Follicular output rate can predict clinical pregnancy in women with unexplained infertility undergoing IVF/ICSI: a prospective cohort study.

This study aimed to determine whether follicular output rate (FORT) can predict the clinical pregnancy rate in women with unexplained infertility undergoing IVF/ICSI. This was a prospective study conducted at Dar El Teb subfertility centre in Cairo between June 2014 and July 2016. A total of 303 women with unexplained infertility, who were undergoing IVF/ICSI, were divided into three groups according to FORT tertile values. FORT was calculated as pre-ovulatory follicle count/antral follicle count × 100. There was a progressive and significant increase from the low to the high FORT groups in the clinical pregnancy rate (29.9%, 43.3% and 57.8%; P < 0.001), number of retrieved oocytes (5.4 ± 1.5, versus 6.8 ± 2.8, and 7.4 ± 2.1; P < 0.001), and fertilization rate (48.4 ± 21.8 versus 55.3 ± 20.3 and 57.4 ± 19.2; P = 0.006). Multivariate logistic regression analysis revealed that the correlation between FORT and pregnancy was independent of potential confounding factors (P = 0.008). We concluded that FORT is an independent variable affecting the clinical pregnancy rate in IVF/ICSI cycles. Higher FORT values had better oocyte yield and clinical pregnancy rates in women with unexplained infertility undergoing IVF/ICSI with potentially normal ovarian response.

Numerical investigation of sand erosion rate in a horizontal axis wind turbine.

Renewable energy represents an important alternative solution for many energy problems nowadays and a tool for a healthier environment by reducing carbon footprints resulting from burning fossil fuels. However, more work needs to be done towards maximizing the energy produced from renewable energy methods and making sure that the infrastructure used stays in service for a longer duration. Sand erosion phenomena is responsible for the degradation of the wind turbine blades and hence the decrease in their performance and life. In the current research, a numerical study of both performance and sand erosion of a Small-Scale Horizontal Axis Wind Turbine (SS-HAWT) is carried out. This study introduces new sights of instantaneous and forecasted erosion rates within the blade of the wind turbines. Three-dimensional E216 airfoil blades of radius 0.5 m are established according to blade element momentum theory. Sand particles with different mass flow rates of 0.001, 0.002 and 0.003 kg/s and uniform diameters of 50, 100 and 200 µm have been selected as eroding particles under two different average air velocities of 8 m/s and 10 m/s. The results indicate that the performance of wind turbines is enhanced as the flow separation at the suction side is shifted to the trailing edge. Furthermore, the optimum tip speed ratio is about 5 at an air velocity of 8 m/s with a power coefficient of 0.432. In terms of erosion findings, V-shaped scars are reported near the leading edge of the blades. In addition, the instantaneous erosion rate grows exponentially with the tip speed ratio. Therefore, the yearly prediction of maximum erosion depth at the optimum operating conditions is obtained to be 5.7 mm/year in some spots of the turbine blades.

Superantigenicity of streptococcal M protein.

M proteins that define the serotypes of group A streptococci are powerful blastogens for human T lymphocytes. The mechanism by which they activate T cells was investigated and compared with the conventional T cell mitogen phytohemagglutinin, and the known superantigen staphylococcal enterotoxin B. Although major histocompatibility complex (MHC) class II molecules are required for presentation, there is no MHC restriction, since allogeneic class II molecules presented the bacterial protein to human T cells. Type 5 M protein appears to bind class II molecules on the antigen-presenting cells and stimulate T cells bearing V beta 8 sequences. Our results indicate that this streptococcal M protein is a superantigen and suggest a possible mechanism of its role in the pathogenesis of the postinfectious autoimmune sequelae.

T cell receptor V gene usage by human T cells stimulated with the superantigen streptococcal M protein.

M proteins, the major virulence factor of group A streptococci, have been implicated in the pathogenesis of acute rheumatic fever (ARF) and other streptococcal related autoimmune diseases. A 22-kD fragment of M type 5 protein is a potent stimulant of human T cells and has recently been shown by our laboratory to belong to the newly designated family of superantigens. Using flow cytometry and the polymerase chain reaction, we demonstrate that this molecule reacts with subsets of human T cells expressing specific T cell receptor (TCR) V beta elements, namely V beta 2, 4, and 8. We employed similar techniques to analyze the TCR V alpha usage of pep M5-stimulated T cells. These studies revealed that the preferential usage of particular V alpha elements is not specific for the superantigen; rather, it may reflect the repertoire of the individual being tested. The expansion of a large number of T cells bearing specific TCR V beta sequences by M protein may account for its role in mediating the pathogenesis of post-streptococcal diseases. Furthermore, the preferential usage of TCR V alpha elements in certain individuals may be an important factor that predisposes them to development of self-reactivity.

Ursodeoxycholic acid in neonatal hepatitis and infantile paucity of intrahepatic bile ducts: review of a historical cohort.

We retrospectively reviewed the role of ursodeoxycholic acid in infants having nonsurgical cholestasis attending the Hepatology Clinic, New Children Hospital, Cairo University, Egypt, from 1985 until 2005. Files of 496 infants with neonatal hepatitis and 97 with intrahepatic bile duct paucity were included; of them 241 (48.6%) and 52 (46.4%) received 20-40 mg/kg/day ursodeoxycholic acid for 319.2 +/- 506.9 days and 480.3 +/- 583.3 days, respectively. The outcome of infants with neonatal hepatitis with intake of ursodeoxycholic acid and those without was: 108 (44.8%) and 179 (70.2%) successful (P = 0.000), 11 (4.6%) and 13 (5.1%) improved (P = 0. 474), 112 (46.5%) and 61 (23.9%) suffered failed outcome (P = 0.000), and 10 (4.1%) and 2 (0.78%) died (P = 0.014), respectively. Likelihood of successful outcome with ursodeoxycholic acid intake was 0.345 (P = 0.000), and that of deterioration was 2.76 (P = 0.000). For those having intrahepatic bile duct paucity likelihood of successful outcome with ursodeoxycholic acid intake was 0.418 (P = 0.040) and that of deterioration was 2.64 (P = 0.028). Ursodeoxycholic acid failed in management of this cohort of infants with nonsurgical cholestasis.

Voltammetric and spectroscopic studies on binding of antitumor Morin, Morin-Cu complex and Morin-beta-cyclodextrin with DNA.

A systematic comparative study of the binding of antitumor Morin and its complexes with DNA has been investigated in the Britton-Robison (BR) buffer solutions using voltammetric and spectroscopic methods. The results show that Morin molecule, acting as an intercalator, is inserted into the cavity of the beta-cyclodextrin (beta-CD) as well as into the base stacking domain of the DNA double helix. The interaction of Morin-Cu complex or the inclusion complex of Morin-beta-CD with ds-DNA causes hypochromism in the absorption spectra, along with pronounced changes in the electrochemical behavior of the Morin complexes. An isobestic point and a new spectrum band appeared indicating the formation of the new system of Morin-Cu-DNA at lambda(m)=391 nm and Morin-beta-CD-DNA at lambda(m)=375 nm. The intercalation of Morin-Cu and Morin-beta-CD complexes with DNA produces an electrochemically inactive supramolecular complex. The binding constants were calculated from the increase of the solubility, the strong hypochromism, and the decrease in peak current of Morin and its complexes upon the addition of the host molecules. Calculation of the thermodynamic parameters of the interaction of the inclusion complex of Morin-beta-CD with DNA, including Gibbs free energy change, Helmholz free energy and entropy change shows that the complexation is a spontaneous process of association.

Twin penile skin flap, is it the answer for repair of long anterior urethral strictures?

OBJECTIVE: To present our twin ventral penile skin flap technique for the management of complex long anterior urethral strictures not caused by lichen sclerosis (LS), with evaluation of surgical outcome and complications. PATIENTS AND METHODS: We retrospectively reviewed patients diagnosed with long complex anterior urethral strictures who were all referred to Ain Shams University hospital and operated on by three reconstructive surgeons. The surgical procedure was carried out as follows: exposure of the urethra through a ventral longitudinal penile skin incision and another perineal incision; two ventral longitudinal dartos-based penile skin flaps are used for urethral augmentation as onlay flaps. Clinical data were collected in a dedicated database. Preoperative, intraoperative, and postoperative follow-up data for each patient were recorded and analysed. A descriptive data analysis was performed. RESULTS: Between January 2012 and February 2015, 47 patients diagnosed by urethrograms as having long anterior urethral strictures, with a mean (SD, range) length of 17.56 (2.09; 14-21) cm, were managed by twin penile skin flap repair. Four patients were lost to follow-up, thus 43 patients constituted the study cohort. The mean (range) follow-up period was 31 (22-36) months. The overall success rate was 95.35% (41/43). At 12-months postoperatively, the 41 successful cases had a mean (SD, range) peak urinary flow rate of 20.26 (3.06, 14-25) mL/s and American Urological Association Symptom Score of 5.6 (1.85, 3-8). Postoperative complications included urethrocutaneous fistula in three patients (6.97%), mild sacculation of the flap in seven patients (16.52%), post-micturition dribbling in 34 patients (79.07%), decreased penile girth in two patients (4.65%), and chordae of <15° with no need for repair in three patients (6.97%). CONCLUSIONS: In the presence of a favourable urethral plate and ample non-hirsute penile skin, one-stage twin penile skin flap urethroplasty provides excellent results for non-LS related complex strictures, with minimal acceptable complications. It proved to be especially efficient in circumcised patients.

Evidence for a streptococcal superantigen-driven process in acute guttate psoriasis.

Recent studies have suggested that T cells play a critical role in the pathogenesis of psoriasis. Guttate psoriasis is a well-defined form of psoriasis frequently associated with streptococcal throat infection. This study tested the hypothesis that T cells in acute guttate psoriasis skin lesions may be activated by streptococcal superantigens. Peripheral blood as well as lesional and perilesional skin biopsies were analyzed for T cell receptor V beta repertoire using monoclonal antibodies against 10 different V beta families. Skin biopsies from all patients with acute guttate psoriasis, but not skin biopsies from patients with acute atopic dermatitis or inflammatory skin lesions induced in normal subjects with sodium lauryl sulfate, demonstrated selective accumulation of V beta 2+ T cells (P < 0.05). The expansion of V beta 2+ T cells occurred in both the CD4+ and the CD8+ T cell subsets. Sequence analysis of T cell receptor beta chain genes of V beta 2-expressing T cells from skin biopsies of patients with guttate psoriasis showed extensive junctional region diversity that is more compatible with a superantigen rather than a conventional (nominal) antigen-driven T cell response. All streptococcal isolates from patients with guttate psoriasis secreted streptococcal pyrogenic exotoxin C, a superantigen known to stimulate marked V beta 2+ T cell expansion. These data support the concept that acute guttate psoriasis is associated with superantigenic stimulation of T cells triggered by streptococcal superantigen(s).

Clinical and microbiological efficacy of MDT in the treatment of diabetic foot ulcers.

OBJECTIVE: To assess the clinical and microbiological efficacy of maggot debridement therapy (MDT) in the management of diabetic foot ulcers unresponsive to conventional treatment and surgical intervention. METHOD: Consecutive diabetic patients with foot wounds presenting at the vascular surgery unit and the diabetic foot unit of Alexandria Main University Hospital were selected for MDT. Lucilia sericata medicinal maggots were applied to the ulcers for three days per week. Changes in the percentage of necrotic tissue and ulcer surface area were recorded each week over the 12-week follow-up period. Semiquantitative swab technique was used to determine the bacterial load before and after MDT. RESULTS: The sample comprised 10 patients with 13 diabetic foot ulcers. The mean baseline ulcer surface area was 23.5cm2 (range 1.3-63.1), and the mean percentage of necrotic tissue was 74.9% (range 29.9-100). Complete debridement was achieved in all ulcers in a mean of 1.9 weeks (range 1-4). Five ulcers (38.5%) were completely debrided with one three-day MDT cycle. The mean reduction in ulcer size was significant at 90.2%, and this occurred in a mean of 8.1 weeks (range 2-12). The mean weekly reduction in ulcer size was 16.1% (range 8.3-50). Full wound healing occurred in 11 ulcers (84.6%) within a mean of 7.3 weeks (range 2-10). The bacterial load of all ulcers reduced sharply after the first MDT cycle to below the 10(5) threshold, which facilitates healing. CONCLUSION: The results highlight the potential benefits of MDT in diabetic wound care in developing countries. MDT was proved to be a rapid, simple and efficient method of treating these ulcers.

Superantigens of gram-positive bacteria: structure-function analyses and their implications for biological activity.

Just as we thought that we know everything about superantigens, new molecular and structural studies indicate that we have only just begun to unravel the secrets of these fascinating molecules. Recent structure-function analysis of superantigens from Gram-positive bacteria, with emphasis on their interaction with major histocompatibility complex molecules, could help us decipher the role of superantigens in disease, identify host factors that potentiate their effects and design drugs that specifically block their activity.

Induction of interleukin 2 production but not methionine adenosyltransferase activity or S-adenosylmethionine turnover in Jurkat T-cells.

We have recently reported that methionine adenosyltransferase (MAT) in resting human peripheral blood T-cells is primarily present in the form of a precursor which we named lambda. This protein decreases upon cell stimulation, as both MAT activity and the amount of the catalytic alpha/alpha' subunits of the enzyme increase. When resting cells are activated by phytohemagglutinin, the decrease in lambda and increase in alpha/alpha' occurs after interleukin 2 (IL-2) production and before DNA synthesis. The human T-leukemia cell line, Jurkat, is unique in its ability to produce IL-2 in response to exogenous stimuli such as T-cell mitogens and therefore provides a convenient model for studying biochemical reactions involved in T-cell activation. In this study the regulation of MAT activity and S-adenosylmethionine (AdoMet) in resting and activated Jurkat cells was investigated. Here we report that MAT activity in unstimulated Jurkat cells is about 10- and 3-fold higher than the activity in resting and activated peripheral blood mononuclear cells, respectively. Activation of Jurkat cells with phytohemagglutinin resulted in increased IL-2-production, but not an increase in MAT activity. Identical results were obtained using freshly isolated cells from acute lymphoblastic leukemia patients. AdoMet utilization and pool size were approximately 3- and 10-fold higher, respectively, in Jurkat cells compared to peripheral blood mononuclear cells, and both parameters were unaffected by phytohemagglutinin stimulation. Jurkat MAT was determined to be structurally indistinguishable from enzyme from T- or B-leukemia cells but was different from resting, normal T-cells in that it lacked the lambda form. Furthermore, unlike MAT in resting T-cells, the relative amounts of the alpha, alpha', and beta subunits of the enzyme did not change throughout the course of IL-2 induction. We conclude that AdoMet metabolism and MAT activity in Jurkat cells are constitutively high and that induction of IL-2 synthesis in these cells is independent of changes in AdoMet synthesis or turnover. The lack of the lambda form and the difference in MAT regulation between leukemic T-cells and peripheral blood mononuclear cells may be exploited in the design of specific chemotherapeutic agents.

ANTIMICROBIAL ACTIVITY FOR EXCRETION AND SECRETION OF THE GREENBOTTLE FLY LARVAE LUCILIA SERICATA (MEIGEN) (DIPTERA: CALLIPHORIDAE).

Sterile larval excretion/secretion (ES) exhibited antibacterial activity against some species of bacteria. They were shown to inhibit the growth of Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis Gram-negative bacteria Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae and Fungi Geotricum candidum and Aspergillus fumigatus thus exhibited limited inhibitory effect towards Gram-positive bacteria Streptococcus pyogenes and Staphylococcus epidermidis and Gram-negative Proteous vulgaris and Fungi Syncephalastrum racemosum, Candida albicans, that effect was slowed down when challenged with secretion on a solid media but no zone of complete inhibition was detectqd. Growth inhibiting activity was determined in liquid growth media using the Gram-positive, Gram-negative bacterial and fungal strains as indicator organisms.

Regulation of human lymphocyte S-adenosylmethionine synthetase by product inhibition.

A steady-state kinetic analysis of human S-adenosylmethionine synthetase indicates that the reaction is Bi Ter with ordered addition of ATP and L-methionine and release of S-adenosylmethionine as the first product. Pyrophosphate and phosphate are then released randomly. I-Parabolic inhibition by phosphate with respect to ATP indicates that this product must bind to more than one site. A model in which phosphate binds to the pyrophosphate site gives a rate equation that is consistent with the kinetic data. Values have been determined for those constants in the equation that are large enough to evaluate, and the in vitro kinetic behavior of S-adenosylmethionine synthetase can be predicted at substrate and product concentrations that are expected intracellularly. Inhibition by combinations of products, especially pyrophosphate and phosphate, is synergistic. Of particular interest is the ability of pyrophosphate and phosphate to increase the sensitivity of the enzyme to inhibition by S-adenosylmethionine. This phenomenon may play a role in regulating steady-state cellular concentrations of S-adenosylmethionine.

Regulation of S-adenosylmethionine synthetase activity in cultured human lymphocytes.

S-Adenosylmethionine (AdoMet), inorganic pyrophosphate (PPi) and inorganic phosphate (Pi) are potent product inhibitors of AdoMet synthetase and have been postulated to play a role in increasing AdoMet levels and turnover in peripheral blood mononuclear cells (PBM) after stimulation with phytohemagglutinin (PHA). Measurements of these metabolites in PHA-stimulated PBM showed the expected 2- to 3-fold increases in AdoMet after 8 h, and smaller increases in PPi and Pi. Since the kinetic model requires substantial decreases in PPi and Pi in response to PHA, product inhibition cannot explain the observed changes in AdoMet metabolism in this system. A 2.5-fold increase in AdoMet synthetase catalytic activity was found in crude extracts of PBM within 8 h of PHA-stimulation and probably accounts for increased cellular levels and utilization of AdoMet. Immunochemical analyses with a monoclonal antibody specific for the alpha/alpha' subunits of human lymphocyte AdoMet synthetase showed that these increases in catalytic activity were not associated with increases in immunoreactive protein. The ratio of catalytic activity to immunoreactivity in stimulated cells was 4-fold higher than in unstimulated controls and almost identical to that found in extracts from the human B-lymphocyte line WI-L2. Unstimulated PBM appear to contain substantial amounts of AdoMet synthetase alpha/alpha' subunit with reduced or absent catalytic activity, which can be activated by PHA-stimulation.

Differential effect on polyamine metabolism in mitogen- and superantigen-activated human T-cells.

Polyamines are important for regulation of lymphocyte differentiation and proliferation. Mitogens induce synthesis of ornithine decarboxylase (ODC), the rate limiting enzyme in polyamine biosynthesis. Since mitogens stimulate T-cells by non-physiological routes, the role of polyamine metabolism in T-cell receptor (TCR)-mediated T-cell activation has not been adequately evaluated. The effect of phytohemagglutinin (PHA) and staphylococcal enterotoxin B (SEB) on T-cell ODC and polyamine synthesis was compared. ODC activity was 6-11-fold higher in PHA compared to SEB stimulated T-cells. These differences were not attributed to differences in the magnitude of T-cell proliferation. Kinetics of ODC and polyamine synthesis were also different in PHA- and SEB-stimulated T-cells. In PHA-stimulated cells ODC levels and the induction of putrescine and spermidine synthesis peaked 6 h prior to peak IL-2 production, while in SEB-stimulated cells, ODC levels and polyamine synthesis peaked 6-12 h after IL-2 production. Differences in the temporal relationship between IL-2 production and polyamine induction in mitogen- versus superantigen-stimulated cells may account for the significant inhibition of the proliferative response by alpha-difluoromethylornithine following PHA but not SEB stimulation. Polyamine metabolism is regulated differently in T-cells stimulated via TCR engagement than with polyclonal mitogens.

Distinct patterns of protein binding to the MAT2A promoter in normal and leukemic T cells.

The metabolism of S-adenosylmethionine (AdoMet), a key molecule in regulating T cell differentiation and proliferation, is different in normal and leukemic T cells. To delineate the basis for these differences we studied the transcriptional regulation of human methionine adenosyltransferase II (MAT II), which catalyzes AdoMet synthesis in these cells. Recently, we identified an Sp1 site in the proximal promoter of the MAT2A gene, which encodes the alpha2 catalytic subunit of MAT II, that is essential for the in vitro and in vivo promoter activity in Jurkat leukemic T cells, and that involves binding of the nuclear factors Sp2 and Sp3, but not Sp1. Here, the in vitro and in vivo activity of the proximal MAT2A promoter in normal resting, PHA-stimulated, and leukemic human T cells was compared. Significantly different patterns of protein factor interaction in the proximal region of the MAT2A promoter were found. Normal resting and activated T cells produced complexes of significantly lower molecular weight than those formed in leukemic T cells. Supershift studies coupled with analysis of proteins bound to the proximal promoter suggest that low levels of expression of Sp2 and Sp3 in normal T cells may be responsible for the difference in the in vitro promoter activity between normal and leukemic cells. Mutation of the key Sp1 site equally reduced the in vivo promoter activity in normal and malignant T cells; by contrast, it had significantly different effects on protein-DNA interactions in normal and leukemic T cells. Together, the data support the idea that differences in protein-DNA interactions may contribute to significant differences in MAT2A regulation in normal and malignant cells.

Characterization of distinct forms of methionine adenosyltransferase in nucleated, and mature human erythrocytes and erythroleukemic cells.

Two peaks of methionine adenosyltransferase (MAT) activity from human erythrocytes were partially purified on a DEAE-cellulose column. Using anti-MAT antibodies, a 60 kDa form of MAT, referred to as rho was identified in peak I. Although rho represented the major MAT protein in crude erythrocyte extracts, the enzyme was very labile and accounted for only 6% of the total MAT activity. Peak II enzyme was stable, and consisted of the previously described catalytic alpha (53 kDa) subunit and the beta subunit (38 kDa), both of which are found in activated human lymphocytes and leukemic cells of lymphoid origin. Mature normal and polycythemic erythrocytes contained predominantly rho as the major MAT protein, while nucleated erythrocytes and reticulocytes contained predominantly the lambda (68 kDa), the major form found in resting human lymphocytes. Human erythroleukemic cells (HEL 92.1.7) contained the alpha, alpha' and beta subunits of MAT, and in this regard was indistinguishable from MAT found in activated lymphocytes and leukemic cells of lymphoid origin (Jurkat). Since rho was generated during the incubation of extracts from resting lymphocytes, which contain predominantly lambda, in the absence of protease inhibitors; the rho form of MAT appears to be derived from the lambda form by proteolytic cleavage. The data indicate that distinct forms of MAT are present at different stages of erythrocyte maturation and reveal the presence of a new form of MAT with reduced activity compared to previously described forms.

Antigenic conservation of primary structural regions of S-adenosylmethionine synthetase.

Although the physical and kinetic properties of S-adenosylmethionine (AdoMet) synthetases from different sources are quite different, it appears that these enzymes have structurally or antigenically conserved regions as demonstrated by studies with AdoMet synthetase specific antibodies. Polyclonal anti-human lymphocyte AdoMet synthetase crossreacted with enzyme from rat liver (beta isozyme), Escherichia coli and yeast. In addition, polyclonal anti-E. coli enzyme and antibodies to synthetic peptides copying several regions of the yeast enzyme reacted with the human gamma and rat beta isozymes. Antibodies to yeast SAM1 encoded protein residues 6-21, 87-113 and 87-124 inhibited the activity of human lymphocyte AdoMet synthetase, while antibodies to residues 272-287 had no effect on the enzyme activity. Our results suggest that these conserved regions may be important in enzyme activity.

HLA class II associations with rheumatic heart disease are more evident and consistent among clinically homogeneous patients.

BACKGROUND: Discrepancies in reported HLA class II associations with rheumatic heart disease (RHD) may have been due to inaccuracies of serological typing reagents and/or lack of defined clinical classification of patients analyzed. The molecular association between HLA and RHD was investigated in patients with defined clinical outcome. METHODS AND RESULTS: Class II allele/haplotype distribution was determined in 2 groups of RHD patients (n=88) and a control group (n=59). Patients were divided into the mitral valve disease (MVD) category (ie, those with mitral regurgitation with or without mitral stenosis) and the multivalvular lesions (MVL) category, with impairment of aortic and/or tricuspid valves in addition to mitral valve damage. The MVD category (n=65) accounted for 74% of patients and included significantly fewer recurrent RF episodes compared with MVL patients (P=0.002). CONCLUSIONS: Significant increases in DRB1*0701 and DQA1*0201 alleles and DRB1*0701-DQA1*0201 haplotypes were found in patients. Removal of the MVL patients from analysis increased the strength of HLA associations among the MVD sample. The frequency of DQA1*0103 allele was decreased and the DQB1*0603 allele was absent from the patient group, suggesting that these alleles may confer protective effects against RHD. DQ alleles in linkage disequilibrium with DR alleles appear to influence risk/protection effect: whereas the DRB1*13-DQA1*0501-3-DQB1*0301 haplotype showed a trend toward risk, the DRB1*13-DQA1*0103-DQB1*0603 haplotype was absent in the RHD sample. Our data indicate that certain class II alleles/haplotypes are associated with risk or protection from RHD and that these associations appear to be stronger and more consistent when analyzed in patients with relatively more homogeneous clinical manifestations.

Superantigen-based immunotherapy: a phase I trial of PNU-214565, a monoclonal antibody-staphylococcal enterotoxin A recombinant fusion protein, in advanced pancreatic and colorectal cancer.

PURPOSE: To establish the maximum-tolerated dose (MTD) and define the toxicities of a single-dose infusion of PNU-214565, a recombinant Escherichia coli-derived fusion protein of Staphylococcal enterotoxin A (SEA) and the Fab-fragment of the C242 monoclonal antibody in patients with advanced colorectal and pancreatic carcinomas. To investigate the capability of PNU-214565 to induce a superantigen (SAg) response resulting in cytokine production and tumor regression. PATIENTS AND METHODS: Twenty-one patients (age range, 39 to 76 years; median, 64; 12 men, nine women; 18 colorectal, three pancreatic cancers) were treated with a single 3-hour infusion of PNU-214565, with doses ranging from 0.01 to 1.5 ng/kg. All patients had prior chemotherapy and a good performance status Eastern Cooperative Oncology Group [ECOG] performance status [PS] = 0 [n = 10]; PS = 1 [n = 11]), 10 had prior radiation, and 18 had prior surgery. RESULTS: Fever and hypotension were the most common toxicities. Fever of any grade occurred in 16 of 21 patients (76%): four of 21 (19%) with grade 2 and two of 21 (9.5%) with grade 3. Hypotension of any grade occurred in 13 of 21 (62%): four of 21 with grade 2 and one of 21 (5%) with grade 3. Interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF alpha) induction correlated with toxicity. In the two patients with grade 3 fever, peak IL-2 and TNF alpha levels were 2.9 IU/mL and 165 pg/mL, and 8.3 IU/mL and 245 pg/mL, respectively. Transient, > or = 50% decreases in circulating monocytes were observed in 17 of 21 patients as early as 0.5 hours (median time, 2 hours) from the start of infusion. Decreases (mean 33%) in circulating lymphocytes were observed in seven of 21 patients. All three patients with grade 3 toxicity were treated at the 0.5-ng/kg dose. The significance of baseline anti-SEA, human antimouse antibody (HAMA), CA242-soluble antigen levels, and T-cell receptor variable beta region (TCR V beta) subsets and histocompatibility leukocyte antigen-DR (HLA-DR) genotypes was assessed as possible predictors of toxicity. All toxicities were transient and easily managed. No grade 3 toxicity occurred at the higher dose levels. CONCLUSION: PNU-214565, a SAg-based tumor targeted therapy, is safe when given as a single 3-hour infusion at doses up to 1.5 ng/kg. The MTD for a single dose was not determined. The safety of a repeated dose schedule is currently under investigation, beginning with doses determined to be safe in this trial.