Combined inhibition of ß-catenin and Bcr-Abl synergistically targets tyrosine kinase inhibitor-resistant blast crisis chronic myeloid leukemia blasts and progenitors in vitro and in vivo.

Tyrosine kinase inhibitor (TKI) resistance and progression to blast crisis (BC), both related to persistent ß-catenin activation, remain formidable challenges for chronic myeloid leukemia (CML). We observed overexpression of ß-catenin in BC-CML stem/progenitor cells, particularly in granulocyte-macrophage progenitors, and highest among a novel CD34+CD38+CD123hiTim-3hi subset as determined by CyTOF analysis. Co-culture with mesenchymal stromal cells (MSCs) induced the expression of ß-catenin and its target CD44 in CML cells. A novel Wnt/ß-catenin signaling modulator, C82, and nilotinib synergistically killed KBM5T315I and TKI-resistant primary BC-CML cells with or without BCR-ABL kinase mutations even under leukemia/MSC co-culture conditions. Silencing of ß-catenin by short interfering RNA restored sensitivity of primary BCR-ABLT315I/E255V BC-CML cells to nilotinib. Combining the C82 pro-drug, PRI-724, with nilotinib significantly prolonged the survival of NOD/SCID/IL2Rγ null mice injected with primary BCR-ABLT315I/E255V BC-CML cells. The combined treatment selectively targeted CML progenitors and inhibited CD44, c-Myc, survivin, p-CRKL and p-STAT5 expression. In addition, pretreating primary BC-CML cells with C82, or the combination, but not with nilotinib alone, significantly impaired their engraftment potential in NOD/SCID/IL2Rγ-null-3/GM/SF mice and significantly prolonged survival. Our data suggest potential benefit of concomitant ß-catenin and Bcr-Abl inhibition to prevent or overcome Bcr-Abl kinase-dependent or -independent TKI resistance in BC-CML.

Apoptosis repressor with caspase recruitment domain is regulated by MAPK/PI3K and confers drug resistance and survival advantage to AML.

The apoptosis repressor with caspase recruitment domain (ARC) protein is known to suppress both intrinsic and extrinsic apoptosis. We previously reported that ARC expression is a strong, independent adverse prognostic factor in acute myeloid leukemia (AML). Here, we investigated the regulation and role of ARC in AML. ARC expression is upregulated in AML cells co-cultured with bone marrow-derived mesenchymal stromal cells (MSCs) and suppressed by inhibition of MAPK and PI3K signaling. AML patient samples with RAS mutations (N = 64) expressed significantly higher levels of ARC than samples without RAS mutations (N = 371) (P = 0.016). ARC overexpression protected and ARC knockdown sensitized AML cells to cytarabine and to agents that selectively induce intrinsic (ABT-737) or extrinsic (TNF-related apoptosis inducing ligand) apoptosis. NOD-SCID mice harboring ARC-overexpressing KG-1 cells had significantly shorter survival than mice injected with control cells (median 84 vs 111 days) and significantly fewer leukemia cells were present when NOD/SCID IL2Rγ null mice were injected with ARC knockdown as compared to control Molm13 cells (P = 0.005 and 0.03 at 2 and 3 weeks, respectively). Together, these findings demonstrate that MSCs regulate ARC in AML through activation of MAPK and PI3K signaling pathways. ARC confers drug resistance and survival advantage to AML in vitro and in vivo, suggesting ARC as a novel target in AML therapy.

Oxytocinergic regulation of endogenous as well as drug-induced mood.

The interconnections between the serotonin and oxytocin pathways in the brain suggest that changes in oxytocin levels - arising from natural or drug-induced stimuli - lead to measureable changes in mood. In this paper, we review our findings in the context of what is known about the roles of oxytocin and vasopressin in the expression of a range of behaviours. In our first set of studies we investigated whether stimulation of oxytocin and vasopressin receptors, via central or systemic drug administration, would produce behavioural changes indicative of anti-depressant or anxiolytic activity. In our second study we investigated whether oxytocin receptor activation might be implicated in the interoceptive effects experienced with the popular party drug, MDMA ('ecstasy'). Our first study demonstrated that carbetocin, an oxytocin analogue, had anti-depressant actions following systemic and central administration, effects which were blocked by the oxytocin and vasopressin 1A receptor antagonist, atosiban. Carbetocin also had anxiolytic effects in the elevated plus maze. In an evaluation of the complementary nature of oxytocin and vasopressin, we found that systemic administration of desmopressin, a vasopressin analogue, was anxiogenic; its effects blocked by atosiban which on its own produced robust anxiolytic behavioural changes. In our second study, we evaluated MDMA's interoceptive effects using a drug discrimination paradigm. Carbetocin partially substituted for MDMA, while atosiban interfered with MDMA discrimination, suggesting that oxytocin receptor activation contributes to MDMA-related interoceptive cues. The results of these and other clinical and preclinical studies suggest that oxytocin, as well as its closely related counterpart vasopressin, may provide alternative therapeutic targets for the treatment of mood disorders such as anxiety and depression. The possibility that oxytocin release may contribute to the perception of and processes underlying natural and drug-induced behavioural reinforcement offers exciting prospects for future study.

Validation of the APLS age-based vital signs reference ranges in a Chinese population.

UNLABELLED: Reference ranges for vital signs may differ significantly among children of different ethnic origins. AIM: (1) To validate the Advanced Paediatric Life Support (APLS) age-based vital signs reference ranges in Chinese children in Hong Kong. (2) To derive age-based centile curves for systolic blood pressure, heart rate and respiratory rate for Chinese children. (3) To summarize the reference ranges in a table format appropriate for applying APLS to ethnic Chinese patients. METHOD: A cross-sectional study was performed on a population of healthy Chinese children recruited from 8 kindergartens and 6 primary schools in Hong Kong. Trained operators visit the sites to obtain measurements. Age-groups: small toddlers (12-23 months); pre-school (24-59 months); and school (60-143 months). Z-test was used to assess statistical significance for proportions of each parameter falling outside the APLS reference range. One-sample t-test was used for comparison with APLS means according to age-groups. LMS Chartmaker Pro v2.3 software was used to describe the data in centile curves. RESULTS: A total of 1353 patients (55.1% boys) were included. For heart rate, systolic blood pressure and respiratory rate respectively, 34.1%, 55.9% and 55.7% of corresponding measurements were outside the APLS age-based reference ranges. In the 'pre-school' and 'school' age-groups, the mean value for blood pressure is significantly higher, and the mean values for heart rate and respiratory rate significantly lower, in comparison to APLS mean values. CONCLUSION: Independently derived vital signs reference ranges are more appropriate for use when applying APLS to Chinese patients in Hong Kong.

Disease severity prediction for nursing home-acquired pneumonia in the emergency department.

BACKGROUND: Prediction rules exist for the assessment of community-acquired pneumonia but their use in nursing home-acquired pneumonia (NHAP) remains undefined. The objectives of this study were to compare the prognostic ability for severe NHAP of five prediction rules (PSI, CURB-65, M-ATS, R-ATS, España rule), and to evaluate their usefulness to identify patients with less severe disease in the emergency department for outpatient care. METHODS: A prospective observational study of consecutive NHAP patients was conducted at a university teaching hospital emergency department in Hong Kong between January 2004 and June 2005. The primary outcome was severe pneumonia (defined as combined 30-day mortality and/or intensive care unit (ICU) admission). RESULTS: 767 consecutive NHAP patients were included. Mean (SD) age was 83.4 (9.0) years; 350 (45.6%) were male and 644 (84.0%) had coexisting illness. 95 patients died within 30 days (12.4%), five patients were admitted to the ICU (0.7%) and 98 patients had severe pneumonia (12.8%). Sensitivity and specificity of each decision rule ranged from 37.8% to 95.9% and 15.1% to 87.6% respectively. The overall predictive performance of each rule was between 0.627 and 0.712. The negative likelihood ratios of PSI (0.27) and CURB-65 (0.23) were lower than M-ATS (0.71), R-ATS (0.45) and España (0.39). After excluding 204 patients with either poor functional status or those >90 years of age, sensitivities of M-ATS (96.0%) and R-ATS (100%) improved greatly with negative likelihood ratios of <0.1. CONCLUSION: PSI and CURB-65 are useful for identification of patients with less severe NHAP.

Age-based formulae to estimate children's weight in the emergency department.

OBJECTIVE: To develop an age-based weight estimation rule in a Chinese population and to compare its performance with existing formulae. DESIGN: Population-based observational study. SETTING: Schools and kindergartens in Hong Kong. SUBJECTS: Healthy Chinese children aged 1-10 years old on their last birthday. INTERVENTIONS: Weight was measured to the nearest 0.2 kg. MAIN OUTCOME MEASURES: Linear regression was used to derive a simple formula relating weight to the child's age on his or her last birthday. The accuracy and precision of different age-based weight formulae was compared using coefficient of variation, Bland Altman plots, and by determining the proportion of children with estimates >30% outside the actual weight. RESULTS: The Chinese Age Weight Rule is a simple linear formula that is more accurate than and at least as precise as any other age-based weight estimation rule: weight in kg=(3 × age last birthday)+5. It is accurate and precise in children <7 years old, but all age-based weight estimates are imprecise in older children. CONCLUSIONS: The Chinese Age Weight Rule should be used in a Chinese population in preference to any other age-based weight estimation rule. Caution should be taken when using it in older children in whom other weight-estimation tools may be more appropriate.

Multilayer limb quasi-static electromagnetic modeling with experiments for Galvanic coupling type IBC.

Intra-body communication (IBC) is a new, emerging, short-range and human body based communication methodology. It is a technique to network various devices on human body, by utilizing the conducting properties of human tissues. For currently fast developed Body area network(BAN)/Body sensor network(BSN), IBC is believed to have advantages in power consumption, electromagnetic radiation, interference from external electromagnetic noise, security, and restriction in spectrum resource. In this article, the authors propose an improved mathematical model, which includes both electrical properties and proportion of human tissues, for IBC on a human limb. By solving the mathematical model analytically on four-layer system (skin, fat, muscle, and bone) and conducting in-vivo experiment, a comparison has been conducted.

Mid-arm circumference can be used to estimate children's weights.

INTRODUCTION: Accurate measurement of children's weight is rarely possible in paediatric resuscitation, and rapid estimates are made to ensure appropriate drug and fluid doses and equipment selection. Weight is commonly estimated from formulae based on children's age, or from their height using the Broselow tape. Foot-length and mid-arm circumference have also been suggested as the basis of weight-estimation formulae. OBJECTIVES: To determine which of age, height, foot-length or mid-arm circumference had the strongest relationship with weight in healthy children, to derive a simple weight-estimation formula from the strongest correlate, and to compare its performance with existing weight-estimation tools. METHODS: This was a population-based prospective observational study of Hong Kong Chinese children aged 1-11 years old last birthday. Weight was measured to the nearest 0.2 kg; height, foot-length and mid-arm circumference to the nearest 0.1 cm. Multiple regression analysis was used to determine the strongest independent relationships with weight, and linear regression analysis derived a weight-estimation formula. Accuracy and precision of this formula were compared with standard age-based and height-based weight-estimation methods. RESULTS: Mid-arm circumference had the strongest relationship with weight, and this relationship grew stronger with age. The formula, weight [kg]=(mid-arm circumference [cm]-10) x 3, was at least as accurate and precise as the Broselow method and outperformed the age-based rule in school-age children, but was inadequate in pre-school children. CONCLUSION: This weight-estimation formula based on mid-arm circumference is reliable for use in school-age children, and an arm-tape could be considered as an alternative to the Broselow tape in this population.

Predictors of important neurological causes of dizziness among patients presenting to the emergency department.

OBJECTIVES: Dizziness is a common presenting complaint in the emergency department (ED). This prospective study describes the incidence, causes and outcome of ED patients presenting with dizziness and tries to identify predictors of central neurological causes of dizziness. METHODS: Single-centre prospective observational study in a university teaching hospital ED in Hong Kong. All ED patients (> or = 18 years old) presenting with dizziness were recruited for 1 month. Symptoms, previous health, physical findings, diagnosis and disposition were recorded. The outcome at 3 months was evaluated using hospital records and telephone interviews. Follow-up was also performed at 55 months using computerised hospital records to identify patients with subsequent stroke and those who had died. RESULTS: 413 adults (65% female, mean 57 years) were recruited. The incidence of dizziness was 3.6% (413/11 319). Nausea and/or vomiting (46%) and headache (20%) were the commonest associated findings. Hypertension (33%) was the commonest previous illness. Central neurological causes of dizziness were found in 6% (23/413) of patients. Age > or = 65 years (OR=6.13, 95% CI 1.97 to 19.09), ataxia symptoms (OR=11.39, 95% CI 2.404 to 53.95), focal neurological symptoms (OR=11.78, 95% CI 1.61 to 86.29), and history of previous stroke (OR=3.89, 95% CI 1.12 to 13.46) and diabetes mellitus (OR=3.57, 95% CI 1.04 to 12.28) predicted central causes of dizziness. CONCLUSIONS: Most dizzy patients had benign causes. Several clinical factors favoured a diagnosis of central neurological causes of dizziness.

Modeling for intra-body communication with bone effect.

Intra-body communication (IBC) is a new, different "wireless" communication technique based on the human tissue. This short range "wireless" communication technology provides an alternative solution to wearable sensors, home health system, telemedicine and implanted devices. The development of the IBC enables the possibilities of providing less complexity and convenient communication methodologies for these devices. By regarding human tissue as communication channel, IBC making use of the conductivities properties of human tissue to send electrical signal from transmitter to receiver. In this paper, the authors proposed a new mathematical model for galvanic coupling type IBC based on a human limb. Starting from the electromagnetic theory, the authors treat human tissue as volume conductor, which is in analogous with the bioelectric phenomena analysis. In order to explain the mechanism of galvanic coupling type technique of IBC, applying the quasi-static approximation, the governing equation can be reduced to Laplace Equation. Finally, the analytical model is evaluated with on-body measurement for testing its performance. The comparison result shows that the developed mathematical model can provide good approximation for galvanic coupling type IBC on human limb under low operating frequencies.

Simple electrical model and initial experiments for intra-body communications.

Intra-Body Communication(IBC) is a short range "wireless" communication technique appeared in recent years. This technique relies on the conductive property of human tissue to transmit the electric signal among human body. This is beneficial for devices networking and sensors among human body, and especially suitable for wearable sensors, telemedicine system and home health care system as in general the data rates of physiologic parameters are low. In this article, galvanic coupling type IBC application on human limb was investigated in both its mathematical model and related experiments. The experimental results showed that the proposed mathematical model was capable in describing the galvanic coupling type IBC under low frequency. Additionally, the calculated result and experimental result also indicated that the electric signal induced by the transmitters of IBC can penetrate deep into human muscle and thus, provide an evident that IBC is capable of acting as networking technique for implantable devices.

Cost-consequence analysis comparing 2-octyl cyanoacrylate tissue adhesive and suture for closure of simple lacerations: a randomized controlled trial.

STUDY OBJECTIVE: We investigate the cost difference between conventional suture and tissue adhesive methods in simple wound closure. METHODS: A cost-consequence analysis was conducted alongside a nonblinded randomized controlled trial comparing 2-octyl cyanoacrylate tissue adhesive with conventional suture in simple lacerations closure in emergency departments (EDs) of a university teaching hospital and a major regional hospital in Hong Kong. One hundred eighty-six adult patients with simple lacerations of length within 8 cm were randomized to receive tissue adhesive (93 patients) or conventional suture (93 patients) for wound closure. The primary outcome measures were the costs to the Hospital Authority and the charges on participants incurred in each treatment method. The secondary outcome measures included the cosmetic visual analog scale, visual analog scale, Wound Evaluation Score, total time spent in each closure method, and the overall patients' satisfaction on the whole process of wound management. RESULTS: The 2 groups had similar baseline characteristics. The tissue adhesive method incurred a higher cost to the Hospital Authority (216.12 [US $27.70] versus 171.33 [US $21.96]; absolute difference 44.79 [US $5.74] [95% confidence interval (CI) 32.76 to 55.95 [US $4.20 to 7.14]]) but a lower charge to patients (109.68 [US $14.06] versus 156.96 [US $20.12]; absolute difference 47.28 [US $6.06] [95% CI, 35.58 to 58.98 [US $4.56 to 7.56]) than the conventional suture method. The mean cosmetic visual analog scale score, visual analog scale score, and Wound Evaluation Score of the 2 groups were similar at various intervals within 3 months after wound closure. Compared with the suture group, the tissue adhesive group had a shorter median procedure time, fewer patients had wound erythema or swelling after wound closure, fewer patients required analgesics on discharge at ED, and there was a higher overall patient satisfaction score. CONCLUSION: Simple wounds closed by tissue adhesives incur a higher cost to the Hospital Authority than the conventional suture but may be favored by patients because of lower personal charge.

Features discriminating SARS from other severe viral respiratory tract infections.

This study investigated the discriminatory features of severe acute respiratory syndrome (SARS) and severe non-SARS community-acquired viral respiratory infection (requiring hospitalization) in an emergency department in Hong Kong. In a case-control study, clinical, laboratory and radiological data from 322 patients with laboratory-confirmed SARS from the 2003 SARS outbreak were compared with the data of 253 non-SARS adult patients with confirmed viral respiratory tract infection from 2004 in order to identify discriminatory features. Among the non-SARS patients, 235 (93%) were diagnosed as having influenza infections (primarily H3N2 subtype) and 77 (30%) had radiological evidence of pneumonia. In the early phase of the illness and after adjusting for baseline characteristics, SARS patients were less likely to have lower respiratory symptoms (e.g. sputum production, shortness of breath, chest pain) and more likely to have myalgia (p < 0.001). SARS patients had lower mean leukocyte and neutrophil counts (p < 0.0001) and more commonly had "ground-glass" radiological changes with no pleural effusion. Despite having a younger average age, SARS patients had a more aggressive respiratory course requiring admission to the ICU and a higher mortality rate. The area under the receiver operator characteristic curve for predicting SARS when all variables were considered was 0.983. Using a cutoff score of >99, the sensitivity was 89.1% (95%CI 82.0-94.0) and the specificity was 98.0% (95%CI 95.4-99.3). The area under the receiver operator characteristic curve for predicting SARS when all variables except radiological change were considered was 0.933. Using a cutoff score of >8, the sensitivity was 80.7% (95%CI 72.4-87.3) and the specificity was 94.5% (95%CI 90.9-96.9). Certain clinical manifestations and laboratory changes may help to distinguish SARS from other influenza-like illnesses. Scoring systems may help identify patients who should receive more specific tests for influenza or SARS.

The Role of RCAS1 and oxytocinase in immune tolerance during pregnancy.

OBJECTIVES: To determine and compare the level of RCAS1 (receptor-binding cancer antigen expressed in SiSo cells) in placentas at term as well as oxytocinase/cystine amino peptidase (CAP) serum level a few days before labor in order to evaluate their possible role in the regulation of maternal immune response during pregnancy and in initiation of labor. METHODS: We estimated the RCAS1 content in 44 placental tissue samples, using Western blot method. We also assessed CAP serum level by its enzymatic activity, using L-cystine-di-beta-naphthylamide as a synthetic substrate. The statistical analysis was performed using Shapiro-Wilk procedure. Student's t test was applied to compare the differences between parametric data. A value of p < 0.05 was considered significant. RESULTS: RCAS1 was found in all placental tissue samples examined. The differences in the RCAS1 relative amount depended on the onset of labor, with the highest level in induced labor and the lowest in spontaneous labor. The differences were also observed in the CAP serum level with the highest level in pregnant women whose labor was induced. CONCLUSIONS: We have observed a link between the expression of the two proteins examined and the onset of the labor. Therefore, we posit that RCAS1 and CAP may play a role in the downregulation of the maternal immune response during pregnancy and may participate in the initiation of the labor.

Performance specification for lower limb orthotic devices.

OBJECTIVE: To establish the range of forces and moments applied to lower limb orthoses during ambulation by routine users. DESIGN: Well-established gait analysis techniques were used to determine the loading at the major joints. It was assumed that the joint moments were transmitted by the orthosis encompassing any particular joint. Two hundred and five assessments of 164 patients were successfully completed by a consortium of four gait laboratories in Europe. The orthosis specification and patient clinical data were also recorded. BACKGROUND: The design and development of orthoses has occurred largely by evolution rather than by formal engineering methods. In particular, formal design has been hampered by a lack of information on the forces and moments applied during ambulation. METHODS: A standard gait analysis procedure was employed to capture the data. In-house biomechanical models were used to calculate the joint loading. Data were normalised with respect to patient weight and leg length. RESULTS: It was found that the median maximum normalised ankle moment transmitted by an ankle foot orthosis was 0.15 and the maximum knee moment was 0.09. The greatest moment transmitted by the hip joint of a hip knee ankle foot orthosis was also 0.09. There was a wide variation in the data due to differences in the impairments of the test subjects. CONCLUSION: It is possible to estimate the loads transmitted by an orthosis using established gait analysis procedures without the need for load measurement transducers. There is now a need both to collect a larger representative dataset and to perform validation studies with transducers.

Functional improvement after physiotherapy with a continuous infusion of local anaesthetics in patients with complex regional pain syndrome.

Three patients were referred to our pain clinic with evidence of complex regional pain syndrome in their extremities. Two presented at the atrophic stage with joint contractures. Multiple analgesics had been prescribed without long-lasting relief. Physiotherapy was required to improve physical activity but was severely limited by pain. We instituted local anaesthetic infusion with the possibility of self-supplementation to facilitate physiotherapy; two via brachial plexus catheters for hand pain and one via epidural catheter for knee pain. Although their resultant pain scores were variable after cessation of local anaesthetic infusion, all the affected joints exhibited marked improvement in range of movement. We propose that this technique is a useful option for patients in all stages of complex regional pain syndrome where the emphasis is now directed toward functional improvement.

The ASA Physical Status Classification: inter-observer consistency. American Society of Anesthesiologists.

The American Society of Anesthesiologists (ASA) physical status classification system has previously been shown to be inconsistently applied by anaesthetists. One hundred and sixty questionnaires were sent out to all specialist anaesthetists in Hong Kong. Ten hypothetical patients, identical to those of a similar study undertaken 20 years ago, each with different types and degrees ofphysical disability were described. Respondents were asked about their country of training and type of anaesthetic practice and to assign an ASA classification status for each patient. Ninety-seven questionnaires were returned (61%) after two mailings. Agreement for each patient within groups, between groups and overall comparisons were made. Percentage of agreement was between 31 to 85%. Overall correlation was only fair in all groups (Kappa indices: 0.21-0.4). We found that the current pattern of inter-observer inconsistency of classification was similar to that 20 years ago and exaggerated between locally and overseas trained specialists (P<0.05). The validity of the ASA system, its usefulness and the need for a new, more precise scoring system is discussed.

Submental intubation in a patient with beta-thalassaemia major undergoing elective maxillary and mandibular osteotomies.

A 33-yr-old woman with marked maxillo-facial deformities as a result of underlying beta-thalassaemia major was to undergo corrective maxillary and mandibular osteotomies. The placement of an endotracheal tube posed a problem in this patient because of anatomical deformities in her nasal passage, surgical constraints on using the oral route, and reluctance of the patient to have a tracheostomy. This case report describes the use of a submental tracheal intubation technique, and the associated anaesthetic difficulties encountered in patients with this pathology.

Self-starting mode locking in a Cr:forsterite laser by use of non-epitaxially-grown semiconductor-doped silica films.

We demonstrate RF sputtered, non-epitaxially-grown semiconductor nanocrystallite-doped silica films for mode locking a Cr:forsterite laser. We controlled the size and the optical properties of the nanocrystallites by varying the ratio of InAs to SiO(2) during fabrication. Femtosecond pump-probe measurements were performed to characterize the nonlinear optical properties of these films, revealing their lower saturation fluences. Using the InAs-doped silica films as saturable absorbers permitted self-starting Kerr-lens mode locking (KLM), generating pulses of 25-fs duration with 91-nm spectral bandwidth at 1.3 microm . We also describe saturable-absorber mode-locked operation without KLM and investigate its dependence on intracavity dispersion.

Validation of apple cider pasteurization treatments against Escherichia coli O157:H7, Salmonella, and Listeria monocytogenes.

Time and temperature pasteurization conditions common in the Wisconsin cider industry were validated using a six-strain cocktail of Escherichia coli O157:H7 and acid-adapted E. coli O157:H7 in pH- and degrees Brix-adjusted apple cider. Strains employed were linked to outbreaks (ATCC 43894 and 43895, C7927, and USDA-FSIS-380-94) or strains engineered to contain the gene for green fluorescent protein (pGFP ATCC 43894 and pGFP ATCC 43889) for differential enumeration. Survival of Salmonella spp. (CDC 0778. CDC F2833, and CDC H0662) and Listeria monocytogenes (H0222, F8027, and F8369) was also evaluated. Inoculated cider of pH 3.3 or 4.1 and 11 or 14 degrees Brix was heated under conditions ranging from 60 degrees C for 14 s to 71.1 degrees C for 14 s. A 5-log reduction of nonadapted and acid-adapted E. coli O157:H7 was obtained at 68.1 degrees C for 14 s. Lower temperatures, or less time at 68.1 degrees C, did not ensure a 5-log reduction in E. coli O157:H7. A 5-log reduction was obtained at 65.6 degrees C for 14 s for Salmonella spp. L. monocytogenes survived 68.1 degrees C for 14 s, but survivors died in cider within 24 h at 4 degrees C. Laboratory results were validated with a surrogate E coli using a bench-top plate heat-exchange pasteurizer. Results were further validated using fresh unpasteurized commercial ciders. Consumer acceptance of cider pasteurized at 68.1 degrees C for 14 s (Wisconsin recommendations) and at 71.1 degrees C for 6 s (New York recommendations) was not significantly different. Hence, we conclude that 68.1 degrees C for 14 s is a validated treatment for ensuring adequate destruction of E. coli O157:H7, Salmonella spp., and L. monocytogenes in apple cider.