Hippocampal Resting State Functional Connectivity Associated with Physical Activity in Periadolescent Children.

Periadolescence is a neurodevelopmental period characterized by structural and functional brain changes that are associated with cognitive maturation. The development of the functional connectivity of the hippocampus contributes to cognitive maturation, especially memory processes. Notably, hippocampal development is influenced by lifestyle factors, including physical activity. Physical activity has been associated with individual variability in hippocampal functional connectivity. However, this relationship has not been characterized in a developmental cohort. In this study, we aimed to fill this gap by investigating the relationship between physical activity and the functional connectivity of the hippocampus in a cohort of periadolescents aged 8-13 years (N = 117). The participants completed a physical activity questionnaire, reporting the number of days per week they performed 60 min of physical activity; then, they completed a resting-state functional MRI scan. We observed that greater physical activity was significantly associated with differences in hippocampal functional connectivity in frontal and temporal regions. Greater physical activity was associated with decreased connectivity between the hippocampus and the right superior frontal gyrus and increased connectivity between the hippocampus and the left superior temporal sulcus. Capturing changes in hippocampal functional connectivity during key developmental periods may elucidate how lifestyle factors including physical activity influence brain network connectivity trajectories, cognitive development, and future disease risk.

Predicting alcohol use with subjective and objective measures of cognitive function in healthy college students.

Objective: The current study examined the association between subjective and objective cognitive measures and alcohol use in college students. Objective cognitive impairment is associated with alcohol use, however subjective cognitive impairment remains understudied in at-risk populations. Participants: Data were collected from 140 undergraduate students at a mid-sized private university. Methods: We used the Behavior Rating Inventory for Executive Function-Adult (BRIEF-A) and the Rey-Osterrieth Complex Figure Task (ROCF) as our subjective and objective measures of cognitive functioning respectively. Results: In our regression model, the BRIEF-A was significantly associated with the AUDIT in college students such that more poorly perceived cognitive functioning predicted higher degrees of problematic drinking. However, the relationship between the ROCF and drinking was less clear. Conclusions: Our study shows that perception of one's cognitive functioning is related to alcohol use and may be a potential risk factor for hazardous drinking in college students. Our results also suggest that subjective functioning is more strongly related to alcohol use than objective functioning, however further research is needed to replicate our results.

Frostbite and Immersion Foot Care.

Historically, cold injury, hypothermia, and frostbite have been severe problems for military units on the battlefield. Kenneth D. Orr and David C. Fainer captured these difficulties in their book, Cold Injuries in Korea During Winter of 1950-51, still cited in military medical readiness training. While not common in modern conflicts, the potential exists for large numbers of these casualties in war and during training.

Phase I Trial of Dabrafenib and Pazopanib in BRAF Mutated Advanced Malignancies.

PURPOSE: Several tumor types carry BRAF mutations and vascular endothelial growth factor pathway upregulation. Resistance mechanisms to BRAF inhibitors can include platelet-derived growth factor-ß upregulation. Dabrafenib, a BRAF inhibitor, and pazopanib, a multikinase inhibitor that targets vascular endothelial growth factor and platelet-derived growth factor, have not been combined previously. This phase I study was designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of the combination. PATIENTS AND METHODS: Patients with any advanced BRAF mutated malignancy with adequate organ function were eligible. Prior use of dabrafenib or pazopanib was not allowed. Dosages started at dabrafenib 50 mg twice a day and pazopanib 400 mg daily on dose level (DL) 1, with maximum dosages of 150 mg twice a day and 800 mg daily on DL5. Pharmacokinetics and BRAF V600E plasma clone were measured, and efficacy was evaluated by imaging and tumor markers every 8 weeks. RESULTS: Twenty-three patients with 11 different tumor histologies were enrolled in five DLs. Two dose-limiting toxicities were observed-a grade 3 bowel perforation on DL3 and grade 3 arthralgia on DL5. Common drug-related adverse events included nausea (52%), skin papules (43%), diarrhea (39%), hand-foot syndrome (30%), anemia (26%), rash (22%), vomiting (22%), hypophosphatemia (22%), and transaminitis (22%). Five patients (22%) experienced a partial response, including low-grade ovarian serous carcinoma, thyroid cancer, and glioblastoma multiforme, and two patients (appendiceal and thyroid cancer) had stable disease > 6 months. Pharmacokinetic measurements revealed pazopanib levels < 17.5 µg/mL in 80% of treated patients at steady state, particularly at DL5. BRAF V600E plasma copies correlated with response and progression. CONCLUSION: Combination dabrafenib and pazopanib had no unexpected toxicities, and durable partial responses were observed at DL3 or greater. Dose escalation beyond DL5 may be considered as pazopanib levels were suboptimal as a result of drug interaction with dabrafenib.

Clinical prevalence and associated intraoperative surgical complications of reproductive tract lesions in pot-bellied pigs undergoing ovariohysterectomy: 298 cases (2006-2016).

To address the current dearth of clinically relevant publications regarding ovariohysterectomy (OVH) in the domestic pot-bellied pig (PBP), the present study aims to report prevalence of uterine lesions, intraoperative complications, and short and long-term survival in this species (n=298). Prevalence of lesions included uterine neoplasia 11.4 per cent (34/298), pyometra 1.6 per cent (5/298) and cystic endometrial hyperplasia 5 per cent (15/298). Pigs at least six years of age were statistically more likely to have a uterine lesion (less than P=0.001). Smooth muscle tumours represented the most frequent neoplasm. Haemorrhage was the most common intraoperative complication in 23 per cent (8/34) of pigs with neoplasia. Pigs without reproductive tract lesions were statistically more likely to survive to hospital discharge than those with lesions (P=0.001). Short-term survival, defined as survival to hospital discharge, of pigs with reproductive tract lesions was 89 per cent (48/54). Pigs with pyometra were least likely to survive to discharge 60 per cent (3/5). Long-term survival (≥1 year) was 93 per cent (14/15) for pigs with neoplasia. Practitioners should be aware of significantly higher rate of neoplastic and inflammatory diseases in PBP at least six years of age. To minimise morbidity and mortality in PBP undergoing OVH, the present study suggests the procedure should be performed prior to six years of age.

A Phase I/II Trial of Panobinostat in Combination With Lenalidomide in Patients With Relapsed or Refractory Hodgkin Lymphoma.

BACKGROUND: Lenalidomide and panobinostat have shown single-agent efficacy of 14% to 50% and 27% to 58%, respectively, in Hodgkin lymphoma (HL). This phase I/II study was conducted to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide combined with panobinostat in relapsed/refractory HL. PATIENTS AND METHODS: In the phase I trial, previously treated patients with classical or lymphocyte-predominant HL received escalating doses of lenalidomide on days 1 to 21 and panobinostat 3 times a week (TIW) every 28 days. Dose-limiting toxicity (DLT) was defined during cycle 1. When the MTD was determined, a phase II study was conducted to determine overall response (OR). RESULTS: Twenty-four patients enrolled; 11 in the phase I and 13 in phase II portions. No DLTs were observed but 2 patients who received 25 mg lenalidomide and 20 mg panobinostat experienced neutropenia and thrombocytopenia > 14 days in cycle 2, leading to selection of 25 mg lenalidomide on days 1 to 21 and 15 mg panobinostat TIW for the phase II dose. In all 24 patients, Grade 3 to 4 toxicities consisted of neutropenia (58%), thrombocytopenia (42%), lymphopenia (25%), and febrile neutropenia (25%). OR was 16.7% (2 complete response [CR] and 2 partial response). One patient with CR had lymphocyte-predominant HL and received 22 cycles. Median progression-free survival and overall survival were 3.8 and 16.4 months, respectively. CONCLUSION: Although the combination of panobinostat and lenalidomide appears safe in patients with relapsed/refractory HL, the limited efficacy and significant rates of neutropenia and febrile neutropenia observed do not support further evaluation of this combination in HL.

Randomized Phase 2 Trial of the Oncolytic Virus Pelareorep (Reolysin) in Upfront Treatment of Metastatic Pancreatic Adenocarcinoma.

Pelareorep causes oncolysis in tumor cells with activated Ras. We hypothesized that pelareorep would have efficacy and immunomodulatory activity in metastatic pancreatic adenocarcinoma (MPA) when combined with carboplatin and paclitaxel. A randomized phase 2 study (NCT01280058) was conducted in treatment-naive patients with MPA randomized to two treatment arms: paclitaxel/carboplatin + pelareorep (Arm A, n = 36 evaluable patients) versus paclitaxel/carboplatin (Arm B, n = 37 evaluable patients). There was no difference in progression-free survival (PFS) between the arms (Arm A PFS = 4.9 months, Arm B PFS = 5.2 months, P = 0.6), and Kirsten rat sarcoma viral oncogene (KRAS) status did not impact outcome. Quality-adjusted Time without Symptoms or Toxicity analysis revealed that the majority of PFS time was without toxicity or progression (4.3 months). Patient immunophenotype appeared important, as soluble immune biomarkers were associated with treatment outcome (fractalkine, interleukin (IL)-6, IL-8, regulated on activation, normal T cell expressed and secreted (RANTES), and vascular endothelial growth factor (VEGF)). Increased circulating T and natural killer (NK)-cell subsets were also significantly associated with treatment outcome. Addition of pelareorep was associated with higher levels of 14 proinflammatory plasma cytokines/chemokines and cells with an immunosuppressive phenotype (Tregs, cytotoxic T lymphocyte associated protein 4 (CTLA4)(+) T cells). Overall, pelareorep was safe but does not improve PFS when administered with carboplatin/paclitaxel, regardless of KRAS mutational status. Immunologic studies suggest that chemotherapy backbone improves immune reconstitution and that targeting remaining immunosuppressive mediators may improve oncolytic virotherapy.

Collaborative care for a patient with bipolar disorder in primary care: a case example.

OBJECTIVE: The objective was to describe the process of care and treatment outcomes of a 36-year-old man with bipolar disorder treated using a collaborative care model in primary care. METHODS: We reviewed and summarized relevant clinical data describing the patient's care including the medical record, consultant's reports and discussions with treating clinicians. A meeting was held with experienced consulting psychiatrists to discuss the case. RESULTS: Several barriers to delivery of high-quality care existed including initial loss to follow-up, few social supports and lack of follow-through at the community mental health center existed, along with presence of factors that negatively influence bipolar disorder outcomes including initial unopposed antidepressant use at baseline, concurrent alcohol use and co-occurring anxiety symptoms. Despite these barriers, the collaborative care team was able to engage the patient in care and achieve the patient's and team's treatment goals. CONCLUSION: Delivery of primary-care-based collaborative care was associated with reduction of bipolar disorder symptoms and improved functioning in a patient with bipolar disorder.

A phase I trial of flavopiridol in relapsed multiple myeloma.

PURPOSE: Flavopiridol is primarily a cyclin-dependent kinase-9 inhibitor, and we performed a dose escalation trial to determine the maximum tolerated dose and safety and generate a pharmacokinetic (PK) profile. METHODS: Patients with a diagnosis of relapsed myeloma after at least two prior treatments were included. Flavopiridol was administered as a bolus and then continuous infusion weekly for 4 weeks in a 6-week cycle. RESULTS: Fifteen patients were treated at three dose levels (30 mg/m(2) bolus, 30 mg/m(2) CIV to 50 mg/m(2) bolus, and 50 mg/m(2) CIV). Cytopenias were significant, and elevated transaminases (grade 4 in 3 patients, grade 3 in 4 patients, and grade 2 in 3 patients) were noted but were transient. Diarrhea (grade 3 in 6 patients and grade 2 in 5 patients) did not lead to hospital admission. There were no confirmed partial responses although one patient with t(4;14) had a decrease in his monoclonal protein >50 % that did not persist. PK properties were similar to prior publications, and immunohistochemical staining for cyclin D1 and phospho-retinoblastoma did not predict response. CONCLUSIONS: Flavopiridol as a single agent given by bolus and then infusion caused significant diarrhea, cytopenias, and transaminase elevation but only achieved marginal responses in relapsed myeloma (ClinicalTrials.gov identifier NCT00112723).

Endovascular approaches to arteriovenous fistula.

AVFs differ in their characteristics, natural history, and response to interventions. These differences need to be considered when planning treatment. Endovascular treatments have emerged as a mainstay of treatment of all types of AVMs. They can be used as definitive therapy for acquired arteriovenous malformation, in remote or high-risk locations, and in elderly or otherwise debilitated patients. Endovascular control is often helpful in open repair of acquired AVF. Endovascular techniques are essential in the management of congenital AVF and are the first line of interventional therapy. In these cases, repeated interventions are the rule, and careful imaging and planning is the key to success.

120-day comparative analysis of adhesion grade and quantity, mesh contraction, and tissue response to a novel omega-3 fatty acid bioabsorbable barrier macroporous mesh after intraperitoneal placement.

PURPOSE: This study aimed to evaluate adhesion formation, mesh contraction, and tissue response to an omega-3 fatty acid barrier-coated lightweight polypropylene mesh (C-Qur) after intra-abdominal placement, and compare these properties to those of other commercially available meshes. MATERIALS AND METHODS: After randomization, 3 x 3 cm pieces of Atrium C-Qur, Mesh ProLite Ultra, Composix, Parietex, Proceed, Sepramesh, and DualMesh were sewn to the intact peritoneum on either side of a midline incision in 41 New Zealand white rabbits. Necropsy was performed at 120 days, and explants were evaluated for adhesion grade, adhesion amount, and mesh contraction. Histologic evaluation included extent of capsule formation, abdominal wall tissue ingrowth, degrees of inflammation and vascularization of the surrounding tissue, and the presence of mesothelialization. Results. There were no significant differences between the C-Qur mesh and the commercially available meshes tested with regard to adhesion grade or amount, although percentage adhesion coverage for the C-Qur mesh was much less than for Composix and Proceed. The C-Qur mesh contracted less than all meshes, significantly less (P < .05) than DualMesh or Proceed. DualMesh exhibited the greatest amount of capsule formation and inflammation on its parietal side as compared with the other meshes. CONCLUSIONS: Placing lightweight polypropylene mesh with an omega-3 fatty acid barrier coating intraperitoneally results in more favorable adhesion characteristics compared with Composix and Proceed meshes at 120-day explantation after intraperitoneal placement. The minimal amount of contraction and favorable tissue response in comparison to other commercially available meshes makes C-Qur mesh a practical alternative for laparoscopic and open ventral hernia repair.

Probing conserved helical modules of portal complexes by mass spectrometry-based hydrogen/deuterium exchange.

The Double-stranded DNA bacteriophage P22 has a ring-shaped dodecameric complex composed of the 84 kDa portal protein subunit that forms the central channel of the phage DNA packaging motor. The overall morphology of the P22 portal complex is similar to that of the portal complexes of Phi29, SPP1, T3, T7 phages and herpes simplex virus. Secondary structure prediction of P22 portal protein and its threading onto the crystal structure of the Phi29 portal complexes suggested that the P22 portal protein complex shares conserved helical modules that were found in the dodecameric interfaces of the Phi29 portal complex. To identify the amino acids involved in intersubunit contacts in the P22 portal ring complexes and validate the threading model, we performed comparative hydrogen/deuterium exchange analysis of monomeric and in vitro assembled portal proteins of P22 and the dodecameric Phi29 portal. Hydrogen/deuterium exchange experiments provided evidence of intersubunit interactions in the P22 portal complex similar to those in the Phi29 portal that map to the regions predicted to be conserved helical modules.

Laparoscopic gastric resection for gastrointestinal stromal tumors.

BACKGROUND: This study aimed to review clinical outcomes for patients selected to undergo laparoscopic resection for gastrointestinal stromal tumor (GIST) of the stomach. METHODS: All 112 laparoscopic gastric resections performed from February 1995 to March 2007 were reviewed. Pre- and postoperative variables were analyzed, and data are given as mean +/- standard deviation. RESULTS: Laparoscopic gastric resection was attempted for 63 GIST in 61 patients (31 men and 30 women) with a mean age was 59.1 +/- 19 years. The tumors were located at the fundus (n = 19), antrum (n = 18), body (n = 17), gastroesophageal junction/cardia (n = 7), and pylorus (n = 2). Common presentations were upper gastrointestinal bleed (n = 29) and incidental finding on esophagogastroduodenoscopy (n = 17). The laparoscopic procedures performed were partial gastrectomy (n = 52), antrectomy (n = 4), esophagogastrectomy (n = 3), and endoscopically assisted and/or transgastric resection (n = 3). There was one conversion to open procedure for control of bleeding from the spleen. The mean tumor size was 3.8 +/- 1.8 cm. Negative surgical margins were achieved in all but one case. The mean operative time was 151.9 +/- 67.3 min, and the mean estimated blood loss was 97.4 +/- 200.7 ml. A regular diet was resumed at a mean of 2.9 +/- 1.6 days, and the mean length of hospital stay was 3.9 +/- 2.2 days. The perioperative complication rate was 16.4% including deep vein thrombosis postoperative bleed, anastomotic stricture, and incisional hernia. One mortality occurred, due to respiratory failure. The GISTs included 48 rated as low risk, six rated as intermediate risk, and nine rated as high malignant potential. At a mean follow-up period of 15 +/- 21.8 months (range, 0-103 months), three of nine patients with high malignant potential GIST experienced, respectively, metastatic disease to the liver, liver and lung, and peritoneum. At this writing, all the other patients are disease free. CONCLUSIONS: Laparoscopic gastric resection for GIST is a feasible option. Adequate oncologic resection was achieved with 98.4% of patients chosen for laparoscopic resection. Resection margin positivity and recurrence rates are low after laparoscopic approaches for appropriately selected patients with GIST, demonstrating favorable characteristics.

Kinetic analysis of the role of intersubunit interactions in human immunodeficiency virus type 1 capsid protein assembly in vitro.

The human immunodeficiency virus type 1 (HIV-1) capsid protein (CA) plays a crucial role in both assembly and maturation of the virion. Numerous recent studies have focused on either the soluble form of CA or the polymer end product of in vitro CA assembly. The CA polymer, in particular, has been used to study CA-CA interactions because it is a good model for the CA interactions within the virion core. However, analysis of the process of in vitro CA assembly can yield valuable insights into CA-CA interactions and the mechanism of core assembly. We describe here a method for the analysis of CA assembly kinetics wherein the progress of assembly is monitored by using turbidity. At pH 7.0 the addition of either of the isolated CA domains (i.e., the N or the C domain) to an assembly reaction caused a decrease in the assembly rate by competing for binding to the full-length CA protein. At pH 8.0 the addition of the isolated C domain had a similar inhibitory affect on CA assembly. However, at pH 8.0 the isolated N domain had no affect on the rate of CA assembly but, when mixed with the C domain, it alleviated the C-domain inhibition. These data provide biochemical evidence for a pH-sensitive homotypic N-domain interaction, as well as for an N- and C-domain interaction.