Role of light chain variable region in myeloma with light chain deposition disease: evidence from an experimental model

Light chain deposition disease (LCDD) results from a propensity of some human monoclonal L chains to form tissue deposits. We designed an experimental model for in vivo expression of human kappa L chain sequences in mice and compared a somatically mutated LCDD chain with a closely related control kappa chain, both encoded by the unique V kappa IV gene. Mice secreting the LCDD chain but not those producing the control chain showed deposits with a distribution similar to that observed in patients. These data show that discrete changes in V region sequences can play a major role in tissue deposition of human L chains.     

Advancement of multiple myeloma from diagnosis through plateau phase to progression does not involve a new B-cell clone: evidence from the Ig heavy chain gene

The Ig heavy chain (IgH) gene was used as a marker to investigate clonal succession and the origin of the neoplastic cell in multiple myeloma. The polymerase chain reaction (PCR) was used to amplify a section of the rearranged IgH gene at diagnosis and at progression in 21 patients who had exhibited a plateau phase. A monoclonal PCR product was seen for 16 of the patients and the product present at progression was of the same molecular weight as that at diagnosis. This finding suggests that the IgH rearrangement present at diagnosis and progression was the same. This was confirmed by sequencing the IgH gene in 10 patients. The IgH genes were found to be hypermutated at diagnosis, but no further hypermutation occurred during the course of the disease. The results provide evidence that the neoplastic cell in myeloma may originate as a memory B cell, plasmablast, or plasma cell, and suggest that progression beyond the plateau phase is not caused by clonal succession.     

Digital and conventional chest images: observer performance with Film Digital Radiography System

The Film Digital Radiography System (FilmDRS) is a device with a laser optical film digitizer, 2,000 X 2,000 X 12-bit memory, and a 1,000-line video display. To evaluate the adequacy of this device for general radiography of the chest, four readers independently analyzed both radiographs and the corresponding video display of the digitized chest images of 150 patients, consisting of 100 images of abnormalities and 50 normal images. The overall results indicate equal sensitivity for the two systems. The FilmDRS, with interactive windowing, proved superior in the detection of hilar and mediastinal disease. X-ray film was superior in allowing detection of hyperlucent states. There was equivalent sensitivity for other disease categories. Superior specificity was achieved with conventional radiographs.     

Kinetics of intraocular cytokines in the suppression of experimental autoimmune uveoretinitis by type I IFN

The systemic administration of IFN-alpha/beta was previously found to suppress inflammation in rats with experimental autoimmune uveoretinitis (EAU); however, an effect on the systemic immune response was not identified. In order to investigate an immunological basis for suppression at the intraocular level, rats immunized with interphotoreceptor retinoid-binding protein (IRBP) were administered daily intramuscular injections of 10(5) IU IFN-alpha/beta and cytokines were measured by ELISA in intraocular extracts prepared by ultrasonification at various timepoints throughout the course of EAU. In control EAU, intraocular concentrations of IFN-gamma were found to be non-detectable on day 8 before the onset of inflammation, significantly elevated on day 12 at peak inflammation (182+/-106 pg/ml), then non-detectable again on day 16 after inflammation had begun to subside. In contrast, intraocular IFN-gamma in IFN-alpha/beta- treated rats remained non-detectable or low at all timepoints. Measurement of intraocular IL-2 revealed no difference between the two groups of rats. Intraocular IL-4 concentrations were elevated in rats treated with IFN-alpha/beta, although this cytokine was also detected in the same range in controls as well as normal rats. Finally, intraocular IL-10 was non-detectable on day 8, significantly elevated at peak inflammation on day 12 (588+/-139 pg/ml), then decreased to low levels on day 16 in control EAU rats, while remaining non-detectable or low in IFN-alpha/beta-treated rats. These results suggest that acute inflammation in IRBP-induced EAU in rats involves both IFN-gamma and IL- 10 at the local intraocular level, and that systemic administration of IFN-alpha/beta inhibits EAU via a mechanism that involves suppression of both cytokines.      

The Remission of Post-Transplant Nephrotic Syndrome Clinicopathologic Characterization

Among 67 renal transplant recipients with nephrotic syndrome (NS), nine episodes were reversible in eight patients. Biopsies showed minimal-change disease, focal segmental membranous glomerulonephritis and acute glomerulitis, IgA nephropathy and acute glomerulitis or thrombotic microangiopathy, and chronic transplant nephropathy with or without acute glomerulitis. NS developed 1-4 months post transplant in the four patients with minimal-change disease, but later (33-151 months) in the others. At onset, serum creatinine was normal or elevated. Treatment included calcium-channel blockers, angiotensin-converting enzyme inhibitors, or both, together with routine antirejection therapy. Remission was achieved 4-12 months after onset, when renal function remained normal in four, improved in four, and worsened in one. At last follow-up, six patients still had remission and functional grafts. One lost graft to chronic transplant nephropathy while NS remained in remission. In the remaining patient, proteinuria, which was due to chronic transplant glomerulopathy unrelated to the initial minimal-change disease-associated NS, recurred 50 months post transplant. Remission of post-transplant NS is possible. It is often associated with minimal-change diseases and less frequently with other glomerular lesions, including acute glomerulitis. Reversible post-transplant NS does not have an adverse effect on the renal allografts.     

Characterization of lymphocyte β-adrenoceptor activity and Gs-protein in patients with rheumatic heart valvular disease

Summary— In order to test whether the β-adrenoceptor activity in rheumatic heart valvular disease depends on the ventricular load conditions, we determined their density and binding affinity to [¹²⁵I]-iodocyanopindolol in lymphocytes, as well as plasma catecholamine and cAMP levels in 69 patients with regurgitant and stenotic lesions of the aortic and mitral valves. The patients were classified as having left ventricular pressure overload (LVP), left ventricular volume overload (LVV), mixed lesions (MOL) or right ventricular pressure overload (RVP). The β-adrenoceptor activity was determined by radioligand binding methods, catecholamines by high performance liquid chromatography using an electrochemical detector and cAMP by radioimmunoassay. The mean β-adrenoceptor density (B_max) of the control group was 60.1 ± 9.5 /mol ( n = 29) per 10⁶ lymphocytes. In the study population, the density was decreased by 83% in LVP, 78% in LVV, 87% in MOL and 86% in RVP. Plasma norepinephrine was elevated by 89% in LVP and 60% in MOL, epinephrine by 43% in LVP, 50% in VOL, 115% in MOL and 20% in RVP, while dopamine was not significantly changed, and cAMP was slightly elevated in all four groups. Screening for activating mutational changes in the G_sα-protein gave negative results, possibly dissociating the elevation in plasma cAMP from stimulatory effects of such abnormalities in the G_s-protein signaling. These results show a significant attenuation in lymphocyte β-adrenoceptor density of patients with rheumatic heart valvular disease, irrespective of the type of the prevailing ventricular load conditions. The reduction in receptor density is accompanied by a significant increase in plasma norepinephrine levels in patients with a left ventricular pressure overload and epinephrine in those with volume overload.