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Background: This systematic review and meta-analysis explored the relationship between cognitive phenotypes of compulsivity and impulsivity and clinical variables in obsessive-compulsive disorder (OCD).Methods: We searched Pubmed, Scopus, Cochrane Library and PsychINFO databases until February 2023 for studies comparing patients with OCD and healthy controls on cognitive tests of compulsivity and impulsivity. The study followed PRISMA guidelines and was pre-registered on PROSPERO (CRD42021299017).Results: Meta-analyses of 112 studies involving 8,313 participants (4,289 patients with OCD and 4,024 healthy controls) identified significant impairments in compulsivity (g = -0.58, [95%CI -0.68, -0.47]; k = 76) and impulsivity (g = -0.48, [95%CI -0.57, -0.38]; k = 63); no significant difference between impairments. Medication use and comorbid psychiatric disorders were not significantly related to impairments. No associations were revealed with OCD severity, depression/anxiety, or illness duration. Conclusion: Cognitive phenotypes of compulsivity and impulsivity in patients with OCD appear to be orthogonal to clinical variables, including severity of OCD symptomatology. Their clinical impact is poorly understood and may require different clinical assessment tools and interventions.

PDF file - 187K, Negative controls for ST6Gal-I staining of tissue sections

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PDF file - 166K, Validation of ST6Gal-I antibody

This cross-sectional study aimed to explore specific online behaviours and their association with a range of underlying psychological and other behavioural factors during the COVID-19 pandemic. Eight countries (Italy, Spain, the United Kingdom, Lithuania, Portugal, Japan, Hungary, and Brazil) participated in an international investigation involving 2223 participants (M = 33 years old; SD = 11), 70% of whom were females. Participants were surveyed for specific type of Internet use severity, appearance anxiety, self-compassion, and image and use of performance-enhancing drugs (IPEDs). Results were compared cross-culturally. The mean time spent online was 5 h (SD = ±3) of daily browsing during the pandemic. The most commonly performed activities included social networking, streaming, and general surfing. A strong association between these online behaviours and appearance anxiety, self-compassion, and IPEDs use was found after adjustment for possible confounders, with higher scores being associated with specific online activities. Significant cross-cultural differences also emerged in terms of the amount of time spent online during the initial stages of the COVID-19 pandemic.

Background Cholelithiasis is a frequent complication in pediatric sickle cell disease (SCD). Though it is standard practice to perform a cholecystectomy in pediatric SCD patients with symptoms of cholelithiasis, the use of elective cholecystectomy for asymptomatic patients remains controversial. Procedure Records of 191 pediatric sickle cell patients with cholelithiasis who underwent cholecystectomy were retrospectively reviewed. Patients classified as follows: (i) elective—no preoperative symptoms, cholelithiasis on screening ultrasound, comprehensive preoperative plan; (ii) symptomatic—preoperative symptoms of cholelithiasis on diagnostic ultrasound, comprehensive preoperative plan; or (iii) emergent—hospitalization for acute cholecystitis symptoms, cholelithiasis on diagnostic ultrasound, limited preoperative preparation. We compared the morbidity of cholecystectomy by examining pre- and post-cholecystectomy hospital admission days, length of stay for cholecystectomy, and surgical complications. Results Patients with SCD underwent a total of 191 cholecystectomies over a 10-year period: 51 elective, 110 symptomatic, and 30 emergent. Patients who required emergent cholecystectomy had a longer postoperative hospitalization time than elective or symptomatic cholecystectomy (7.3 vs 4.3, P < 0.001). Baseline values for total bilirubin and aspartate aminotransferase (AST) were significantly elevated (P < 0.02 and P < 0.07, respectively) in patients requiring emergent cholecystectomy. Conclusions This represents the largest reported retrospective review of pediatric cholelithiasis and cholecystectomy in SCD to date. These data strongly suggest that elective cholecystectomy decreases morbidity associated with emergent cholecystectomy. The overall outcomes for symptomatic and elective patients are favorable. However, our study indicates the need for prospective studies to identify clinical indicators for those emergent patients.

OBJECTIVE: To determine whether curve magnitude of scoliosis at presentation correlates with BMI. METHODS: Retrospective chart review of 180 patients presenting with scoliosis was performed. Curve pattern and magnitude, Risser status, occurrence of surgery, zip code, height and weight, race, and insurance status were recorded. Relationships were examined by Spearman rank and Pearson correlations, and logistic regression analysis was used to determine odds ratios. RESULTS: For both thoracic and lumbar curve patterns, there was a correlation between BMI and curve magnitude. Spearman rank correlation was 0.19 for thoracic (P = .03) and 0.24 for lumbar curves (P = .02). Overweight or obese patients were not more likely, however, to present with curves at higher risk of progression or more likely to have surgical intervention. With respect to potential confounding socioeconomic variables, thoracic curve magnitude was negatively correlated with median family income (Spearman rank correlation –0.17, P = .04). Curve magnitude was not correlated with race, distance, or insurance payer. CONCLUSIONS: Patients with high BMI and scoliosis are more likely to present with larger curves, but not more likely to require surgery. This is concerning because of the national trend of increasing childhood obesity and because scoliosis treatment may be more complicated in larger curves. Socioeconomic factors may also be barriers to access.

Background Increased severity of illness in patient with acute hematogenous osteomyelitis (AHO) with methicillin-resistant Staphylococcus aureus (MRSA) necessitates prompt intervention, but overtreatment of methicillin-sensitive S. aureus (MSSA) may contribute to antibiotic resistance. Therefore, predicting methicillin sensitivity in suspected AHO is desirable. A previously published prediction algorithm has not performed well in settings with high prevalence of MRSA. We sought to develop a predictive equation using presenting factors to predict MRSA in our patient population with a predominance of MRSA. Methods A retrospective chart review was performed. Consecutive cases of AHO with positive blood or bone cultures were identified at a single children's hospital. Presenting features were recorded including duration of symptoms, weight-bearing, prior antibiotic use, vital signs, complete blood count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Univariate comparison was made between the groups with MRSA and MSSA. Continuous variables were compared with t tests and discrete variables were compared using the Fischer exact test. Logistic regression was performed using a forward stepwise regression to develop a model to predict MRSA. Results A total of 68 patients formed the study group, and 60% had MRSA (41 MRSA, 27 MSSA). Temperature, respiratory rate, heart rate, white blood cell count, absolute neutrophil count (ANC), ESR), and CRP were significantly higher in MRSA cases, whereas platelets were lower. Logistic regression resulted in a model utilizing temperature, ANC, and CRP. This model correctly predicted 87% of cases (92% of MRSA and 79% of MSSA) with an area under the curve of 0.919±0.035 with a 95% confidence interval of 0.851, 0.987. Conclusion A logistic regression model incorporating temperature, ANC, and CRP correctly predicts methicillin resistance of S. aureus in 87% of cases. The model differs from one developed at an institution with a low rate of MRSA. Prediction of MRSA could help direct antibiotic management, whereas prediction of MSSA could help prevent overuse of antibiotics directed against MRSA. Level of evidence Diagnostic study level IV.

Background Measurement of serum creatinine (SCr) and urine creatinine (UCr) is regularly used in clinical and research settings. For small animal experiments and for studies in which sample collection is spare (i.e. neonatal cohorts), measuring SCr and UCr using tiny amounts of sample (as low as 10 mcl) would maximize exploration and minimize iatrogenic blood loss. Methods We performed an evaluation in six healthy adults to determine differences between SCr and UCr values in different methodologies and storage environments and time. Study was conducted using 20 mcl of sample. Analyses were done using two-way repeated measures of ANOVA. Results Scr values showed no significant differences between LC/MS vs. Jaffe. However, the SCr using LC/MS method was lowest when measured immediately compared to other time points (F = 7.2; P< 0.001). Similarly, Jaffe measurements showed changes in the mean differences over time; however, these were not significant. UCr values were consistently higher using LC/MS than Jaffe (F = 19; P< 0.01), and UCr changed over time (F = 8.7; P < 0.02). In addition, the interaction term for method and time was also significant (F = 5.8; P < 0.04) which reflects the stability of the Jaffe measurements over time whereas the LC/MS measurements declined; especially after being frozen for 1 year (P < 0.001). Conclusion UCr measured by Jaffe is lower than samples measured by LC/MS. UCr measurements by LC/MS vary more over time, mostly due to the sample measured after 1 year; therefore, storage of urine for more than 90 days measured by LC/MS may provide altered results.

OBJECTIVE Chronic blood transfusion therapy reduces clinical events in children with sickle cell anemia but increases risk for an iron-related liver injury. Liver biopsy is the gold standard technique for quantifying liver iron content (LIC) and evaluating liver pathology. Ferritin, liver enzymes, and R2* magnetic resonance imaging of the liver are obtained as surrogate markers. In this study we compared surrogate markers with the gold standard, liver biopsy, in assessing liver histology. METHODS We conducted a retrospective review of 259 liver biopsies in 109 children with sickle cell anemia on chronic transfusion therapy and chelation therapy during a 9-year period at a single center. Liver pathology was compared with LIC, ferritin, and alanine aminotransferase. RESULTS Ferritin correlates with LIC (r = 0.74, P

How cellular metabolic activities regulate autophagy and determine the susceptibility to oxidative stress and ultimately cell death in neuronal cells is not well understood. An important example of oxidative stress is 4-hydroxynonenal (HNE), which is a lipid peroxidation product that is formed during oxidative stress, and accumulates in neurodegenerative diseases causing damage. The accumulation of toxic oxidation products such as HNE, is a prevalent feature of neurodegenerative diseases, and can promote organelle and protein damage leading to induction of autophagy. In this study, we used differentiated SH-SY5Y neuroblastoma cells to investigate the mechanisms and regulation of cellular susceptibility to HNE toxicity and the relationship to cellular metabolism. We found that autophagy is immediately stimulated by HNE at a sublethal concentration. Within the same time frame, HNE induces concentration dependent CASP3/caspase 3 activation and cell death. Interestingly, both basal and HNE-activated autophagy, were regulated by glucose metabolism. Inhibition of glucose metabolism by 2-deoxyglucose (2DG), at a concentration that inhibited autophagic flux, further exacerbated CASP3 activation and cell death in response to HNE. Cell death was attenuated by the pan-caspase inhibitor Z-VAD-FMK. Specific inhibition of glycolysis using koningic acid, a GAPDH inhibitor, inhibited autophagic flux and exacerbated HNE-induced cell death similarly to 2DG. The effects of 2DG on autophagy and HNE-induced cell death could not be reversed by addition of mannose, suggesting an ER stress-independent mechanism. 2DG decreased LAMP1 and increased BCL2 levels suggesting that its effects on autophagy may be mediated by more than one mechanism. Furthermore, 2DG decreased cellular ATP, and 2DG and HNE combined treatment decreased mitochondrial membrane potential. We conclude that glucose-dependent autophagy serves as a protective mechanism in response to HNE.

The objective of this study was to evaluate extracellular matrix metalloproteinase (EMMPRIN) as a novel target in orthotopic pancreatic cancer murine models. MIA PaCa-2 human pancreatic tumor cells were implanted in groups 1 and 3–7, whereas MIA PaCa-2 EMMPRIN knockdown cells were implanted in group

The contribution of nitric oxide (NO) to the pathophysiology of asthma remains incompletely defined despite its established pro- and anti-inflammatory effects. Induction of the inducible nitric oxide synthase (iNOS), arginase and superoxide pathways is correlated with increased airway hyperresponsiveness (AHR) in asthmatic subjects. To determine the contributions of these pathways in proximal and distal airways, we compared bronchial wash (BW) to traditional bronchoalveolar lavage (BAL) for measurements of reactive nitrogen/oxygen species, arginase activation, and cytokine/chemokine levels in asthmatic and normal subjects. Levels of NO were preferentially elevated in the BAL, demonstrating higher-level NOS activation in the distal airway compartment of asthmatic subjects. In contrast, DHE+ cells which have the potential to generate reactive oxygen species were found to be increased in both proximal and distal airway compartments of asthmatics compared to controls. Different patterns of cytokines and chemokines were observed, with a predominance of epithelial cell-associated mediators in the BW as compared to macrophage/monocyte-derived mediators in the BAL of asthmatic subjects. Our study demonstrates differential production of reactive species and soluble mediators within the distal airways as compared to the proximal airways in asthma. These results indicate that cellular mechanisms are activated in the distal airways of asthmatics and must be considered in the development of therapeutic strategies for this chronic inflammatory disorder.

Children with sickle cell anemia are at risk for brain injury. Physicians obtain brain magnetic resonance imaging (MRI) for clinical indications to determine if a patient has developed a brain injury. Controversy exists whether all children with sickle cell anemia should undergo MRI screening. This retrospective study evaluates the clinical and laboratory correlates for brain injury in 124 MRIs obtained for a variety of clinical indications. Seizure, sensory, or motor events were statistically associated with the highest risk for brain injury while less specific neurologic complaints of headache or poor school performance were not associated. Children with high systolic blood pressure, leukocytosis, and severe anemia demonstrate a higher probability for brain injury. These results indicate that brain MRI should be obtained on all children with seizure, sensory, or motor events. These data suggest that less specific neurologic symptoms should be screened if physical findings or abnormal lab or vital signs exist.

The objective of this study is to evaluate the therapeutic response to a novel monoclonal antibody targeting human extracellular matrix metalloproteinase inducer (EMMPRIN) in combination with gemcitabine in a pancreatic-tumor xenograft murine model by sequential 2-deoxy-2-[18F]fluoro-D-glucose ((18)F-FDG) positron emission tomography/computed tomgraphy (PET/CT) imaging.Four groups of SCID mice bearing orthotopic pancreatic tumor xenografts were injected with phosphate-buffered saline, gemcitabine (120 mg/kg BW), anti-EMMPRIN antibody (0.2 mg), or combination, respectively, twice weekly for 2 weeks, while (18)F-FDG PET/CT imaging was performed weekly for 3 weeks. Changes in mean standardized uptake value (SUV(mean)) of (18)F-FDG and volume of tumors were determined.The tumor SUV(mean) change in the group receiving combination therapy was significantly lower than those of the other groups. Tumor-volume changes of groups treated with anti-EMMPRIN monotherapy or combined therapy were significantly lower than that of the control group.These data provide support for clinical studies of anti-EMMPRIN therapy with gemcitabine for pancreatic cancer treatment.

Bone bars (BB) are struts of normal trabecular bone that cross the medullary portions of the metaphysis and diaphysis at right angles to the long axis of the shaft. The purpose of this investigation was to determine whether the presence of bone bars (BB) identified on radiographs of the proximal femurs and tibia, predict lower bone mineral density (BMD) as evaluated with dual-energy x-ray absorptiometry (DXA) in the lumbar spine, total hip, or femoral neck. A total of 134 sequential DXA patients underwent radiography of the pelvis, hips, and both knees. The radiographs were evaluated for the presence of BB by two musculoskeletal radiologists who were blinded to DXA results. A t test was used to evaluate the relationship of BB to BMD and a Chi-square test was used to determine if BB were equally distributed among the categories of normal BMD, low bone mass (osteopenia), and osteoporosis. BB were associated with lower BMD at all measured sites. BB at the intertrochanteric and proximal tibial sites were the most predictive of low BMD while supraacetabular and distal femur BB were less predictive. Osteoporosis or osteopenia is seen in 60–91% of those with BB depending on the side and reader. It is only seen in about 40% of those without BB. We conclude that the presence of BB suggest decreased BMD and when correlated with other clinical information, might support further evaluation of BMD.

Introduction It is often not possible to determine whether small nodules detected on computed tomography (CT) in oncology patients are metastatic. We evaluated a group of oncology patients to determine the outcome of small pulmonary nodules and whether they can be ignored in the therapeutic decision process. Materials and Methods Radiology reports of thoracic CTs from a 2-year period were searched for keywords indicating a small pulmonary nodule. All CT images were evaluated by two thoracic radiologists for nodules 4 mm or less. There were 102 cases that met criteria for inclusion. Results Forty-seven had follow-up CT of less than 365 days, and 55 had follow-up CT for more than 365 days. For those with less than 365 days, the observed nodule was increased (17, 36%), increased and new nodules (9, 19%); stable (19, 40%); stable but new nodules developed (1); and decreased (1). For those with greater than 365 days follow-up, the observed nodule was increased (3, 5%); stable (51, 93%); and stable but new nodule developed (1). Combined, 28% of patient';s nodules increased (90% were within 365 days; 25% within 203 days; and 14% within 14 days). Conclusion In oncologic patients, 28% of small pulmonary nodules detected at initial CT will increase in size, suggesting metastasis. This increase in size tends to occur early, and follow-up CT in 3 months and 6 months would be appropriate in further evaluation. Small nodules that are stable in size for more than 365 days are unlikely to be pulmonary metastasis.

The obsessive-compulsive (OC) spectrum has been discussed in the literature for two decades. Proponents of this concept propose that certain disorders characterized by repetitive thoughts and/or behaviors are related to obsessive-compulsive disorder (OCD), and suggest that such disorders be grouped together in the same category (i.e. grouping, or "chapter") in DSM. This article addresses this topic and presents options and preliminary recommendations to be considered for DSM-V. The article builds upon and extends prior reviews of this topic that were prepared for and discussed at a DSM-V Research Planning Conference on Obsessive-Compulsive Spectrum Disorders held in 2006. Our preliminary recommendation is that an OC-spectrum grouping of disorders be included in DSM-V. Furthermore, we preliminarily recommend that consideration be given to including this group of disorders within a larger supraordinate category of "Anxiety and Obsessive-Compulsive Spectrum Disorders." These preliminary recommendations must be evaluated in light of recommendations for, and constraints upon, the overall structure of DSM-V.

A goal of radiologists is to use computed tomography (CT) imaging less frequently in younger patients because of radiation exposure. We evaluated abdominal CT use among patients hospitalized for acute pancreatitis at a tertiary care hospital and compared estimated radiation doses with disease severity and patient age.We performed a retrospective analysis of numbers and types of CTs performed on patients with acute pancreatitis (1036 admissions, 869 patients; mean age, 50.8 y); 566 had 1081 abdominopelvic CTs performed from October 1, 2001, to September 30, 2006. Effective dose estimates for abdominopelvic CTs were used to estimate exposure. Disease severities were stratified using Balthazar CT grades and severity indexes.The mean number of abdominopelvic CTs per patient, per hospitalization, was 1.9 (range, 1-12); the mean number was 3.0 over the 5-year period (range, 1-19). During hospitalization, each patient was exposed to a mean estimated radiation dose of 31.03 +/- 26.4 mSv (range, 14.7-176.9 mSv). Patients with pancreatitis grades D or E (n = 233) compared with grades A through C (n = 333) had longer periods of hospitalization (mean, 23.3 vs 10.8 d; P.001), more days as an inpatient (mean, 2.54 vs 1.45 d; P.001), more total CT scans (mean, 4.02 vs 2.37; P.001), and higher total effective radiation doses (mean, 53.5 vs 35 mSv; P.0001). Linear regression revealed a relationship between dose and disease grade, but not patient age.Regardless of age, patients with severe acute pancreatitis undergo more abdominopelvic CTs as inpatients and outpatients and are exposed to higher doses of radiation compared with patients with less severe disease. Awareness of CT ordering patterns for patients with acute pancreatitis may aid in the development of alternate imaging strategies to reduce radiation exposure in this population, especially for younger patients.

Goals: To define both risks and costs of optimal care of patients with gastric acid hypersecretion. Background: The management of Zollinger-Ellison syndrome and other gastric acid hypersecretory disorders remains challenging. The optimal strategy for follow-up including gastric acid analysis, laboratory studies, and endoscopy is unknown but important given the potential complications from uncontrolled acid secretion. Study: Over the last 18 years, patients with gastric acid hypersecretory disorders have been followed prospectively with gastric acid analysis and endoscopy titrating oral lansoprazole and evaluating for complications. Protocol driven charges were calculated using the most recent information available. Results: After 1 year of treatment optimization, 19 of 67 patients had 43 relapses, (once only in 10 patients). Risk markers for relapse included: (1) antrectomy, 67% relapsed versus 21% in unoperated patients; (2) basal acid output > 5 mmol/h (risk = 5.17); and (3) poor compliance. On treatment, 79% of 58 intact patients (excluding antrectomy) were lesion-free; 11 % had only 1 relapse. Thus 90% were well managed with optimized lansoprazole alone. Protocol driven charges exceeded $25,000 the first year and $7000 annually thereafter. Conclusions: Relapse is infrequent and generally mild with acid secreting status closely monitored. The ideal strategy to balance costs and testing awaits further study.

Certain types of metallic objects apparently have high attenuation (a white image) on dual-energy X-ray absorptiometry (DXA) scan images, but instead show up as black (black hole artifacts). When small, these artifacts may easily be missed on visual inspection. We hypothesized that such "black hole" artifacts could have a significant effect on bone mineral density (BMD) results. Human use approval (Institutional Review Board [IRB]) was obtained to publish patient scans and an IRB waiver was obtained for nonhuman research. We placed individual surgical clips and cassettes of clips of tantalum, stainless steel and titanium, and a bullet over the third lumbar vertebra (L3) of a Hologic spine phantom. In addition, 4 or 8 individual tantalum or stainless steel clips and tantalum squares were placed over L3 of cadaveric spines (high-density spine L1–L4 BMD=1.049g/cm 2 ) and low-density spine BMD (L1–L4 BMD=0.669g/cm 2 ) with attached soft tissues. Stainless steel and titanium clips scanned as white objects with DXA. A bullet and tantalum clips scanned black (black holes). All clip types were visible on single-energy scans as white objects. Eight tantalum clips significantly lowered L3 BMD compared to 4 or 0 clips in the high-density spine. There were no significant differences in BMD L1–L4 between 0, 4, and 8 tantalum clips in the high-density spine. In the low-density spine, 8 tantalum clips over L3 had significantly lower BMD compared to 4 tantalum clips overlying L3 and 4 clips lateral to L3 and 4 clips over L3. All of these scenarios had lower L3 BMD than no tantalum clips overlying L3. The BMD of L1–L4 was lowest with 8 clips at L3, but was not significantly different than no clips overlying L3. Eight tantalum clips lateral to L3 was significantly higher than no clips over L3. Black hole artifacts can occur in DXA scans containing certain metals like tantalum surgical clips. Although these surgical clips could decrease BMD at a localized area, they do not significantly decrease the L1–L4 spine BMD in a high-density spine specimen. In a low-density spine specimen, tantalum clips do have the potential to alter BMD of a single vertebral body and L1–L4. Attention should be paid to the possibility of black hole artifacts on DXA scans and the effect they may have on spine results. Viewing scans in the single-energy mode can be used to verify the presence of tantalum clips.

In this report, which is an update of a guideline published in 2002 (Bandelow et al. 2002, World J Biol Psychiatry 3:171), recommendations for the pharmacological treatment of anxiety disorder, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD) are presented. Since the publication of the first version of this guideline, a substantial number of new randomized controlled studies of anxiolytics have been published. In particular, more relapse prevention studies are now available that show sustained efficacy of anxiolytic drugs. The recommendations, developed by the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-traumatic Stress Disorders, a consensus panel of 30 international experts, are now based on 510 published randomized, placebo- or comparator-controlled clinical studies (RCTs) and 130 open studies and case reports. First-line treatments for these disorders are selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) and the calcium channel modulator pregabalin. Tricyclic antidepressants (TCAs) are equally effective for some disorders, but many are less well tolerated than the SSRIs/SNRIs. In treatment-resistant cases, benzodiazepines may be used when the patient does not have a history of substance abuse disorders. Potential treatment options for patients unresponsive to standard treatments are described in this overview. Although these guidelines focus on medications, non-pharmacological were also considered. Cognitive behavioural therapy (CBT) and other variants of behaviour therapy have been sufficiently investigated in controlled studies in patients with anxiety disorders, OCD, and PTSD to support them being recommended either alone or in combination with the above medicines.

Individuals with obsessive-compulsive disorder (OCD) experience recurrent obsessive and/or compulsive thoughts and behaviours which cause them distress, and significantly impair their daily lives. The disorder is thought to have a chronic course and a low rate of remission, as evidenced by mainly clinical samples. Longitudinal psychiatric epidemiological studies are few and far between. This article presents the findings relating to OCD from one such study, the Zurich Study: OCD defined according to DSM-5 criteria had a high prevalence rate and frequently a chronic course but it had a long-term remission rate of almost 60%, which is higher than hitherto believed. OCD was generally highly comorbid with other disorders and particularly closely associated with social phobia.

Prevention of tumors induced by environmental carcinogens has not been achieved. Skin tumors produced by polyaromatic hydrocarbons, such as 7,12-dimethylbenz(a)anthracene (DMBA), often harbor an H-ras point mutation, suggesting that it is a poor target for early immunosurveillance. The application of pyrosequencing and allele-specific PCR techniques established that mutations in the genome and expression of the Mut H-ras gene could be detected as early as 1 d after DMBA application. Further, DMBA sensitization raised Mut H-ras epitope–specific CTLs capable of eliminating Mut H-ras+ preneoplastic skin cells, demonstrating that immunosurveillance is normally induced but may be ineffective owing to insufficient effector pool size and/or immunosuppression. To test whether selective pre-expansion of CD8 T cells with specificity for the single Mut H-ras epitope was sufficient for tumor prevention, MHC class I epitope–focused lentivector-infected dendritic cell– and DNA-based vaccines were designed to bias toward CTL rather than regulatory T cell induction. Mut H-ras, but not wild-type H-ras, epitope-focused vaccination generated specific CTLs and inhibited DMBA-induced tumor initiation, growth, and progression in preventative and therapeutic settings. Transferred Mut H-ras–specific effectors induced rapid tumor regression, overcoming established tumor suppression in tumor-bearing mice. These studies support further evaluation of oncogenic mutations for their potential to act as early tumor-specific, immunogenic epitopes in expanding relevant immunosurveillance effectors to block tumor formation, rather than treating established tumors.

Objective. To optimize forearm radiocephalic fistula success, many programs recommend a minimal cephalic vein diameter of 0.25 cm or greater on preoperative sonographic mapping. It is not established, however, whether a vein diameter before or after application of a tourniquet should be used in determining suitability for creation of a forearm fistula. Methods. Before forearm radiocephalic fistula placement, preoperative sonographic mapping measured the cephalic vein diameter before and after application of a tourniquet. The patients fell into 2 groups: those with a pretourniquet vein diameter of 0.25 cm or greater (group 1) and those with a pretourniquet vein diameter of less than 0.25 cm that increased to 0.25 cm or greater after application of the tourniquet (group 2). The adequacy of each fistula for dialysis was determined clinically. Results. Among 73 radiocephalic fistulas with known clinical outcomes, 28 were in group 1, and 45 were in group 2, on the basis of sonography. Fistula success rates were similar in group 1 patients (11 [39%] of 28) and group 2 patients (15 [33%] of 45) (P = .624, Fisher exact test). Inclusion of group 2 patients increased the number of patients recommended for placement of forearm fistulas and increased the total number of usable forearm fistulas from 11 to 26. The overall success rate of forearm fistulas was lower in women (19% versus 50%; P = .015, Fisher exact test). Conclusions. The use of a venous tourniquet increases the number of patients eligible for forearm fistulas without decreasing the adequacy rate of these fistulas. Therefore, a tourniquet should routinely be used in patients with small cephalic veins on pretourniquet evaluation.

Objective To compare glycemic control, safety, and parental satisfaction in preschool-aged diabetic children randomized to treatment either with continuous subcutaneous insulin infusion (CSII) or intensive insulin injection therapy. Study design This clinical trial enrolled 42 patients Results Thirty-seven patients completed 6 months of therapy. There was a significant decrease in HbA1c during the study period for both groups (from 8.9% ± 0.6% to 8.6% ± 0.6% at 3- and 6-month visits). At 3 months, children using pumps had a significantly lower HbA1c than the injection group (8.4% vs 8.8%); however, by 6 months the two groups were similar (8.5% vs 8.7%). No differences in pre-meal blood sugar variabilities were seen between groups. Children on pumps had increases in the number of meter-detected episodes of hypoglycemia. Pump therapy was safe and well tolerated. No episodes of ketoacidosis occurred in either group, whereas one hypoglycemic seizure occurred in each group. Parents reported satisfaction with CSII, with 95% of families continuing on CSII beyond the 6-month study period. Conclusion Pump therapy in preschool-aged children was not associated with clinically significant differences in glycemic control as compared with intensive injection therapy. The rationale for initiating CSII in this age group should be based on patient selection and lifestyle preference.

Purpose: To evaluate common duct (CD) dilation by computed tomography (CT) in patients with intact gallbladders and diameter change over time in remote and interval cholecystectomy patients, frequency of visualization of the CD, and its relationship to age. Methods: This IRB-approved retrospective study evaluated baseline CD diameter, intrahepatic biliary dilation, and interval duct diameter change in patients with CTs ≥ 2 years apart (n = 324), in block-randomized order by two blinded board-certified radiologists. 272 patients were divided into three groups: (1) prior cholecystectomy before the first CT, (2) cholecystectomy between the first and last CTs, and (3) no cholecystectomy. A subset of 191 nonoperated patients was evaluated for age-related dilation. Results: Group 1 ducts were significantly larger than the other groups at both baseline and follow-up CTs (p

Previous gene microarray studies have shown that expression of 14-3-3θ is significantly decreased in an α-synuclein transgenic mouse model. In this study, we tested whether α-synuclein can regulate 14-3-3θ transcription. We demonstrate that the 14-3-3θ mRNA level is decreased in SH-SY5Y cells overexpressing α-synuclein. Luciferase activity under the control of the 14-3-3θ promoter is reduced both in stable SH-SY5Y cells constitutively overexpressing α-synuclein and in doxycycline-inducible SH-SY5Y cells upon α-synuclein induction, suggesting that the regulation of 14-3-3θ by α-synuclein occurs at the transcriptional level. Knockdown of α-synuclein by RNA interference does not increase the 14-3-3θ mRNA level. These findings suggest that α-synuclein represses 14-3-3θ transcription under pathologic conditions, but that regulation of 14-3-3θ expression is not a function of endogenous α-synuclein at baseline.

OBJECTIVES To evaluate changes in the common duct diameter on sonography over time in patients with and without cholecystectomy. METHODS We retrospectively evaluated the common duct diameter, central biliary dilatation, and interval change in 1079 patients who underwent sonography at least 2 years apart over a 6-year period. A board-certified radiologist, blinded to clinical and laboratory data, measured the duct diameter. A total of 893 patients (568 female and 325 male) were divided into 3 groups: group 1, remote cholecystectomy before sonography (mean, 9.7 years before sonography; n = 117); group 2, interval cholecystectomy between the first and second sonographic examinations (n = 56); and group 3, no cholecystectomy (n = 720). All groups were stratified by age, and group 3 was also stratified by the absence (n = 528) or presence (n=192) of gallstones. RESULTS Duct diameters at baseline and follow-up averaged 4.5 and 5.2, 3.6 and 4.9, and 3.5 and 3.9 mm in groups 1, 2, and 3, respectively. Group 1 ducts were larger at baseline than in the other groups (P < .001). At follow-up, group 2 ducts showed a greater interval diameter increase than the other groups (P < .001). In a subanalysis of each group based on age, there was a mild increase in duct size with increasing age, although not clinically significant and within normal limits. In group 3 patients who never had gallstones, there was a significant small increase in duct size over decades (P < .001). The baseline duct sizes for patients with gallstones were not significantly different from those who never had gallstones (P = .15). CONCLUSIONS Patients with remote cholecystectomy have larger common duct diameters than those with no or interval cholecystectomy. Most asymptomatic patients with or without cholecystectomy have a normal common duct diameter.

Alain Cuna,1 Jegen Kandasamy,1 Naomi Fineberg,2 Brian Sims1 1Department of Pediatrics, Division of Neonatology, 2Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA Background: B-type natriuretic peptide (BNP) is a cardiac biomarker useful in screening for pulmonary hypertension (PH) in adults. It is possible that BNP may also be useful in detecting PH among preterm infants with bronchopulmonary dysplasia (BPD). Objective: To determine the utility of BNP for identification of PH among preterm infants with BPD. Methods: We retrospectively identified preterm infants with BPD who underwent screening echocardiography for suspected PH and had serum BNP levels measured within 10 days before or after echocardiography. Eligible infants were classified based on echocardiographic diagnosis of either PH or no PH. Median and interquartile ranges (IQR) of BNP values were compared, and area under the curve (AUC) of receiver operator characteristic (ROC) analysis was used to determine the optimum threshold value for detection of PH. Results: Twenty-five preterm infants with BPD (mean gestational age 26.5 ± 1.7 weeks, mean birth weight 747 ± 248 g) were identified. The median difference in days between echocardiography and BNP measurement was 1 day (IQR 0–3, range 0–10 days). Based on echocardiography, 16 were diagnosed with PH and nine without PH. No significant difference in terms of gestational age, birth weight, sex, race, or respiratory support was found between the two groups. Median (IQR) BNP values of those with PH were higher than those without PH (413 [212–1178] pg/mL versus 55 [21–84] pg/mL, P < 0.001). AUC of ROC analysis showed that a BNP value of 117 pg/mL had 93.8% sensitivity and 100% specificity for detecting PH. Conclusion: BNP estimation may be useful for screening of PH in infants with BPD. Keywords: B-type natriuretic peptide, pulmonary hypertension, bronchopulmonary dysplasia, biological markers, prematurity

Parkinson's disease is a neurodegenerative movement disorder. The histopathology of Parkinson's disease comprises proteinaceous inclusions known as Lewy bodies, which contains aggregated α-synuclein. Cathepsin D (CD) is a lysosomal protease previously demonstrated to cleave α-synuclein and decrease its toxicity in both cell lines and mouse brains in vivo. Here, we show that pharmacological inhibition of CD, or introduction of catalytically inactive mutant CD, resulted in decreased CD activity and increased cathepsin B activity, suggesting a possible compensatory response to inhibition of CD activity. However, this increased cathepsin B activity was not sufficient to maintain α-synuclein degradation, as evidenced by the accumulation of endogenous α-synuclein. Interestingly, the levels of LC3, LAMP1, and LAMP2, proteins involved in autophagy-lysosomal activities, as well as total lysosomal mass as assessed by LysoTracker flow cytometry, were unchanged. Neither autophagic flux nor proteasomal activities differs between cells over-expressing wild-type versus mutant CD. These observations point to a critical regulatory role for that endogenous CD activity in dopaminergic cells in α-synuclein homeostasis which cannot be compensated for by increased Cathepsin B. These data support the potential need to enhance CD function in order to attenuate α-synuclein accumulation as a therapeutic strategy against development of synucleinopathy. Insufficiencies in the autophagy-lysosome pathway may contribute to neurodegenerative disease pathogenesis and progression. We found that a catalytically inactive mutant cathepsin D (D295N CD) decreases endogenous CD activity, similar to inhibition of endogenous CD activity by the addition of CD inhibitor, PepA, leads to accumulation of α-synuclein, without significant changes of overall autophagy activities. As accumulation of α-synuclein is a main pathological feature of Parkinson's disease (PD), this study further demonstrate a crucial role of CD activities in attenuation of synucleinopathies such as PD.

The ST6Gal-I sialyltransferase adds an α2-6–linked sialic acid to the N-glycans of certain receptors. ST6Gal-I mRNA has been reported to be upregulated in human cancer, but a prior lack of antibodies has limited immunochemical analysis of the ST6Gal-I protein. Here, we show upregulated ST6Gal-I protein in several epithelial cancers, including many colon carcinomas. In normal colon, ST6Gal-I localized selectively to the base of crypts, where stem/progenitor cells are found, and the tissue staining patterns were similar to the established stem cell marker ALDH1. Similarly, ST6Gal-I expression was restricted to basal epidermal layers in skin, another stem/progenitor cell compartment. ST6Gal-I was highly expressed in induced pluripotent stem (iPS) cells, with no detectable expression in the fibroblasts from which iPS cells were derived. On the basis of these observations, we investigated further an association of ST6Gal-I with cancer stem cells (CSC). Selection of irinotecan resistance in colon carcinoma cells led to a greater proportion of CSCs compared with parental cells, as measured by the CSC markers CD133 and ALDH1 activity (Aldefluor). These chemoresistant cells exhibited a corresponding upregulation of ST6Gal-I expression. Conversely, short hairpin RNA (shRNA)-mediated attenuation of ST6Gal-I in colon carcinoma cells with elevated endogenous expression decreased the number of CD133/ALDH1-positive cells present in the cell population. Collectively, our results suggest that ST6Gal-I promotes tumorigenesis and may serve as a regulator of the stem cell phenotype in both normal and cancer cell populations. Cancer Res; 73(7); 2368–78. ©2012 AACR.

Pediatric acute care nurses questioned the practice of weighing disposable infant diapers immediately after voiding. This study asked the research question, "Does volume of saline, diaper configuration, and/or size of diaper statistically effect changes in diaper weights over time?" The method was an experimental, laboratory model. Pre-set volumes of saline were added to disposable diapers that were then left folded or unfolded. Each diaper was weighed immediately post-wetting and re-weighed at hourly intervals for seven hours. Data were analyzed using a repeated measures analysis of variance (RMANOVA) with balanced data (F-test). Diaper weight changes over time were statistically significant for all time points and for all volumes regardless of diaper size; however, the changes in weight were small and without clinical significance. It is appropriate to weigh diapers at the end of eight hours without risk of altering subsequent fluid management of patients in open-air, non-humidified environments. This practice has led to more efficient use of nurses' time with fewer interruptions for patients and families.

Cathepsin D (CD) is a lysosomal aspartyl protease which plays an important role in α-synuclein degradation, and neuronal survival. CD knockout mice die by post-natal day 25 ± 1 due to intestinal necrosis. We analyzed the young adult male heterozygous mice, and found no behavior abnormalities in the heterozygous mice compared to wildtype littermates. LC3-II, p62, and α-synuclein levels are similar, while LAMP1 is higher in the striatum in CD heterozygous compared to wildtype mice. Interestingly, we found that dopamine and metabolites in the striatum and olfactory bulbs are at higher levels than wildtype littermates, while the DOPAC/DA and HVA/DA ratio remain similar between wildtype and CD heterozygous mice. In response to sub-chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, dopamine, DOPAC, and HVA are depleted to similar levels in the striatum in both heterozygous and wildtype mice. Dopamine synthesizing enzyme tyrosine hydroxylase, metabolic enzyme monoamine oxidase, and catechol-O-methyltransferase (COMT) levels are similar in the striatum in wildtype and heterozygous mice. These studies provide valuable information regarding how lysosomal function may contribute to neurochemical homeostasis in animal models.

The goal of the study was to assess the efficacy of combined extracellular matrix metalloprotease inducer (EMMPRIN)- and death receptor 5 (DR5)-targeted therapy for pancreatic adenocarcinoma in orthotopic mouse models with multimodal imaging. Cytotoxicity of anti-EMMPRIN antibody and anti-DR5 antibody (TRA-8) in MIA PaCa-2 and PANC-1 cell lines was measured by ATPlite assay in vitro. The distributions of Cy5.5-labeled TRA-8 and Cy3-labeled anti-EMMPRIN antibody in the 2 cell lines were analyzed by fluorescence imaging in vitro. Groups 1 to 12 of severe combined immunodeficient mice bearing orthotopic MIA PaCa-2 (groups 1–8) or PANC-1 (groups 9–12) tumors were used for in vivo studies. Dynamic contrast-enhanced–MRI was applied in group 1 (untreated) or group 2 (anti-EMMPRIN antibody). The tumor uptake of Tc-99m-labeled TRA-8 was measured in group 3 (untreated) and group 4 (anti-EMMPRIN antibody). Positron emission tomography/computed tomography imaging with 18F-FDG was applied in groups 5 to 12. Groups 5 to 8 (or groups 9 to 12) were untreated or treated with anti-EMMPRIN antibody, TRA-8, and combination, respectively. TRA-8 showed high killing efficacy for both MIA PaCa-2 and PANC-1 cells in vitro, but additional anti-EMMPRIN treatment did not improve the cytotoxicity. Cy5.5–TRA-8 formed cellular caps in both the cell lines, whereas the maximum signal intensity was correlated with TRA-8 cytotoxicity. Anti-EMMPRIN therapy significantly enhanced the tumor delivery of the MR contrast agent, but not Tc-99m–TRA-8. Tumor growth was significantly suppressed by the combination therapy, and the additive effect of the combination was shown in both MIA PaCa-2 and PANC-1 tumor models. Mol Cancer Ther; 11(2); 405–15. ©2011 AACR.

Cell differentiation is associated with changes in metabolism and function. Understanding these changes during differentiation is important in the context of stem cell research, cancer, and neurodegenerative diseases. An early event in neurodegenerative diseases is the alteration of mitochondrial function and increased oxidative stress. Studies using both undifferentiated and differentiated SH-SY5Y neuroblastoma cells have shown distinct responses to cellular stressors, however the mechanisms remain unclear. We hypothesized that since the regulation of glycolysis and oxidative phosphorylation are modulated during cellular differentiation, this would change bioenergetic function and the response to oxidative stress. To test this, we used retinoic acid (RA) to induce differentiation of SH-SY5Y cells and assessed changes in cellular bioenergetics using extracellular flux analysis. After exposure to RA, the SH-SY5Y cells had an increased mitochondrial membrane potential, without changing mitochondrial number. Differentiated cells exhibited greater stimulation of mitochondrial respiration with uncoupling and an increased bioenergetic reserve capacity. The increased reserve capacity in the differentiated cells was suppressed by the inhibitor of glycolysis, 2-deoxy-D-glucose (2-DG). Furthermore, we found that differentiated cells were substantially more resistant to cytotoxicity and mitochondrial dysfunction induced by reactive lipid species 4-hydroxynonenal (HNE) or the reactive oxygen species generator 2,3-dimethoxy-1,4-naphthoquinone (DMNQ). We then analyzed the levels of selected mitochondrial proteins and found an increase in complex IV subunits which we propose contributes to the increase in reserve capacity in the differentiated cells. Furthermore, we found an increase in MnSOD that could, at least in part, account for the increased resistance to oxidative stress. Our findings suggest that profound changes in mitochondrial metabolism and antioxidant defenses occur upon differentiation of neuroblastoma cells to a neuron-like phenotype.

The rod photoreceptor cGMP-gated cation channel has an essential role in phototransduction functioning as the primary point for calcium and sodium entry into the rod outer segment. The channel consists of two subunits, α and β. The α-subunit can function in isolation as an ion channel, and the β-subunit modulates channel activity and has a structural role. We previously reported that a mouse knockout (KO) of the β-subunit and related glutamic acid–rich proteins (GARPs) attenuates rod function and causes structural alterations and slowly progressive retinal degeneration. Here, we have extended our functional analyses of the KO mice evaluating rod and cone function using the electroretinogram in mice up to 4 months of age. Retinal stratification is preserved in the knockout mice at 3 months, and a significant number of cones remain up to 7 months based on PNA staining of cone sheaths. Electroretinography of KO mice at 1 month old revealed a diminished dark-adapted b-wave and normal light-adapted b-wave compared to wild-type mice. Over the next 3 months, both dark- and light-adapted b-wave amplitudes declined, but the reduction was greater for dark-adapted b-wave amplitudes. In one-month-old mice, the critical flicker frequency (CFF) was substantially lower for the KO mice at scotopic intensities, but normal at photopic intensities. CFF values remained stable in the KO mice as the b-wave amplitudes decreased with age. Declining b-wave amplitudes confirm an RP phenotype of rod followed by cone degeneration. Flicker responses show that the cone circuits function normally at threshold despite significant losses in the maximum light-adapted b-wave amplitude. These results confirm that rods are marginally functional in the absence of the β-subunit and in addition show that CFF may be a more sensitive measure of remaining functional cone vision in animal models of RP undergoing progressive rod–cone degeneration.

Pancreatic cancer has the highest fatality rate of all cancers and is the fourth leading cause of cancer death in the United States.1 The nonspecific and variable symptoms of pancreatic cancer often lead to late-stage disease at the time of diagnosis, and the majority of the newly diagnosed pancreatic cancers are unresectable.2 Gemcitabine is a standard drug for unresectable pancreatic cancer3; a small survival benefit of radiation therapy in combination with gemcitabine has been reported in patients with localized unresectable pancreatic cancer compared to gemcitabine monotherapy,4 whereas any of the conventional chemotherapeutic agents, such as 5-fluorouracil, cisplatin, irinotecan, and oxaliplatin, did not improve the survival of patients with advanced pancreatic cancer when added to gemcitabine.5–8 More recently, anti–epidermal growth factor receptor (EGFR) has been investigated as a targeted therapy for pancreatic cancer. EGFR regulates cell proliferation and differentiation and is expressed in a marked percentage of cases ranging from 45 to 95%.9,10 EGFR expression is associated with aggressive tumor growth and poor clinical prognosis.11 Erlotinib (a small molecule targeting EGFR) or cetuximab (anti-EGFR monoclonal antibody) combined with gemcitabine significantly improved the survival of patients with advanced pancreatic cancer over gemcitabine monotherapy.10,12 Combination therapy with erlotinib and gemcitabine is considered a newer standard for locally advanced, unresectable, or metastatic pancreatic cancer, recently approved by the Food and Drug Administration. However, there is a wide range of drug sensitivities among individuals with pancreatic cancer. Because the characteristics of an individual tumor vary among patients, it would be ideal to tailor the therapeutic strategy to each patient by detecting the early tumor response and in turn to increase the probability for a favorable outcome. Individualized optimal treatment, called personalized medicine, can be guided by molecular biomarkers obtained from biopsies or by the use of imaging biomarkers. Although minimally invasive biopsy techniques are available,13 they still involve pain, stress, and risk to patients. Biopsies can potentially stimulate neoangio-genesis by damaging tumor tissue and can also increase the risk of metastases by increasing circulating tumor cells. It has also been argued that data obtained from a small portion of the tumor mass may not be representative of the entire tumor response. This may be particularly important when the response to therapy is tumor necrosis. Therefore, noninvasive imaging might be an approach that addresses these problems for pancreatic cancer patients as it can minimize patient discomfort and the risk of inducing metastasis and can be used to evaluate the response of the entire tumor to therapy. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) noninvasively measures pharmacokinetic parameters in microvasculature by quantifying the transfer of a contrast agent from the vascular space to the extravascular-extracellular space over time.14 Effective cancer therapies disrupt tumor vascular angiogenesis, leading to a decrease in microvessel density, perfusion, and permeability. These features can be measured by DCE-MRI prior to a quantifiable tumor volume decrease or morphologic change. DCE-MRI has been clinically used for evaluating the early therapeutic efficacy of drugs for solid cancers such as glioblastoma,15 breast cancer,16,17 head and neck cancer,18 colorectal cancer,19 and renal cell cancer.20 The purpose of this study was to evaluate DCE-MRI as an early prognostic tool to identify and characterize effective anti-EGFR therapy with and without concurrent chemotherapy using cetuximab and irinotecan in an orthotopic murine pancreatic cancer model.

Background: This study evaluated the effect of 17β-estradiol (E2) administration on cardiovascular parameters in male rats after trauma-hemorrhage and for an extended period (3 hours) of severe hypotension, based on blood-pool single photon emission computed tomography imaging. Methods: After a 5-cm midline laparotomy, male Sprague-Dawley rats were injected intravenously with 99mTc-bovine serum albumin; the animals were then bled for >45 minutes to reach maximum bleedout (MBO; removal of 60% of the circulating blood volume). E2 (1 mg/kg body weight, 0.4 mL/kg) or vehicle (cyclodextrin [CD], 0.4 mL/kg) was injected intravenously at MBO; no additional fluid was administered for 3 hours. Imaging was performed continually for a maximum of 3 hour post-MBO. The percentages of injected dose in heart, brain, liver, and kidney were quantified from the imaging (n = 8/group) at 0 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, and 180 minutes post-MBO. Mixed model analysis of variance was used to analyze the difference between the two groups over six imaging time points (30–180 minutes post-MBO). Results: The percentages of injected dose of 99mTc-bovine serum albumin in heart, kidney, and liver after E2 administration were significantly higher than those after CD administration (p = 0.036, 0.025, and 0.028 for heart, kidney, and liver, respectively), whereas those in brain were not different between E2 and CD administration (p = 0.343). Conclusions: The significantly larger blood volume maintained in heart, kidney, and liver of rats after E2 therapy compared with control supports the notion that E2 produces salutary effects on the cardiovascular system after trauma-hemorrhage and even extended periods of severe hypotension.