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The efficacy and safety of valsartan were studied in 90 children (mean age: 3.2 years; 60% male; 30% black) with systolic blood pressure (SBP) > or =95th percentile. Nineteen percent received valsartan in addition to previous antihypertensive therapy. Subjects were randomly assigned to low-, medium-, or high-dose valsartan for 2 weeks (phase 1) and then reassigned randomly to placebo or to remain on the same valsartan dose for 2 additional weeks (phase 2). After this, subjects were enrolled into a 52-week, open-label phase during which valsartan was dosed to achieve SBP <95th percentile. Statistically significant reductions in SBP and diastolic blood pressure of approximately 8.5 mm Hg and 5.7 mm Hg, respectively, were observed at the end of phase 1 in all of the valsartan dose groups. SBP and diastolic blood pressure were also significantly lower during phase 2 in valsartan recipients compared with placebo recipients. SBP <95th percentile was achieved in 77.3% of subjects during the open-label phase. Adverse events were minor and occurred at similar frequencies in each of the 3 dose groups in phase 1 and at equal frequencies in the valsartan and placebo arms in phase 2. Serious adverse events and drug-related adverse events occurred infrequently during both the double-blind (2.2% and 5.6%, respectively) and open-label (14.8% and 6.8%, respectively) portions of the study. Valsartan treatment had no demonstrable negative effects on growth and development. In this study, the first trial of an antihypertensive agent conducted in children <6 years of age, valsartan effectively lowered SBP and diastolic blood pressure compared with placebo.

We formulated a novel cellular automata (CA) model for HIV dynamics and drug treatment. The model is built upon realistic biological processes, including the virus replication cycle and mechanisms of drug therapy. Viral load, its effect on infection rate, and the role of latently infected cells in sustaining HIV infection are among the aspects that are explored and incorporated in the model. We assume that the calculation of the number of cells in the neighborhood which influences the center cell's state is based on the viral load. This variable-cell neighborhood enables the simulation of an infection rate that is correlated to the viral load. This approach leads to a new and flexible way of modeling HIV dynamics and allows for the simulation of different antiretroviral drug treatments based on their individual and combined effects. The results of the simulation show the three phases of HIV dynamics (acute, chronic, and AIDS) and the additional drug response phase when drug treatment is added. The dynamics from the model qualitatively match clinical data. Drug treatment combinations with reverse transcriptase inhibitors and protease inhibitors are simulated using various drug efficacies. The results indicate that the model can be very useful in evaluating different drug therapy regimens.

Over the past 20 months, reports claiming the generation of induced pluripotent stem (iPS) cells with characteristics identical to those of embryonic stem (ES) cells from nonembryonic tissue have captured great attention in both the scientific community and the general public. In the light of the continuing controversy over the use of ES cells, these reports have profound ramifications. This review calls into question the validity of many claims made in these reports--claims that have led to the rapid and premature acceptance of using iPS cells as a viable alternative to using normal stem cells for regenerative therapy. How convincing is the evidence supporting the various claims made for the iPS cells? Are there other more plausible explanations for the same observations? What are these iPS cells? Are they really safe for therapeutic use? Should the iPS technique be considered, in the absence of any direct evidence for induction and reprogramming, as a realistic alternative for somatic cell nuclear transfer (SCNT) to generate ES-like cells? This review attempts to encourage reflections on and offer alternative views for key aspects of iPS cells and studies.

Background: Occurrence of tumors at multiple sites is a hallmark of malignant cancers and contributes to the high mortality of cancers. The formation of multi-site cancers (MSCs) has conventionally been regarded as a result of hematogenous metastasis. However, some MSCs may appear as unusual in the sense of vascular dissemination pattern and therefore be explained by alternative metastasis models or even by non-metastatic independent formation mechanisms., Results: Through literature review and incorporation of recent advance in understanding aging and development, we identified two alternative mechanisms for the independent formation of MSCs: 1) formation of separate tumors from cancer-initiating cells (CICs) mutated at an early stage of development and then diverging as to their physical locations upon further development, 2) formation of separate tumors from different CICs that contain mutations in some convergent ways. Either of these processes does not require long-distance migration and/or vascular dissemination of cancer cells from a primary site to a secondary site. Thus, we classify the formation of these MSCs from indigenous CICs (iCICs) into a new mechanistic category of tumor formation - multigenesis., Conclusion: A multigenesis view on multi-site cancer (MSCs) may offer explanations for some "unusual metastasis" and has important implications for designing expanded strategies for the diagnosis and treatment of cancers.

Combination immunotherapy with anti-CD20 and anti-CD22 mAbs shows promising activity in non-Hodgkin lymphoma. Therefore, bispecific mAbs (bsAbs) were recombinantly constructed from veltuzumab (humanized anti-CD20) and epratuzumab (humanized anti-CD22) and evaluated in vitro and in vivo. While none of the parental mAbs alone or mixed had notable antiproliferative activity against Burkitt lymphoma cells when not cross-linked, the bsAbs [eg, anti-CD20 IgG-anti-CD22 (scFv)(2)] were inhibitory without cross-linking and synergistic with B-cell antigen (BCR)-mediated inhibition. The bsAbs demonstrated higher antibody-dependent cellulary cytoxicity (ADCC) activity than the parental mAbs, but not complement-dependent cytoxicity (CDC) of the parental CD20 mAb. Cross-linking both CD20 and CD22 with the bsAbs resulted in the prominent redistribution of not only CD20 but also CD22 and BCR into lipid rafts. Surprisingly, appreciable translocation of CD22 into lipid rafts was also observed after treatment with epratuzumab. Finally, the bsAbs inhibited Daudi lymphoma transplant growth, but showed a significant advantage over the parental anti-CD20 mAb only at the highest dose tested. These results suggest that recombinantly fused, complementary, bispecific, anti-CD20/22 antibodies exhibit functional features distinct from their parental antibodies, perhaps representing new candidate therapeutic molecules.

Background: Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) is an outcome study investigating aggressive antihypertensive combination treatment. It has achieved a larger fraction of overall patients with blood pressure (BP) <140/90 mmHg (73.3%) and diabetic patients <130/80 mmHg (43.3%) at 12 months of follow-up than any other large outcomes trial. We have analyzed baseline predictors of BPs and BP control at 12 months., Methods: Blinded baseline and 12-month BP was available in 10,173 patients of whom 6132 had diabetes. Univariate and multivariate logistic regression models were used for BP control at 12 months; simple and multiple regression models were used for absolute BP value at 12 months. A stepwise procedure was used to select significant predictors in multivariate analyses., Results: Mean (SD) BP fell from 145.5/80.2 mmHg (18.2/10.7 mmHg) at randomization to 132.7/74.7 mmHg (16/9.6 mmHg) at 12 months. The main baseline predictors of achieving BP control were region (USA), Caucasian race and taking lipid-lowering drugs. The predictors of uncontrolled BP were higher baseline systolic BP values, more previous antihypertensive medications, proteinuria and previous thiazide use., Conclusion: Patients in the USA, Caucasians and patients taking lipid-lowering therapy were most likely to reach BP targets with combination therapy. Strong predictors of uncontrolled hypertension were more severe hypertension, an established need for more antihypertensive drugs and target organ damage.

Background: This study compared the efficacy and safety of amlodipine/benazepril (10/40 mg/day and 10/20 mg/day) with amlodipine 10 mg/day in patients whose blood pressure (BP) was not adequately controlled with amlodipine monotherapy., Methods: After a lead-in period with amlodipine monotherapy, 812 non-responder patients (mean sitting diastolic BP > or =95 mmHg) were randomized to one of three treatment groups. Ambulatory BP monitoring was conducted in 276 patients., Results: Treatment with amlodipine/benazepril 10/40 mg/day and 10/20 mg/day resulted in a decrease of mean sitting systolic and mean sitting diastolic BP by 13.3/12.7 mmHg and 12.1/11.6 mmHg, respectively, compared with monotherapy (6.6/8.5 mmHg) (p < 0.0001). Both combinations resulted in more responders than monotherapy (74% and 65% vs. 54%; p < 0.0001 and p < 0.0085, respectively). Amlodipine/benazepril 10/40 mg/day and 10/20 mg/day decreased ambulatory systolic and diastolic BP by 9.9/6.7 mmHg and 7.4/5.2 mmHg compared with monotherapy (p < 0.0001). The incidence of pedal edema was lower in the amlodipine/benazepril combinations compared with monotherapy (4.5%, 5.5% vs. 9.2%, respectively, p=NS). No significant metabolic side-effects were noted among the combination groups., Conclusion: Amlodipine/benazepril combinations were well tolerated and resulted in significant BP reductions and better BP responder rates than amlodipine monotherapy.

We have generated mutator strains of Bacillus anthracis Sterne by using directed gene knockouts to investigate the effect of deleting genes involved in mismatch repair, oxidative repair, and maintaining triphosphate pools. The single-knockout strains are deleted for mutS, mutY, mutM, or ndk. We also made double-knockout strains that are mutS ndk or mutY mutM. We have measured the levels of mutations in the rpoB gene that lead to the Rif(r) phenotype and have examined the mutational specificity. In addition, we examined the mutational specificity of two mutagens, 5-azacytidine and N-methyl-N'-nitro-N-nitroso-guanidine. The mutY and mutM single knockouts are weak mutators by themselves, but the combination of mutY mutM results in very high mutation rates, all due to G:C --> T:A transversions. The situation parallels that seen in Escherichia coli. Also, mutS knockouts are strong mutators and even stronger in the presence of a deletion of ndk. The number of sites in rpoB that can result in the Rif(r) phenotype by single-base substitution is more limited than in certain other bacteria, such as E. coli and Deinococcus radiodurans, although the average mutation rate per mutational site is roughly comparable. Hotspots at sites with virtually identical surrounding sequences are organism specific.

Background: ACCOMPLISH is a "new-generation" hypertension trial assessing single-tablet combination therapy for initial treatment of high-risk hypertension. At baseline, 97% of subjects were treated with anti-hypertensive medication at entry, but only 37% of participants had blood pressure (BP) control (<140/90 mmHg). Single-tablet combination therapy may improve control rates., Methods: The mean BP change from baseline at the end of 6 months (the time point when subjects should have had all of the drug titrations to achieve BP control) was examined for 10,704 randomized patients. Within-group changes were examined using t-tests. Comparisons between subgroups were made using analysis of variance (ANOVA) and covariance (ANCOVA)., Results: Mean (+/-SD) BP fell from 145+/-18/80+/-11 mmHg at randomization to 132+/-16/74+/-10 mmHg. The 6-month BP control rate was 73% in the overall trial (78% in the US), 43% in diabetics and 40% in patients with renal disease. Of the patients uncontrolled, 61% were not on maximal medications, suggesting potential increases in control rates. Serious hypotensive events occurred in 1.8% of participants., Conclusion: ACCOMPLISH BP control rates are the highest of any multi-national trial to date. Whereas current guidelines recommend combination therapy only for stage 2 hypertension, in this trial it is expedient and safe for both stage 1 and 2 hypertension.

ACCOMPLISH is the first trial designed to compare the effects on major fatal and non-fatal cardiovascular endpoints of two forms of antihypertensive combination therapy: benazepril plus hydrochlorothiazide and amlodipine plus benazepril in hypertensive patients at high cardiovascular risk. Enrollment for this trial is now complete and this report describes the clinical characteristics of the study cohort. Patients with hypertension and a previous history of cardiovascular events, strokes or diabetes mellitus were randomized to double-blind treatment with either of the two combination regimens. The data in this report detail the clinical history and demographic characteristics in patients immediately prior to randomization to study drugs. A total of 11,454 patients were randomized. Mean age (+/-SD) was 68.4+/-6.9 years, 60% were men, and 1360 (12%) were African American. Mean body mass index (BMI) was 31.0+/-6.3 kg/m(2). At study entry, 46% of patients had a history of acute coronary syndromes, coronary artery bypass grafts or percutaneous coronary interventions; 13% had a history of stroke. A history of diabetes mellitus was reported in 6928 (60%) of patients. Mean blood pressure at baseline (on prior hypertension therapy) was 145.4/80.0 mmHg; only 38% of patients had a BP less than 140/90 mmHg. Overall, 97% of patients had received previous antihypertensive treatment (74% on at least two drugs); 53% were on oral diabetes therapy or insulin, 68% on anti-lipid therapy and 63% on anti-platelet agents. In summary, the ACCOMPLISH trial has recruited hypertensive patients at high risk of cardiovascular morbidity and mortality. It is noteworthy that the mean BMI of 31 in this cohort is clearly above the accepted diagnostic criterion of obesity and that 60% of patients are diabetic, possibly reflecting secular trends in clinical disease.

Alpha-2,3-sialyltransferase (Lst) is expressed on the outer membrane of Neisseria gonorrhoeae and Neisseria meningitidis and sialylates surface lipooligosaccharide (LOS), facilitating resistance to complement-mediated killing. The enzyme is constitutively expressed from a single gene (lst) and does not undergo antigenic or phase variation. We observed that Triton X-100 extracts of N. gonorrhoeae strain F62 contain about fivefold more sialyltransferase (Stase) activity than extracts of N. meningitidis strain MC58 [symbol: see text]3 a serogroup B acapsulate mutant. We confirmed and expanded upon this observation by showing that extracts of 16 random N. gonorrhoeae isolates contain various amounts of Stase activity, but, on average, 2.2-fold-more Stase activity than extracts of 16 N. meningitidis clinical isolates, representing several serogroups and nongroupable strains. Northern and real-time reverse transcription-PCR analysis of lst transcript levels in N. gonorrhoeae and N. meningitidis revealed that N. gonorrhoeae strains express more lst transcript than N. meningitidis strains. Although transcript levels correlate with average Stase activity observed in the two species, there was not a direct correlation between lst transcript levels and Stase activity among individual isolates of each species. Comparison of lst upstream (5'lst) regions of N. gonorrhoeae and N. meningitidis revealed striking sequence differences characteristic of the two pathogens. N. gonorrhoeae 5'lst regions possess 30-bp and 13-bp elements present as single elements or as tandem repeats that exist only as single elements in the 5'lst regions of N. meningitidis isolates. In addition, the 5'lst regions of N. meningitidis strains have 105-bp transposon-like Correia elements which are absent in N. gonorrhoeae. Chromosomal N. gonorrhoeae 5'lst::lacZ translational fusions expressed 4.75 +/- 0.09-fold (n = 4) higher beta-galactosidase (beta-gal) activity than N. meningitidis 5'lst::lacZ fusions in a host-independent manner, indicating differential expression is governed at least in part by sequence variations in the 5'lst regions. Reporter fusion assays and promoter-mapping analysis revealed that N. gonorrhoeae and N. meningitidis use different promoters with different strengths to transcribe lst. In N. gonorrhoeae, a strong sigma 70 promoter 80 bp upstream of the translational start site is used to transcribe lst, whereas this promoter is inactive in N. meningitidis. In N. meningitidis, a weak sigma 70 promoter at the 3' terminus of a 105-bp Correia repeat-enclosed element 99 bp upstream of the translational start site is used to transcribe lst. We conclude that differential Stase expression between N. gonorrhoeae and N. meningitidis is due at least in part to differential lst gene transcription.

To examine factors influencing long-term ozone (O3) exposures by children living in urban communities, the authors analyzed longitudinal data on personal, indoor, and outdoor O3 concentrations, as well as related housing and other questionnaire information collected in the one-year-long Harvard Southern California Chronic Ozone Exposure Study. Of 224 children contained in the original data set, 160 children were found to have longitudinal measurements of O3 concentrations in at least six months of 12 months of the study period. Data for these children were randomly split into two equal sets: one for model development and the other for model validation. Mixed models with various variance-covariance structures were developed to evaluate statistically important predictors for chronic personal ozone exposures. Model predictions were then validated against the field measurements using an empirical best-linear unbiased prediction technique. The results of model fitting showed that the most important predictors for personal ozone exposure include indoor O3 concentration, central ambient O3 concentration, outdoor O3 concentration, season, gender, outdoor time, house fan usage, and the presence of a gas range in the house. Hierarchical models of personal O3 concentrations indicate the following levels of explanatory power for each of the predictive models: indoor and outdoor O3 concentrations plus questionnaire variables, central and indoor O3 concentrations plus questionnaire variables, indoor O3 concentrations plus questionnaire variables, central O3 concentrations plus questionnaire variables, and questionnaire data alone on time activity and housing characteristics. These results provide important information on key predictors of chronic human exposures to ambient O3 for children and offer insights into how to reliably and cost-effectively predict personal O3 exposures in the future. Furthermore, the techniques and findings derived from this study also have strong implications for selecting the most reliable and cost-effective exposure study design and modeling approaches for other ambient pollutants, such as fine particulate matter and selected urban air toxics.

Objective: Tegaserod is a 5-HT(4) receptor partial agonist that increases peristaltic activity of the intestinal tract. It is approved for the treatment of patients with irritable bowel syndrome with constipation (IBS-C). IBS is a chronic gastrointestinal disorder of function that is reported to be associated with an increased incidence of abdominal surgery including cholecystectomy. The effect of tegaserod on nongut digestive organs, such as the gallbladder and biliary tract, has not been previously investigated. Therefore, this study aimed to evaluate the effects of tegaserod on gallbladder contractility and on functional status of the sphincter of Oddi during both the interdigestive and the digestive periods in healthy female subjects and in female patients with IBS-C., Methods: During a 6-wk, double-blind, placebo-controlled crossover study, gallbladder contractility and concomitant change in luminal diameter of the common hepatic duct (CHD) and the common bile duct (CBD, both proximal and distal) in response to a standard liquid meal were quantified using real-time ultrasonography. Changes in luminal diameter of the CHD and the CBD were used as a surrogate marker for sphincter of Oddi function. Ultrasound measurements were conducted every 15 min from 45 min before, to 60 min after the test meal to observe the impact of tegaserod on gallbladder volume and any concomitant change in the diameters of the CHD and the CBD that developed in response to gallbladder contraction. The ultrasound measurements of gallbladder contractility, along with the CHD and the CBD diameters, were repeated after each of the two 2-wk periods of treatment with tegaserod or placebo. The recommended dose of tegaserod (6 mg b.i.d.) for IBS-C patients was used in healthy female subjects (n = 13) and female patients with IBS-C (n = 20). Twice this dose (12 mg b.i.d.) was also evaluated in an additional 20 female patients with IBS-C. Statistical evaluations were conducted using a two-sided analysis of variance (ANOVA)., Results: Gallbladder contractility variables including ejection fraction, ejection rate and ejection period, fasting and residual volume, and maximal emptying, were similar after 2 wk of treatment with tegaserod 6 mg b.i.d. and placebo in healthy female subjects and female patients with IBS-C. There were no significant changes in the luminal diameters of the CHD or the CBD after tegaserod compared to placebo in any cohort. Additionally, no significant dilation (> or =7 mm in diameter) of the CHD or CBD was observed during maximal gallbladder emptying. Similar results were also observed when tegaserod was given at 12 mg b.i.d. in patients with IBS-C. Tegaserod treatment had no significant effect on plasma CCK concentration in response to the test meal. No significant abdominal pain or unexpected adverse events were reported during the study., Conclusions: This study showed no significant pharmacodynamic effect of tegaserod on gallbladder contractility or on CBD and CHD diameters as a surrogate marker of sphincter of Oddi function during both the interdigestive (fasting) and the digestive (postprandial) periods in healthy female subjects and female patients with IBS-C.

Purpose: A new humanized anti-CD20 monoclonal antibody (MAb), IMMU-106, was evaluated to elucidate its action as an antilymphoma therapeutic, as a single agent, and in combination with the anti-CD22 MAb, epratuzumab., Experimental Design: Antiproliferative effects, apoptotic effects, and the ability of IMMU-106 to mediate complement-mediated cytotoxicity and antibody-dependent cellular cytotoxicity on a panel of non-Hodgkin's lymphoma (NHL) cell lines were compared with the chimeric anti-CD20 MAb, rituximab, and evaluated in light of the various levels of antigen expression by the cell lines. In vivo therapy studies were performed in SCID mice bearing disseminated Raji lymphoma., Results: The mechanisms of cytotoxicity of IMMU-106 were found to be similar to rituximab, and include direct apoptosis, antibody-dependent cellular cytotoxicity, and complement-mediated cytotoxicity. IMMU-106 was also found to be very similar to rituximab in terms of antigen-binding specificity, binding avidity, and dissociation constant. Treatment of Raji-bearing SCID mice with IMMU-106 yielded median survival increases of up to 4.2-fold compared with control mice. Survival in mice treated with IMMU-106 plus epratuzumab was compared with IMMU-106 treatment alone. Although the combined treatment did not improve median survival, an increased proportion of long-term survivors was observed. An enhanced antiproliferative effect was also observed in vitro in SU-DHL-6 cells when IMMU-106 was combined with epratuzumab. These findings are consistent with the up-regulation of CD22 expression observed after pretreatment of NHL cells in vitro with CD20 MAb (IMMU-106)., Conclusions: It is expected that in humans IMMU-106 should be at least as effective as rituximab and, due to its human framework construction, it may exhibit different pharmacokinetic, toxicity, and therapy profiles. In addition, it may be possible to enhance efficacy by combination therapy comprised of anti-CD20 and other B-cell lineage targeting MAbs, such as epratuzumab. The current results emphasize that in vitro as well as in vivo studies with many of the NHL cell lines were generally predictive of the known activity of anti-CD20 MAbs in NHL patients, as well as the enhanced efficacy of epratuzumab combined with rituximab observed in early clinical trials.

Five bacterial strains were isolated from anaerobic enrichment cultures that had originated from inoculations with samples collected from the deep subsurface environments of the millions-of-years-old, geologically and hydrologically isolated Piceance Basin in Colorado. Small-subunit rRNA gene-based analyses indicated that all of these bacteria were closely related to Thermoanaerobacter ethanolicus, with similarities of 99.4 to 99.5%. Three isolates (X513, X514, and X561) from the five bacterial strains were used to examine physiological characteristics. These thermophilic bacteria were able to use acetate, glucose, hydrogen, lactate, pyruvate, succinate, and xylose as electron donors while reducing Fe(III), cobalt(III), chromium(VI), manganese(IV), and uranium(VI) at 60 degrees C. One of the isolates (X514) was also able to utilize hydrogen as an electron donor for Fe(III) reduction. These bacteria exhibited diverse mineral precipitation capabilities, including the formation of magnetite (Fe(3)O(4)), siderite (FeCO(3)), rhodochrosite (MnCO(3)), and uraninite (UO(2)). The gas composition of the incubation headspace and the ionic composition of the incubation medium exerted profound influences on the types of minerals formed. The susceptibility of the thermophilic Fe(III)-reducing cultures to metabolic inhibitors specific for ferric reductase, hydrogenase, and electron transport indicated that iron reduction by these bacteria is an enzymatic process.

Whole genome sequences of Neisseria meningitidis strains Z2491 and MC58 and Neisseria gonorrhoeae FA1090 were analyzed for Correia repeats (CR) and CR-enclosed elements (CREE). A total of 533, 516, and 256 copies of CR and 270, 261, and 102 copies of CREE were found in these three genomes, respectively. The lengths of CREE range from 28 to 348 bp, and the lengths of multicopy CREE appear mainly in the ranges of 154 to 156 bp and 105 to 107 bp. The distribution of CREE lengths is similar between the two N. meningitidis genomes, with a greater number of 154- to 156-bp CREE (163 and 152 copies in N. meningitidis strain Z2491 and N. meningitidis strain MC58, respectively) than 105- to 107-bp CREE (72 and 77 copies). In the N. gonorrhoeae strain FA1090 genome there are relatively more 105- to 107-bp CREE (51 copies) than 154- to 156-bp CREE (36 copies). The genomic distribution of 107-bp CREE also shows similarity between the two N. meningitidis strains (15 copies share the same loci) and differences between N. meningitidis strains and N. gonorrhoeae FA1090 (only one copy is located in the same locus). Detailed sequence analysis showed that both the terminal inverted repeats and the core regions of CREE are composed of distinct basic sequence blocks. Direct TA dinucleotide repeats exist at the termini of all CREE. A survey of DNA sequence upstream of the sialyltransferase gene, lst, in several Neisseria isolates showed that 5 N. meningitidis strains contain a 107-bp CREE in this region but 25 N. gonorrhoeae strains show an exact absence of a 105-bp sequence block (i.e., the 107-bp CREE without a 5' TA dinucleotide) in the same region. Whole-genome sequence analysis confirmed that this 105-bp indel exists in many homologous 107-bp CREE loci. Thus, we postulate that all CREE are made of target TA with indels of various lengths. Analysis of 107-bp CREE revealed that they exist predominantly in intergenic regions and are often near virulence, metabolic, and transporter genes. The abundance of CREE in Neisseria genomes suggests that they may have played a role in genome organization, function, and evolution. Their differential distribution in different pathogenic Neisseria strains may contribute to the distinct behaviors of each Neisseria species.

Background: Anti-CD3 immunotoxins are broad-spectrum immunosuppressive agents in a wide range of organ transplantation animal models with potential use in eliciting antigen-specific tolerance. However, the anti-CD3 immunotoxins used in animal studies do not cross-react with human T cells, limiting extrapolation to humans and hindering clinical development., Methods: Three anti-human CD3-directed immunotoxins, DT389-scFv(UCHT1), scFv(UCHT1)-PE38, and UCHT1-CRM9, were compared in vitro and in transgenic mice, tg(epsilon)600+/-, that have T cells expressing both human and murine CD3epsilon antigens., Results: These immunotoxins were extraordinarily potent in vitro against human or transgenic mouse T cells, with IC50 values in cellular assays ranging from pM to fM. Systemic administration of these immunotoxins dose-dependently depleted >99% of tg(epsilon)600+/- lymph node and spleen T cells in vivo. Depletion was specific for T cells. The loss of the concanavalin A-induced, but not the lipopolysaccharide-induced, splenic proliferative response from immunotoxin-treated animals further demonstrated specific loss of T-cell function. Immunotoxin treatment prolonged fully allogeneic skin graft survival in tg(epsilon)600+/- recipients to 25 days from 10 days in untreated animals. T-cells recovered to approximately 50% of normal levels after approximately 22 days in animals with or without skin grafts; T-cell recovery correlated with skin graft rejection. All three immunotoxins elicited >100 day median survival of fully allogeneic heterotopic heart grafts. By 100 days, T cells recovered to normal numbers in these animals, but the grafts showed chronic rejection., Conclusion: These immunotoxins profoundly deplete T cells in vivo and effectively prolong allogeneic graft survival.

Graft vessel disease (GVD) is a major cause of graft loss after the first year following transplantation. GVD is a complex, multifunctional process that involves immunological as well as non-immunological events such as ischaemia/reperfusion injury. An important target cell to interfere with the development of GVD is the smooth muscle cell (SMC). Somatostatin (SRIF) analogues have been shown previously to inhibit the proliferation of SMC in vitro and in vivo. We provide evidence that Sandostatin, an octapeptide SRIF analogue that is known to have anti-proliferative properties on SMC proliferation, inhibits vascular remodelling in a rat angioplasty model. Furthermore, in two allotransplantation models, Sandostatin effectively interferes with the development of signs of chronic rejection/GVD. The role of the different SRIF receptor subtypes in chronic graft rejection is currently under investigation.