A multi-institutional randomized controlled trial comparing first-generation transrectal high-resolution micro-ultrasound with conventional frequency transrectal ultrasound for prostate biopsy.

Objectives: To study high-frequency 29 MHz transrectal side-fire micro-ultrasound (micro-US) for the detection of clinically significant prostate cancer (csPCa) on prostate biopsy, and validate an image interpretation protocol for micro-US imaging of the prostate. Materials and methods: A prospective randomized clinical trial was performed where 1676 men with indications for prostate biopsy and without known prostate cancer were randomized 1:1 to micro-US vs conventional end-fire ultrasound (conv-US) transrectal-guided prostate biopsy across five sites in North America. The trial was split into two phases, before and after training on a micro-US image interpretation protocol that was developed during the trial using data from the pre-training micro-US arm. Investigators received a standardized training program mid-trial, and the post-training micro-US data were used to examine the training effect. Results: Detection of csPCa (the primary outcome) was no better with the first-generation micro-US system than with conv-US in the overall population (34.6% vs 36.6%, respectively, P = .21). Data from the first portion of the trial were, however, used to develop an image interpretation protocol termed PRI-MUS in order to address the lack of understanding of the appearance of cancer under micro-US. Micro-US sensitivity in the post-training group improved to 60.8% from 24.6% (P < .01), while specificity decreased (from 84.2% to 63.2%). Detection of csPCa in the micro-US arm increased by 7% after training (32% to 39%, P < .03), but training instituted mid-trial did not affect the overall results of the comparison between arms. Conclusion: Micro-US provided no clear benefit over conv-US for the detection of csPCa at biopsy. However, it became evident during the trial that training and increasing experience with this novel technology improved the performance of this first-generation system.

A personalised medicine approach for ponatinib-resistant chronic myeloid leukaemia.

BACKGROUND: Chronic myeloid leukaemia (CML) is characterised by the presence of a fusion driver oncogene, BCR-ABL1, which is a constitutive tyrosine kinase. Tyrosine kinase inhibitors (TKIs) are the central treatment strategy for CML patients and have significantly improved survival rates, but the T315I mutation in the kinase domain of BCR-ABL1 confers resistance to all clinically approved TKIs, except ponatinib. However, compound mutations can mediate resistance even to ponatinib and remain a clinical challenge in CML therapy. Here, we investigated a ponatinib-resistant CML patient through whole-genome sequencing (WGS) to identify the cause of resistance and to find alternative therapeutic targets. PATIENTS AND METHODS: We carried out WGS on a ponatinib-resistant CML patient and demonstrated an effective combination therapy against the primary CML cells derived from this patient in vitro. RESULTS: Our findings demonstrate the emergence of compound mutations in the BCR-ABL1 kinase domain following ponatinib treatment, and chromosomal structural variation data predicted amplification of BCL2. The primary CD34(+) CML cells from this patient showed increased sensitivity to the combination of ponatinib and ABT-263, a BCL2 inhibitor with a negligible effect against the normal CD34(+) cells. CONCLUSION: Our results show the potential of personalised medicine approaches in TKI-resistant CML patients and provide a strategy that could improve clinical outcomes for these patients.

The variety of leukemic stem cells in myeloid malignancy.

Human acute myeloid leukemias (AMLs) are sustained by leukemic stem cells (LSCs) that generate through aberrant differentiation the blast cells that make up the bulk of the malignant clone. LSCs were first identified as rare cells with an immunophenotype shared with normal hematopoietic stem cells (HSCs). However, refinements of xenotransplantation assays, alternative methods of quantitation and syngeneic murine models have all led to an appreciation that LSCs display marked variability in frequency, immunophenotype and differentiation potential, both between and even within leukemias. Insights from next-generation sequencing efforts have dramatically extended understanding of the mutational landscape and clonal organization of AML and have added an additional layer of complexity to the biology of LSCs: a requirement to consider the effect of the various recurrently occurring genetic lesions in AML on the initiation and maintenance of leukemic subclones. Despite these advances, cure rates in AML remain substantially unchanged in recent years. A renewed focus on the biological properties of chemotherapy-resistant LSCs, a cellular entity of prime clinical importance, will be required to develop additional therapeutic strategies to enhance patient outcomes.

Signatures of the Z = 82 shell closure in α-decay process.

In recent experiments at the velocity filter Separator for Heavy Ion reaction Products (SHIP) (GSI, Darmstadt), an extended and improved set of α-decay data for more than 20 of the most neutron-deficient isotopes in the region from lead to thorium was obtained. The combined analysis of this newly available α-decay data, of which the (186)Po decay is reported here, allowed us for the first time to clearly show that crossing the Z = 82 shell to higher proton numbers strongly accelerates the α decay. From the experimental data, the α-particle formation probabilities are deduced following the Universal Decay Law approach. The formation probabilities are discussed in the framework of the pairing force acting among the protons and the neutrons forming the α particle. A striking resemblance between the phenomenological pairing gap deduced from experimental binding energies and the formation probabilities is noted. These findings support the conjecture that both the N = 126 and Z = 82 shell closures strongly influence the α-formation probability.

General surgery in patients with a bleeding diathesis: how we do it.

BACKGROUND: This study was undertaken to assess perioperative management, postoperative complications, and the adequacy of perioperative plasma factor levels in a regional hemophilia center. METHODS: A total of 113 consecutive patients (75 men, 38 women; median age 48 years, range 18-86 years) with bleeding disorders undergoing general surgical and endoscopic procedures (144 procedures: 15 urgent, 129 elective) were reviewed. The episodes were identified from a prospectively collected database at a regional hemophilia center from 1998 to the end of 2008. In all, 46% of the surgical patients had hemophilia A, 38% had von Willebrand disease, 6% had hemophilia B, 5% had factor XI deficiency, and 4% had other disorders. RESULTS: Procedures carried out were endoscopic in 40%, minor in 25%, and intermediate and major in 35%. There were two postoperative deaths, both in patients undergoing urgent major procedures. Postoperative complications occurred after 7.6% (4.0% hemorrhagic, 3.6% nonhemorrhagic) of the procedures. Four of six patients with postoperative hemorrhage required further operative intervention. The median dose of clotting factor for Hemophilia A patients was 2240 U for endoscopic procedures, 7500 U for minor procedures, and 23,500 U for intermediate/major procedures. In hemophiliacs, the mean preoperative plasma factor level attained was 129 IU/dl (SD 16) in patients who developed postoperative hemorrhagic complications and 125 IU/dl (SD 37) in those who did not have bleeding, indicating that in no case was hemorrhage attributable to inadequate factor replacement. CONCLUSIONS: General surgical and endoscopic procedures can be performed with low morbidity and mortality rates when there is appropriate factor replacement and good support from the hemophilia team.

Barrier agents for adhesion prevention after gynaecological surgery.

BACKGROUND: Pelvic adhesion can form as a result of inflammation, endometriosis or surgical trauma. During pelvic surgery, strategies to reduce pelvic adhesion formation may include placing synthetic barrier agents such as oxidised regenerated cellulose, polytetrafluoroethylene or Fibrin sheets between the pelvic structures. OBJECTIVES: To assess the effect of physical barriers used during pelvic surgery in women of reproductive age on pregnancy rates, pelvic pain, or postoperative adhesion reformation. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched September 2007) which is based on regular searches of MEDLINE, EMBASE, CINAHL, PsycINFO and CENTRAL, plus handsearching of 20 relevant journals and conference proceedings, and searches of several key grey literature sources. In addition, companies were contacted for unpublished trials. SELECTION CRITERIA: Any randomised controlled trials (RCTs) comparing the use of physical barriers versus no treatment or other physical barriers in the prevention of adhesions in women undergoing gynaecological surgery. DATA COLLECTION AND ANALYSIS: Review authors assessed trial eligibility and quality. MAIN RESULTS: Sixteen RCTs were included. Five trials randomised patients while the remainder randomised pelvic organs. Laparoscopy (six trials) and laparotomy (10 trials) were the primary surgical techniques. Indications for surgery included myomectomy (five trials), ovarian surgery (five trials), pelvic adhesions (four trials), endometriosis (one trial), and mixed (one trial). Eleven trials assessed Interceed versus no treatment, two assessed Interceed versus Gore-Tex, one trial assessed Gore-Tex versus no treatment, and one trial assessed Seprafilm versus no treatment. A single trial assessed Fibrin sheet versus no treatment. No studies reported pregnancy or reduction in pain as outcomes. The use of Interceed was associated with reduced incidence of pelvic adhesion formation, both new formation and reformation following laparoscopic surgery or laparotomy. However, this result should be interpreted with caution. Gore-Tex was more effective than no barrier or Interceed in preventing adhesion formation. There was only limited evidence that Seprafilm was effective in preventing adhesion formation following myomectomy and no evidence to support Fibrin sheet. AUTHORS' CONCLUSIONS: The absorbable adhesion barrier Interceed reduces the incidence of adhesion formation following laparoscopy and laparotomy, but there are insufficient data to support its use to improve pregnancy rates. Gore-Tex may be superior to Interceed in preventing adhesion formation but its usefulness is limited by the need for suturing and later removal. There was no evidence of effectiveness of Seprafilm and Fibrin sheet in preventing adhesion formation.

Complications of lumbar drainage after thoracoabdominal aortic aneurysm repair.

OBJECTIVES: Paraplegia remains a frequent complication of thoracoabdominal aortic aneurysm (TAAA) repair. Many adjunct therapies have been developed to address this complication. Lumbar drainage is frequently used in an attempt to decrease intrathecal pressure and improve intramedullary perfusion pressure. The effectiveness of this therapy is unclear, and the complications of lumbar drainage used for this indication are unknown. We present a case of intraspinal hematoma with significant neurologic deficit after TAAA repair and review the associated complications of lumbar drains placed for TAAA. METHODS: The charts of all patients undergoing operations for TAAA repair were reviewed. Patients who underwent perioperative placement of a lumbar drain were included regardless of aneurysm type or etiology. Demographics, Crawford grade, and perioperative parameters and complications were reviewed. RESULTS: Sixty-five patients underwent TAAA repair with 62 (95%) receiving a preoperative lumbar drain. There were two (3.2%) intraspinal hemorrhagic complications, including one patient with a poor neurologic outcome. No infections or other complications directly related to drainage were identified. Multivariate logistic regression analysis failed to demonstrate a significant association between lumbar drain complications and perioperative and intraoperative parameters such as blood loss or hypotension, level of drain placement, and Crawford grade. CONCLUSIONS: Lumbar drainage is a frequent adjunct to TAAA repair. However, placement of the drain itself can be associated with significant complications whose aggravating factors may be unidentifiable. Complications resulting from lumbar drainage should be considered in any patient who has postoperative lower extremity neurologic deficits.

Collagen membrane/fleece composite film reduces adhesions in the presence of bleeding in a rabbit uterine horn model.

OBJECTIVE: Determination of efficacy in presence of bleeding of CDS, a collagen/membrane fleece composite, in a rabbit uterine horn simple abrasion model. DESIGN: Randomized, controlled, and blinded study involving standard abrasion of the uterine horns with induction of moderate mesouterine bleeding. SETTING: Research laboratory. PATIENT(S): New Zealand White rabbits. INTERVENTION(S): No treatment (surgical control), CDS film, or INTERCEED barrier (negative reference control). MAIN OUTCOME MEASURE(S) AND RESULT(S): The extent (percent length uterine horn) with adhesions was assessed after 29 or 30 days. Adhesions formed in surgical controls to an extent (85.6% +/- 4.6%) consistent with historic data for this model. INTERCEED failed to reduce adhesions (78.1% +/- 7.7%) indicating that the test conditions of inadequate hemostasis were validated. CDS film, despite this inadequate hemostasis, reduced the extent of adhesions (31% +/- 7.4%; P<.01). Both the tenacity (P=.0008) and degree of uterine convolution (P=.000003) was reduced by CDS film but not by INTERCEED. CONCLUSION(S): Under conditions of inadequate hemostasis CDS effected a reduction in adhesion development. CDS may be useful adjuvant for procedures where hemostasis is difficult to achieve.

Heat resistance of Listeria monocytogenes.

The heat resistance data on Listeria monocytogenes in culture media and foods are summarized. Most heat resistance data for foods have been obtained in dairy, meat, poultry, and egg products. Limited data have been published on seafood, fruits, and vegetables. The methodologies employed have evolved over time; hence data from earlier experiments are not directly comparable to more recent studies. Many factors influence the heat resistance of L. monocytogenes. Variation exists among different strains in their ability to withstand heat treatment. In addition, heat resistance is influenced by age of the culture, growth conditions, recovery media, and characteristics of foods such as salt content, a(w), acidity, and the presence of other inhibitors. Listeriae are more heat resistant than most other nonspore-forming foodborne pathogens, and thus, processing recommendations based on data from experiments with Salmonella spp. or pathogenic Escherichia coli may not be sufficient to eliminate similar numbers of L. monocytogenes. The data provided in this review may prove useful for food processors in determining appropriate times and temperatures for producing foods free of vegetative pathogens.

Barrier agents for preventing adhesions after surgery for subfertility.

BACKGROUND: Pelvic adhesions can be the result of inflamation, endometriosis or surgical trauma. Prevention of postoperative adhesions (either new or reoccurance) has been postulated by using barriers to prevent two surfaces being in contact. When pelvic surgery is being undertaken strategies to reduce pelvic adhesions occurring may be undertaken and these include barrier agents which are placed between the pelvic structures. Two synthetic barriers with differential characteristics are commercially available: oxidised regenerated cellulose (Interceed) and polytetrafluoroethylene (PTFC) (GoreTex). OBJECTIVES: The objective of this review was to assess the effect of mechanical barriers (materials interposed between pelvic structures to prevent adherence of serosal surfaces) used during pelvic surgery in women of reproductive age on pregnancy rates, pelvic pain, or postoperative adhesion reformation. SEARCH STRATEGY: The Cochrane Menstrual Disorders and Subfertility Group specialised register of controlled clinical trials was undertaken. In addition, companies were contacted for unpublished trials. SELECTION CRITERIA: Randomised controlled trials or controlled clinical trials of barriers versus no treatment or other barriers in women undergoing fertility preserving pelvic surgery. DATA COLLECTION AND ANALYSIS: Reviewers assessed eligibility and trial quality. MAIN RESULTS: 15 randomised controlled trials were included. Five trials randomised patients while the remainder randomised pelvic organs. Laparoscopy was the primary surgical technique in six trials while the remaining trials were laparotomy. Indications for surgery included myomectomy (five trials), ovarian surgery (four trials), pelvic adhesions (six trials), endometriosis (two trials) and mixed (one trial). Thirteen trials assessed Interceed versus no treatment, two assessed Interceed versus Gore-Tex, one trial assessed Gore-Tex versus no treatment, and one trial assessed Seprafilm versus no treatment. No study reported pregnancy or reduction in pain as an outcome. The use of Interceed in women was associated with reduced incidence of pelvic adhesion formation, both new formation and re-formation following laparoscopic surgery and after laparotomy. Gore-Tex was more effective than no barrier or Interceed in preventing adhesion formation. There was limited evidence that Seprafilm was effective in preventing adhesion formation in women following myomectomy. REVIEWER'S CONCLUSIONS: The absorbable adhesion barrier Interceed reduces the incidence of adhesion formation, both new formation and re-formation, at laparoscopy and laparotomy, but there are insufficient data to support its use to improve pregnancy rates. Gore-Tex may be superior to Interceed in preventing adhesion formation but its usefulness is limited by the need for suturing and later removal. There was no evidence of effectiveness of Seprafilm in preventing adhesion formation.

Antibacterial efficacy of gentamicin encapsulated in pH-sensitive liposomes against an in vivo Salmonella enterica serovar typhimurium intracellular infection model.

Encapsulation of gentamicin in liposomes can be used to achieve intracellular delivery and broaden the clinical utility of this drug. We have previously described a novel, rationally designed, pH-sensitive liposomal carrier for gentamicin that has superior in vitro efficacy against intracellular infections compared to the efficacies of both free gentamicin and non-pH-sensitive liposomal controls. This liposomal carrier demonstrated pH-sensitive fusion that was dependent on the presence of unsaturated phosphatidylethanolamine (PE) and the pH-sensitive lipid N-succinyldioleoyl-PE. The pharmacokinetics and biodistribution of the free and liposomal gentamicin were examined in mice bearing a systemic Salmonella enterica serovar Typhimurium infection. Encapsulation of gentamicin in pH-sensitive liposomes significantly increased the concentrations of the drug in plasma compared to those of free gentamicin. Furthermore, the levels of accumulation of drug in the infected liver and spleen were increased by 153- and 437-fold, respectively, as a result of liposomal encapsulation. The increased accumulation of gentamicin in the liver and spleen effected by liposomal delivery was associated with 10(4)-fold greater antibacterial activity than that associated with free gentamicin in a murine salmonellosis model. These pH-sensitive liposomal antibiotic carriers with enhanced in vitro activity could be used to improve both in vivo intracellular drug delivery and biological activity.

Subjective science: Kenneth Spence's human learning research program.

This article examines Kenneth Spence's human learning research from 1949 to 1967. His works show the conditioning field to be in turmoil over basic issues during this time. These issues included whether determinism should be accepted, how to interpret a psychological test score, what psychometric properties a test should have, and how to use theoretical constructs. Turmoil occurred because behaviors and events had different meanings and degrees of importance to different investigators. Thus, what appeared as "objective" scientific change in the conditioning field was really the adaptation of personal preferences in word meanings, research goals, and research methods. These issues also indicate disputes about definitions and purposes of scientific activity during Spence's era.

Transrectal ultrasound-guided biopsy of the prostate: relation between ASA use and bleeding complications.

OBJECTIVE: To determine the relation between ASA ingestion and the incidence of bleeding complications after transrectal ultrasound (TRUS)-guided biopsy of the prostate. METHODS: Overall, 1810 patients with suspected prostate disease were followed after biopsy. ASA use was determined before the procedure. A TRUS-guided sextant biopsy was performed and patients were contacted immediately and by follow-up telephone call to determine whether there were any immediate or delayed bleeding complications. RESULTS: Overall, 46 subjects (2.5%) had bleeding complications. Of the 54 subjects reporting current use of ASA, 2 (3.7%) had such complications. This difference was not significant. CONCLUSION: There was no evidence of an association between the use of ASA and postbiopsy bleeding complications.

Effect of different barriers of oxidized regenerated cellulose (ORC) on cecal and sidewall adhesions in the presence and absence of bleeding.

Adhesion formation after bowel surgery is a significant problem. The objective of this study was to evaluate two adhesion barriers composed of oxidized regenerated cellulose (ORC) in a model of bowel surgery, with and without bleeding. Ceca of female New Zealand White rabbits were abraded with gauze and a 3 x 5 cm patch of peritoneum and underlying muscle was excised from the right sidewall. Animals were randomized to receive no treatment, INTERCEED Barrier (Ethicon, Inc.), or neutralized INTERCEED (nTC7). ORC fabrics were applied to the excision site. Seven days later the percentage of the site and length of cecum with adhesions were estimated. The study was replicated in the presence of blood by nicking small vessels near the site sufficient to saturate the fabrics with blood. With hemostasis, the percentage of the sidewall with adhesions was reduced (p < .01) from 63.2 +/- 14.7% in controls (n = 6) to 4 +/- 2.7% with INTERCEED Barrier (n = 6) and 3 +/- 1.2% (n = 5) with nTC7. With bleeding, however, control (n = 5) levels of adhesions (67 +/- 17.5%) were reduced significantly with nTC7 (5.5 +/- 4%, n = 4; p < .01), but not INTERCEED Barrier (34.2 +/- 18.4%, n = 4). Similar trends were observed when the extent of adherent cecum was examined, since the cecum was the main site of adherence to the sidewall. However in the presence of blood, there was no effect of INTERCEED Barrier on cecal adhesions. We conclude that with hemostasis, both absorbable fabrics of ORC reduced adhesion formation between the injured cecum and abdominal sidewall. The effectiveness of INTERCEED Barrier, but not nTC7, was reduced but not eliminated in the presence of bleeding. This confirms similar observations in models of gynecologic surgery.

Metaanalysis of the safety and efficacy of an adhesion barrier (Interceed TC7) in laparotomy.

OBJECTIVE: To evaluate the safety and efficacy of an oxidized, regenerated, cellulose adhesion barrier (Interceed TC7) in the reduction of pelvic adhesions. STUDY DESIGN: Clinical studies published or completed by December 31, 1994, evaluating the barrier used at laparotomy were considered for a metaanalysis. RESULTS: Of 10 studies (n = 560) identified, data from 7 (n = 389) met the inclusion criteria for determining the reduction in the incidence of adhesions and 5 (n = 311) for determining the reduction in adhesion extent (raw surface area after adhesiolysis). There was a 24.2 +/- 3.3% difference in the incidence of adhesions (P < .001) between barrier-treated and untreated sites. Adhesion-free outcomes were 1.5-2.5 times more likely at barrier-treated sites than at sites with good surgical technique alone (odds ratio = 2.89; 95% confidence interval = 2.15-3.90). Barrier treatment resulted in a greater reduction (1.1 +/- 0.4 cm2) in adhesion extent (raw surface area) than good surgical technique alone (P < .001). Four adverse events were recorded; they were typical of those seen after surgery. No event was considered to be definitely related to the use of the barrier. CONCLUSION: The barrier significantly reduced the incidence and extent of adhesions as compared with no treatment, confirming the conclusion from individual studies that it is safe and effective in pelvic laparotomy surgery.

The rates of adhesion development and the effects of crystalloid solutions on adhesion development in pelvic surgery.

OBJECTIVE: To document rates of adhesion development after abdomino-pelvic surgery, stratified by adhesion type, access method, and use of crystalloid solution instillates. DESIGN: Reports from a MEDLINE search (1/1/1966-12/18/1996) detailing rates of adhesion development and meeting the inclusion criteria were subjected to meta-analysis. SETTING: Meta-analysis. PATIENT(S): Patients undergoing abdomino-pelvic surgery. INTERVENTION(S): Intraperitoneal crystalloid solution instillates. MAIN OUTCOME MEASURE(S): Percentage adhesion-free outcome in patients ("patients") or surgical sites ("sites"). RESULT(S): Adhesion-free outcome (sites) was lowest for reformed (26.3% laparotomy; 14.3% laparoscopy), higher for de novo 1b (direct trauma) (45.2% laparotomy, 37.2% laparoscopy), and highest for de novo 1a (indirect trauma) adhesions (82.4% laparoscopy). Crystalloid solution instillates reduced adhesion-free outcome at sites (45.2% versus 20% de novo 1b adhesions in laparotomy) and in patients (43.5% versus 19.9% reformed, laparotomy; 71.7% versus 25% de novo 1b, laparoscopy). CONCLUSION(S): Adhesion-free outcome was lowest for reformed, higher for de novo 1b, and highest for de novo 1a adhesions. Surprisingly, it was lower in laparoscopy than in laparotomy for de novo 1b and reformed adhesions. Crystalloid instillates did not increase adhesion-free outcome. Although limited by the retrospective and heterogeneous nature of the data, these conclusions nonetheless provide a basis on which to formulate future hypotheses.