Bronchiectasis is associated with delayed diagnosis and adverse outcomes in the New Zealand Common Variable Immunodeficiency Disorders cohort study.

Common variable immunodeficiency disorders (CVID) are multi-system disorders where target organ damage is mediated by infective, autoimmune and inflammatory processes. Bronchiectasis is probably the most common disabling complication of CVID. The risk factors for bronchiectasis in CVID patients are incompletely understood. The New Zealand CVID study (NZCS) is a nationwide longitudinal observational study of adults, which commenced in 2006. In this analysis, the prevalence and risk factors for bronchiectasis were examined in the NZCS. After informed consent, clinical and demographic data were obtained with an interviewer-assisted questionnaire. Linked electronic clinical records and laboratory results were also reviewed. Statistical methods were applied to determine if variables such as early-onset disease, delay in diagnosis and increased numbers of infections were associated with greater risk of bronchiectasis. One hundred and seven adult patients with a diagnosis of CVID are currently enrolled in the NZCS, comprising approximately 70% of patients known to have CVID in New Zealand. Fifty patients (46·7%) had radiologically proven bronchiectasis. This study has shown that patients with compared to those without bronchiectasis have an increased mortality at a younger age. CVID patients with bronchiectasis had a greater number of severe infections consequent to early-onset disease and delayed diagnosis. Indigenous Maori have a high prevalence of CVID and a much greater burden of bronchiectasis compared to New Zealand Europeans. Diagnostic latency has not improved during the study period. Exposure to large numbers of infections because of early-onset disease and delayed diagnosis was associated with an increased risk of bronchiectasis. Earlier diagnosis and treatment of CVID may reduce the risk of bronchiectasis and premature death in some patients.

Using Hypothetical Scenarios to Address Social Desirability Bias: Investigating Student Perceptions, Evaluations, and Motivations of Cheating and Academic Integrity in the General Chemistry Laboratory.

Supporting students with upholding the principles of academic integrity is an important aspect of teaching. Academic integrity is especially important in chemistry laboratory classrooms, where students gain hands-on experience related to research and scientific practices. Prior literature on academic integrity largely focuses on catching and preventing cheating, describing various factors commonly associated with cheating behaviors. This body of literature assumes that students neutralize their feelings about cheating to engage in unethical behavior. In contrast, for this study, we began with the assumption that students intend to act ethically; to this end, we sought to investigate students' perceptions, evaluations, and motivations related to cheating and academic integrity. We interviewed 24 students enrolled in general chemistry laboratories and asked questions related to cheating and academic integrity. Additionally, to address concerns about social desirability bias affecting students' responses, we asked students questions involving hypothetical scenarios related to academic integrity that were contextualized within the chemistry laboratory classroom. In our analysis, we found that students held common views about cheating and academic integrity in general but diverged in their responses to the hypothetical scenarios. Our findings suggest the importance of providing clearer, more direct instruction regarding what counts as cheating and how to engage in academically honest behavior within the chemistry laboratory classroom.

Isolation of rat/rat T cell hybrids using W/Fu C58(NT)D as fusion partner.

Functional rat/rat T cell hybrids were isolated for the first time by the fusion of spleen cells from rats tolerized to the hapten TNP to a HAT-sensitive rat thymoma (C58(NT)D). 11 fusions using different protocols were attempted to assess the optimal conditions for high hybridization frequency of the desired specificity. Interestingly, the cell density requirement of the non-transformed fusion partner took precedence over that of the C58 cell line, i.e., rat cells needed to be at high density after fusion, but others have reported that mouse cells prefer a much lower density even when the same line (C58) is used. Six fusions yielded hybridomas with between 3% and 70% of wells containing hybrids after three weeks of culture, depending on the protocol used. Phenotypically, all of the hybrids and clones tested expressed the W3/25 (rat CD4) antigen, but no OX-8 (rat CD8) or immunoglobulin molecules. A minority of hybrids were found to secrete factors able to suppress (a) proliferation, (b) antibody production, and (c) cells bearing IL-2 receptors, but none appeared to suppress the production of IL-2 itself. In contrast to non-transformed rat T cell lines, the T hybrids isolated were easy to grow to high densities, clone and freeze without the need to add exogenous antigen or lymphokines to the cultures at any stage.

Platelet aggregation following defibrination with ancrod.

In vitro platelet aggregation was studied in dogs following defibrination with Ancrod. There was marked inhibition of aggregation immediately after defibrination. A gradual return toward normal aggregation was observed over the 96 hours study period, but aggregation was still abnormal at 96 hours after defibrination. There was an inverse and highly significant correlation between aggregation and fibrin degradation product level. Fibrinogen was not measurable after defibrination for the entire study period. Aggregation was thus independent of fibrinogen concentration in this study.

Peroxisomal disorders: clinical and biochemical studies in 15 children and prenatal diagnosis in 7 families.

We describe the main clinical and biochemical findings in 15 patients with peroxisomal disorders, together with the results of 11 prenatal investigations for Zellweger syndrome. The initial laboratory diagnosis depended in most cases on demonstration of elevated very long chain fatty acids in plasma, but follow-up studies using cultured fibroblasts were essential for complete classification. The patient group comprises nine cases of Zellweger syndrome, one of neonatal adrenoleucodystrophy, two of infantile Refsum disease, one of bifunctional protein deficiency, and two of rhizomelic chondrodysplasia punctata. The study illustrates the clinical and biochemical variability of this group of patients and the detailed studies that are required for classification.

Application of a flowchart for the detection of lysosomal storage diseases in 105 high-risk Brazilian patients.

Lysosomal storage diseases (LSD) are a group of more than 40 disorders, many of them with overlapping phenotype, in which clinical diagnosis is often difficult. Definitive diagnosis is based on enzyme assays, a large number of such assays usually being necessary during the investigation of each patient. In addition, there will frequently be a need for tissue culture in order to provide enough material for analysis. Taking into account these difficulties, we designed a flowchart for the detection of LSD that is based on 2 sets of tests requiring only random urine and heparinized blood. Here we describe this routine and report the results of its application to 105 Brazilian patients in whom a LSD was suspected. We think that the application of this rationale represents a saving of work and costs, and should be of special interest to genetic centers in developing countries.

Subcutaneous mastectomy: acute complications and long-term follow-up.

Subcutaneous mastectomy as performed at our institution from 1965 to 1979 was an operation with high morbidity. The risk of complication appears to have been decreased with a two-stage approach. Long-term results were disappointing, with a high incidence of capsular contracture. The incidence of capsular contracture appears to have been reduced by subpectoral placement of the implants. One breast carcinoma occurred 10 years after subcutaneous mastectomy.

Disappearance of the polyurethane cover of the Ashley Natural Y prosthesis.

Polyurethane foam implanted in our patient was neither inert nor permanent. Clinical observations and animal studies suggest that all polyurethanes implanted to date have slowly disintegrated and have been absorbed in tissue. This process takes several years to complete. The exact time sequence and histology are not known.

Elicitation of the oculocardiac reflex during endoscopic forehead lift surgery.

Elicitation of the oculocardiac reflex is a well-documented phenomenon encountered during ophthalmologic surgical procedures. Familiarity with and prompt recognition of this entity has significantly reduced the morbidity associated with it; however, potentially lethal arrhythmias and cardiac arrest still occur. We report elicitation of the reflex during manipulation of the supraorbital nerve during endoscopic forehead lift surgery. To our knowledge this is the first case of elicitation of the oculocardiac reflex reported during endoscopic forehead lift surgery.

Environmental osmolarity and neurosecretory neurones in Lymnaea stagnalis (L.).

Cell body volume and Alcian blue-Alcian Yellow staining properties of neurosecretory neurones in the brain of Lymnaea stagnalis were compared for snails kept in de-ionised water and standard tapwater. In the same experiment, the ionic content of the blood, blood volume and body weight and environmental ionic composition were measured. Five days of immersion in de-ionised water resulted in significant decreases in body weight, blood volume and blood, Na+ and Cl- concentrations but no change in blood Ca2+, K+,and HCO3- concentrations, compared with controls. No consistently significant differences across the 5 day period were found in cell body volumes for Dark Green Cells, Yellow Cells or Light Green Cells (used as a control) when these volumes were compared for large numbers of cells from snails kept in de-ionised water and standard tapwater. However, the number of Yellow Cells which could be counted in snails kept in de-ionised water was lower than the number from standard tapwater by day 2 of the experiment and lower for Yellow-green Cells by day 5. We interpret this lower number to be the result of depletion of Alcian blue-Alcian Yellow stained neurosecretory material in these cells which made them impossible to distinguish. This was confirmed by examination of visceral Yellow Cells which could be identified on the basis of known location close to the visceral-right parietal connective.

Induction of catalytic activity in proteins by lyophilization in the presence of a transition state analogue.

The induction of catalytic activity in proteins by lyophilization in the presence of a transition state analogue (biomolecular imprinting) has been attempted. It was shown that proteins which were freeze-dried with n-isopropyl-4-nitrobenzyl-amine (a transition state analogue for the reaction of dehydrofluorination of 4-fluoro-4-[p-nitrophenyl] butan-2-one) displayed higher beta-elimination activity as compared to their-non-imprinted counterparts. It was also found that native bovine serum albumin has a high dehydrofluorination activity towards the above substrate with kinetic parameters rather similar to those of a catalytic antibody prepared by Shokat et al. (1989). A comparison of the kinetic parameters determined in this study with those obtained for analogous catalytic antibodies and imprinted polymers was made.

Spectral responsivity of the white-black channel.

Three subjects viewed, foveally and monocularly, a monochromatic test field of 0.6-deg diameter that was surrounded by a white annulus of 0.6-deg inner diameter and 4.5-deg outer diameter. The wavelength of the central test field was varied in steps of 10 nm from 440 to 640 nm, and its luminance was set to 100 Td. Center and surround were flashed together for 2 sec every 4 sec. The subjects adjusted the luminance of the surround so that the central field was perceived as having equal amounts of whiteness and blackness. The luminance of the surround required for this balance point varied with the wavelength of the test field in a manner that closely resembled a heterochromatic brightness matching function obtained under similar conditions. Control experiments ruled out the possibility that the subjects were making brightness matches between center and surround fields. Additional evidence was provided suggesting that the spectral responsivity of the putative white-black channel is best represented by a photopic spectral sensitivity curve based on equal brightness.

Parent-parent support in the care of high-risk newborns.

Despite the expertise of professional personnel in supporting parents of high-risk infants, parents with similar previous experiences can play a strong adjunctive role also. One program in which these parents were used as the key resource is described, including organization, actual operation, results, and problems.

A chimeric antibody with dual Fc regions (bisFabFc) prepared by manipulations at the IgG hinge.

A new chimeric antibody for therapeutic use in human cancer is described. First the derivative FabFc was prepared by linking Fab' gamma from monoclonal antibody to Fc gamma from human normal IgG1. The bismaleimide linking agent forms a thioether bond with an SH group released by reduction of SS bonds in the hinge of each constituent. It follows that one of the original two SS bonds in the Fc hinge still has both its S atoms free, and this bond is reformed by thiol-disulphide interchange. The lone free SH in the Fc hinge can now be used to join two FabFc molecules through a similar bismaleimide linker to yield bisFabFc. As regards antibody activity against target cells, bisFabFc can be univalent, bivalent, or bispecific. Its juxtaposed dual Fc regions are designed to promote cooperative binding of effectors, and bisFabFc is indeed notably more powerful than its parent FabFc molecules in promoting complement lysis and antibody-dependent cellular cytotoxicity. However it is not possible at present to distinguish the separate contributions of Fc architecture, antibody affinity and other factors towards this improvement. In the present state of development a variety of FabFc against a given neoplasm may be prepared in high yield from mouse IgG1 and IgG2a antibodies, and when convenient dimerized to bisFabFc in any combination of specificities.

Argininosuccinate lyase: a new autoantigen in liver disease.

Anti-liver cytosol 1 autoantibody (LC1) characterizes a severe form of autoimmune hepatitis (AIH), staining the cytoplasm of periportal hepatocytes and targeting an unidentified 60-kD liver cytosolic antigen. To identify its target, we used high-titre anti-LCI+ sera from two patients with AIH to screen 18 cytoplasm enzymes with periportal location by double immunodiffusion (DDI). Both sera gave a broad precipitin line against human liver cytosol, suggesting that they may recognize two distinct antigens, a possibility confirmed by the appearance of two precipitin lines when DDI conditions were optimized (0.8% agarose and 3% polyethylene glycol (PEG)). Experiments by DDI and Western blot (WB) identified a liver cytosolic autoantigen of 50 kD, different from LC1, giving a line of identity with argininosuccinate lyase (ASL). Reactivity to ASL was then investigated by DDI and WB in 57 patients with AIH, 17 with primary biliary cirrhosis (PBC), 15 with chronic hepatitis B virus (HBV) infection, 13 with alphal-antitrypsin deficiency, 17 with Wilson's disease, 18 with extrahepatic autoimmune disorders, and in 48 healthy controls. Anti-ASL was found in 16% of AIH and 23% of PBC patients by DDI and in 14% of AIH, 23% of PBC and 20% of HBV patients by WB. No argininosuccinate was present in the urine of four anti-ASL+ patients tested, excluding an inhibition of enzymatic activity by anti-ASL. The addition of anti-ASL+ serum to human fibroblast cultures induced a significant increase in ASL activity. ASL is a new autoantigen in liver disease and its clinical relevance warrants further investigation.

Expression of a kinase-deficient IGF-I-R suppresses tumorigenicity of rhabdomyosarcoma cells constitutively expressing a wild type IGF-I-R.

Previous results have shown that the insulin-like growth factor type I receptor (IGF-I-R) plays a critical role in the control of rhabdomyosarcoma (RMS) growth. The purpose of this study was to investigate whether a mutated IGF-I-R, when expressed in RMS cells, may interfere with the function of the endogenous wild-type IGF-I-R. We also examined whether the expression of a mutated IGF-I-R may induce phenotypic changes in RMS cells. We used here the mutated IGF-I-R with a lysine to arginine residue 1003 substitution, called IGF-I-KR, which carries a mutation in the ATP-binding domain of the intracellular beta subunit, while the extracellular, ligand binding alpha subunit remains unchanged. We observed that the expression of this mutated IGF-I-KR markedly decreased the response of RMS cells to stimulation with IGF-I. While stimulation with IGF-I increases the autophosphorylation of IGF-I-R in the parent cells, stimulation with IGF-I failed to produce a comparable increase in autophosphorylation in the cells expressing the mutated IGF-I-KR. We also observed a decreased plating efficiency of cells expressing the mutated IGF-I-KR. Consistently, a decrease of RMS growth in vivo was observed in an animal model. Our data suggest that the IGF/IGF-I-R signaling pathway may be inhibited by expressing a mutated IGF-I-KR and that such a mutant gene could be utilized in developing novel therapeutic strategies to suppress RMS growth. 1998.

Prospective trials of dexamethasone and aerosolized gentamicin in the treatment of inhalation injury in the burned patient.

The addition of an inhalation injury to a cutaneous burn results in a significant increase in patient mortality rates, both from early pulmonary edema and, later, Gram-negative pneumonitis. Steroids have been shown to decrease mortality in an inhalation injury model. Aerosolization of gentamicin has been used successfully to treat severe bronchial infections. Therefore, a prospective, randomized trial was undertaken to evaluate both these drugs. Sixty burned patients, with inhalation injury confirmed by bronchoscopy and 133Xenon scan, were studied: 30 patients received either dexamethasone or saline placebo for 3 days; serial pulmonary functions were measured on those able to cooperate; another 30 patients received either aerosolized gentamicin or placebo for 10 days. Both drug-treated groups were comparable to their controls in age and mean burn size. Results of the steroid trial showed no major differences in mortality, pulmonary complications, or changes in pulmonary functions. Results of the gentamicin trial showed no major differences in mortality, time of death, or pulmonary and septic complications between treated and control groups.