Characterization of efficacy and safety of pathogen inactivated and quarantine plasma in routine use for treatment of acquired immune thrombotic thrombocytopenic purpura.

BACKGROUND: Auto-immune thrombotic thrombocytopenic purpura (TTP) is a morbid multi-organ disorder. Cardiac involvement not recognized in initial disease descriptions is a major cause of morbidity. Therapeutic plasma exchange (TPE) requires exposure to multiple plasma donors with risk of transfusion-transmitted infection (TTI). Pathogen inactivation (PI) with amotosalen-UVA, the INTERCEPT Blood System for Plasma (IBSP) is licensed to reduce TTI risk. METHODS: An open-label, retrospective study evaluated the efficacy of quarantine plasma (QP) and IBSP in TTP and defined treatment emergent cardiac abnormalities. Medical record review of sequential patient cohorts treated with QP and IBSP characterized efficacy by remission at 30 and 60 days (d) of treatment, time to remission, and volume (L/kg) of plasma required. Safety outcomes focused on cardiac adverse events (AE), relapse rates, and mortality. RESULTS: Thirty-one patients (18 IBSP and 13 QP) met study criteria for auto-immune TTP. The proportions (%) of patients in remission at 30 d (IBSP = 61·1, QP = 46·2, P = 0·570) and 60 d (IBSP = 77·8, QP = 76·9, P = 1·00) were not different. Median days to remission were less for IBSP (15·0 vs. 24·0, P = 0·003). Relapse rates (%) 60 d after remission were not different between cohorts (IBSP = 7·1, QP = 40·0, P = 0·150). ECG abnormalities before and during TPE were frequent; however, cardiac AE and mortality were not different between treatment cohorts. CONCLUSIONS: Cardiac and a spectrum of ECG findings are common in TTP. In this study, IBSP and QP had similar therapeutic profiles for TPE.

Patient outcomes and amotosalen/UVA-treated platelet utilization in massively transfused patients.

BACKGROUND: Amotosalen/UVA-treated platelet concentrates (PCs) have demonstrated efficacy for treating and preventing bleeding in clinical trials and in routine use; however, most studies were performed in haematology/oncology patients. We investigated efficacy during massive transfusion (MT) in general hospitalized patients. METHODS: Universal amotosalen/UVA treatment (INTERCEPT Blood System) of platelets was introduced at a large Austrian medical centre. We performed a retrospective cohort analysis comparing component use, in-hospital mortality and length of stay after MT that included platelet transfusion, for two periods (21 months each) before and after implementation. RESULTS: A total of 306 patients had MT. Patients were mostly male (74%) and ≥18 years old (99%), including 93 liver transplant, 97 cardiac or vascular surgery and 51 trauma patients. There were no differences in demographics between the periods. Component use on the day and within 7 days of the MT event was unchanged post-IBS implementation, except trauma patients received fewer RBCs on the day. The mean ratio of RBC:platelets:plasma on the day of the MT was close to 1:1:1 in both periods, except for liver transplants with MT who received more plasma components. Overall, in-hospital mortality (preimplementation = 27·6% vs. postimplementation = 24·0%; P = 0·51) and median time to discharge (preimplementation = 27 vs. postimplementation = 23 days; P = 0·37) did not change, except for cardiac and vascular surgery patients who were discharged earlier. CONCLUSION: The introduction of amotosalen/UVA-treated, pathogen-reduced PC did not adversely affect clinical outcomes in massively transfused patients in terms of blood product usage, in-hospital mortality and length of stay for a range of clinical indications for platelet transfusion support.

Impact of platelet pathogen inactivation on blood component utilization and patient safety in a large Austrian Regional Medical Centre.

BACKGROUND: In clinical studies, pathogen inactivation (PI) of platelet concentrates (PC) with amotosalen and UVA light did not impact patient risk for haemorrhage but may affect transfusion frequency and component utilization. We evaluated the influence of platelet PI on PC, red cell concentrate (RCC) and plasma use and safety in routine practice in a large regional hospital. STUDY DESIGN AND METHODS: Comparative effectiveness of conventional vs. PI-treated PC was analysed during two 21-month periods, before and after PI implementation. RESULTS: Similar numbers of patients were transfused in the pre-PI (control, 1797) and post-PI (test, 1694) periods with comparable numbers of PC (8611 and 7705, respectively). The mean numbers of PC per patient transfused (4·8 vs. 4·5, P = 0·43) were not different but days of PC support (5·9 vs. 5·0, P < 0·01) decreased. Most patients received RCC (86·8% control vs. 84·8% test, P = 0·90) with similar mean numbers transfused (10·8 vs. 10·2 RCC, P = 0·22), and fewer patients (55·4% control vs. 44·7% test, P < 0·01) received less plasma units (mean 9·9 vs. 7·8, respectively, P < 0·01) in the test period. The frequencies of transfusion-related adverse events (AE) were comparable (1·3% vs. 1·4%, P = 0·95). Analysis of haematology-oncology (522 control, 452 test), cardiac surgery (739 control, 711 test), paediatric (157 control, 130 test) and neonate (23 control, 20 test) patients revealed no increase in PC, plasma and RCC utilization, or AE. CONCLUSION: Component utilization and patient safety were not impacted by adoption of PI for PC. RCC use per patient was comparable, suggestive of no increase in significant bleeding.

[Enhancing Soft-tissue Reattachment with Artificial Mesh in Joint Endoprosthetic Reconstruction for Bone Tumors].

Objective: To investigate the operative method and clinical application of the BARD(®) Mesh in enhancing joint stability and function of endoprosthetic reconstruction for bone tumors. Methods: From Jan 2013 to Jun 2015, the clinical data of 51 patients aged (44.75±23.18) years underwent wide resection of tumor and endoprosthetic reconstruction using the BARD(®) Mesh were collected. Among them, 27 were male and 24 were female. The surgical treatments received by these patients included 5 shoulder arthroplasties, 12 elbow replacements, 12 hip replacements and 32 knee replacements (including 24 femoral tumors and 8 tibial tumors). According to the pathologic type, there were 12 metastatic tumors, 20 osteosarcomas, 7 chondrosarcomas, 5 malignant fibrous histiocytomas, 4 giant cell tumors of bone, 1 Ewing sarcoma, 1 leiomyosarcoma and 1 pigmented villonodular synovitis (pvns). These patients received extensive tumor resection, tumorous prosthesis replacement, preserved articular capsule and muscles repair with artificial mesh and endoprosthesis wrapping. The curative effect including joints range of motion and Musculoskeletal Tumour Society Scores (MSTS) were evaluated. Results: The median follow-up time was (19.75±8.17) months. The drainages were removed out on an average of 4 days after operation. The postoperative complications included 2 superficial incision infection, 1 deep incision infection and 1 osteofascial compartment syndrome, infection or dislocation of prosthesis wasn't observed. The mean active flexion of shoulder joint after replacement was (34.00±10.84)°, mean active abduction was (20.00±9.35)° and the mean MSTS was 19.80±9.54. The superior rate of shoulder flexion function was 0. The mean active flexion of elbow joint after replacement was (75.00±7.07)°, mean active abduction was (-5.00±7.07)° and the mean MSTS was 25.00±2.83. The superior rate of elbow flexion function was 50.0% (1/2). The mean active flexion of hip joint after replacement was (86.67±20.60)°, mean active abduction was (2.08±4.98)° and the mean MSTS was 25.42±1.78. The superior rate of hip flexion function was 83.3% (10/12). The mean active flexion of knee joint after replacement was (89.69±22.39)°, mean active abduction was (-0.63±1.68)° and the mean MSTS was 23.31±2.09. The superior rate of knee flexion function was 50.0%(16/32). Among them, the superior rate of femoral flexion function was 66.7% (16/24), the superior rate of tibial flexion function was 0. All of patients were satisfied with the curative effect of operation at the end of follow-up time. Conclusions: The BARD(®) Mesh may enhance the attachment of soft-tissue to endoprosthesis, improve the joint stability, decrease the endoprosthetic infection and dislocation, facilitate the attachment of tendon to endoprosthesis and recover the muscular motivation after endoprosthetic reconstruction. This plays an important role in joint stability and motivation reconstruction of soft-tissue impairment, effectively prevents surgical complications.

A prospective, active haemovigilance study with combined cohort analysis of 19,175 transfusions of platelet components prepared with amotosalen-UVA photochemical treatment.

BACKGROUND AND OBJECTIVES: A photochemical treatment process (PCT) utilizing amotosalen and UVA light (INTERCEPT(™) Blood System) has been developed for inactivation of viruses, bacteria, parasites and leucocytes that can contaminate blood components intended for transfusion. The objective of this study was to further characterize the safety profile of INTERCEPT-treated platelet components (PCT-PLT) administered across a broad patient population. MATERIALS AND METHODS: This open-label, observational haemovigilance programme of PCT-PLT transfusions was conducted in 21 centres in 11 countries. All transfusions were monitored for adverse events within 24 h post-transfusion and for serious adverse events (SAEs) up to 7 days post-transfusion. All adverse events were assessed for severity (Grade 0-4), and causal relationship to PCT-PLT transfusion. RESULTS: Over the course of 7 years in the study centres, 4067 patients received 19,175 PCT-PLT transfusions. Adverse events were infrequent, and most were of Grade 1 severity. On a per-transfusion basis, 123 (0.6%) were classified an acute transfusion reaction (ATR) defined as an adverse event related to the transfusion. Among these ATRs, the most common were chills (77, 0.4%) and urticaria (41, 0.2%). Fourteen SAEs were reported, of which 2 were attributed to platelet transfusion (<0.1%). No case of transfusion-related acute lung injury, transfusion-associated graft-versus-host disease, transfusion-transmitted infection or death was attributed to the transfusion of PCT-PLT. CONCLUSION: This longitudinal haemovigilance safety programme to monitor PCT-PLT transfusions demonstrated a low rate of ATRs, and a safety profile consistent with that previously reported for conventional platelet components.

Recombinant human kallistatin inhibits angiogenesis by blocking VEGF signaling pathway.

Kallistatin has been recognized as an endogenous angiogenic inhibitor. However, the underlying molecular mechanism remains poorly understood. Taking it into account that vascular endothelial growth factor (VEGF) has been implicated in all aspects of normal and pathological vasculogenesis and angiogenesis. In this study, we investigated whether VEGF signaling pathway was impacted by the anti-angiogenic effect of recombinant human kallistatin (rhKal). We found that the rhKal inhibited proliferation as well as induced apoptosis of cultured human umbilical vein endothelial cells (HUVECs) in both concentration- and time-dependent manners. The rhKal also suppressed the VEGF-induced migration and tube formation of HUVECs. Furthermore, our data revealed that the rhKal suppressed the VEGF165-stimulated tyrosine phosphorylation of VEGFR-2 as well as its downstream signal molecular activation. The inhibition of receptor phosphorylation was correlated with a decrease in VEGF-triggered phosphorylation of angiogenesis signal molecules AKT and ERK, but not stress-related JNK. Taken together, these findings added the knowledge for us to understand the anti-angiogenic mechanism of kallistatin, which suggested that the rhKal could be worth as a candidate compound for further development for the purpose of anti-angiogenic therapies.

Unilateral biportal endoscopic spine surgery for lumbar spinal stenosis: a systematic review and meta-analysis.

OBJECTIVE: Lumbar spinal stenosis is the most common spinal degenerative disease in patients over 60 years, and the unilateral biportal endoscopic (UBE) spine surgery treatment of lumbar spinal stenosis (LSS) has achieved preliminary clinical results. This systematic review and meta-analysis aimed to reveal the clinical efficacy of UBE for LSS and provide evidence for clinical practice. MATERIALS AND METHODS: PubMed, Embase, Web of Science, and Cochrane databases were searched for literature. The papers selected were those published from inception till October 2021. The selected pieces of literature were graded for evidence using the Oxford Centre for Evidence-Based Medicine: Levels of Evidence (March 2009). Outcomes measures were operation time, blood loss, complication rate, admission period, Visual Analogue Scale (VAS)-back, VAS-leg, and Oswestry Disability Index (ODI) score, and radiological outcomes. The mean comparisons were based on VAS and ODI scores. RESULTS: A total of 823 patients with a single LSS segment were included from the selected nine studies. There were nine studies comparing UBE clinical outcomes and micro-endoscopic unilateral laminotomy for bilateral decompression (M-ULBD). The meta-analysis revealed that the UBE group had better VAS-leg and -back scores in the first week postoperatively [total: mean difference (MD) = -0.96, 95% confidence interval (CI): -1.19, -0.74, p < 0.00001; total: MD = -1.69, 95% CI: -1.93, -1.45, p < 0.00001], 1st month postoperatively (total: MD = -0.35, 95% CI: -0.61, -0.08, p = 0.01; total: MD = -0.40, 95% CI: -0.68, -0.12, p = 0.005), 6th month postoperatively (total: MD = -0.22, 95% CI: -0.35, -0.08, p = 0.002; total: MD = -0.24, 95% CI: -0.40, -0.07, p = 0.005), and UBE group also performed better in ODI score at 1st month postoperatively (total: MD = -3.36, 95% CI: -4.26, -2.46, p < 0.00001). There was no significant difference in VAS-leg and -back scores between both groups at the 3rd and 12th month postoperatively, and ODI scores did not significantly differ between both groups at 3, 6, and 12 months postoperatively (all p > 0.05). CONCLUSIONS: UBE has achieved good preliminary clinical results and may be a minimally invasive alternative surgery for patients with single segmental LSS.

Sox11 regulates survival and axonal growth of embryonic sensory neurons.

Sensory neurons transduce various stimuli including temperature, pain, and touch from the periphery to the central nervous system. Sensory neuron development is governed by a combination of extracellular cues and specific gene expression. We demonstrated that the transcription factor Sox11 was highly expressed in the developing sensory neurons. To test the function of Sox11, we used a knockin mouse model where the entire coding region of Sox11 was replaced by a LacZ reporter. The ablation of Sox11 caused severe reduction in sensory neuron survival in the trigeminal and dorsal root ganglia, although it did not affect migration of neural crest cells or acquisition of major sensory neuron subtypes. We further demonstrated that ablating Sox11 caused an arrest of axonal outgrowth in vivo and in vitro. This defect could not be fully rescued by blocking cell death. Our data suggest that Sox11 is a key regulator of sensory neuron development.

[Spatiotemporal changes of COVID-19 outbreak in Shanghai].

Objective: To clarify the epidemiological characteristics and spatiotemporal clustering dynamics of COVID-19 in Shanghai in 2022. Methods: The COVID-19 data presented on the official websites of Municipal Health Commissions of Shanghai during March 1, 2022 and May 31, 2022 were collected for a spatial autocorrelation analysis by GeoDa software. A logistic growth model was used to fit the epidemic situation and make a comparison with the actual infection situation. Results: Pudong district had the highest number of symptomatic and asymptomatic infectants, accounting for 29.30% and 35.58% of the total infectants. Differences in cumulative attack rates and infection rates among 16 districts (P<0.001) were significant. The rates were significantly higher in Huangpu district than in other districts. The attack rate of COVID-19 from March 1, 2022 to May 31, 2022 had a global spatial positive correlation (P<0.05). Spatial distribution of COVID-19 attack rate was different at different periods. The global autocorrelation coefficient from March 16 to March 29, April 6 to April 12 and May 18 to May 24 had no statistical significance (P>0.05). Our local autocorrelation analysis showed that 22 high-high clustering areas were detected in eight periods.The high-risk hot-spot areas have experienced a "less-more-less" change process. The growth model fitting results were consistent with the actual infection situation. Conclusion: There was a clear spatiotemporal correlation in the distribution of COVID-19 in Shanghai. The comprehensive prevention and control measures of COVID-19 epidemic in Shanghai have effectively prohibited the growth of the epidemic, not only curbing the spatially spread of high-risk epidemic areas, but also reducing the risk of transmission to other cities.

Analysis of thrombin-antithrombin complex contents in plasma and hematoma fluid of hypertensive intracerebral hemorrhage patients after clot removal.

BACKGROUND AND PURPOSE: Animal experiments indicate that the cerebral thrombin is associated with secondary brain damage after intracerebral hemorrhage (ICH). This study was aimed to investigate the concentrations of thrombin-antithrombin complex (TAT) in hematoma fluid and plasma of the patients with ICH after surgery and analyze the correlation between TAT complex levels and severity of ICH. METHODS: Sixty patients with ICH were enrolled. Craniotomy for removal of intracranial blood clot was performed within 24h after ICH. Hematoma fluid and plasma were collected on postoperative days 1, 2, and 4. The plasma obtained from healthy subjects and cerebrospinal fluid from patients without cerebrovascular diseases served as controls, respectively. Enzyme-linked immunosorbent assay was used to determine the concentrations of TAT complex in the patients and controls. RESULTS: TAT complex concentrations in both postoperative plasma and hematoma fluid of patients with ICH were significantly higher than those of the controls (P<0.01). In patients with ICH, hematoma fluid had a higher TAT complex level than plasma (P<0.01). The preoperative hemorrhage volume and postoperative TAT complex levels in plasma and hematoma fluid correlated positively with National Institutes of Health stroke scale and negatively with Glasgow coma score (P<0.01). CONCLUSION: This study indicates that TAT complex levels of plasma and hematoma fluid correlate positively with the severity of ICH. Determination of the plasma TAT complex concentration is helpful for the evaluation of the severity of post-ICH brain injury.

Genomic sequence of an avian paramyxovirus type 1 strain isolated from Muscovy duck (Cairina moschata) in China.

The complete sequence of an avian paramyxovirus type 1 (APMV-1) strain, FP1/02, isolated from Muscovy duck in China, was determined. Sequence analysis indicated that the complete genome of strain FP1/02 contained 15,192 nucleotides (nt), following the rule of six. The genome contained an extra 6-nt insertion in the non-coding region of the NP gene when compared with other APMV-1 strains, such as strains La Sota and Beaudette C. The cleavage site of the F protein was (112)R-R-Q-K-R↓F(117), indicating that the FP1/02 strain was virulent, but the morbidity and mortality varied with the species of duck. Genotypic analysis based on the F gene revealed that APMV-1 FP1/02 was a member of genotype VII. Phylogenetic analysis showed that the FP1/02 strain shared high identity with other APMV-1 strains such as ZJ1, SF02 and NA-1 isolated from geese.

Estimating Local Cellular Density in Glioma Using MR Imaging Data.

BACKGROUND AND PURPOSE: Increased cellular density is a hallmark of gliomas, both in the bulk of the tumor and in areas of tumor infiltration into surrounding brain. Altered cellular density causes altered imaging findings, but the degree to which cellular density can be quantitatively estimated from imaging is unknown. The purpose of this study was to discover the best MR imaging and processing techniques to make quantitative and spatially specific estimates of cellular density. MATERIALS AND METHODS: We collected stereotactic biopsies in a prospective imaging clinical trial targeting untreated patients with gliomas at our institution undergoing their first resection. The data included preoperative MR imaging with conventional anatomic, diffusion, perfusion, and permeability sequences and quantitative histopathology on biopsy samples. We then used multiple machine learning methodologies to estimate cellular density using local intensity information from the MR images and quantitative cellular density measurements at the biopsy coordinates as the criterion standard. RESULTS: The random forest methodology estimated cellular density with R 2 = 0.59 between predicted and observed values using 4 input imaging sequences chosen from our full set of imaging data (T2, fractional anisotropy, CBF, and area under the curve from permeability imaging). Limiting input to conventional MR images (T1 pre- and postcontrast, T2, and FLAIR) yielded slightly degraded performance (R2 = 0.52). Outputs were also reported as graphic maps. CONCLUSIONS: Cellular density can be estimated with moderate-to-strong correlations using MR imaging inputs. The random forest machine learning model provided the best estimates. These spatially specific estimates of cellular density will likely be useful in guiding both diagnosis and treatment.

A dominant strain of Elizabethkingia anophelis emerged from a hospital water system to cause a three-year outbreak in a respiratory care center.

BACKGROUND: Elizabethkingia species are ubiquitous bacteria but uncommonly cause human infection. An outbreak of Elizabethkingia anophelis bacteraemia was observed in a respiratory care center of a tertiary hospital in Taiwan from 2015 to 2018. METHODS: Clinical and environmental isolates were collected for the outbreak investigation. Pulsed-field gel electrophoresis (PFGE) and complete-genome sequencing were conducted to elucidate the mechanism of transmission. FINDINGS: The three-year outbreak involved 26 patients with E. anophelis bacteraemia and the incidence significantly increased during the outbreak period compared with that observed from 2010 to 2014 (P<0.05). All 26 clinical isolates during the outbreak period belonged to a cluster by PFGE analysis. In contrast, the PFGE pattern was heterogeneous among comparative historical strains. Hospital tap water was highly contaminated by Elizabethkingia species (18/34, 52.9%); among that, five E. anophelis belonged to the outbreak cluster (5/18, 27.8%). As for the inanimate surface survey, 3.4% sites (4/117) revealed positive growth of E. anophelis including two from feeding tubes/bags and two from sputum suction regulators. All four isolates belonged to the outbreak clone. The outbreak strain had no apparent relationship to currently known E. anophelis strains worldwide through complete-genome sequencing analysis. Specific infection control strategies aimed at water source control and environmental disinfection were implemented subsequently and the outbreak ended in mid-2018. CONCLUSIONS: A specific E. anophelis strain was identified from a three-year outbreak. The elucidation of the mechanism of dominance and intra-hospital transmission is crucial for development of corresponsive infection control policies and outbreak control.

Imaging-Based Algorithm for the Local Grading of Glioma.

BACKGROUND AND PURPOSE: Gliomas are highly heterogeneous tumors, and optimal treatment depends on identifying and locating the highest grade disease present. Imaging techniques for doing so are generally not validated against the histopathologic criterion standard. The purpose of this work was to estimate the local glioma grade using a machine learning model trained on preoperative image data and spatially specific tumor samples. The value of imaging in patients with brain tumor can be enhanced if pathologic data can be estimated from imaging input using predictive models. MATERIALS AND METHODS: Patients with gliomas were enrolled in a prospective clinical imaging trial between 2013 and 2016. MR imaging was performed with anatomic, diffusion, permeability, and perfusion sequences, followed by image-guided stereotactic biopsy before resection. An imaging description was developed for each biopsy, and multiclass machine learning models were built to predict the World Health Organization grade. Models were assessed on classification accuracy, Cohen κ, precision, and recall. RESULTS: Twenty-three patients (with 7/9/7 grade II/III/IV gliomas) had analyzable imaging-pathologic pairs, yielding 52 biopsy sites. The random forest method was the best algorithm tested. Tumor grade was predicted at 96% accuracy (κ = 0.93) using 4 inputs (T2, ADC, CBV, and transfer constant from dynamic contrast-enhanced imaging). By means of the conventional imaging only, the overall accuracy decreased (89% overall, κ = 0.79) and 43% of high-grade samples were misclassified as lower-grade disease. CONCLUSIONS: We found that local pathologic grade can be predicted with a high accuracy using clinical imaging data. Advanced imaging data improved this accuracy, adding value to conventional imaging. Confirmatory imaging trials are justified.

Comparison of anti-Xa activity after a single intravenous bolus of low-dose enoxaparin in patients with and without end-stage renal disease.

This study was designed to evaluate anti-Xa activity hourly during the first 3 h after a single intravenous bolus of 0.5 mg/kg enoxaparin in 30 patients with end-stage renal disease (ESRD) who underwent haemodialysis, and in 30 patients with normal or mildly reduced renal function who underwent coronary angiography for chest pain (non-ESRD group). Mean +/- SD haemodialysis time was 3.9 +/- 0.3 h in the ESRD group. Of 24 patients diagnosed with coronary artery disease in the non-ESRD group, 20 underwent percutaneous coronary intervention (PCI). A peak anti-Xa activity > 0.5 IU/ml 10 min after enoxaparin injection was obtained in 90% and 93% of the non-ESRD and ESRD patients, respectively. The percentages of patients with peak anti-Xa activity in the target range (0.5 - 1.5 IU/ml) were similar in the two groups (non-ESRD 80%, ESRD 93%). Adequate anti-Xa activity (> 0.5 IU/ml) lasted about 2 h in both groups. It is concluded that a single intravenous low-dose enoxaparin (0.5 mg/kg) bolus provides anti-Xa activity adequate for elective PCI within 2 h irrespective of whether or not the patient had ESRD.

Virtual memory CD8 T cells expanded by helminth infection confer broad protection against bacterial infection.

Epidemiological data and animal studies suggest that helminth infection exerts potent immunomodulatory effects that dampen host immunity against unrelated pathogens. Despite this notion, we unexpectedly discovered that prior helminth infection resulted in enhanced protection against subsequent systemic and enteric bacterial infection. A population of virtual memory CD8 T (CD8 TVM) cells underwent marked expansion upon infection with the helminth Heligmosomoides polygurus by an IL-4-regulated, antigen-independent mechanism. CD8 TVM cells disseminated to secondary lymphoid organs and established a major population of the systemic CD8 T cell pool. IL-4 production elicited by protein immunization or selective activation of natural killer T cells also results in the expansion of CD8 TVM cells. Notably, CD8 TVM cells expanded by helminth infection are sufficient to transfer innate non-cognate protection against bacteria to naïve animals. This innate non-cognate "collateral protection" mediated by CD8 TVM might provide parasitized animals an advantage against subsequent unrelated infections, and represents a potential novel strategy for vaccination.

Clinicopathological and prognostic significance of preoperative serum epidermal growth factor levels in patients with oral squamous cell carcinoma.

Epidermal growth factor (EGF) promotes tumourigenesis and tissue repair of epithelial and mesenchymal cells and has a role in chemotaxis, mitogenesis, cell motility, and cytoprotection. It also enhances the growth of cancers. EGF may therefore have a role in the initiation or promotion of oral carcinogenesis. The cases of 152 patients with oral squamous cell carcinoma whose preoperative serum EGF level was determined by enzyme-linked immunosorbent assay were analyzed retrospectively, along with those of 40 age- and sex-matched controls. Patients with higher levels of EGF were more likely to have neck lymph node metastasis (P=0.026), advanced stage cancer (P=0.04), and a worse survival status (P=0.0019). Multivariate analysis using the Cox proportional hazards model indicated that the EGF level was an independent predictor of poor survival (hazard ratio 1.99, P=0.018). Patients with higher preoperative serum EGF levels had significantly poorer cancer-specific survival by Kaplan-Meier analysis (P=0.032). This study indicates that a higher preoperative serum EGF level is associated with neck lymph node metastasis, more advanced stage, and poor survival. EGF should be considered as a potential prognostic biomarker and a therapeutic target for patients with oral cancer.

Genetic basis for a lower prevalence of deficient CYP2D6 oxidative drug metabolism phenotypes in black Americans.

Debrisoquin hydroxylase (CYP2D6) is a cytochrome P450 enzyme that catalyzes the metabolism of > 30 commonly prescribed medications. Deficiency in CYP2D6 activity, inherited as an autosomal recessive trait, was found to be significantly less common in American blacks (1.9%) than whites (7.7%). To determine the genetic basis for this difference, inactivating CYP2D6 mutations were assessed by allele-specific PCR amplification and RFLP analyses of genomic DNA from 126 unrelated whites and 127 unrelated blacks. Blacks had a twofold lower frequency (8.5 versus 23%, P = 0.001) of the CYP2D6(B) mutation (point mutation at intron 3/exon 4 splice site), while complete deletion of the CYP2D6 gene (5.5% blacks, 2.4% whites), and the CYP2D6(A) mutation (single nucleotide deletion in exon 5; 0.24% blacks, 1.4% whites) were not different between the two groups. The prevalence of heterozygous genotypes was significantly lower in blacks (25 versus 42% of extensive metabolizers, P = 0.009), consistent with the observed prevalence of the deficient trait in blacks and whites. We conclude that the same CYP2D6 mutations lead to a loss of functional expression in blacks and whites, but American blacks have a lower prevalence of the deficient trait due to a lower frequency of the CYP2D6(B) mutation. This could explain racial differences in drug effects and disease risk.

Etiology of nongonococcal urethritis. Evidence for Chlamydia trachomatis and Ureaplasma urealyticum.

Chlamydia trachomatis, Ureaplasma urealyticum (T-mycoplasma), and Hemophilus vaginalis have previously been considered possible etiological agents in nongonococcal urethritis (NGU). In this study, current C. trachomatis infection was confirmed by culture and (or) micro-immunofluorescence serology in 26 of 69 men experiencing afirst episode of NGU, and 1 of 39 with no urethritis. Serum IgM immunofluorescent antibody to chlamydia was demonstrated in 16 of 20 men with chlamydia culture positive NGU, and 3 of 39 with chlamydia culture negative NG, and none of 34 with no urethritis. 9 of 10 culture positive men with less than or equal to 10 days symptoms developed immunofluorescent antibody seroconversion in paired sera. U. realyticum was isolated significantly more often and in significantly higher concentration from first voided urine from chlamydia-negative cases of NGU than from chlamydia-positive NGU. Ureaplasmacidal antibody titers increased fourfold in six men, four of whom had negative cultures for for unreaplasma. H. vaginalis was isolated from c9 of 33 men with no urethritis and 2 of 69 with NGU. C. trachomatis is susceptible, and U. urealyticum is resistant to sulfonamides. A 10-day course of sulfisoxazole therapy produced improvement in 13 of 13 chlamydia-positive, unreaplasma-negative, and only 14 of 29 chlamydia-negative, unreaplasma-positive NGU cases (P less than 0.002). Thus, culture, serology, and response to therapy support the etiologic role of chlamydia in NGU. Quantitative culture and response to therapy suggest U. unrealyticum may cause many cases of chlamydia-netative NGU.