Low density lipoprotein receptor related protein 1 and 6 gene variants and ischaemic stroke risk.

BACKGROUND AND PURPOSE: Low density lipoprotein receptor related proteins (LRPs) 1 and 6 have been implicated in cerebral ischaemia. In addition, genetic variation in LRP1 and LRP6 has been linked with various factors that are related to risk of ischaemic stroke. The aim of this study was to examine the association of LRP1 and LRP6 gene variants with risk of ischaemic stroke as part of the Ischemic Stroke Genetics Study (ISGS). METHODS: A Caucasian series (434 stroke patients, 319 controls) and an African American series (161 stroke patients, 116 controls) were included. Fourteen LRP6 variants and three LRP1 variants were genotyped and assessed for association with ischaemic stroke. RESULTS: In the Caucasian series, significant associations with ischaemic stroke were observed for LRP6 rs2075241 [odds ratio (OR) 0.42, P = 0.023], rs2302685 (OR 0.44, P = 0.049), rs7975614 (OR 0.07, P = 0.017), rs10492120 (OR 0.62, P = 0.036) and rs10743980 (OR 0.66, P = 0.037). Risk of ischaemic stroke was significantly lower for carriers of any of these five protective LRP6 variants (24.0% of subjects) compared to non-carriers (OR 0.57, P = 0.003). The protective association for LRP6 rs2075241 was observed at a similar magnitude across ischaemic stroke subtypes, whilst the effects of rs23022685, rs10492120 and rs10743980 were most apparent for cardioembolic and large vessel stroke. In the African American series, LRP1 rs11172113 was associated with an increased risk of stroke (OR 1.89, P = 0.006). CONCLUSIONS: The results of our preliminary study provide evidence that LRP6 and LRP1 variants may be associated with risk of ischaemic stroke. Validation in larger studies is warranted.

Nutcracker esophagus: demographic, clinical features, and esophageal tests in 115 patients.

Nutcracker esophagus (NE) is a common esophageal motility disorder chacterized by high amplitude peristaltic contractions in the distal esophagus. While previous studies have examined selected aspects of this condition (e.g. pathogenesis and treatment), there is a paucity of data regarding demographic and clinical features in large cohorts of patients. The aim of this study was to describe demographics, clinical features, comorbidities, time to diagnosis, source of patient referral by specialty, and medication use in a large cohort of patients with NE. We retrospectively analyzed consecutive cases of NE diagnosed from 2008-2010. The electronic medical records of these patients were reviewed, and relevant information was extracted. We identified 115 patients with NE. The median age was 62 years (range 25-87 years), and 63% were female. The median time patients experienced symptoms prior to diagnosis was 24 months (0-480 months). Most patients presented to an internal medicine consultant (42%) or to a gastroenterologist (35%). Presenting symptoms were chest pain (31%) and dysphagia (21%). Gastroesophageal reflux disease (GERD) symptoms were common: heartburn occurred in 51% of patients, 77% had a prior history of GERD, and 78% were receiving acid suppressive medications. GERD was confirmed by testing in at least 35%. Psychiatric comorbidity occurred in 24% with half the patients receiving psychotropic medications. Irritable bowel syndrome (IBS) and fibromyalgia co-existed in 15% and 12% of patients, respectively. Surprisingly, opioids were prescribed to 26% of patients. No statistically significant correlation was found between esophageal motility parameters and symptoms. In this study, NE patients were more commonly middle-aged females experiencing a considerable amount of time between symptom onset and diagnosis. Many were initially evaluated by internists for dysphagia or chest pain and had a history of GERD. Medication prescribed prior to diagnoses frequently involved acid suppression, but narcotic and psychotropic prescriptions were also commonly used. Central sensitization syndromes (fibromyalgia and IBS), psychiatric comorbidity, and reflux commonly coexisted. Our study suggests that future investigations should address the role and interaction of GERD and psychiatric disorders in NE.

Avoiding stay in the intensive care unit after liver transplantation: a score to assign location of care.

Select liver transplantation (LT) recipients in our program are transferred from operating room to postanesthesia care unit for recovery and extubation with transfer to the ward, completely eliminating an intensive care unit (ICU) stay. Developing a reliable method to determine patients suitable for fast-tracking would be of practical benefit to centers considering this practice. The aim of this study was to create a fast-tracking probability score that could be used to predict successful assignment of care location after LT. Recipient, donor and operative characteristics were assessed for independent association with successful fast-tracking to create a probability score. Of the 1296 LT recipients who met inclusion criteria, 704 (54.3%) were successfully fast-tracked and 592 (45.7%) were directly admitted to the ICU after LT. Based on nine readily available variables at the time of LT, we created a scoring system that classified patients according to the likelihood of being successfully fast-tracked to the surgical ward, with an area under the curve (AUC) of 0.790 (95% CI: 0.765-0.816). This score was validated in an independent group of 372 LT with similar AUC. We describe a score that can be used to predict successful fast-tracking immediately after LT using readily available clinical variables.

Genetic variants associated with myocardial infarction in the PSMA6 gene and Chr9p21 are also associated with ischaemic stroke.

BACKGROUND: Ischaemic stroke shares common traditional risk factors with coronary artery disease (CAD) and myocardial infarction (MI). This study evaluated whether genetic risk factors for CAD and MI also affect susceptibility to ischaemic stroke in Caucasians and African Americans. METHODS: Included in the study were a Caucasian series (713 ischaemic stroke patients, 708 controls) and a small African American series (166 ischaemic stroke patients, 117 controls). Twenty single-nucleotide polymorphisms (SNPs) previously shown to be associated with CAD or MI were genotyped and assessed for association with ischaemic stroke and ischaemic stroke subtypes using odds ratios (ORs) from multivariable logistic regression models. RESULTS: In Caucasians, four SNPs on chromosome 9p21 were significantly associated with risk of cardioembolic stroke, the strongest of which was rs1333040 (OR 1.55, P = 0.0007); similar but weaker trends were observed for small vessel stroke, with no associations observed regarding large vessel stroke. Chromosome 9p21 SNPs were also associated with risk of ischaemic stroke in African Americans (rs1333040, OR 0.65, P = 0.023; rs1333042, OR 0.55, P = 0.070; rs2383207, OR 0.55, P = 0.070). The PSMA6 SNP rs1048990 on chromosome 14q13 was associated with overall ischaemic stroke in both Caucasians (OR 0.80, P = 0.036) and African Americans (OR 0.31, P = 0.020). CONCLUSIONS: Our results provide evidence that chromosome 9p21 variants are associated with cardioembolic ischaemic stroke in Caucasians and with overall ischaemic stroke in African Americans. The PSMA6 variant rs1048990 also appears to affect susceptibility to ischaemic stroke in both populations. These findings require validation, particularly the preliminary findings regarding African Americans given the small size of that series.

Evaluation of risk factors for cytomegalovirus infection and disease occurring within 1 year of liver transplantation in high-risk patients.

BACKGROUND: Recent studies have demonstrated that cytomegalovirus (CMV) infection and disease are associated with increased risk of graft loss and death in high-risk (donor CMV seropositive/recipient CMV seronegative) liver transplant recipients (LTR) despite effective antiviral chemoprophylaxis. Predictors of CMV infection and disease in this important population are incompletely defined. METHODS: A retrospective cohort study of 227 high-risk first LTR who received primary anti-CMV chemoprophylaxis during the first 100 days after transplant was performed. A large number of patient, donor, operative, and post-transplant potential risk factors were collected. Associations of potential risk factors for CMV infection or disease that occurred during the first year after transplant were assessed using Cox regression models. After Bonferroni adjustment for multiple testing, P-values ≤0.00125 (associations with CMV infection) and ≤0.00122 (associations with CMV disease) were considered as statistically significant. RESULTS: CMV infection and disease occurred in 91 (40%) and 43 (19%) of LTR, respectively. In multivariable analysis, increased risk of CMV infection was observed for patients with lower model for end-stage liver disease (MELD) score (P = 0.025), lower total bilirubin (P = 0.014), and longer operative time (P = 0.038), whereas increased risk of CMV disease was seen in patients with lower MELD score (P = 0.026), lower total bilirubin (P = 0.044), and lower international normalized ratio (P = 0.043). However, after adjustment for multiple testing, none of these findings approached statistical significance. CONCLUSION: Our results suggest that interventions designed to prevent CMV infection and disease should be applied to all high-risk LTR until more definitive predictors of these complications are identified.

Esophageal spasm: demographic, clinical, radiographic, and manometric features in 108 patients.

Diffuse esophageal spasm (DES) remains insufficiently understood. Here we aimed to summarize the demographic, clinical, radiographic, and manometric features in a large cohort of patients with DES. We identified all consecutive patients diagnosed with DES from 2000 to 2006 at Mayo Clinic Florida. The computerized records of these patients were reviewed to extract relevant information. We performed 2654 esophageal motilities during that period. There were 108 patients with esophageal spasm, and 55% were female. Median age was 71 years. The most common leading symptom was dysphagia in 55, followed by chest pain in 31. Weight loss occurred in 28 patients. The median of time from onset of symptoms to diagnosis was 48 months (range 0-480), with a median of time from the first medical consultation to diagnosis of 8 months (range 0-300). The most frequent comorbidities were hypertension and psychiatric problems. At presentation, 81 patients were taking acid-reducing medications, and 49 patients were taking psychotropic drugs. An abnormal esophagogram was noted in 46 of 76 patients with this test available, but most radiographic findings were nonspecific with the typical 'corkscrew' appearance seen in only three patients. Gastroesophageal reflux disease (GERD) was diagnosed by pH testing or endoscopy in 41 patients. We did not find any difference between the rate of simultaneous contractions or esophageal amplitude between patients with a leading symptom of dysphagia and those with chest pain. DES is an uncommon motility disorder that often goes unrecognized for years. Physicians should be aware of the clinical heterogeneity of DES and consider motility testing early in the course of unexplained esophageal symptoms. Given the high prevalence of GERD in DES, the role of GERD and the impact of acid-reducing therapy in DES deserve further study.

Use of remdesivir for COVID-19 pneumonia in patients with advanced kidney disease: A retrospective multicenter study.

Background and objectives: Remdesivir, an antiviral drug routinely used in the treatment of COVID-19 has not yet received FDA approval for use in patients with advanced kidney disease defined as GFR < 30 mL/min/1.73 m2. There is concern that an excipient in Veklury (Gilead's proprietary name for remdesivir) called sulfobutylether-beta-cyclodextrin (SBECD), which is renally cleared, may accumulate and reach toxic levels in patients with advanced kidney disease. The aim of this study was to summarize characteristics and incidence of adverse events of chronic kidney disease (CKD) patients who received remdesivir during hospitalization.Design, setting, participants, and measurements.We retrospectively studied patients admitted to one of several hospitals of the Mayo Clinic Foundation with the diagnosis of COVID-19 pneumonia and CKD. Laboratory values were also measured when remdesivir was first administered and stopped. All analyses were performed in the overall patient group and three separate subgroups of patients with a GFR ≥ 15, a GFR < 15 and dialysis, and a GFR < 15 and no dialysis. Results: A total of 444 CKD patients who were admitted to the hospital with COVID-19 pneumonia between May 2020 and September 2021 were included. Information was collected on patient characteristics, hospitalization, and adverse events. In the overall cohort, median age was 72 years (Range: 21-100 years), 55.2 % of patients were male, and most (86.5 %) were Caucasian. CKD stage was 3 for 114 patients (25.7 %), 4 for 229 patients (51.6 %), and 5 for 101 patients (22.7 %). A total of 146 patients (32.9 %) were admitted to the ICU, 103 (23.2 %) died in the hospital, and 120 (27.0 %) were on dialysis. The proportion of patients with an adverse event did not differ dramatically between the GFR ≥ 15 (20.9 %), GFR < 15 and dialysis (30.2 %), and GFR < 15 and no dialysis (32.3 %) groups (P = 0.12). Conclusion: Our results suggest that the use of remdesivir in patients with very severe CKD is safe, even in those who are not on renal replacement therapy.

Association of cytomegalovirus infection and disease with death and graft loss after liver transplant in high-risk recipients.

In the era of effective antiviral chemoprophylaxis, cytomegalovirus (CMV) disease has been inconsistently associated with increased mortality in liver transplant (LT) recipients. A retrospective study evaluating the association of CMV infection and disease occurring within 1 year of transplant with the endpoints of death or the combined endpoint of graft loss or death was undertaken in a cohort of 227 CMV donor seropositive, recipient seronegative first LT recipients. Associations were evaluated using Cox proportional hazards regression models. CMV infection and disease occurred in 91 (40%) and 43 (19%) patients, respectively. Forty-eight (21%) died while 58 (26%) sustained graft loss or death. In multivariable analysis, CMV infection was associated with an increased risk of death (RR: 2.24, p = 0.008) and graft loss or death (RR: 2.85, p < 0.001). CMV disease was also associated with an increased risk of death (RR: 2.73, p = 0.003) and graft loss or death (RR: 3.04, p = 0.001). CMV infection and disease occurring within the first year after LT in high-risk recipients is associated with increased risk of death and of graft loss or death. Investigation of strategies to further reduce the risk of CMV infection and disease in high-risk LT recipients is warranted.

Association of surgeon with surgical site infection after liver transplantation.

Surgical site infection (SSI) after liver transplantation has been associated with increased risk of allograft loss and death. Identification of modifiable risk factors for these infections is imperative. To our knowledge, intraoperative practices associated with transplant surgeons have not been assessed as a risk factor. A retrospective cohort study of risk factors for SSI after 1036 first liver transplantations completed by seven surgeons at a single center between 2003 and 2008 was undertaken. Cox proportional hazards models were used to evaluate the association between surgeons and SSIs. SSIs were identified in 166 of 1036 patients (16%). Single variable analysis showed strong evidence of an association between surgeon and SSI (p = 0.0007); the estimated cumulative incidence of SSI ranged from 7% to 24%. This result was consistent in multivariable analysis adjusting for potentially confounding variables (p = 0.002). The occurrence of organ-space or deep SSI varied significantly among surgeons in both single variable analysis (p = 0.005) and multivariable analysis (p = 0.006). These findings provide evidence that differences in the surgical practices of individual surgeons are associated with risk for SSI after liver transplantation. Identification of specific surgical practices associated with risk of SSI is warranted.

Death-associated protein kinase 1 variation and Parkinson's disease.

BACKGROUND AND PURPOSE: Mutations of the LRRK2 gene are now recognized as major risk factors for Parkinson's disease. The Lrrk2 protein is a member of the ROCO family, which also includes Lrrk1 and Dapk1. Functional genetic variants of the DAPK1 gene (rs4877365 and rs4878104) have been previously associated with Alzheimer's disease. METHODS: Herein, we assessed the role of DAPK1 variants (rs4877365 and rs4878104) in risk of Parkinson's disease with Sequenom iPLEX genotyping, employing one Taiwanese series (391 patients with Parkinson's disease, 344 controls) and five separate Caucasian series' (combined sample size 1962 Parkinson's disease patients, 1900 controls). RESULTS: We observed no evidence of association for rs4877365 and rs4878104 and risk of Parkinson's disease in any of the individual series or in the combined Caucasian series under either an additive or recessive model. CONCLUSION: These specific DAPK1 intronic variants do not increase the risk of Parkinson's disease. However, further functional studies are required to elucidate the potential therapeutic implications with the dimerization of the Dapk1 and Lrrk2 proteins.

SNCA, MAPT, and GSK3B in Parkinson disease: a gene-gene interaction study.

BACKGROUND AND PURPOSE: Recent evidence suggests that variation in the SNCA, MAPT, and GSK3B genes interacts in affecting risk for Parkinson disease (PD). In the current study, we attempt to validate previously published findings, evaluating gene-gene interactions between SNCA, MAPT, and GSK3B in association with PD. METHODS: Three Caucasian PD patient-control series from the United States, Ireland, and Norway (combined n = 1020 patients and 1095 controls) were genotyped for SNCA rs356219, MAPT H1/H2-discriminating SNP rs1052553, and GSK3B rs334558 and rs6438552. RESULTS: Our findings indicate that as previously reported, the SNCA rs356219-G allele and MAPT rs1052553 (H1 haplotype) were both associated with an increased risk of PD, whilst contrary to previous reports, GSK3B variants were not. No pair-wise interaction was observed between SNCA, MAPT, and GSK3B; the risk effects of SNCA rs356219-G and MAPT rs1052553-H1 were seen in a similar manner across genotypes of other variants, with no evidence suggesting synergistic, antagonistic, or deferential effects. CONCLUSIONS: In the Caucasian patient-control series examined, risk for PD was influenced by variation in SNCA and MAPT but not GSK3B. Additionally, those three genes did not interact in determining disease risk.

Interobserver agreement and accuracy among international experts with probe-based confocal laser endomicroscopy in predicting colorectal neoplasia.

BACKGROUND AND STUDY AIMS: A recently developed probe-based, confocal laser endomicroscopy (pCLE) system provides images of surface colonic epithelium in vivo during any endoscopy. Our objective was to assess interobserver agreement, sensitivity, specificity, and overall accuracy in the diagnosis of neoplasia using pCLE. PATIENTS AND METHODS: 53 patients undergoing surveillance and screening colonoscopies were enrolled. A total of 75 lesions, were detected and all were inspected by pCLE prior to sampling or polypectomy. Intravenous fluorescein was used to optimize tissue contrast. Three pCLE users, blinded to histopathologic and endoscopic findings, reviewed the set of video sequences for crypt architecture, vessel architecture, and colorectal neoplasia diagnosis. Histopathologic diagnosis from the corresponding biopsies was the reference gold standard. RESULTS: Of the 75 colorectal lesions, 50 were neoplastic and 25 non-neoplastic. Interobserver agreement was moderate to good for the classification of neoplasia (kappa 0.55, 78 % pairwise agreement), and moderate for vessel architecture (kappa 0.41, 67 % pairwise agreement) and crypt architecture (kappa 0.49, 69 % pairwise agreement). In distinguishing between neoplastic and non-neoplastic lesions, sensitivity, specificity, and accuracy were 76 %, 72 % and 75 %, respectively. When videos of good or excellent quality only were considered, interobserver agreement for classification of neoplasia was higher (kappa 0.83, 92 % pairwise agreement), as were sensitivity (88 %), specificity (89 %), and accuracy (88 %). CONCLUSION: An international collaboration group had moderate to good interobserver agreement using a pCLE system to predict neoplasia, which is acceptable for this study.

Association of the MAPT locus with Parkinson's disease.

BACKGROUND AND PURPOSE: Whilst an association between the tau gene (MAPT)-containing H1 haplotype and supranuclear gaze palsy (PSP) has long been recognized, the effect of H1 on risk for Parkinson's disease (PD) has remained more contentious. METHODS: Herein, we examined the association of H1 and PD in three Caucasian PD patient-control series from Ireland, Norway, and the US (combined: n = 2619), by genotyping two H1/H2 single nucleotide polymorphisms (SNPs) in MAPT (rs1052553) and in the Saitohin gene (rs62063857) and one H1-specific SNP (rs242557). RESULTS: We identified a significant association between H1/H2 and risk of PD (rs1052553 OR: 1.43, CI: 1.23-1.64; rs62063857 OR: 1.45, CI: 1.27-1.67), but no effect of the H1-specific SNP rs242557 (OR: 0.92, CI: 0.82-1.03). CONCLUSIONS: Our findings show that the H1 haplotype is a significant risk factor for PD. However, one H1-specific SNP (rs242557) previously implicated in PSP did not alter the risk of PD, indicating that distinct H1 sub-haplotypes probably drive the associations with PD and PSP.

Calbindin-1 association and Parkinson's disease.

BACKGROUND AND PURPOSE: Calcium levels have been proposed to play an important role in the selective vulnerability of nigrostriatal dopaminergic neurons in Parkinson's disease (PD). Recently, an association was reported between the calcium buffer, calbindin (rs1805874) and risk of PD in a Japanese patient-control series. METHODS: We genotyped rs1805874 in four independent Caucasian patient-control series (1543 PD patients, 1771 controls). RESULTS: There was no evidence of an association between rs1805874 and disease risk in individual populations or in the combined series (odds ratio: 1.04, 95% CI: 0.82-1.31, P = 0.74). DISCUSSION: Our study shows there is no association between rs1805874 and risk for PD in four Caucasian populations. This suggests the effect of calbindin on PD risk displays population specificity.

Segmentation of the Globus Pallidus Internus Using Probabilistic Diffusion Tractography for Deep Brain Stimulation Targeting in Parkinson Disease.

BACKGROUND AND PURPOSE: Although globus pallidus internus deep brain stimulation is a widely accepted treatment for Parkinson disease, there is persistent variability in outcomes that is not yet fully understood. In this pilot study, we aimed to investigate the potential role of globus pallidus internus segmentation using probabilistic tractography as a supplement to traditional targeting methods. MATERIALS AND METHODS: Eleven patients undergoing globus pallidus internus deep brain stimulation were included in this retrospective analysis. Using multidirection diffusion-weighted MR imaging, we performed probabilistic tractography at all individual globus pallidus internus voxels. Each globus pallidus internus voxel was then assigned to the 1 ROI with the greatest number of propagated paths. On the basis of deep brain stimulation programming settings, the volume of tissue activated was generated for each patient using a finite element method solution. For each patient, the volume of tissue activated within each of the 10 segmented globus pallidus internus regions was calculated and examined for association with a change in the Unified Parkinson Disease Rating Scale, Part III score before and after treatment. RESULTS: Increasing volume of tissue activated was most strongly correlated with a change in the Unified Parkinson Disease Rating Scale, Part III score for the primary motor region (Spearman r = 0.74, P = .010), followed by the supplementary motor area/premotor cortex (Spearman r = 0.47, P = .15). CONCLUSIONS: In this pilot study, we assessed a novel method of segmentation of the globus pallidus internus based on probabilistic tractography as a supplement to traditional targeting methods. Our results suggest that our method may be an independent predictor of deep brain stimulation outcome, and evaluation of a larger cohort or prospective study is warranted to validate these findings.

Thromboelastography as a Predictor of Outcomes Following Liver Transplantation.

BACKGROUND: Thromboelastography (TEG) has been used perioperatively during liver transplantation (LT) to provide a real-time global hemostasis assessment for targeted blood product replacement. We aimed to analyze the relationship between post-LT TEG results and outcomes. METHODS: We retrospectively analyzed patients undergoing LT from November 2008 to December 2014 at Mayo Clinic Florida. All 441 single-organ 1st-time LT patients aged ≥18 years requiring post-LT intensive care unit management were included. TEG parameters including r time, k time, α angle, and maximum amplitude were measured regularly during the first 24 hours after LT. Outcomes included return to the operating room secondary to bleeding, length of hospitalization, survival, and early allograft dysfunction. RESULTS: A prolonged and/or lengthening r time, k time, and r+k time were all independently associated with increased length of hospitalization after LT. Increased maximum amplitude on the first post-LT TEG was associated with early allograft dysfunction. No notable associations of TEG parameters with survival or return to operating room were observed. CONCLUSIONS: The association of absolute and temporal TEG value changes with increased length of hospitalization and early allograft dysfunction suggests that TEG may have a role in identifying patients at high risk for these outcomes.

The cause of coagulopathy after peritoneovenous shunt for malignant ascites.

Thirty-five patients with malignant ascites who received a peritoneovenous shunt were studied to determine the type and duration of postoperative coagulopathy. Coagulation factors were measured before and on the first and third day after the placement of a Denver peritoneovenous shunt; 1 to 10 L of ascites was removed at operation. Levels of platelets, antithrombin III, plasminogen, antiplasmin, fibrinogen, and factors V and VIII decreased by the first postoperative day but did not change further through the third day. The levels of fibrinolytic split products increased on day 1 but were lower by day 3. The platelet count reduction by the third day correlated with the hematocrit change (-0.031). The prothrombin and activated partial thromboplastin times remained normal postoperatively. The patterns of change were similar for patients with positive (n = 18) and negative (n = 17) ascites cytologic findings, with elevated (n = 24) and normal (n = 11) preoperative fibrinolytic split product levels, and elevated bilirubin value (greater than 25 mumol/L; n = 9), and no jaundice (n = 26). Bleeding did not occur. The data indicated that plasminogen-rather than thromboplastin-activated fibrinolysis occurred and that platelet reduction was largely dilutional. The reactions were not progressive when ascites was removed operatively.

Nimbolide targets BCL2 and induces apoptosis in preclinical models of Waldenströms macroglobulinemia.

Neem leaf extract (NLE) has medicinal properties, which have been attributed to its limonoid content. We identified the NLE tetranorterpenoid, nimbolide, as being the key limonoid responsible for the cytotoxicity of NLE in various preclinical models of human B-lymphocyte cancer. Of the models tested, Waldenströms macroglobulinemia (WM) cells were most sensitive to nimbolide, undergoing significant mitochondrial mediated apoptosis. Notably, nimbolide toxicity was also observed in drug-resistant (bortezomib or ibrutinib) WM cells. To identify putative targets of nimbolide, relevant in WM, we used chemoinformatics-based approaches comprised of virtual in silico screening, molecular modeling and target-ligand reverse docking. In silico analysis revealed the antiapoptotic protein BCL2 was the preferential binding partner of nimbolide. The significance of this finding was further tested in vitro in RS4;11 (BCL2-dependent) tumor cells, in which nimbolide induced significantly more apoptosis compared with BCL2 mutated (Jurkat BCL2(Ser70-Ala)) cells. Lastly, intraperitoneal administration of nimbolide in WM tumor xenografted mice, significantly reduced tumor growth and IgM secretion in vivo, while modulating the expression of several proteins as seen on immunohistochemistry. Overall, our data demonstrate that nimbolide is highly active in WM cells, as well as other B-cell cancers, and engages BCL2 to exert its cytotoxic activity.

Efatutazone, an oral PPAR-γ agonist, in combination with paclitaxel in anaplastic thyroid cancer: results of a multicenter phase 1 trial.

PURPOSE: A phase 1 study was initiated to determine the safety, potential effectiveness, and maximal tolerated dose and recommended phase 2 dose of efatutazone and paclitaxel in anaplastic thyroid cancer. EXPERIMENTAL DESIGN: Patients received efatutazone (0.15, 0.3, or 0.5 mg) orally twice daily and then paclitaxel every 3 weeks. Patient tolerance and outcomes were assessed, as were serum efatutazone pharmacokinetics. RESULTS: Ten of 15 patients were women. Median age was 59 years. Seven patients received 0.15 mg of efatutazone, 6 patients received 0.3 mg, and 2 patients received 0.5 mg. One patient receiving 0.3 mg of efatutazone had a partial response from day 69 to day 175; 7 patients attained stable disease. Median times to progression were 48 and 68 days in patients receiving 0.15 mg of efatutazone and 0.3 mg of efatutazone, respectively; corresponding median survival was 98 vs 138 days. The median peak efatutazone blood level was 8.6 ng/mL for 0.15-mg dosing vs 22.0 ng/mL for 0.3-mg twice daily dosing. Ten patients had grade 3 or greater adverse events (Common Terminology Criteria for Adverse Events), with 2 of these (anemia and edema) related to efatutazone. Thirteen events of edema were reported in 8 patients, with 2 of grade 3 or greater. Eight patients had ≥1 serious adverse event, with 1 of these (anemia) attributed to efatutazone and 1 (anaphylactic reaction) related to paclitaxel. The maximal tolerated dose was not achieved. Angiopoietin-like 4 was induced by efatutazone in tissue biopsy samples of 2 patients. CONCLUSIONS: Efatutazone and paclitaxel in combination were safe and tolerated and had biologic activity.

Oesophageal eosinophilic infiltration in patients with noncardiac chest pain.

BACKGROUND: Eosinophilic oesophagitis clinically presents with recurrent episodes of dysphagia and food impaction. Recently, we observed patients with noncardiac chest pain and eosinophilic oesophagitis. AIMS: To estimate the prevalence of abnormal eosinophilic infiltration in noncardiac chest pain patients and examine diagnostic utility of demographic, clinical and endoscopic variables to predict eosinophilic oesophagitis. METHODS: Retrospective study of 171 consecutive patients referred for EGD evaluation of noncardiac chest pain. Endoscopic signs consistent with eosinophilic oesophagitis were recorded. The histological findings were grouped as normal: 0-5 eosinophils/high power field (e/hpf), indeterminate: 6-20 e/hpf, and eosinophilic oesophagitis: ≥21 e/hpf. Abnormal eosinophilic infiltration was defined as ≥6 e/hpf. RESULTS: Abnormal eosinophilic infiltrate was noted in 24 patients (14%). Thirteen (8%) had indeterminate counts, while 11 (6%) had eosinophilic oesophagitis. Compared with normal, those with abnormal oesophageal eosinophilic infiltration were more likely to be male (71% vs. 34%, P=0.001), have allergies (29% vs. 12%, P=0.050), have current GER symptoms (42% vs. 18%, P=0.013), rings (54% vs. 22%, P=0.002), furrows (21% vs. 1%, P<0.001) and abnormal eosinophilic oesophagitis findings on endoscopy (67% vs. 32%, P=0.001). Of the 24 abnormal patients, 23 (96%) were either male or had rings, furrows, or white specks. Conversely, 68 of 69 patients (99%) who were female did not have rings, furrows, or white specks, and endoscopy was normal. Eight patients (33%) with abnormal eosinophilic infiltration had a normal endoscopy. CONCLUSIONS: Eosinophilic oesophagitis should be considered in the evaluation of noncardiac chest pain. Our findings suggest that oesophageal biopsies should be obtained particularly in males with recurrent unexplained chest pain, whether endoscopy is normal or abnormal.