Unilateral nephrectomized SHR/NDmcr-cp rat shows a progressive decline of glomerular filtration with tubular interstitial lesions.

In patients with diabetic kidney disease (DKD), the estimated glomerular filtration rate (eGFR) or creatinine clearance rate (Ccr) is always used as an index of decline in renal function. However, there are few animal models of DKD that could be used to evaluate renal function based on GFR or Ccr. For this reason, it is desirable to develop animal models to assess renal function, which could also be used for the evaluation of novel therapeutic agents for DKD. Therefore, we aimed to develop such animal model of DKD by using spontaneously hypertensive rat (SHR)/NDmcr-cp (cp/cp) rats with the characteristics of obese type 2 diabetes and metabolic syndrome. As a result, we have found that unilateral nephrectomy (UNx) caused a chronic Ccr decline, development of glomerular sclerosis, tubular lesions, and tubulointerstitial fibrosis, accompanied by renal anemia. Moreover, losartan-mixed diet suppressed the Ccr decline in UNx-performed SHR/NDmcr-cp rats (UNx-SHR/cp rats), with improvement in renal anemia and histopathological changes. These results suggest that UNx-SHR/cp rats could be used as a DKD model for evaluating the efficacy of therapeutic agents based on suppression of renal function decline.

Pathophysiological analysis of uninephrectomized db/db mice as a model of severe diabetic kidney disease.

Diabetic nephropathy, included in diabetic kidney disease (DKD), is the primary disease leading to end-stage renal disease (ESRD) or dialysis treatment, accounting for more than 40% of all patients with ESRD or receiving dialysis. Developing new therapeutics to prevent the transition to ESRD or dialysis treatment requires an understanding of the pathophysiology of DKD and an appropriate animal model for drug efficacy studies. In this study, we investigated the pathophysiology of diabetic kidney disease with type 2 diabetes in uninephrectomized db/db mice. In addition, the nephrectomized db /db mice from 10 weeks to 42 weeks were used to assess the efficacy of long-term administration of the angiotensin-II-receptor antagonist losartan. The blood and urinary biochemical parameters, main pharmacological endpoint of the losartan therapy, were periodically measured. And at the end, histopathological analysis was performed. Uninephrectomized db/db mice clearly developed obesity and hyperglycemia from young age. Furthermore, they showed renal pathophysiological changes, such as increased urinary albumin-creatinine ratio (UACR) (the peak value 3104 ± 986 in 40-week-old mice), glomerular hypertrophy and increased fibrotic areas in the tubulointerstitial tubules. The blood pressure in the losartan group was significantly low compared to the normotensive Vehicle group. However, as expected, Losartan suppressed the increase in UACR (829±500) indicating the medication was sufficient, but the histopathological abnormalities including tubular interstitial fibrosis did not improve. These results suggest that the uninephrectomized db/db mice are useful as an animal model of the severe DKD indicated by the comparison of the efficacy of losartan in this model with the efficacy of losartan in clinical practice.

Transient ischemic attack without self-awareness of symptoms witnessed by bystanders: analysis of the PROMISE-TIA registry.

BACKGROUND AND PURPOSE: A transient ischemic attack (TIA) can occur without self-awareness of symptoms. We aimed to investigate characteristics of patients with a tissue-based diagnosis of TIA but having no self-awareness of their symptoms and whose symptoms were witnessed by bystanders. METHODS: We used data from the multicenter registry of 1414 patients with a clinical diagnosis of TIA. For patients without evidence of ischemic lesions on imaging, clinical characteristics were compared between patients with and without self-awareness of their TIA symptoms. RESULTS: Among 896 patients (559 men, median age of 70 years), 59 (6.6%) were unaware of their TIA symptoms, but had those symptoms witnessed by bystanders. Patients without self-awareness of symptoms were older and more frequently female, and more likely to have previous history of stroke, premorbid disability, and atrial fibrillation, but less likely to have dyslipidemia than those with self-awareness. Patients without self-awareness of symptoms arrive at hospitals earlier than those with self-awareness (P < 0.001). ABCD2 score was higher in patients without self-awareness of symptoms than those with self-awareness (median 5 vs. 4, P = 0.002). Having no self-awareness of symptoms was a significant predictor of ischemic stroke within 1 year after adjustment for sex, ABCD2 score, and onset to arrival time (hazard ratio = 2.44, 95% confidential interval: 1.10-4.83), but was not significant after further adjustment for arterial stenosis or occlusion. CONCLUSIONS: Patients with a TIA but having no self-awareness of their symptoms might have higher risk of subsequent ischemic stroke rather than those with self-awareness, suggesting urgent management is needed even if patients have no self-awareness of symptoms.

Fatal intracranial haemorrhage occurring after oral anticoagulant treatment initiation for secondary stroke prevention in patients with atrial fibrillation.

BACKGROUND AND PURPOSE: In this pooled analysis of seven multicentre cohorts potential differences were investigated in the incidence, characteristics and outcomes between intracranial haemorrhages (ICHs) associated with the use of non-vitamin K antagonist oral anticoagulants (NOAC-ICH) or with vitamin K antagonists (VKA-ICH) in ischaemic stroke patients after oral anticoagulant treatment initiation for atrial fibrillation (AF). METHODS: Data from 4912 eligible AF patients who were admitted in a stroke unit with ischaemic stroke or transient ischaemic attack and who were treated with either VKAs or NOACs within 3 months post-stroke were included. Fatal ICH was defined as death occurring during the first 30 days after ICH onset. A meta-analysis of available observational studies reporting 30-day mortality rates from NOAC-ICH or VKA-ICH onset was additionally performed. RESULTS: During 5970 patient-years of follow-up 71 participants had an ICH, of whom 20 were NOAC-ICH and 51 VKA-ICH. Patients in the two groups had comparable baseline characteristics, except for the higher prevalence of kidney disease in VKA-ICH patients. There was a non-significant higher number of fatal ICH in patients with VKAs (11 events per 3385 patient-years) than in those with NOACs (three events per 2623 patient-years; hazard ratio 0.32, 95% confidence interval 0.09-1.14). Three-month functional outcomes were similar (P > 0.2) in the two groups. The meta-analysis showed a lower 30-day mortality risk for patients with NOAC-ICH compared to VKA-ICH (relative risk 0.70, 95% confidence interval 0.51-0.95). CONCLUSIONS: Non-vitamin K oral anticoagulants for intracranial haemorrhages and VKA-ICH occurring during secondary stroke prevention of AF patients have comparable baseline characteristics and outcomes except for the risk of fatal ICH within 30 days, which might be greater in VKA-ICH.

Transnasal inferior meatal antrostomy with a mucosal flap for post-Caldwell-Luc mucoceles in the maxillary sinus.

OBJECTIVE: Transnasal inferior meatal antrostomy is increasingly used for the treatment of post-Caldwell-Luc mucoceles in maxillary sinus. This study aimed to report the outcomes after inferior meatal antrostomy with a mucosal flap for recurrent mucoceles. METHOD: The records of patients who had undergone transnasal inferior meatal antrostomy with or without a mucosal flap were reviewed. RESULTS: Transnasal endoscopic inferior meatal antrostomy with or without a mucosal flap was performed in 21 and 49 patients, respectively. No complications were observed. A closing of the antrostomy was found in 9 (18.4 per cent) of the 49 patients who underwent antrostomy without a mucosal flap. No closings were observed in the 21 patients who underwent antrostomy with a mucosal flap. There was a significant difference in the rate of closing for surgery with and without the mucosal flap. CONCLUSION: Transnasal endoscopic inferior meatal antrostomy with a mucosal flap is a safe method for the treatment of post-Caldwell-Luc maxillary mucoceles that effectively prevents recurrence.

Impact of B-type natriuretic peptide (BNP) on development of atrial fibrillation in people with Type 2 diabetes.

AIMS: To examine if a simple biomarker can identify people with diabetes who are at high risk of atrial fibrillation. METHODS: A retrospective cohort study was conducted at a single centre in people with Type 2 diabetes referred to our department between January 2000 and December 2007. In 517 consecutive people without any history, signs or symptoms of atrial fibrillation at baseline, the association between baseline B-type natriuretic peptide level and future atrial fibrillation incidence was examined, with adjustments for other potentially confounding factors. RESULTS: A total of 28 people were diagnosed with new-onset atrial fibrillation during a median 6-year follow-up. When people were categorized into three groups according to B-type natriuretic peptide clinical thresholds (20 and 100 pg/ml), hazard ratios for the development of atrial fibrillation in the middle and highest B-type natriuretic peptide groups were 2.8 and 9.4, respectively, compared with the lowest B-type natriuretic peptide group. Time-dependent receiver-operating curve analysis identified a threshold for B-type natriuretic peptide to detect atrial fibrillation development of 52.8 pg/ml (sensitivity 75.2%, specificity 68.8%). The B-type natriuretic peptide predictive value was independent of and similar to that of left atrial size and ventricular dimension. CONCLUSION: In people with Type 2 diabetes, high baseline B-type natriuretic peptide levels were significantly associated with future atrial fibrillation development.

Serum WFA(+) -M2BP is a non-invasive liver fibrosis marker that can predict the efficacy of direct-acting anti-viral-based triple therapy for chronic hepatitis C.

BACKGROUND: The Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA(+) -M2BP) is a new liver fibrosis glycobiomarker with unique fibrosis-related glyco-alteration. WFA(+) -M2BP is also a useful surrogate marker for the risk of developing hepatocellular carcinoma and for the liver functional reserve. AIM: To evaluate the diagnostic ability of WFA(+) -M2BP for liver fibrosis in the clinical setting and the clinical utility of WFA(+) -M2BP for predicting the efficacy of direct-acting anti-viral (DAA) treatment for chronic hepatitis C patients. METHODS: The study included 159 genotype 1 hepatitis C patients who received DAA-based treatment (telaprevir or simeprevir) combined with pegylated-interferon alpha plus ribavirin (108 telaprevir- and 51 simeprevir-based triple treatment). The relation between baseline serum WFA(+) -M2BP and treatment efficacy was evaluated. RESULTS: The serum WFA(+) -M2BP level significantly increased with the progress of liver fibrosis. Area under the receiver operating characteristic curve analysis identified 2.17 as the cut-off index (COI) for WFA(+) -M2BP for diagnosing advanced fibrosis. The sustained virological response (SVR) rate was significantly, negatively correlated with the serum WFA(+) -M2BP level. Multiple logistic regression analysis found a low serum WFA(+) -M2BP level (<2.17 COI) to be independently associated with SVR (odds ratio, 4.35, P = 0.027). Even for prior nonresponders and patients with the interleukin-28B minor allele or histological advanced fibrosis, treatment outcome was favourable for patients with a low serum WFA(+) -M2BP level. CONCLUSION: Serum WFA(+) -M2BP is a non-invasive liver fibrosis marker useful for predicting the efficacy of DAA-based triple therapy for chronic hepatitis C patients.

Sprouty2 inhibition promotes proliferation and migration of periodontal ligament cells.

OBJECTIVES: We previously demonstrated that a dominant-negative Sprouty2 (Spry2) mutation promotes osteoblast proliferation and differentiation after basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) stimulation, whereas it diminishes proliferation of gingival epithelial cells, thereby inducing favourable conditions for periodontal tissue regeneration. In this study, we investigated how Spry2 inhibition affects the cellular physiology of periodontal ligament (PDL) cells. METHODS: A total of 1-17 PDL cells (multipotent clonal human PDL cell line) were stimulated with bFGF and EGF after transfection of Spry2 siRNA. Cell proliferation, migration, ALP staining, real-time PCR, Western blot and immunofluorescence assays were performed. RESULTS: ERK1/2 activation and proliferation of 1-17 PDL cells were significantly upregulated by the addition of Spry2 siRNA in the presence of bFGF and EGF. In addition, Spry2 siRNA reduced transcription of osteogenesis-related genes and ALP staining relative to control cells. Furthermore, it increased AKT/phosphatidylinositol 3-kinase (PI3K) phosphorylation; consequently, Rac1 but not Cdc42 was activated, thereby promoting lamellipodia formation, cell proliferation and migration after stimulation by bFGF and EGF. CONCLUSION: Spry2 combined with bFGF and EGF stimulation reduced PDL cell migration and proliferation with inducing osteoblastic differentiation. These in vitro findings may provide a molecular basis for novel therapeutic approaches for establishing periodontal tissue regeneration.

The relationship between the pre-admission CHA2DS2-VASc score and proximal artery occlusion in patients with acute stroke and atrial fibrillation.

BACKGROUND AND PURPOSE: The CHA2DS2-VASc score is associated with severity and outcome of ischaemic stroke in patients with atrial fibrillation (AF). It was hypothesized that a high CHA2DS2-VASc score was related to severity and outcome because of its association with proximal artery occlusion (PAO). This study aimed to elucidate the relationship between the CHA2DS2-VASc score and PAO and to determine whether the effect of the CHA2DS2-VASc score on severity or outcome is independent of PAO. METHODS: Acute stroke patients with AF were retrospectively enrolled. PAO was defined as occlusion at the internal carotid artery or proximal middle cerebral artery on admission magnetic resonance angiography. Multivariable analyses were performed to identify independent factors associated with PAO and determine the associations of the CHA2DS2-VASc score with the initial National Institutes of Health Stroke Scale (NIHSS) score and poor functional outcome (discharge modified Rankin scale score 4-6). RESULTS: In all, 213 patients [102 women; median age 80 (interquartile range 71-86) years; NIHSS score 16 (9-22)] were enrolled. On multivariable analysis, the CHA2DS2-VASc score (odds ratio 1.40, 95% confidence interval 1.12-1.76 per 1 point) was independently associated with PAO and correlated with the initial NIHSS score (standardized coefficient 0.198, P = 0.017). This association was not significant after further adjustment for PAO (0.080, P = 0.241). The CHA2DS2-VASc score was independently related to poor outcome even adjusted for PAO (odds ratio 1.39, 95% confidence interval 1.03-1.88). CONCLUSION: The CHA2DS2-VASc score was associated with PAO in acute ischaemic stroke patients with AF. The CHA2DS2-VASc score may be correlated with the NIHSS score through the presence of PAO and with poor functional outcome independently of PAO.

Simple clinical predictors of stroke outcome based on National Institutes of Health Stroke scale score during 1-h recombinant tissue-type plasminogen activator infusion.

BACKGROUND AND PURPOSE: An index for predictors of stroke outcome was determined based on the National Institutes of Health Stroke Scale (NIHSS) scores during 1-h intravenous administration of recombinant tissue-type plasminogen activator (rt-PA). METHODS: Stroke patients with baseline NIHSS score ≥8 and occlusion at the internal carotid or middle cerebral arteries (ICA, MCA) were retrospectively studied from a prospective single-center registry. NIHSS scores and inverse change from baseline scores (ΔNIHSS) were assessed at 30 min and 1 h after rt-PA infusion. Patients were divided into two groups according to arterial occlusion sites: group P, ICA or proximal M1; and group D, distal M1 or M2. A modified Rankin Scale score of 2-6 at 3 months was defined as an unfavorable outcome. RESULTS: In all 108 patients, the cutoff NIHSS score predicting unfavorable outcome was ≥12 and cutoff ΔNIHSS scores were ≤2 at both 30 min and 1 h. In group P (n = 36), the cutoff NIHSS score was ≥14 at both 30 min and 1 h and cutoff ΔNIHSS scores were ≤1 at 30 min and ≤2 at 1 h. Unfavorable outcome was seen in all patients with NIHSS1 h ≥ 14, ΔNIHSS30 min ≤ 1 and ΔNIHSS1 h ≤ 2. In group D (n = 72), the cutoff NIHSS scores were ≥12 at both 30 min and 1 h, and cutoff ΔNIHSS scores were ≤2 at 30 min and ≤7 at 1 h; 90% of patients with unfavorable outcome showed ΔNIHSS1 h ≤ 7. CONCLUSION: NIHSS and ΔNIHSS during 1-h rt-PA infusion seemed predictive of 3-month outcome when the site of arterial occlusion was identified prior to rt-PA.

Intravenous thrombolysis for patients with reverse magnetic resonance angiography and diffusion-weighted imaging mismatch: SAMURAI and NCVC rt-PA Registries.

BACKGROUND AND PURPOSE: The characteristics of reverse magnetic resonance angiography and diffusion-weighted imaging (MRA-DWI) mismatch (RMM), defined as a large DWI lesion in the absence of major artery occlusion (MAO), remain unknown, especially in patients treated with intravenous recombinant tissue plasminogen activator (rt-PA). METHODS: Patients with stroke in the middle cerebral artery territory were included. Early ischaemic changes (EIC) were assessed with the Alberta Stroke Program Early CT Score on DWI (DWI-ASPECTS). All patients were divided into four groups based on the presence of MAO and a DWI-ASPECTS cut-off value of <7. RMM was defined as DWI-ASPECTS <7 without MAO. Clinical characteristics, symptomatic intracerebral hemorrhage (sICH) and favorable functional outcome (modified Rankin Scale score 0-2) at 90 days were compared amongst the four groups. RESULTS: Of the 486 patients enrolled (167 women, median age 74 years, median initial National Institutes of Health Stroke Scale score 13), reverse MRA-DWI mismatch was observed in 24 (5%). Of the clinical characteristics, cardioembolism was the only factor that was independently associated with RMM [odds ratio (OR) 5.49, 95% confidence interval (CI) 1.25-24.1]. Multivariable analyses revealed that patients with RMM more commonly had sICH than those with DWI-ASPECTS ≥ 7 irrespective of the presence (OR 5.44, 95% CI 1.13-26.1) or absence (13.1, 2.07-83.3) of MAO, and they had a more favorable functional outcome than those with DWI-ASPECTS < 7 plus MAO (7.45, 2.39-23.2). CONCLUSION: RMM was observed in 5% of patients treated with rt-PA and associated with cardioembolism. Patients with RMM may benefit from thrombolysis compared with those with EIC with MAO, although increment in the rate of sICH is a concern.

Valuable antiviral therapeutic options for the treatment of chronic hepatitis C patients with thrombocytopenia.

Thrombocytopenia in patients with chronic hepatitis C may represent an obstacle for the initiation of antiviral treatment. The aim of this study was to evaluate factors predictive of successful pegylated interferon (PEG-IFN) α2b and ribavirin (RBV) treatment for patients with thrombocytopenia with no history of splenectomy or partial splenic embolization. One hundred and fifty-one chronic hepatitis C patients (genotype 1: n = 110, genotype 2: n = 41) with TCP (<100 × 10(9) /L) at baseline were enrolled. Pretreatment variables included interleukin 28B (IL28B) genotype (rs8099917) and homoeostasis model assessment of insulin resistance score (HOMA-IR). The kinetics of haemoglobin and platelets according to the inosine triphosphatase (ITPA) genotype (rs1127354) were investigated. Sustained virological response (SVR) was significantly more frequent in hepatitis C virus (HCV) genotype 2 (65.9%) than in genotype 1 (34.5%) patients (P < 0.0001). Multiple logistic regression analysis of HCV genotype 1 extracted IL28B TT genotype [odds ratio (OR) 5.97, P = 0.006] and HOMA-IR <2.5 (OR 7.14, P = 0.0016) as significant independent pretreatment predictors of SVR. The analyses of HCV genotype 2 showed that HOMA-IR was significantly related to SVR, but IL28B genotype was not. Patients with ITPA CC genotype showed a significant haemoglobin reduction and lower degree of platelets decrease than those with ITPA CA/AA genotypes. The most common reason for premature discontinuation of treatment was the development of hepatocellular carcinoma (n = 8, 5.3%). In conclusion, HOMA-IR is a useful predictor of SVR for patients with thrombocytopenia infected with HCV genotype 1 or 2 treated with PEG-IFNα2b and RBV. The inclusion of IL28B, ITPA genotypes and HOMA-IR adds valuable therapeutic information.

Run-up to participation in ATACH II in Japan.

Intracerebral hemorrhage (ICH) is a major cause of morbidity and mortality in Japan. Seventeen Japanese institutions are participating in the Antihypertensive Treatment for Acute Cerebral Hemorrhage (ATACH) II Trial (ClinicalTrials.gov no. NCT01176565; UMIN 000006526). This phase III trial is designed to determine the therapeutic benefit of early intensive systolic blood pressure (BP) lowering for acute hypertension in ICH patients. This report explains the long run-up to reach the start of patient registration in ATACH II in Japan, including our preliminary study, a nationwide survey on antihypertensive treatment for acute ICH patients, a multicenter study for hyperacute BP lowering (the SAMURAI-ICH study), revision of the official Japanese label for intravenous nicardipine, and construction of the infrastructure for the trial.

MR imaging of IgG4-related disease in the head and neck and brain.

SUMMARY: IgG4-related disease is characterized by histologic fibrosis with IgG4-positive plasma cell infiltration. Our study evaluated MR imaging features of IgG4-related disease in the head and neck and brain. Images from 15 patients were retrospectively evaluated for the location, signal intensity, and enhancement patterns of lesions. Lacrimal gland enlargement was observed in 8 cases. Other lesions included orbital pseudotumor in 5, pituitary enlargement in 5, and cranial nerve enlargement in 7; the infraorbital nerve was involved in 4. All lesions were hypointense on T2-weighted images, which is typical for IgG4-related lesions. Multiple sites were involved in the head and neck and brain in 11 patients. The diagnosis of IgG4-related disease should be considered in a patient presenting with T2 hypointense lacrimal gland, pituitary, or cranial nerve enlargement, or a T2 hypointense orbital mass, especially if multiple sites in the head and neck are involved in the presence of elevated serum IgG4.

Serum pepsinogen and Helicobacter pylori infection--a Japanese population study.

The decreased ratio of serum pepsinogen (PG) I and II has good correlation with the presence of atrophic gastritis. A total of 1,540 residents aged 30-89 years were enrolled into this study to investigate which serum PG level of residents with Helicobacter pylori infection would represent an adjunct to the diagnosis and progression of atrophic gastritis. All participants received esophagogastroduodenoscopy. Serum antibody to H. pylori (anti-H. pylori) was measured by an enzyme-linked immunosorbent assay (ELISA). Serological atrophic gastritis was defined as serum PG I isozyme level ≤70 ng/ml and a PG I/II ratio of ≤3.0. Of the 1,540 participants, 923 (59.9%) were positive for anti-H. pylori. Serological atrophic gastritis was found significantly more often in anti-H. pylori-positive participants (40.8%) than in anti-H. pylori-negative participants (7.9%) (p ≤ 0.0001). The endoscopic findings of anti-H. pylori-positive participants with serological atrophic gastritis were significantly more frequent by 4.06 times for atrophic gastritis (p ≤ 0.0001) than anti-H. pylori-negative participants without serological atrophic gastritis. Eight anti-H. pylori-positive participants were diagnosed with gastric cancer, but no cancer was found in anti-H. pylori-negative participants without serological atrophic gastritis. Serum PG testing is clinically useful for the prediction of gastric lesions in H. pylori-infected persons.

SS-MIX: a ministry project to promote standardized healthcare information exchange.

OBJECTIVES: To promote healthcare information exchange between providers and to allow hospital information systems (HIS) export information in standardized format (HL7 and DICOM) in an environment of wide-spread legacy systems, which only can export data in proprietary format. METHODS: Through the Shizuoka prefecture EMR project in 2004-2005, followed by the ministry's SS-MIX project, many software products have been provided, which consist of 1) a standardized storage to receive HL7 v2.5 messages of patient demographics, prescription orders, laboratory results, and diagnostic disease in ICD-10, 2) a referral letter creation system, 3) a formatted document creation system, 4) a progress note/nursing record system, and 5) an archive/viewer to incorporate incoming healthcare data CD and allow users to view on HIS terminal. Meanwhile, other useful applications have been produced, such as adverse event reporting and clinical information retrieval. To achieve the above-mentioned objectives, these software products were created and propagated, because users can use these software products, provided that their HIS can export the above information to the standardized storage in HL7 v2.5 format. RESULTS: In 20 hospitals of Japan, the standardized storage has been installed and some applications have been used. As major HIS vendors are shipping HIS with HL7 export function since 2007, HIS of 594 hospitals in Japan became capable of exporting data in HL7 v2.5 format (as of March 2010). CONCLUSIONS: In high CPOE installation rate (85% in 400+ bed hospitals), though most of them only capable of exporting data in proprietary format, prefecture and ministry projects were effective to promote healthcare information exchange between providers. The standardized storage became an infrastructure for many useful applications, and many hospitals started using them. Ministry designation of proposed healthcare standards was effective so as to allow vendors to conform their products, and users to install them.

Prior antiplatelet therapy and outcome following intracerebral hemorrhage: a systematic review.

OBJECTIVES: Antiplatelet therapy (APT) promotes bleeding; therefore, APT might worsen outcome in patients with intracerebral hemorrhage (ICH). We performed a systematic review and meta-analysis to address the hypothesis that pre-ICH APT use is associated with mortality and poor functional outcome following ICH. METHODS: The Medline and Embase databases were searched in February 2008 using relevant key words, limited to human studies in the English language. Cohort studies of consecutive patients with ICH reporting mortality or functional outcome according to pre-ICH APT use were identified. Of 2,873 studies screened, 10 were judged to meet inclusion criteria by consensus of 2 authors. Additionally, we solicited unpublished data from all authors of cohort studies with >100 patients published within the last 10 years, and received data from 15 more studies. Univariate and multivariable-adjusted odds ratios (ORs) for mortality and poor functional outcome were abstracted as available and pooled using a random effects model. RESULTS: We obtained mortality data from 25 cohorts (15 unpublished) and functional outcome data from 21 cohorts (14 unpublished). Pre-ICH APT users had increased mortality in both univariate (OR 1.41, 95% confidence interval [CI] 1.21 to 1.64) and multivariable-adjusted (OR 1.27, 95% CI 1.10 to 1.47) pooled analyses. By contrast, the pooled OR for poor functional outcome was no longer significant when using multivariable-adjusted estimates (univariate OR 1.29, 95% CI 1.09 to 1.53; multivariable-adjusted OR 1.10, 95% CI 0.93 to 1.29). CONCLUSIONS: In cohort studies, APT use at the time of ICH compared to no APT use was independently associated with increased mortality but not with poor functional outcome.