Quantifying renal allograft loss following early antibody-mediated rejection.

Unlike antibody-mediated rejection (AMR) with clinical features, it remains unclear whether subclinical AMR should be treated, as its effect on allograft loss is unknown. It is also uncertain if AMR's effect is homogeneous across donor (deceased/live) and (HLA/ABO) antibody types. We compared 219 patients with AMR (77 subclinical, 142 clinical) to controls matched on HLA/ABO-compatibility, donor type, prior transplant, panel reactive antibody (PRA), age and year. One and 5-year graft survival in subclinical AMR was 95.9% and 75.7%, compared to 96.8% and 88.4% in matched controls (p = 0.0097). Subclinical AMR was independently associated with a 2.15-fold increased risk of graft loss (95% CI: 1.19-3.91; p = 0.012) compared to matched controls, but not different from clinical AMR (p = 0.13). Fifty three point two percent of subclinical AMR patients were treated with plasmapheresis within 3 days of their AMR-defining biopsy. Treated subclinical AMR patients had no difference in graft loss compared to matched controls (HR 1.73; 95% CI: 0.73-4.05; p = 0.21), but untreated subclinical AMR patients did (HR 3.34; 95% CI: 1.37-8.11; p = 0.008). AMR's effect on graft loss was heterogeneous when stratified by compatible deceased donor (HR = 4.73; 95% CI: 1.57-14.26; p = 0.006), HLA-incompatible deceased donor (HR = 2.39; 95% CI: 1.10-5.19; p = 0.028), compatible live donor (no AMR patients experienced graft loss), ABO-incompatible live donor (HR = 6.13; 95% CI: 0.55-67.70; p = 0.14) and HLA-incompatible live donor (HR = 6.29; 95% CI: 3.81-10.39; p < 0.001) transplant. Subclinical AMR substantially increases graft loss, and treatment seems warranted.

Quantifying the risk of incompatible kidney transplantation: a multicenter study.

Incompatible live donor kidney transplantation (ILDKT) offers a survival advantage over dialysis to patients with anti-HLA donor-specific antibody (DSA). Program-specific reports (PSRs) fail to account for ILDKT, placing this practice at regulatory risk. We collected DSA data, categorized as positive Luminex, negative flow crossmatch (PLNF) (n = 185), positive flow, negative cytotoxic crossmatch (PFNC) (n = 536) or positive cytotoxic crossmatch (PCC) (n = 304), from 22 centers. We tested associations between DSA, graft loss and mortality after adjusting for PSR model factors, using 9669 compatible patients as a comparison. PLNF patients had similar graft loss; however, PFNC (adjusted hazard ratio [aHR] = 1.64, 95% confidence interval [CI]: 1.15-2.23, p = 0.007) and PCC (aHR = 5.01, 95% CI: 3.71-6.77, p < 0.001) were associated with increased graft loss in the first year. PLNF patients had similar mortality; however, PFNC (aHR = 2.04; 95% CI: 1.28-3.26; p = 0.003) and PCC (aHR = 4.59; 95% CI: 2.98-7.07; p < 0.001) were associated with increased mortality. We simulated Centers for Medicare & Medicaid Services flagging to examine ILDKT's effect on the risk of being flagged. Compared to equal-quality centers performing no ILDKT, centers performing 5%, 10% or 20% PFNC had a 1.19-, 1.33- and 1.73-fold higher odds of being flagged. Centers performing 5%, 10% or 20% PCC had a 2.22-, 4.09- and 10.72-fold higher odds. Failure to account for ILDKT's increased risk places centers providing this life-saving treatment in jeopardy of regulatory intervention.

Abnormalities of in vitro lymphocyte responses during rubella virus infections.

In vitro rubella virus infections of lymphocytes from normal adult humans impaired their responsiveness to phytohemagglutinin (PHA) stimulations; a situation which seemed analogous to the PHA unresponsiveness of peripheral lymphocytes from babies with the congenital rubella syndrome. Such in vitro viral infection of normal cells also decreased the synthesis of normal nucleic acids and structural proteins, and abrogated the enhanced DNA synthesis induced by pokeweed and specific antigen stimulations. Furthermore, it was shown that live rubella virus, but not ultraviolet-irradiated virus, was necessary for the impaired mitogenic responses of normal leukocytes. These observations are interpreted to favor the view that the virus achieves its inhibitory effect on the action of mitogens by interference either directly or indirectly at an intracellular site. Such an action could reduce the functional potential of lymphocytes and impair their effectiveness as immunologically competent cells or as effectors in immunologic reactions.

Viral inhibition of lymphocyte response to phytohemagglutinin.

The response to phytohemagglutinin by lymphocytes from eight of fourteen patients with congenital rubella was inhibited, whereas that of lymphocytes from patients with other diseases was not. The response of normal lymphocytes infected in vitro was also inhibited. The results suggest that early association of lymphocytes with virus inhibits the function of the cell and contributes to persistent carrying of virus in congenital rubella. This phenomenon may be a means of detecting viruses not now recognizable by routine methods of tissue culture.

An evaluation of the performance of cDNA microarrays for detecting changes in global mRNA expression.

The cDNA microarray is one technological approach that has the potential to accurately measure changes in global mRNA expression levels. We report an assessment of an optimized cDNA microarray platform to generate accurate, precise and reliable data consistent with the objective of using microarrays as an acquisition platform to populate gene expression databases. The study design consisted of two independent evaluations with 70 arrays from two different manufactured lots and used three human tissue sources as samples: placenta, brain and heart. Overall signal response was linear over three orders of magnitude and the sensitivity for any element was estimated to be 2 pg mRNA. The calculated coefficient of variation for differential expression for all non-differentiated elements was 12-14% across the entire signal range and did not vary with array batch or tissue source. The minimum detectable fold change for differential expression was 1.4. Accuracy, in terms of bias (observed minus expected differential expression ratio), was less than 1 part in 10 000 for all non-differentiated elements. The results presented in this report demonstrate the reproducible performance of the cDNA microarray technology platform and the methods provide a useful framework for evaluating other technologies that monitor changes in global mRNA expression.

Fine structure of lymphocytes from an immune deficient child before and after administration of transfer factor.

Lymphocytes from a male infant delivered by Cesarean section and placed into a germ-free environment were examined by electron microscopy (EM). The child had a sex-linked severe combined immunodeficiency. The lymphocytes were atypical, having sparse cytoplasm with little rough endoplasmic reticulum (ER) but abundant smooth ER. The nuclear membrane was pulled away from the nuclear space, and no evidence of nuclear pores or aggregated ribosomes was found. Mitochondria were intact. Repeated injections of the subject during the 9-month period with KLH, typhoid vaccine, and diphtheria toxoid yielded no significant observable change in the fine structure of the lymphocytes. At 11 months, the subject was given transfer factor. Following repeated injections of this material, the original cell type was still present but a new type of lymphocyte was also observed by EM examination. The new cell type resembled a more normal lymphocyte. It had a higher density of cytoplasmic material, in comparison with cells prior to administration of transfer factor. It was smaller in size with some aggregated ribosomes, had detectable amounts of rough ER, and more intact nuclear membranes. This new type of lymphocyte may represent a small population of B lymphocytes perhaps stimulated by T cells made immunocompetent by transfer factor.

A longitudinal study of T and B lymphocytes from a three-year-old patient with severe combined immunodeficiency (SCID) in 'gnotobiotic protection'.

Fluctuations in the percentages and absolute numbers of T and B lymphocytes were observed in the peripheral blood of a patient with severe combined immunodeficiency maintained in a gnotobiotic environment. Up to 24 months of age, 72-86% of the lymphocytes had surface membrane immunoglobulin (SMIg), 37-47% bore a receptor for C3(EAC-RFC), and 3-12.5% formed spontaneous rosettes with sheep erythrocytes (E-RFC). These values persisted until 30 months, after which shifts in the percentages and absolute numbers of T and B cells were observed. A significant decrease in the proportion of SMIg-bearing cells to 20-40% (169-405 mm3), and EAC-RFC to 10.5-39% (114-259 mm3), was accompanied by a general increase in the proportion of T cells to 19-60% (141-1026 mm3), representing a lymphoid subpopulation approach to normal levels.

Optic nerve manifestations of human congenital cytomegalovirus infection.

A Latin American male and a white female infant who had a cytomegalovirus infection on the first day of life had unilateral optic nerve hypoplasia. A white male infant who had cytomegalovirus isolated at 5 weeks of age had a unilateral partial coloboma of the optic nerve. A 4-month-old black infant with cytomegalovirus infection diagnosed at 2 days of age had a unilateral complete coloboma of the optic nerve associated with microphthalmia. Optic nerve involvement was an important manifestation of this disease.

A semi-empirical pressure analysis for anatomy constrained by elastic support.

A mathematical foundation is developed for the computation of pressures exerted on portions of the anatomy constrained by elastic fabric support. General formulae are derived for curvatures of an ellipsoidal model corresponding to orthogonal tension components at the point of measurement. It is found that the pressure contributions from both tension components are significant to first order in the longitudinal variation of circumference over an axial test zone, because while the transverse curvature approaches the zeroth order cylindrical approximation, its longitudinal counterpart does not.

Viral gastroenteritis.

As our ability to control many of the common infectious diseases has increased, attention has turned toward the less common or less severe infections. It is clear that worldwide, significant numbers of the cases of gastroenteritis in both adults and children are caused by viruses. Many of these viruses now are quite well understood and their control appears to be on the horizon. Many other etiologic agents are just being identified and will present a challenge to researchers and practitioners alike.

On-site and distance education of emergency medicine personnel with a human patient simulator.

BACKGROUND: Infrequent use of emergency medical skills eventually leads to skill degradation. Even during residency training, certain skills may be infrequently encountered. The use of human patient simulators (HPS) is one means by which these skills may be practiced with sufficient numbers to learn and maintain emergency skills. OBJECTIVE: To assess the efficacy and feasibility of training isolated emergency medical personnel with a HPS. DESIGN/METHODS: A sophisticated HPS was placed at the Roosevelt Roads Naval Hospital, Puerto Rico. A convenience sample of emergency naval personnel enrolled in a training program consisting of five HPS-based scenarios. Both on-site (instructor in the room) and off-site (instructor in the United States) training was provided. A pre/post-test design was used to assess the efficacy of HPS training using a survey with a Likert scale measuring participant-perceived preparedness, self-efficacy, and perceptions of HPS training. RESULTS: Eighteen emergency medical personnel participated in the educational program. Eight were physicians, and the remainder were emergency medical technicians and U.S. Navy medical corpsmen. Perceived preparedness and self-efficacy improved overall and for each individual scenario. Participants rated the training highly and felt that it was better than conventional noninteractive mannequins. Off-site training was found to be feasible despite the low-bandwidth services available: Internet (56 K) and telephone service. Participants readily accepted off-site training. CONCLUSIONS: HPS education improves perceived preparedness and self-efficacy in U.S. Navy emergency medical personnel. This type of training may be an important adjunct for emergency medical providers who infrequently have the opportunity to apply learned emergency medical care skills. The use of HPS with distant interactive education capability allows isolated medical personnel the opportunity to practice skills unconstrained by time or distance.

Immune deficiency in congenital rubella and other viral infections.

No immunologic explanation has been found for the chronicity commonly observed in congenital viral infections. In the presence of a humoral immune response, there is continued viral excretion--in rubella for many months, and in the herpes viruses perhaps for life. Infection with rubella early in utero has a profound effect on the developing immune system. Defects observed are: complete immune paralysis, PHA unresponsiveness, immunoglobulin abnormalities, and loss of antibody to rubella. These defects are transient; absence of IgA may be permanent. No such defects have been observed in other congenital viral infections, but precocious development of immune globulin levels and germinal follicles occurs.

Prospective study of congenital cytomegalovirus infection.

The overall incidence of neonates with urinary cytomegalovirus (CMV) excretion was 0.9% of 954 tested. The incidence was twice as high in the lower as in the upper socioeconomic group (SEG). Mothers of infants with CMV infection in the lower SEG reported a greater number of chronic and gestational medical problems and showed a lower mean age than mothers of CMV-infected infants in the upper SEG. The mean age of mothers of CMV-infected infants was not significantly different from the respective control group in either upper or lower SEG. There was no impairment of immune responses in nine prospective or in two referred cases. Although eight of nine prospective cases might have been considered asymptomatic at birth, careful evaluation in the neonatal period showed significant growth inhibition in five, specific clinical changes in seven, and nonspecific clinical changes in all of the nine infants. Thus, "asymptomatic" neonates may demonstrate effects of the infection during the neonatal period.

A paraprotein in severe combined immunodefeciency disease detected by immunoelectrophoretic analysis of plasma.

A qualitative study was made of the plasma immunoglobulins of a child with severe combined immunodeficiency. By immunoelectrophoresis an immunoglobulin with an abnormal electrophoretic mobility was detected. This protein possessed mu heavy chain determinants, gave no detectable reaction with antisera specific for light chains, was of a relatively small molecular size, and was probably not composed of subunits held together by easily reduced disulfide bonds. The light chains that were present in this patient's plasma had a homogeneous electrophoretic mobility. The patient's plasma also contained at least two other immunoglobulins whose antigenic identity could not be established. One of these was abnormal in its electrophoretic mobility. The presence of the abnormal protein with mu determinants in the plasma of the second unrelated child with a similar disease suggests that the detection of this protein may have implications for the diagnosis or classification of immunodeficiency diseases.