from the same hens which were killed at frequent intervals during the ovulatory cycle. Plasma levels of both PGE and PGF peaked at the time of oviposition/ovulation (OP/OV) with PGE showing a second peak 5 hr before these events. Plasma E₁ and E₂ began to rise 7 hr prior to OP/OV reaching maximum levels just before OP. Plasma P rose to a broad preovulatory peak 2–6 hr before OP falling abruptly at OP. The concentration of PGs in the two largest postovulatory follicles (POF-1, POF-2) were similar, both fluctuating considerably during the cycle (10–220 ng/g). On the other hand, a sharp 20-fold increase in PGF levels of the largest preovulatory (PRF) was observed shortly after OP/OV. PGE concentrations in this follicle were relatively low during most of the ovulatory cycle with the exception of a significant peak 5–7 hr before OP/OV. P levels in PRF, ranging from 13.2 to 165.5 ng/g, were also higher than those in the POFs, particularly between 2 to 6 hr prior to OP/OV. E₁ concentrations in all three follicles peaked between 6 and 9 hr after OP/OV and fell to a nadir 17 hr after these events. E₁ then began to rise in the preovulatory phase of the cycle with E₂, which reached a significant peak 6 hr before OP/OV. The increase in plasma PGs at the time of OP gives further evidence that these substances are involved in this process. It is suggested that the plasma PGE increase may be related to the preovulatory LH surge and ovarian PGs may play a role in the establishment of the follicular hierarchy.     

Noninvasive assessment of pacemaker hemodynamics by Doppler echocardiography: importance of left atrial size

The relative decrease in cardiac output with ventricular pacing versus "physiologic" modes was measured noninvasively using Doppler echocardiography in 26 patients. Standard echocardiographic measurements of left ventricular size (diastolic diameter), left ventricular function (shortening fraction) and left atrial size were examined to determine which of these variables might best identify patients more likely to benefit from maintenance of atrioventricular (AV) synchrony. Decreases in relative cardiac output, expressed as reduction in the Doppler-derived flow velocity integral, with loss of AV synchrony ranged from 0 to 43% (mean decrease 21%). There was no correlation between left ventricular size or function and effect of pacing mode on relative cardiac output. There was, however, correlation between left atrial size and sensitivity to pacing mode. Patients with normal left atrial size were significantly more sensitive to loss of AV synchrony. In this subgroup, the decrease in flow velocity integral with ventricular pacing was 32 +/- 11% compared with only 11 +/- 13% in patients with left atrial enlargement. Thus, Doppler echocardiography is useful in assessing optimal pacing mode in the individual patient. Echocardiographically measured left atrial size may identify patients in whom physiologic pacing may be major benefit.