Anti-laminin reactivity and glomerular immune deposition by in vitro recombinant antibodies

Growing evidence suggests that recombinatorial events prior to antigen contact can generate pathogenic autoantibodies in the nonautoimmune individual, thus providing potential disease mediators if conditions arise that permit bypass of tolerance and activation of autoreactive lymphocytes. To examine the disease potential of selected germline antibody genes, Ig were created de novo by in vitro recombination of Ig H and L chains. H chain loss variant (i.e., L-chain only) cell lines were transfected with a DNA construct encoding the variable region and regulatory sequences (LamH) of a nephrotropic murine lupus anti-laminin Ig, and the resultant Ig were examined for in vitro antigen reactivity and in vivo glomerular immune deposition. The results indicate that two light chains, LamL (Vk8, Jk5) and 238L (Vk4, Jk5), expressing unrelated germline V1 genes, combine with LamH to generate Ig that bind basement membrane laminin in vitro, diverge in their capacity to bind ssDNA, and produce two distinct patterns of glomerular immune deposits in vivo: dense mesangial matrix (LamH/LamL) and dramatic linear glomerular basement membrane (LamH/238L) deposits. The Ig genes used by both LamH and 238L are present in nonautoimmune mice as well as in lupus-prone strains. We conclude that certain unmutated Ig genes can contribute to multiple distinct disease associated specificities, including binding to intrinsic kidney antigens, and that mutation is not essential to generate these Ig. Collectively, these observations suggest that pathogenic autoantibodies can be generated in the normal preimmune repertoire by random recombinatorial and somatic events in the absence of mutation.     

Setting thresholds for quality indicators derived from MDS data for nursing home quality improvement reports: an update

BACKGROUND: Determining meaningful thresholds to reinforce excellent performance and flag potential problem areas in nursing home care is critical for preparing reports for nursing homes to use in their quality improvement programs. This article builds on the work of an earlier panel of experts that set thresholds for quality indicators (QIs) derived from Minimum Data Set (MDS) assessment data. Thresholds were now set for the revised MDS 2.0 two-page quarterly form and Resource Utilization Groups III (RUGS III) quarterly instrument. SETTING THRESHOLDS: In a day-long session in October 1998, panel members individually determined lower (good) and upper (poor) threshold scores for each QI, reviewed statewide distributions of MDS QIs, and completed a follow-up Delphi of the final results. REPORTING MDS QIS FOR QUALITY IMPROVEMENT: The QI reports compiled longitudinal data for all residents in the nursing home during each quarter and cumulatively displayed data for five quarters for each QI. A resident roster was provided to the nursing home so that the quality improvement team could identify the specific residents who developed the problems defined by each QI during the last quarter. Quality improvement teams found the reports helpful and easy to interpret. SUMMARY AND CONCLUSIONS: As promised in an earlier report, to ensure that thresholds reflect current practice, research using experts in a panel to set thresholds was repeated as needed. As the MDS instrument or recommended calculations for the MDS QIs change, thresholds will be reestablished to ensure a fit with the instrument and data.     

The role of a single N-linked glycosylation site for a functional epitope of herpes simplex virus type 1 envelope glycoprotein gC

High altitude (HA) living produces physiological changes for adaptation to chronic hypobaric-hypoxemic conditions. Although much is known about these physiologic adaptations, no clear separation has been made regarding what is "native" or "genetic" adaptation and what is "acquired." In this review, we describe the genetic vs. acquired adaptation and only include studies performed in a population native to HA and not in an acclimatized population or trekkers. The changes encountered in animals and humans living at HA in terms of hematology, muscular, respiratory, cerebral, cardiovascular, hormonal, fluid and electrolytes and reproduction, strongly suggest that genetics play a very important role in HA adaptation. Unfortunately, the characteristic physiology of HA natives has not been systematically defined to established specific measurable parameters of adaptation in comparison to the acquired ambient adaptation of the non-native population. Once the parameters are established, we can compare non-native populations exposed to HA that must emulate the HA physiology for a definite adaptation to be present. With measurable parameters, especially in the management of fluids and electrolytes, we can define how long it will take for a sea level native to adapt to an HA altitude. Until these studies are performed, speculation will continue and no rational medical intervention can be offered to HA newcomers who may experience HA difficulties.     

Prognostic significance of colony-stimulating factor receptor expression in ipsilateral breast cancer recurrence

The macrophage colony-stimulating factor receptor (CSF-1R), the product of the c-fms proto-oncogene, regulates normal proliferation and differentiation of macrophages and trophoblasts. Recent research found abnormal expression of CSF-1R in human carcinomas of the breast, endometrium, and ovary. Furthermore, activation of CSF-1R by its ligand has been shown to regulate invasiveness and anchorage-independent growth in breast carcinoma cells. To study the significance of CSF-1R expression in breast cancer, we designed a case-controlled immunohistochemical study. We chose 80 patients from a database of 1200 early stage I or II breast cancer patients treated with conservative surgery and radiation therapy. Expression of CSF-1R in the tumors of 40 patients who experienced an ipsilateral breast tumor recurrence (IBTR) as a primary site of relapse were compared with 40 patients who had not experienced an IBTR. The index and control patients were matched by age, clinical stage, nodal status, and follow-up. Paraffin-embedded sections were immunostained with antibodies directed toward CSF-1R. For the CSF-1R antibody, a total of 28 index cases (70%) demonstrated strong staining, whereas only 16 control cases (40%) demonstrated high immunoreactivity (P = 0.007). The CSF-1R antibody showed a positive correlation for local relapse, but no correlation was found between CSF-1R expression and distant metastasis. In summary, our findings provide evidence for the poor prognostic role of CSF-1R in IBTR.     

Normal relationships between cardiovascular variables in active orthostatism and clinostatism in postural change

OBJECTIVE: Autonomic modulation of hemodynamics, essential for the preservation of homeostasis, is well tested by the abrupt postural change from clinostatism to active orthostatism. The aim of this work was to study normal relationships between the cardiovascular variables in active orthostatism and those in clinostatism. METHODS: Hemodynamic parameters in clinostatism and orthostatism were easily measured in 20 healthy subjects of both sexes, aged between 33 and 78 years, without treatment, using the non-invasive thoracic electric bioimpedance method. RESULTS: Cardiovascular variables values in orthostatism are linearly related with their values in clinostatism. CONCLUSIONS: Results show that cardiovascular variables in active orthostatism are linearly related with their values in clinostatism, each variable being specially regulated. A clinostatism and orthostatism intraindividual correlation was obtained, which provides an easily accessible method of detection and interpretation of autonomic dysfunctions, without deleterious consequences for the subjects, which can be very useful for research on physiopathologic mechanisms.     

Wheat embryo ribonucleates. VIII. The presence of 7-methylguanosine 'cap structures' in the RNA of imbibing wheat embryos

1. By imbibing wheat embryos in media that contain methyl-labelled methionine, it is possible to label both terminal and nonterminal 7-methylguanosine constituents in NaCl-insoluble (2.5 M, 0 degrees C) RNA (iRNA). 2. Most of the 7-[Me-14C]methylguanosine in wheat embryo i[Me-14C]RNA is present in nonterminal positions of polynucleotide chains, probably in ribosomal RNA. 3. By passage through a column of oligo-dT-cellulose, it is possible, to show that most of the 7-[Me-3H]methylguanosine in a 'bound' fraction of i[Me-3]RNA from imbibing wheat embryos is present in terminal 'cap' structures, probably in messenger RNA. 4. Although most of the 7-[Me-3H]methylguanosine in the 'unbound' (to oligo-dT-cellulose) fraction of i[Me-3H]RNA was present in nonterminal positions, there was also a highly significant fraction of 7-[Me-3H]methylguanosine in terminal 'cap' structures. Although it will be a subject of continued investigation, possible reasons why a large fraction of the total 7-[Me-3H]-methylguanosine was present in the 'unbound' fraction, in this present study, are a subject of discussion. 5. Careful analysis failed to reveal the presence of any N6,O2'-di[Me-3H]methyladenosine in the 'unbound' fraction of i[Me-3H]RNA. 6. Factors that might influence the binding of 'cap' oligonucleotides to DEAE-cellulose are the subject of a brief discussion.