Diagnostic laparoscopy to exclude malrotation following inconclusive upper gastrointestinal contrast study in infants.

PURPOSE: We report the use of diagnostic laparoscopy as an alternative to laparotomy in the investigation of infants with clinical features concerning for malrotation and inconclusive upper gastrointestinal contrast study. METHOD: Case note review of all infants in whom laparoscopy was performed during 2016-2020 to investigate for possible malrotation. RESULTS: Eight infants were identified. All presented with acute clinical features of malrotation (bilious vomit) without evidence of an alternate explanatory diagnosis. All underwent upper gastrointestinal contrast study, with three also undergoing abdominal ultrasound. The radiological examinations could not exclude malrotation and all proceeded to laparoscopy. At laparoscopy, the small intestine was run to exclude the presence of midgut volvulus. In six cases, normal rotation was confirmed and no abnormal pathology was found. Two proceeded to laparotomy and underwent correction of malrotation. All infants recovered without complication. CONCLUSION: Laparoscopy is an excellent modality for further investigation of infants presenting acutely in whom intestinal malrotation cannot be formally excluded radiologically. The positive identification of the DJ flexure and cecum in correct anatomical sites, both fixed to the posterior abdominal wall, provides adequate reassurance of low risk of volvulus and avoids a full laparotomy. We recommend diagnostic laparoscopy in cases of inconclusive upper gastrointestinal contrast study.

Straight-to-test for the two-week-wait colorectal cancer pathway under the updated NICE guidelines reduces time to cancer diagnosis and treatment.

INTRODUCTION: The 2015 National Institute for Health and Care Excellence guidelines widened the referral criteria for the two-week-wait pathway for suspected lower gastrointestinal cancer. We implemented a straight-to-test protocol to accommodate the anticipated increase in referrals. We evaluated the impact of these changes for relevant pathway metrics and clinical outcomes using a retrospective cohort study with historic controls. MATERIALS AND METHODS: We analysed data from all patients referred to a teaching hospital via the two-week-wait pathway for suspected lower gastrointestinal cancer under the previous guidelines between 1 March and 31 August 2015 compared with the same period in 2016, when the updated guidelines and straight-to-test protocol had been implemented. RESULTS: In the 2015 cohort, there were 64 cancer diagnoses from 664 referrals (9.6% pick-up) compared with 58 cancer diagnoses from 954 referrals in the 2016 cohort (6.1% pick-up). Our straight-to-test protocol reduced the median time to cancer diagnosis by 12.5 days (P < 0.001) and reduced the median time to cancer treatment by 7.5 days (P < 0.05) An increased proportion of non-colorectal cancers were diagnosed in 2016 compared with 2015, (37.9% vs 17.2%, P < 0.05) and more adenomas were removed in 2016 compared with 2015 (377 vs 193). DISCUSSION AND CONCLUSION: Our straight-to-test protocol has resulted in a reduction in times to cancer diagnosis and cancer treatment, despite an increase in the number of referrals. The new referral criteria have considerable resource implications, but their implementation did not result in an increase in the total number of cancers diagnosed.

Potential errors in relative dose measurements in kilovoltage photon beams due to polarity effects in plane-parallel ionisation chambers.

Plane-parallel ionisation chambers are regularly used to conduct relative dosimetry measurements for therapeutic kilovoltage beams during commissioning and routine quality assurance. This paper presents the first quantification of the polarity effect in kilovoltage photon beams for two types of commercially available plane-parallel ionisation chambers used for such measurements. Measurements were performed at various depths along the central axis in a solid water phantom and for different field sizes at 2 cm depth to determine the polarity effect for PTW Advanced Markus and Roos ionisation chambers (PTW-Freiburg, Germany). Data was acquired for kilovoltage beams between 100 kVp (half-value layer (HVL) = 2.88 mm Al) and 250 kVp (HVL = 2.12 mm Cu) and field sizes of 3-15 cm diameter for 30 cm focus-source distance (FSD) and 4 × 4 cm2-20 × 20 cm2 for 50 cm FSD. Substantial polarity effects, up to 9.6%, were observed for the Advanced Markus chamber compared to a maximum 0.5% for the Roos chamber. The magnitude of the polarity effect was observed to increase with field size and beam energy but was consistent with depth. The polarity effect is directly influenced by chamber design, with potentially large polarity effects for some plane-parallel ionisation chambers. Depending on the specific chamber used, polarity corrections may be required for output factor measurements of kilovoltage photon beams. Failure to account for polarity effects could lead to an incorrect dose being delivered to the patient.

The effect of the native kinematics of the knee on the outcome following total knee arthroplasty.

AIMS: The aim of this study was to investigate differences in pain, range of movement function and satisfaction at three months and one year after total knee arthroplasty (TKA) in patients with an oblique pattern of kinematic graph of the knee and those with a varus pattern. PATIENTS AND METHODS: A total of 91 patients who underwent TKA were included in this retrospective study. Patients (59 women and 32 men with mean age of 68.7 years; 38.6 to 88.4) were grouped according to kinematic graphs which were generated during navigated TKA and the outcomes between the groups were compared. RESULTS: The graphs were varus in 50 patients (55%), oblique in 19 (21%), neutral in 17 (18.5%) and valgus in five (5.5%). After adjustment for pre-operative scores and gender, compared with patients with varus knee kinematics, patients with an oblique kinematic graph had a poorer outcome with lower Knee Society scores at three months (9.2 points, p = 0.038). CONCLUSION: We found four distinct kinematic graphs in knees and that patients with an oblique graph have a poorer outcome in the short-term after TKA. Cite this article: Bone Joint J 2016;98-B:1471-8.

Corrosion at the neck-stem junction as a cause of metal ion release and pseudotumour formation.

We present a series of 35 patients (19 men and 16 women) with a mean age of 64 years (36.7 to 75.9), who underwent total hip replacement using the ESKA dual-modular short stem with metal on-polyethylene bearing surfaces. This implant has a modular neck section in addition to the modular head. Of these patients, three presented with increasing post-operative pain due to pseudotumour formation that resulted from corrosion at the modular neck-stem junction. These patients underwent further surgery and aseptic lymphocytic vaculitis associated lesions were demonstrated on histological analysis. Retrieval analysis of two modular necks showed corrosion at the neck-stem taper. Blood cobalt and chromium levels were measured at a mean of nine months (3 to 28) following surgery. These were compared with the levels in seven control patients (three men and four women) with a mean age of 53.4 years (32.1 to 64.1), who had an identical prosthesis and articulation but with a prosthesis that had no modularity at neck-stem junction. The mean blood levels of cobalt in the study group were raised at 50.75 nmol/l (5 to 145) compared with 5.6 nmol/l (2 to 13) in control patients. Corrosion at neck-stem tapers has been identified as an important source of metal ion release and pseudotumour formation requiring revision surgery. Finite element modelling of the dual modular stem demonstrated high stresses at the modular stem-neck junction. Dual modular cobalt-chrome hip prostheses should be used with caution due to these concerns.

Computer navigated total knee arthroplasty: aspects of a single unit's experience of 777 cases.

The use of computer navigation and conventional techniques in total knee arthroplasty remains controversial. Advocates of computer navigated techniques cite better alignment of components and reduced morbidity associated with avoidance of intramedullary instrumentation as a rationale for their use. In contrast, proponents of conventional techniques argue that better alignment does not correlate with a better functional outcome and that the conventional approach avoids the perceived risk of fracture associated with bicortical insertion of navigation tracker pins. All total knee arthoplasties performed at our institution are prospectively monitored for life in a dedicated Joint Replacement Assessment Clinic (JRAC). Patients are reviewed by physiotherapists, independent of the surgeons who performed surgery, both preoperatively and at six weeks, three and six months, and one, two and five years postoperatively (and every five years thereafter). Patients are assessed using validated outcome measures (Knee Society Score, Western Ontario and McMaster Universities (WOMAC) osteoarthritis index, Short Form SF-36 Health Survey (version 2) and a patient satisfaction score). In addition, at 6 months post surgery, a CT scan of each implanted prosthesis is performed using the Perth CT knee protocol. The findings of a single unit's experience of 777 navigated primary total knee replacements are discussed and critically compared to the body of literature that currently relates to this controversial topic.

N,N'-Dialkylaminoalkylcarbonyl (DAAC) prodrugs and aminoalkylcarbonyl (AAC) prodrugs of 4-hydroxyacetanilide and naltrexone with improved skin permeation properties.

N,N'-Dialkylaminoalkylcarbonyl (DAAC) and aminoalkylcarbonyl (AAC) prodrugs of phenolic drugs acetaminophen (APAP) and naltrexone (NTX) are reported. The effects of incorporation of a basic amine group into the promoiety of an acyl prodrug of a phenolic drug on its skin permeation properties are also presented. DAAC-APAP prodrugs were synthesized via a three-step procedure starting with haloalkylcarbonyl esters which were reacted with five different amines: dimethylamine, diethylamine, dipropylamine, morpholine, and piperidine. The spacing between the amino group and the carbonyl group of the acyl group was 1-3 CH(2). After the hydrolysis of the ester, the carboxylic acid product was subsequently coupled with the parent drug via a dicyclohexyl carbodiimide (DCC) mediated coupling to yield the DAAC-APAP-HCl prodrugs in excellent yields. The AAC prodrugs were synthesized using commercially available Boc-protected amino acids using DCC or EDCI as coupling agents. The yields of the prodrugs synthesized using these two different methods have been compared. Half-lives (t(1/2)) of a few members of the DAAC and AAC series were measured in buffer (pH 6.0, 20mM). The members evaluated in hydrolysis experiments exhibit a t(1/2) range of 15-113min. Among AAC-APAP prodrugs, the isopropyl group in valinate-APAP-HCl exerted a steric effect that increased the t(1/2) value for this prodrug compared to alaninate-APAP-HCl or prolinate-APAP-HCl. The 2-morpholinylacetate-APAP prodrug was able to achieve twice the flux of APAP in in vitro diffusion cell experiments through hairless mouse skin.

A correlation of flux through a silicone membrane with flux through hairless mouse skin and human skin in vitro.

The maximum fluxes of 32 prodrugs and parabens through polydimethylsiloxane membranes from water (EXP log J(MPAQ)) have been correlated with the maximum flux of the same prodrugs and parabens through hairless mouse skin from water (EXP log J(MMAQ)): EXP log J(MMAQ)=0.608 EXP log J(MPAQ)-0.636, r(2)=0.743. The average of the absolute values for the differences between the EXP log J(MMAQ) and the log J(MMAQ) calculated from EXP log J(MPAQ) (Delta log J(MMAQ)) was 0.227 log units. Similarly the maximum fluxes of 11 unrelated permeants through human skin from water (EXP log J(MHAQ)) was correlated with the EXP log J(MPAQ) for the same permeants: EXP log J(MHAQ)=0.516 EXP log J(MPAQ)-0.922, r(2)=0.82 and Delta log J(MHAQ)=0.252 log units. Since the best fit of the databases for EXP log J(MPAQ), log J(MMAQ) and log J(MHAQ) was to the Roberts-Sloan (RS) model, and the dependency of RS on a balance in lipid and aqueous solubility for optimization of topical delivery has been established, the present correlation suggests that the flux through a silicone can be used to predict flux through mouse or human and that the physicochemical properties that lead to optimized flux through one membrane will lead to optimized flux through the others.

A comparison of the fit of flux through hairless mouse skin from water data to three model equations.

Data for the delivery of total species containing parent drugs from water through hairless mouse skin by prodrugs, logJ(MMAQ), has been fitted to the Roberts-Sloan, RS, the Kasting-Smith-Cooper, KSC, and Magnusson-Anissimov-Cross-Roberts, MACR, equations. The RS model which contains a parameter for the dependence of flux on solubility in water, S(AQ), as well as solubility in the lipid isopropyl myristate, S(IPM), gave the best fit: logJ(MMAQ)=-2.30+0.575 logS(IPM)+0.425 logS(AQ)-0.0016MW, r(2)=0.903. The values for the coefficients to the parameters are quite similar to those obtained when the RS model was fit to flux of solutes from water through human skin, logJ(MHAQ). There was no trend in predicting the under or over-performance of prodrugs based on their fit to the RS model and whether they were more or less soluble than their parent drugs. There was an inverse dependence of logJ(MMAQ) on partition coefficients or permeability coefficients similar to that observed for logJ(MHAQ). The similarities in trends for results for logJ(MMAQ) and logJ(MHAQ) suggests that design directives obtained from mouse skin can be extended to design new prodrugs or select new drugs for delivery through human skin.

Computer navigation versus conventional total knee replacement: no difference in functional results at two years.

We previously compared the component alignment in total knee replacement using a computer-navigated technique with a conventional jig-based method. We randomly allocated 71 patients to undergo either computer-navigated or conventional replacement. An improved alignment was seen in the computer-navigated group. The patients were then followed up post-operatively for two years, using the Knee Society score, the Short Form-36 health survey, the Western Ontario and McMaster Universities osteoarthritis index, the Bartlett Patellar pain questionnaire and the Oxford knee score, to assess functional outcome. At two years post-operatively 60 patients were available for assessment, 30 in each group and 62 patients completed a postal survey. No patient in either group had undergone revision. All variables were analysed for differences between the groups either by Student's t-test or the Mann-Whitney U test. Differences between the two groups did not reach significance for any of the outcome measures at any time point. At two years postoperatively, the frequency of mild to severe anterior pain was not significantly different (p = 0.818), varying between 44% (14) for the computer-navigated group, and 47% (14) for the conventionally-replaced group. The Bartlett Patellar score and the Oxford knee score were also not significantly different (t-test p = 0.161 and p = 0.607, respectively). The clinical outcome of the patients with a computer-navigated knee replacement appears to be no different to that of a more conventional jig-based technique at two years post-operatively, despite the better alignment achieved with computer-navigated surgery.

Synthesis and topical delivery of N-alkyl-N-alkyloxycarbonylaminomethyl prodrugs of a model phenolic drug: acetaminophen.

The synthesis, physicochemical characterization and flux of a homologous series of N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) prodrugs of a model phenolic drug, acetaminophen (APAP), have been investigated. The most water soluble member of the series gave the highest transdermal delivery from isopropyl myristate (IPM) through hairless mouse skin. The flux of NANAOCAM prodrugs of APAP was accurately predicted by the Roberts-Sloan (RS) equation.

Topical delivery of N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) prodrugs of theophylline (ThH).

N(7)-(N-Alkyl-N-alkyloxycarbonyl) aminomethyl (NANAOCAM) prodrugs of theophylline (ThH) have been synthesized and characterized by their solubilities in isopropyl myristate (S(IPM)), solubilities in water (S(AQ)), partition coefficients between IPM and pH 4.0 buffer (K(IPM:4.0)) and by their ability to penetrate hairless mouse skin from IPM (J(MIPM)). The most lipid soluble and water soluble member, N-methyl-N-ethyloxy-carbonylaminomethyltheophylline, gave the highest flux through hairless mouse skin from IPM compared to ThH. The flux of NANAOCAM prodrugs of ThH can be accurately predicted by the Roberts-Sloan (RS) equation.

Computer navigation of the acetabular component: a cadaver reliability study.

Our aim was to assess the intra- and inter-observer reliability in the establishment of the anterior pelvic plane used in imageless computer-assisted navigation. From this we determined the subsequent effects on version and inclination of the acetabular component. A cadaver model was developed with a specifically-designed rod which held the component tracker at a fixed orientation to the pelvis, leaving the anterior pelvic plane as the only variable. Eight surgeons determined the anterior pelvic plane by palpating and registering the bony landmarks as reference points. The exact anterior pelvic plane was then established by using anatomically-placed bone screws as reference points. The difference between the surgeons was found to be highly significant (p < 0.001). The variation was significantly larger for anteversion (sd 9.6 degrees ) than for inclination (sd 6.3 degrees ). The present method for registering pelvic landmarks shows significant inaccuracy, which highlights the need for improved methods of registration before this technique is considered to be safe.

Application of the transformed Potts-Guy equation to in vivo human skin data.

Data developed by Wenkers and Lippold for the flux of 10 nonsteroidal anti-inflammatory drugs from light mineral oil (MO) through human skin in vivo has been analyzed using the transformed Potts-Guy equation. The analysis shows that the flux is dependent not only on the solubility in MO (S(MO)), but also on the solubility in acidic water (S(AQ)). This dependence of flux on S(AQ) shows that the previously reported dependence of flux on S(AQ) from in vitro experiments using hairless mouse skin is not an artifact of the in vitro experiments but is due to a characteristic of the skin barrier. Further inspection of the equations used by Wenkers and Lippold in their analyses of their data shows that the equations are variations of the transformed Potts-Guy equation.

Frequency of serum low-density lipoprotein cholesterol measurement and frequency of results < or=100 mg/dl among patients who had coronary events (Northwest VA Network Study).

This population-based, cross-sectional analysis targeted all veterans with coronary heart disease (CHD) who were active patients in primary care or cardiology clinics in the Veterans Health Administration Northwest Network from July 1998 to June 1999. We report guideline compliance rates, including whether low-density lipoprotein (LDL) was measured, and if measured, whether the LDL was < or=100 mg/dl. In addition, we utilized multivariate logistic regression to determine patient characteristics associated with LDL measurements and levels. Of 13,891 active patients with CHD, 5,552 (40.0%) did not have a current LDL measurement. Of those with LDL measurements, 39.1% were at the LDL goal of < or =100 mg/dl, whereas 26.5% had LDL > or =130 mg/dl. Male gender, younger age, history of angioplasty or coronary artery bypass grafting, current hypertension, diabetes mellitus, and angina pectoris were associated with increased likelihood of LDL measurement. Older age and current diabetes and angina were associated with increased likelihood of LDL being < or =100 mg/dl, if measured. Although these rates of guideline adherence in the CHD population compare well to previously published results, they continue to be unacceptably low for optimal clinical outcomes. Attention to both LDL measurement and treatment (if elevated) is warranted.

Divalproex sodium in alcohol withdrawal: a randomized double-blind placebo-controlled clinical trial.

BACKGROUND: Divalproex sodium, an anticonvulsant and antikindling agent and gamma-aminobutyric acid enhancer, has been proposed as an alternative to benzodiazepines for treating alcohol withdrawal. This study reports on a randomized, double-blind, placebo-controlled trial of divalproex sodium in acute alcohol withdrawal. METHODS: Thirty-six hospitalized patients experiencing moderate alcohol withdrawal as measured by a score of at least 10 on the revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar) were randomized to receive either divalproex sodium 500 mg three times per day for 7 days or matched placebo in a double-blind manner. All subjects received a baseline dose of oxazepam and had additional oxazepam available as a rescue medication in accordance with a standard, symptom-triggered detoxification protocol. Mean total milligrams of oxazepam received, progression of withdrawal symptoms, psychological distress as measured by the Symptom Checklist-90, side effects, and adverse outcomes were compared between groups. RESULTS: Use of divalproex sodium resulted in less use of oxazepam (p < 0.033). Group differences seemed primarily driven by those subjects who experienced symptoms above threshold level (CIWA-Ar >or=10) after 12 hr. The progression in severity of withdrawal symptoms (increase in CIWA-Ar above baseline) was also significantly greater in the placebo group (p < 0.05). CONCLUSIONS: This placebo-controlled pilot study suggests that divalproex sodium significantly affects the course of acute alcohol withdrawal and reduces the need for treatment with a benzodiazepine. A more aggressive loading dose strategy may demonstrate a more robust or earlier response.

Attrition prevention with individuals awaiting publicly funded drug treatment.

AIMS: To evaluate the effectiveness of a motivational intervention to reduce attrition from a waiting list for substance abusers seeking publicly funded treatment. DESIGN: Randomized clinical trial comparing an "attrition prevention" condition to standard care while awaiting treatment admission. SETTING: A centralized substance abuse assessment and referral center in Seattle, Washington. PARTICIPANTS: Substance abusers (n = 654) eligible for publicly funded drug abuse treatment. MEASUREMENTS: Alcohol and drug use, substance-related negative consequences, areas in need of help, perceived need for help, emotional status, readiness to change, reasons for seeking and perceived barriers to entering treatment. FINDINGS: Overall, approximately 70% of clients entered treatment, and of these approximately 70% completed their assigned treatment. Those who entered treatment showed significant reductions in substance use and improved psychosocial function at a short-term 3-month follow-up. However, the attrition prevention intervention had no differential effect on treatment entry, completion or outcome compared to the standard waiting list. Further, there were no differences across therapists on these outcome measures. CONCLUSIONS: A motivational attrition prevention intervention did not enhance treatment entry, completion or outcome among treatment-seeking substance abusers. It is suggested that alternative strategies, such as contingency management and case management, may help facilitate treatment entry for individuals seeking publicly funded treatment.

Trauma, symptoms of posttraumatic stress disorder, and associated problems among incarcerated veterans.

OBJECTIVE: To help improve treatment for incarcerated veterans, the study examined exposure to trauma, symptoms of posttraumatic stress disorder (PTSD), functional status, and treatment history in a group of incarcerated veterans. METHODS: A convenience sample of 129 jailed veterans who agreed to receive outreach contact completed the Life Event History Questionnaire, the PTSD Checklist-Civilian Version (PCL-C), and the Addiction Severity Index. Participants who had scores of 50 or above on the PCL-C, designated as screening positive for PTSD, were compared with those whose scores were below 50, designated as screening negative for PTSD. RESULTS: Some 112 veterans (87 percent) reported traumatic experiences. A total of 51 veterans (39 percent) screened positive for PTSD, and 78 veterans (60 percent) screened negative. Compared with veterans who screened negative for PTSD, those who screened positive reported a greater variety of traumas; more serious current legal problems; a higher lifetime use of alcohol, cocaine, and heroin; higher recent expenditures on drugs; more psychiatric symptoms; and worse general health despite more previous psychiatric and medical treatment as well as treatment for substance abuse. CONCLUSIONS: The findings encourage the development of an improved treatment model to keep jailed veterans with PTSD from repeated incarceration.

Topical delivery of 5-fluorouracil (5-Fu) by 3-alkylcarbonyl-5-Fu prodrugs.

The solubilities in isopropyl myristate (SIPM) and pH 4.0 buffer (SAQ) and the partition coefficients between IPM and pH 4.0 buffer (KIPM:AQ) have been measured for a series of 3-alkylcarbonyl-5-fluorouracil prodrugs (3-AC-5-FU). The 3-AC-5-FU prodrugs were all 100 times more soluble in IPM and the first two members of the series were also more soluble in pH 4.0 buffer than 5-FU. The abilities of the 3-AC-5-FU prodrugs to deliver total 5-FU species through hairless mouse skin from IPM suspensions (Ji) were also measured. The 3-propionyl derivative 3, which exhibited the highest SAQ in the series, gave the highest Ji value. The SIPM, SAQ and molecular weights (mw) of the 3-AC-5-FU series correctly predicted the rank order and very closely (0.10 log units) predicted the absolute values for logJi using the transformed Potts-Guy equation. Although the series of 3-AC-5-FU prodrugs was generally quite effective at increasing Ji (2-20 times), the best 3-AC-5-FU prodrug was not as effective as the best 1-alkylcarbonyl-5-FU prodrug (1-AC-5-FU) at increasing Ji and the ability of the 3-AC-5-FU prodrugs to increase the concentration of total 5-FU species in the skin was 2-5 times less than the 1-AC-5-FU prodrugs. Thus, the 1-AC-5-FU prodrugs remain as the best prodrugs with which to enhance the topical delivery of 5-FU.

Inhibition of alpha4 integrin protects against transient focal cerebral ischemia in normotensive and hypertensive rats.

BACKGROUND AND PURPOSE: The present study was performed to determine the role of alpha4 (CD49d), a member of the integrin family of adhesion molecules, in ischemic brain pathology. METHODS: Male spontaneously hypertensive rats (SHR) or Sprague-Dawley rats underwent 60-minute middle cerebral artery occlusion (MCAO) followed by 23-hour reperfusion. Animals were injected intravenously with 2.5 mg/kg anti-rat alpha4 antibody (TA-2) or isotype control antibody (anti-human LFA-3 IgG(1), 1E6) 24 hours before MCAO. Infarct volume was quantified by staining of fresh tissue with tetrazolium chloride and myeloperoxidase activity measured in SHR tissue homogenates 24 hours after MCAO. In SHR, mean arterial blood pressure was recorded before and after MCAO in animals treated with TA-2 and 1E6. Fluorescence-activated cell sorting analysis was performed on peripheral blood leukocytes before and after MCAO. RESULTS: TA-2 treatment significantly reduced total infarct volume by 57.7% in normotensive rats (1E6, 84.2+/-11.5 mm(3), n=17; TA-2, 35.7+/-5.9 mm(3), n=16) and 35.5% in hypertensive rats (1E6, 146.6+/-15.5 mm(3), n=15; TA-2, 94.4+/-25.8 mm(3), n=11). In both strains, TA-2 treatment significantly reduced body weight loss and attenuated the hyperthermic response to MCAO. In SHR, treatment with TA-2 significantly reduced brain myeloperoxidase activity. Resting mean arterial blood pressure was unaffected by treatment. Leukocyte counts were elevated in TA-2-treated rats. Fluorescence-activated cell sorting analysis demonstrated the ability of TA-2 to bind to CD3+, CD4+, CD8+, and CD11b+ cells in both naive animals and after MCAO. CONCLUSIONS: These data demonstrate that inhibition of alpha4 integrin can protect the brain against ischemic brain injury and implicate endogenous alpha4 integrin in the pathogenesis of acute brain injury. The mechanism by which alpha4 integrin inhibition offers cerebroprotection is independent of blood pressure modulation and is likely due to inhibition of leukocyte function.