Natural killer cell expression of Ki67 is associated with elevated serum IL-15, disease activity and nephritis in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder whose pathology involves multiple immune cell types, including B and T lymphocytes as well as myeloid cells. While it is clear that autoantibody-producing B cells, as well as CD4+ T cell help, are key contributors to disease, little is known regarding the role of innate lymphoid cells such as natural killer (NK) cells in the pathogenesis of SLE. We have characterized the phenotype of NK cells by multi-color flow cytometry in a large cohort of SLE patients. While the overall percentage of NK cells was similar or slightly decreased compared to healthy controls, a subset of patients displayed a high frequency of NK cells expressing the proliferation marker, Ki67, which was not found in healthy donors. Although expression of Ki67 on NK cells correlated with Ki67 on other immune cell subsets, the frequency of Ki67 on NK cells was considerably higher. Increased frequencies of Ki67+ NK cells correlated strongly with clinical severity and active nephritis and was also related to low NK cell numbers, but not overall leukopenia. Proteomic and functional data indicate that the cytokine interleukin-15 promotes the induction of Ki67 on NK cells. These results suggest a role for NK cells in regulating the immune-mediated pathology of SLE as well as reveal a possible target for therapeutic intervention.

Factors associated with long-term weight-loss maintenance following bariatric surgery in adolescents with severe obesity.

BACKGROUND/OBJECTIVES: Bariatric surgery produces robust weight loss, however, factors associated with long-term weight-loss maintenance among adolescents undergoing Roux-en-Y gastric bypass surgery are unknown. SUBJECTS/METHODS: Fifty adolescents (mean±s.d. age and body mass index (BMI)=17.1±1.7 years and 59±11 kg m-2) underwent Roux-en-Y gastric bypass surgery, had follow-up visits at 1 year and at a visit between 5 and 12 years following surgery (Follow-up of Adolescent Bariatric Surgery at 5 Plus years (FABS-5+) visit; mean±s.d. 8.1±1.6 years). A non-surgical comparison group (n=30; mean±s.d. age and BMI=15.3±1.7 years and BMI=52±8 kg m-2) was recruited to compare weight trajectories over time. Questionnaires (health-related and eating behaviors, health responsibility, impact of weight on quality of life (QOL), international physical activity questionnaire and dietary habits via surgery guidelines) were administered at the FABS-5+ visit. Post hoc, participants were split into two groups: long-term weight-loss maintainers (n=23; baseline BMI=58.2 kg m-2; 1-year BMI=35.8 kg m-2; FABS-5+ BMI=34.9 kg m-2) and re-gainers (n=27; baseline BMI=59.8 kg m-2; 1-year BMI=36.8 kg m-2; FABS-5+ BMI=48.0 kg m-2) to compare factors which might contribute to differences. Data were analyzed using generalized estimating equations adjusted for age, sex, baseline BMI, baseline diabetes status and length of follow-up. RESULTS: The BMI of the surgical group declined from baseline to 1 year (-38.5±6.9%), which, despite some regain, was largely maintained until FABS-5+ (-29.6±13.9% change). The BMI of the comparison group increased from baseline to the FABS-5+ visit (+10.3±20.6%). When the surgical group was split into maintainers and re-gainers, no differences in weight-related and eating behaviors, health responsibility, physical activity/inactivity, or dietary habits were observed between groups. However, at FABS-5+, maintainers had greater overall QOL scores than re-gainers (87.5±10.5 vs 65.4±20.2, P<0.001) and in each QOL sub-domain (P<0.01 all). CONCLUSIONS: Long-term weight outcomes for those who underwent weight-loss surgery were superior to those who did not undergo surgical treatment. While no behavioral factors were identified as predictors of success in long-term weight-loss maintenance, greater QOL was strongly associated with maintenance of weight loss among adolescents who underwent Roux-en-Y gastric bypass surgery surgery.

Development of IgA nephropathy-like glomerulonephritis associated with Wiskott-Aldrich syndrome protein deficiency.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder caused by mutations in the WAS gene. Glomerulonephritis is a frequent complication, however, histopathological data from affected patients is scarce because the thrombocytopenia that affects most patients is a contraindication to renal biopsies. We found that WASp-deficient mice develop proliferative glomerulonephritis reminiscent of human IgA nephropathy (IgAN). We examined whether increased aberrant IgA production is associated with the development of glomerulonephritis in WASp-deficient mice. Serum IgA and IgA production by splenic B cells was increased in WASp-deficient mice compared to wild-type (WT) mice. A lectin-binding study revealed a reduced ratio of sialylated and galactosylated IgA in the sera from old WASp-deficient mice. Circulating IgA-containing immune complexes showed significantly higher titers in WASp-deficient mice compared to WT mice. These results indicate that the increased IgA production and aberrant glycosylation of IgA may be critically involved in the pathogenesis of glomerulonephritis in WAS.

Death-effector filaments: novel cytoplasmic structures that recruit caspases and trigger apoptosis.

The death-effector domain (DED) is a critical protein interaction domain that recruits caspases into complexes with members of the TNF-receptor superfamily. Apoptosis can also be induced by expressing certain DED-containing proteins without surface receptor cross-linking. Using Green Fluorescent Protein to examine DED-containing proteins in living cells, we show that these proteins cause apoptosis by forming novel cytoplasmic filaments that recruit and activate pro-caspase zymogens. Formation of these filaments, which we term death-effector filaments, was blocked by coexpression of viral antiapoptotic DED-containing proteins, but not by bcl-2 family proteins. Thus, formation of death-effector filaments allows a regulated intracellular assembly of apoptosis-signaling complexes that can initiate or amplify apoptotic stimuli independently of receptors at the plasma membrane.

Encoding of spatial location by posterior parietal neurons.

The cortex of the inferior parietal lobule in primates is important for spatial perception and spatially oriented behavior. Recordings of single neurons in this area in behaving monkeys showed that the visual sensitivity of the retinotopic receptive fields changes systematically with the angle of gaze. The activity of many of the neurons can be largely described by the product of a gain factor that is a function of the eye position and the response profile of the visual receptive field. This operation produces an eye position-dependent tuning for locations in head-centered coordinate space.

A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling.

A conserved domain in the extracellular region of the 60- and 80-kilodalton tumor necrosis factor receptors (TNFRs) was identified that mediates specific ligand-independent assembly of receptor trimers. This pre-ligand-binding assembly domain (PLAD) is physically distinct from the domain that forms the major contacts with ligand, but is necessary and sufficient for the assembly of TNFR complexes that bind TNF-alpha and mediate signaling. Other members of the TNFR superfamily, including TRAIL receptor 1 and CD40, show similar homotypic association. Thus, TNFRs and related receptors appear to function as preformed complexes rather than as individual receptor subunits that oligomerize after ligand binding.

Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations.

Heterozygous mutations encoding abnormal forms of the death receptor Fas dominantly interfere with Fas-induced lymphocyte apoptosis in human autoimmune lymphoproliferative syndrome. This effect, rather than depending on ligand-induced receptor oligomerization, was found to stem from ligand- independent interaction of wild-type and mutant Fas receptors through a specific region in the extracellular domain. Preassociated Fas complexes were found in living cells by means of fluorescence resonance energy transfer between variants of green fluorescent protein. These results show that formation of preassociated receptor complexes is necessary for Fas signaling and dominant interference in human disease.

Homotypic FADD interactions through a conserved RXDLL motif are required for death receptor-induced apoptosis.

Death receptors in the TNF receptor superfamily signal for apoptosis via the ordered recruitment of FADD and caspase-8 to a death-inducing signaling complex (DISC). However, the nature of the protein-protein interactions in the signaling complex is not well defined. Here we show that FADD self-associates through a conserved RXDLL motif in the death effector domain (DED). Despite exhibiting similar binding to both Fas and caspase-8 and preserved overall secondary structure, FADD RDXLL motif mutants cannot reconstitute FasL- or TRAIL-induced apoptosis and fail to recruit caspase-8 into the DISC of reconstituted FADD-deficient cells. Abolishing self-association can transform FADD into a dominant-negative mutant that interferes with Fas-induced apoptosis and formation of microscopically visible receptor oligomers. These findings suggest that lateral interactions among adapter molecules are required for death receptor apoptosis signaling and implicate self-association into oligomeric assemblies as a key function of death receptor adapter proteins in initiating apoptosis.

Percutaneous coronary excimer laser-assisted angioplasty: initial multicenter experience in 141 patients.

Initial multicenter clinical experience with percutaneous coronary excimer laser-assisted angioplasty is described for 158 lesions in 141 patients. Using a xenon chloride (308 nm) excimer laser generator and 1.5 to 1.75 mm catheters, excimer laser angioplasty was attempted at 135 ns pulse width, 25 to 40 Hz repetition rate, 2 to 5 s laser delivery time and 30 to 60 mJ/mm2 energy fluence. Laser success (greater than 20% improvement in luminal diameter) was achieved in 138 (87%) of 158 lesions, with a reduction to less than 50% stenosis noted in 77 lesions (49%). Overall, laser-assisted balloon angioplasty success (less than 50% residual stenosis without major complication) was observed in 129 (91%) of 141 patients. Procedural complications (abrupt closure 1.3%, side branch occlusion 1.9%, intimal dissection 6.3%, embolization 1.3%, filling defect 1.3%, perforation 1.9% and spasm 1.3% and major complications (non-Q wave myocardial infarction 4.8%, emergency coronary bypass surgery 3.5% and death 0%) were infrequent and predominantly related to subsequent balloon angioplasty. In the early follow-up period (range 1 to 10 months, mean 7), 111 (79%) of the 141 patients remain asymptomatic, whereas symptoms have recurred in 27 (19%) and 3 patients (2.1%) have died. Thus, percutaneous coronary excimer laser angioplasty appears to be a feasible and safe procedure. Assessment of the impact of this technology on the acute complications of and restenosis rates after angioplasty awaits further follow-up analysis.

Measurement of molecular interactions in living cells by fluorescence resonance energy transfer between variants of the green fluorescent protein.

Many signal transduction pathways operate through oligomerization of proteins into multi-subunit complexes. Although biochemical assays can identify potential protein-protein interactions, studying these interactions in living cells is more challenging. Fluorescence resonance energy transfer (FRET) has been used as a "spectroscopic ruler" to measure molecular proximity, but these methods have been limited by the need for chemical labeling of target proteins or labeled antibodies. We present methods for examining interactions between target proteins molecularly fused to cyan and yellow variants of the green fluorescent protein (GFP) by FRET in living cells. Flow cytometric and microscope-based methods are described that have been applied to a variety of interacting proteins.

Corticocortical connections of anatomically and physiologically defined subdivisions within the inferior parietal lobule.

The anatomical and functional organization of the inferior parietal lobule was investigated in macaque monkeys by using anterograde and retrograde anatomical tracing techniques and single cell recording techniques in awake, behaving monkeys. The connections of areas 7a and 7b, and of two previously unexplored areas, the lateral intraparietal area (LIP) and the dorsal prelunate area (DP), were examined in detail. Functional mapping experiments were performed in all four areas. Prior to this study the pathways for visual input to area 7a were unclear. In these experiments we found several direct projections from extrastriate visual areas, including the lateral intraparietal (LIP), dorsal prelunate (DP), parieto-occipital (PO), and medial superior temporal (MST) areas into area 7a. Using the observed laminar patterns of connections between areas 7a, LIP, and DP and other extrastriate cortical areas, we were able to construct a hypothetical flow of visual information processing from striate cortex to area 7a. A broader hierarchy was also produced, which relates the positions of areas 7a, 7b, LIP, and DP to various cortical fields in the parietal, temporal, and frontal lobes. By combining single cell recording techniques in trained monkeys with anatomical tracing techniques, we have parceled the inferior parietal lobule into several subdivisions on the basis of both anatomical and physiological grounds. A clear segregation of visual and somatosensory responses was found in the inferior parietal lobule with areas 7a, LIP, and DP being visual and visual-motor and area 7b being primarily somatosensory. A similar segregation was found anatomically with areas 7a, LIP, and DP being interconnected primarily with other visual cortical areas and area 7b being connected with several somatosensory areas. Area 7b was also found to connect to a few visual cortical areas, and these connections likely account for the small but consistent number of visually responsive cells that are found in this region. Areas LIP, DP, and 7a differed in receptive field and saccade-related properties. Area 7a visual receptive fields were very large and usually bilateral with a small but significant number of them having receptive field centers in the ipsilateral visual field. Area DP and LIP receptive fields were smaller and the receptive field peaks were almost always confined to the contralateral visual field. Areas 7a, DP, and LIP all contained cells with saccade-related responses; however, in area 7a there were fewer saccade cells than area LIP, and presaccadic responses were only observed in area LIP.(ABSTRACT TRUNCATED AT 400 WORDS)

T-cell receptor and autoimmune disease.

Since the genes encoding the TCR have been cloned, their structure, organization, pattern of rearrangement, diversification and expression in ontogeny have been classified. However, there are still many important questions to be addressed, such as the nature of thymic education, tolerance, the mechanism of MHC-restricted antigen recognition and the relation between TCR repertoire and autoimmunity. In the future, new approaches to study these issues, such as transgenic mice, X-ray crystallography, and severe combined immune deficiency mice reconstituted with human hematopoietic cells will lead to a more profound understanding of these questions. This will hopefully allow us to manipulate the immune response in different and more effective ways than are currently available.

The origins of aperiodicities in sensory neuron entrainment.

Aperiodic entrainment to rhythmic sensory input was obtained with either a single neuron or an excitatory network model, without addition of a stochastic or "noisy" element. The entrainment properties of primary sensory neurons were well captured by the dynamics of the Hodgkin-Huxley ordinary differential equations with a quiescent resting state or threshold for spike output. The frequency-amplitude parameter space was compressed and aperiodic regimes were small in comparison to those of periodically activated pacemaker-like neurons. Transitions between phase-locked and aperiodic entrainment patterns were predictable and determined by the equation dynamics, supporting the contention that some aperiodicities observed in situ arise from the inherent membrane properties of neurons. When the rhythmically activated neuron was embedded in an excitatory network of Hodgkin-Huxley neurons with heterogeneous synaptic delays, aperiodic entrainment patterns were more frequently encountered and these were associated with asynchronous output from the network. Embedding the rhythmically activated neuron in a network with synaptic delays greatly reduced the range of entrained spike frequencies and increased the variability in the neuronal firing. The temporal coding of sensory stimuli may be dependent on these findings. Sensory stimuli are signaled in the periphery by a mixture of periodic and irregular interspike intervals. Most models of such temporal codes assume intrinsic rhythmicity arising from the ionic currents, with variations attributed to membrane or synaptic noise. In contrast, we demonstrate irregular neural codes that arise completely in the absence of noise. In the proposed model, the sources of these irregular sensory patterns are the extensive cross-connections and resultant interactions between neurons. The balance between the regular and irregular entrainment of a neuron in situ could uniquely identify a stimulus. Other biological mechanisms of modifying the entrainment properties and promoting aperiodic entrainment are discussed.

Humeral fractures without obvious etiologies in children less than 3 years of age: when is it abuse?

OBJECTIVE: To determine the occurrence and frequency of abuse in children with humeral fractures without immediately obvious etiologies who are less than 3 years old and present with arm injuries. METHODS: A retrospective chart review was conducted of all children less than 3 years old treated for a humeral fracture at Children's Hospital Medical Center between July 1, 1990, and September 10, 1993. One hundred twenty-four charts of children with humeral fractures were reviewed for possible abuse using previously developed criteria. Charts were evaluated independently by the investigators. Consensus was reached on classification of each chart into the following categories: abuse, indeterminate, or not abuse. RESULTS: Abuse was diagnosed in 9 of 25 (36%) children less than 15 months of age, but in only 1 of 99 (1%) children older than 15 months (P < .05). Abuse was excluded in 91 of 124 (73%) children. No determination of abuse (indeterminate) could be made in 23 of 124 (18.5%) children. In children less than 15 months of age, abuse was diagnosed in 2 of 10 (20%) with supracondylar fractures and in 7 of 12 (58%) with spiral/oblique fractures. CONCLUSION: The prevalence of abuse in our children presenting with humeral fractures was much lower than in other published reports, especially in the children over the age of 15 months. However, we found a higher prevalence of supracondylar fractures associated with abuse than those same reports. Given these findings, abuse should be considered in all children less than 15 months of age with humeral fractures, including those with supracondylar fractures. The majority of humeral fractures in children are accidental, especially beyond the age of 15 months.

The prevalence of sexually transmitted diseases in children and adolescents evaluated for sexual abuse in Cincinnati: rationale for limited STD testing in prepubertal girls.

OBJECTIVE: To determine the prevalence of Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, syphilis, and human immunodeficiency virus (HIV) infection in sexually abused children and to develop selective criteria for sexually transmitted disease (STD) testing in these children in our community. DESIGN: Prospective. SETTING: University-affiliated children's hospital in Ohio. PARTICIPANTS: All children evaluated at our hospital for sexual abuse were eligible. Eight hundred fifty-five children were evaluated over a 1-year period. The study included 704 girls and 151 boys. Children ranged in age from 3 weeks to 18 years old. METHODS AND RESULTS: Standard STD testing (American Academy of Pediatrics recommendations) was defined as serum rapid plasma reagin test, examination for Trichomonas, N gonorrhoeae culture of the throat, rectum, and genitalia and C trachomatis culture of the rectum and genitalia. STD testing in this study was recommended in children with 1) a history of genital discharge or contact with the perpetrator's genitalia, 2) examination findings of genital discharge or trauma, and 3) all adolescents. HIV testing was obtained in children with risk factors for HIV infection, those with contact with a perpetrator with HIV risk factors, or if the family was concerned about HIV acquisition. A total of 423 children were tested for N gonorrhoeae, 415 for C trachomatis, 275 for syphilis, 208 for Trichomonas, and 140 for HIV. Twelve children were determined to have N gonorrhoeae infection, 11 had C trachomatis infection, and four had Trichomonas infection. Overall, the prevalence of STDs in prepubertal girls was 3.2% and 14.6% in pubertal girls. The prevalence of N gonorrhoeae in prepubertal girls with vaginal discharge was 11.1% and 0% in prepubertal girls without discharge (P < .001). C trachomatis infection was diagnosed in 0.8% of prepubertal girls compared with 7.0% of pubertal girls (P < .001). None of the children tested positive for syphilis or HIV and no males had a STD. CONCLUSIONS: In our community, N gonorrhoeae testing in prepubertal girls can be limited to those with a vaginal discharge on examination unless other risk factors are present. The prevalence C trachomatis and Trichomonas in prepubertal girls is low and may be omitted from routine evaluations. All pubertal girls evaluated for sexual abuse should be tested for STDs because of the high prevalence of asymptomatic infection in this patient population.

Screening for domestic violence in the community pediatric setting.

OBJECTIVE: Children exposed to domestic violence (DV) can experience a variety of adverse effects such as behavior disorders, developmental delay, and child abuse. Recently, the American Academy of Pediatrics recommended that all pediatricians incorporate screening for DV as a part of anticipatory guidance. To date, however, there is little information on how likely women are to disclose DV or whether there are any benefits to screening in the pediatric office setting. The purpose of our pilot study was to gain an understanding of whether screening for DV in the pediatric office setting could be helpful to abused women and their children. METHODS: During a 3-month period, 92% of the women who accompanied their children for a well-child visit to a hospital-based suburban pediatrician were asked about violence in the home with a six-question screening tool. RESULTS: Of the 154 women screened, 47 (31%) revealed DV at some time in their lives. Twenty-five women (17%) reported DV within the past 2 years and were reported to the mandated state agency. There were 5 episodes of child abuse reported of which two had not been previously reported. Interestingly, there were 5 women injured during their most recent pregnancy and who had separated from their abusive partner, but no legal action had been taken to protect them from their partner's return. There was no significant difference in the incidence of DV reported in families with Medicaid (37%) versus private insurance (20%). Before routine DV screening in our office, only one previous DV report had been made in 4 years. CONCLUSIONS: Our preliminary results suggest that many women will reveal DV when screened in the pediatric office setting. Also, there is a subgroup of women, those with young children who have recently separated from their partners, who may particularly benefit from DV screening.

Clinical success, complications and restenosis rates with excimer laser coronary angioplasty. The Percutaneous Excimer Laser Coronary Angioplasty Registry.

The role of excimer laser angioplasty in treating complex coronary artery disease remains uncertain. A randomized trial comparing this new technology with balloon angioplasty cannot be designed until systematic analysis identifies the lesion types that are likely to benefit from treatment with excimer laser angioplasty. In a cohort of 764 patients who had 858 coronary stenoses treated with excimer laser-facilitated angioplasty, relative risk analysis was used to examine acute success, complications and restenosis rates, and the results were compared with those of balloon angioplasty to identify the lesion types that show the greatest benefit with the new treatment. Clinical success was achieved in 657 patients (86%), as indicated by < or = 50% residual stenosis and no in-hospital complication. A major in-hospital complication (death, bypass surgery, or Q-wave or non-Q-wave myocardial infarction) occurred in 58 patients (7.6%). Follow-up angiography was obtained in 70% of eligible patients. Combining angiographic and noninvasive restenosis rates yielded an overall restenosis rate of 46%. Relative risk analysis showed that major complications occurred frequently in lesions at an arterial bifurcation (odds ratio [OR] 5.96 [2.76, 12.6]; p = 0.001). However, certain complex lesions that are difficult to treat with balloon angioplasty (saphenous vein graft lesions, lesions > 10 mm, ostial lesions, calcified stenoses, total occlusions and unsuccessful balloon dilatations), analyzed together as a group, had lower complication rates by univariate (OR 0.59 [0.35, 1.00]; p = 0.051) and multivariate logistic regression (p = 0.006) analyses.(ABSTRACT TRUNCATED AT 250 WORDS)

Predictors of acute and long-term outcome with transluminal extraction atherectomy: the New Approaches to Coronary Intervention (NACI) registry.

The New Approaches to Coronary Intervention (NACI) registry was established to define the role of new coronary devices in overcoming the limitations of balloon angioplasty. The purpose of the present study was to evaluate the acute and long-term efficacy of the transluminal extraction catheter (TEC) device utilizing data from the NACI registry and identify clinical and anatomic patient subsets who may benefit from this device. From 1990-1994, >4,300 patients from 39 clinical sites enrolled consecutive patients treated with one of the 7 new devices to the NACI registry. The study population consists of 331 patients (385 lesions) treated with planned TEC as the sole new device. Of these patients, 243 (292 lesions) were treated for saphenous vein graft (SVG) disease and 88 (93 lesions) for native disease. Patients undergoing SVG treatment were older and more likely to be male. They had lower ventricular function, more unstable angina, and a higher incidence of congestive heart failure. Multivessel disease was more prevalent in the SVG cohort, as was evidence of thrombus before treatment. Although device success was achieved in 50% of SVG lesions and 41% of native lesions, lesion success was achieved in 90% and 78%, respectively, after adjunctive balloon angioplasty, and procedure success rates were 86% and 79%, respectively. The in-hospital major complication (death/Q-wave myocardial infarction/emergency coronary artery bypass graft [CABG] surgery) rate was higher in the SVG cohort (6.2% vs 2.3%), mainly due to higher mortality rate (5.3% vs 1.1%). Multivariate analysis showed that SVG was not an independent predictor for either an in-hospital major complication or clinical failure. The risk factors for major in-hospital complications were history of congestive heart failure (odds ratio = 3.17) and thrombus (odds ratio = 3.36). For clinical failure the risk factors were diabetes (odds ratio = 1.88), thrombus (odds ratio = 2.08), and calcium (odds ratio = 3.09). One-year rates of death, Q-wave myocardial infarction, or any repeat revascularization were 51% in the SVG cohort and 41% in the native cohort. Following adjustment, patients treated for SVG disease did not have a higher risk when compared with those treated for native disease. The factors significantly associated with this composite event at 1 year are male (relative risk = 1.41), patients with history of congestive heart failure (relative risk = 1.56), and total occlusions (relative risk = 1.52). This study shows that for both SVG and native cohorts, device success rates were low with TEC alone, but acceptable lesion success rates were achieved when adjunctive PTCA was used. In-hospital as well as 1-year major complications were higher in the SVG cohort. However, after adjusting for other risk factors, SVG attempt was not significantly associated with either in-hospital or 1-year events.

Excimer laser coronary angioplasty: the New Approaches to Coronary Intervention (NACI) experience.

In the New Approaches to Coronary Intervention (NACI) registry, 887 patients were electively treated with excimer laser coronary angioplasty (ELCA) for coronary artery disease. The Advanced Interventional System (AIS) system was used in 487 cases; the Spectranetics system, in 400. The mean age was 63.4 years. Most patients had unstable angina (60.3%); 43.7% had a prior myocardial infarction; and 18.6% were high risk or inoperable patients. Mean ejection fraction was 55.4%. A total of 1,000 lesions were treated in the 887 patients. Of the 1,000 lesions treated with ELCA in the 887 patients, 36% were in the right coronary artery; 33%, left anterior descending; 13%, circumflex; 3%, left main; and 16.6%, vein graft. By angiographic core laboratory analysis available for 752 (85%) patients with 839 lesions, lesions were 12.76 mm long. The minimum lumen diameter increased to 1.29 mm after the laser and finally to 1.95 mm after adjunctive percutaneous transluminal coronary angioplasty (PTCA) (which was performed in 93% of all lesions), with a final residual stenosis of 32.1% and Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow in 95%. Dissections of grades B, C, or D were seen after 22.0% of initial laser attempts, and postlaser perforations were noted in 2.6%. Additional such dissections accumulated after adjunctive PTCA but the perforation rate remained low. Procedural success was achieved in 84% of patients, but 1.2% died, 0.7% experienced Q-wave myocardial infarction (MI), and 2.7% required emergency bypass surgery. Multiple logistic regression analysis could not identify any independent predictors of these in-hospital complications. One-year mortality was 5.7% and the cumulative incidence of Q-wave MI was 1.5%. Coronary artery bypass graft (CABG) surgery was performed in 15.0% of patients whereas 25.5% required repeat percutaneous intervention with a target lesion revascularization rate of 31%. Independent predictors of death, Q-wave MI, or target lesion revascularization (which, combined, occurred in 35.6% of patients) were the absence of prior MI, ELCA in the circumflex, perforation after the procedure, and small (<2 mm) final minimal lumen diameter. Considering the large number of patients with high-risk lesions, laser angioplasty was performed with excellent procedural success rates and a reasonable incidence of major complications.

Gld and lpr mice: single gene mutant models for failed self tolerance.

Mice homozygous for the gld or lpr mutations develop autoimmunity, and a lymphoproliferative disorder involving accumulation of huge numbers of unusual CD4-CD8-TCR alpha beta lo T cells. Here we review our past work with gld mice, and attempt to explain lymphoproliferation in terms of current models of T cell maturation and self-tolerance induction. The availability of molecular probes to the gene products of lpr and gld should shortly lead to a better understanding of the acquisition of self tolerance during T cell maturation and of autoimmunity.