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Eighty sporadic Wilms’ tumor samples were analyzed by comparative genomic hybridization (CGH) to identify chromosomal regions involved in the etiology of the disease. Twenty percent of the samples showed chromosomal gains or losses. The majority of chromosomal gains and losses were similar to those identified through molecular and cytogenetic studies. Gains were observed on chromosomes 1q, 7q, 8, and 12, whereas losses were found on chromosomes 1p, 4p, 4q, 7p, 16q, 18q, 21q, and 22q. Other genetic aberrations identified in this study included deletions of chromosomes 5p and 15q, as well as gains of discrete loci on chromosomes 3p and 3q. These latter regions have not been previously implicated in Wilms’ tumorigenesis and may contain novel genes relevant to the development and/or progression of this disease. [ABSTRACT FROM AUTHOR]

Accidental needlestick injuries are common in laboratory and health care workers. Injection of atypical pathogens, such as those encountered in the animal laboratory setting, may pose considerable problems at the site of inoculation. We present the case of an otherwise healthy laboratory worker who accidentally self-injected Freund complete adjuvant with heat-killed Mycobacterium tuberculosis into her hand, requiring multiple debridement operations over a prolonged treatment course., (Copyright © 2018 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Background  Earlier, digit viability judged the success of digital replantation. Now, utility health-related quality of life (HRQOL) measures can better assess the impact of digital replantation. Methods  Overall, 264 digital injury patients were sent a regimen of utility measures: Disabilities of the Arm, Shoulder and Hand (DASH) score, European Quality of Life 5 Dimensions, visual analog scale (VAS), time trade-off (TTO), and standard gamble (SG). Overall, 51 patients responded completely to all of these-36 replantation patients and 15 revision amputation patients. The utility results of these patients were stratified between replantation versus revision amputation; dominant hand replantation versus nondominant hand replantation; and dominant hand revision amputation versus nondominant hand revision amputation. Results  The mean VAS score of replant (0.84) and revision amputation (0.75) groups was significantly different ( p  = 0.05). The mean DASH score of dominant hand replantations (29.72) and nondominant hand replantations (17.97) was significantly different ( p  = 0.027). The dominant hand revision amputation had higher anxiety levels in comparison to nondominant hand revision amputation ( p  = 0.027). Patients with two or more digits replanted showed a significant decrease in VAS, TTO, and SG scores in comparison to patients who only had one digit replanted ( p  = 0.009, 0.001, and 0.001, respectively). Conclusions  This study suggests that HRQOL can offer better indices for outcomes of digital replantation. This shows some specific replantation cohorts have a significantly better quality of life when compared with their specific correlating revision amputation cohort. These findings can be employed to further refine indications and contraindications to replantation and help predict the quality of life outcomes., Competing Interests: Conflict of Interest: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Arthroscopic trapeziectomy with suture button suspensionplasty (ATBS) is a relatively new surgical option for the treatment of thumb carpometacarpal (CMC) osteoarthritis. Although ATBS has many potential benefits over alternative surgical treatments for CMC arthritis, little data exist regarding its safety and complication rates. The purpose of this study was to demonstrate that ATBS is associated with a low risk of complications within 1 year of surgery., Methods: A retrospective review of patients treated with ATBS by one senior hand surgeon over a span of 3 years was performed., Results: A total of 153 cases of ATBS were performed in 136 patients. Ninety-seven cases involved arthroscopic hemitrapeziectomies, and 56 involved arthroscopic complete trapeziectomies. There were 44 males and 92 females with a mean age of 62. Thirty-eight percent of the cases were graded as Eaton stage IV, 46% stage III, and 14% stage II CMC arthritis, while 3 cases (2%) were performed as revisions. Mean follow-up duration was 58 weeks. Mean preoperative key pinch strength of the affected versus the unaffected side was 92% compared with 95% postoperatively. Revision surgery was performed in 9 out of 153 cases (<6%). Of those 9 cases, 5 had additional minor bony debridement with subsequent improvement in pain, 3 had the implant repositioned due to button prominence, and 1 patient presented with osteomyelitis of the first and second metacarpals that was successfully treated with button removal and an antibiotic regimen., Conclusions: ATBS is a safe, minimally invasive procedure for treatment of symptomatic stages II through IV thumb CMC arthritis.

Purpose: The RET proto-oncogene has been implicated in breast cancer, and the studies herein describe the preclinical and safety assessment of an anti-RET antibody-drug conjugate (ADC) being developed for the treatment of breast cancer., Experimental Design: RET protein expression was analyzed in breast tumor samples using tissue microarrays. The fully human anti-RET antibody (Y078) was conjugated to the DM1 and DM4 derivatives of the potent cytotoxic agent maytansine using thioether and disulfide linkers, respectively. The resulting compounds, designated Y078-DM1 and Y078-DM4, were evaluated for antitumor activity using human breast cancer cell lines and established tumor xenograft models. A single-dose, 28-day, safety study of Y078-DM1 was performed in cynomolgus monkeys., Results: By immunohistochemistry, RET expression was detected in 57% of tumors (1,596 of 2,800 tumor sections) and was most common in HER2-positive and basal breast cancer subtypes. Potent in vitro cytotoxicity was achieved in human breast cancer cell lines that have expression levels comparable with those observed in breast cancer tissue samples. Dose-response studies in xenograft models demonstrated antitumor activity with both weekly and every-3-weeks dosing regimens. In cynomolgus monkeys, a single injection of Y078-DM1 demonstrated dose-dependent, reversible drug-mediated alterations in blood chemistry with evidence of on-target neuropathy., Conclusions: RET is broadly expressed in breast cancer specimens and thus represents a potential therapeutic target; Y078-DM1 and Y078-DM4 demonstrated antitumor activity in preclinical models. Optimization of the dosing schedule or an alternate cytotoxic agent with a different mechanism of action may reduce the potential risk of neuropathy. Clin Cancer Res; 21(24); 5552-62. ©2015 AACR., (©2015 American Association for Cancer Research.)

Study Objective: In 2007, the WHO adopted surgical safety as the theme for the 2nd global patient safety challenge. Measurement of surgical services was identified as a surgical care area in need of major improvements. Aware of this recommendation, a preliminary study was conducted in our hospital and showed that the incidence of complete necrosis in free flap surgery was 10.0 %, a rate among the highest found in medical literature. In that context, an interactive surgical follow-up platform (PICS) was implemented to monitor outcomes in free flap surgery. The hypothesis was to reduce the short-term failure of microsurgical reconstructions., Patients and Methods: In Summer 2010, the tool for capturing and analyzing data (PICS) was implemented. All patients who underwent free flap reconstruction were prospectively registered in the platform. The primary endpoints to evaluate the effectiveness of the tool are the rates of surgical re-exploration and complete necrosis of the flap., Results: From May 2010 to December 2011, 129 cases of free flap reconstruction were recorded. The rate of total flap necrosis was 10.0 % before database introduction and declined to 3.1 % afterwards (P<0.05). Take-backs occurred in 27.0 % of free flap reconstructions at baseline and in 10.1 % after implementation (P<0.01)., Conclusion: The implementation of PICS is associated with a significant improvement of postoperative short-term outcomes in free flap surgery. This tool is effective to evaluate care services and provides an increased surgical safety for patients. Surgical teams are encouraged to implement a data collection tool in order evaluate operative care on a routine basis., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

A schwannoma is a benign tumour of Schwann cells that presents as a palpable and painless mass on the volar aspect of the hand and wrist. A 44-year-old, right-handed woman, presented for a volar swelling of her right hand. On examination she had a non-pulsatile mass with no fluctuation at the radiopalmar aspect of the right hand, and a soft mass on the volar aspect of the right palm. There was no pain on palpation. An excisional biopsy specimen showed an encapsulated and extrafascicular tumour that originated in the median nerve fascicules. Histological examination showed a median nerve schwannoma measuring 4.0 x 1.5 x 1.2 cm. Differential diagnosis of hand tumours is divided into three categories: tumours of the soft tissue, bone, and skin. Schwannomas of the median nerve make up 0.1%-0.3% of all hand tumours. Symptoms are caused by an entrapment syndrome resulting from the growing tumour. Pain is the most common complaint of schwannomas distal to the wrist. Imaging studies include computed tomography (CT) and magnetic resonance imaging (MRI). It is difficult to differentiate schwanommas from neurofibromas solely on the basis of an MRI. Neurofibroma grows intraneurally and infiltrates the nerve; it has the potential to require resection of all or part of the nerve, leaving a consequent functional deficit. Tumours of the hand are diagnostically challenging and median nerve shwannomas are rare.

To characterize a proprietary therapeutic monoclonal antibody (mAb) candidate, a rigorous biophysical study consisting of 53 Biacore and kinetic exclusion assay (KinExA) experiments was undertaken on the therapeutic mAb complexing with its target antigen. Unexpectedly, the observed binding kinetics depended on the chip used, suggesting that the negatively charged carboxyl groups on CM5, CM4, and C1 chips were adversely affecting the Biacore kinetic results. To study this hypothesis, Biacore solution-phase and KinExA equilibrium titrations, as well as KinExA kinetic measurements, were performed to establish accurate values for the affinity and kinetic rate constants of the binding reaction between antigen and mAb. The results revealed that as the negative charge on the biosensor surface decreased, the binding kinetics and K(D) approached the accurate binding parameters more closely when measured in solution. Two potential causes for the artifactual Biacore surface-based measurements are (i) steric hindrance of antigen binding arising from an interaction of the negatively charged carboxymethyldextran matrix with the mAb, which is a highly basic protein with a pI of 9.4, and (ii) an electrostatic repulsion between the negatively charged antigen and the carboxymethyldextran matrix. Importantly, simple diagnostic tests can be performed early in the measurement process to identify these types of matrix-mediated artifacts., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: No consensus exists among microsurgeons regarding the role of intravenous (IV) heparin in digital replantation/revascularization. The current experience of the Provincial Replantation Center in Quebec was reviewed over a 4-year period., Methods: An initial retrospective review of all revascularized or reimplanted digits at our Replantation Center from April 2004 to April 2006 was conducted. Then, data of all patients treated at our center from January 08 to September 08 were prospectively collected. The two cohorts were compared with regards to demographics, injury characteristics, postoperative thromboprophylaxis medication as well as complication and success rates. Proportions were compared using χ(2) tests/Fisher's exact tests. Multivariate analysis was conducted with logistic regression., Results: 175 digits were treated from April 2004 to April 2006, including 104 revascularizations and 71 amputations. IV heparin was used in 35.1% of the cases and was associated with a 3.59-fold (95% CI, 1.55-8.31) increase risk of developing a complication compared with cases where heparin was not used (P = 0.001). In 2008, 106 digits were treated. IV heparin was used in 14.6% of the cases and was not significantly associated with a higher complication rate compared with cases where heparin was not used (P = 0.612). Both cohorts' success rates were very similar (P = 0.557). The number of complications decreased from the first period (20.5%) to the second one (12.8%)., Conclusion: Routine use of IV heparin following digital replantation and revascularization is not warranted. Surgical technique and type of injury remains the most important predictors for success in these complex procedures., (Copyright © 2011 Wiley-Liss, Inc.)

Glycosylphosphatidylinositol-anchored HDL-binding protein (GPIHBP1) binds both LPL and chylomicrons, suggesting that GPIHBP1 is a platform for LPL-dependent processing of triglyceride (TG)-rich lipoproteins. Here, we investigated whether GPIHBP1 affects LPL activity in the absence and presence of LPL inhibitors angiopoietin-like (ANGPTL)3 and ANGPTL4. Like heparin, GPIHBP1 stabilized but did not activate LPL. ANGPTL4 potently inhibited nonstabilized LPL as well as heparin-stabilized LPL but not GPIHBP1-stabilized LPL. Like ANGPTL4, ANGPTL3 inhibited nonstabilized LPL but not GPIHBP1-stabilized LPL. ANGPTL3 also inhibited heparin-stabilized LPL but with less potency than nonstabilized LPL. Consistent with these in vitro findings, fasting serum TGs of Angptl4(-/-)/Gpihbp1(-/-) mice were lower than those of Gpihbp1(-/-) mice and approached those of wild-type littermates. In contrast, serum TGs of Angptl3(-/-)/Gpihbp1(-/-) mice were only slightly lower than those of Gpihbp1(-/-) mice. Treating Gpihbp1(-/-) mice with ANGPTL4- or ANGPTL3-neutralizing antibodies recapitulated the double knockout phenotypes. These data suggest that GPIHBP1 functions as an LPL stabilizer. Moreover, therapeutic agents that prevent LPL inhibition by ANGPTL4 or, to a lesser extent, ANGPTL3, may benefit individuals with hyperlipidemia caused by gene mutations associated with decreased LPL stability.

Angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4 (ANGPTL4) are secreted proteins that regulate triglyceride (TG) metabolism in part by inhibiting lipoprotein lipase (LPL). Recently, we showed that treatment of wild-type mice with monoclonal antibody (mAb) 14D12, specific for ANGPTL4, recapitulated the Angptl4 knock-out (-/-) mouse phenotype of reduced serum TG levels. In the present study, we mapped the region of mouse ANGPTL4 recognized by mAb 14D12 to amino acids Gln(29)-His(53), which we designate as specific epitope 1 (SE1). The 14D12 mAb prevented binding of ANGPTL4 with LPL, consistent with its ability to neutralize the LPL-inhibitory activity of ANGPTL4. Alignment of all angiopoietin family members revealed that a sequence similar to ANGPTL4 SE1 was present only in ANGPTL3, corresponding to amino acids Glu(32)-His(55). We produced a mouse mAb against this SE1-like region in ANGPTL3. This mAb, designated 5.50.3, inhibited the binding of ANGPTL3 to LPL and neutralized ANGPTL3-mediated inhibition of LPL activity in vitro. Treatment of wild-type as well as hyperlipidemic mice with mAb 5.50.3 resulted in reduced serum TG levels, recapitulating the lipid phenotype found in Angptl3(-/-) mice. These results show that the SE1 region of ANGPTL3 and ANGPTL4 functions as a domain important for binding LPL and inhibiting its activity in vitro and in vivo. Moreover, these results demonstrate that therapeutic antibodies that neutralize ANGPTL4 and ANGPTL3 may be useful for treatment of some forms of hyperlipidemia.

Venous thromboembolic events (VTEs) are an important concern due to their frequently asymptomatic presentation and significant morbidity and/or mortality. The true incidence of this disease process is unknown as (i) screening procedures and (ii) prophylaxis protocols are frequently lacking in this patient population. The purpose of this study was to identify published thromboprophylactic recommendations established in the plastic surgery literature and to provide a review on thromboembolism and current methods of prophylaxis. A systematic evaluation of all published guidelines for thromboembolism prophylaxis in plastic surgery was conducted. We report on 24 studies in favour of, and three studies against, mechanical and/or pharmacological prophylaxis. Thromboprophylactic recommendations were published by a small randomised trial (grade B, level 2), six retrospective studies (grade C, level IV), two literature reviews (grade C, level V), two surveys (grade C, level V), three narrative reviews (Continuing Medical Education) (grade C, level V) and 10 expert recommendations (grade C, level V). The three publications against prophylaxis were composed of a retrospective study (grade C, level IV) and two case series with no control group (grade C, level V). There is a significant paucity of category A or B evidence favouring thromboprophylaxis in the plastic surgery patient population. There is a need for further research in established thromboprophylaxis guidelines in plastic and reconstructive surgery.

Objectives: The use of antimicrobial prophylaxis against surgical site infection (SSI) is widespread in plastic surgery, while results from prospective randomised controlled trials in guiding antibiotic use are lacking. The purpose of this study was to identify the incidence and risk factors for SSI in plastic surgery, and to evaluate the appropriateness of prophylactic antibiotic prescribing habits in a tertiary university centre., Methods: A retrospective chart review was conducted over a 6-month period. Co-morbidities, types of procedure, prophylactic antimicrobial administration, SSI rates, and clinical outcomes were evaluated., Results: The incidence of SSI was 9.3% for 335 procedures. The cumulative incidence of SSI for breast surgery (n=80) was 16.3%, with a 78.8% prescription rate. For head and neck procedures (n=68), the incidence of SSI was 10.3%, with 80.9% of patients receiving antibiotic prophylaxis. For hand and upper limb procedures (n=170), 70.6% of patients received antimicrobial prophylaxis, with a 4.7% SSI incidence. According to category A prophylaxis guidelines published in the plastic surgery literature, over prescribing was identified in 27.5% of breast, 61.8% of head and neck, and 19.4% of hand and upper limb procedures., Conclusions: This is the first study evaluating appropriateness of antimicrobial prophylaxis use by plastic surgeons. Despite widespread use of prophylactic antibiotics, significant SSI rates were still present and frequently responsible for re-hospitalisations and re-interventions. The appropriateness of administration and indications for perioperative prophylactic antibiotic use must be evaluated.

Purpose: Infection rates following median sternotomy vary between 0.2% and 10%. These cases are associated with morbidity and mortality rates between 10% and 25% and 5% and 20%, respectively. The purpose of this study was to evaluate patient outcomes following plastic surgery correction of sternotomy dehiscence (SD)., Methods: All patients operated on for an SD following coronary artery bypass graft surgery (CABG), between 1995 and 2005, with 1 or more flaps, were included., Results: Eighty cases were identified over a 10-year period. The mean age was 64 (+/-9.1) years. Two or more procedures were required in 17.5% of patients, and the mortality rate within 30 days was 12.5%. Significant variability was revealed between the cumulative mortality rates of plastic surgeons, from 0.0% to 50.0%. Multiple associations were identified for poor outcome, including chronic renal insufficiency and early mortality, and obesity with risk of reintervention., Conclusion: Although patients who undergo surgical correction of a deep sternal infection usually tolerate their intervention well, the mortality within 30 days remains high. This study has identified several factors explaining morbidity and mortality in this patient population.

We used gene knockout mice to explore the role of Angiopoietin-like-4 (Angptl4) in lipid metabolism as well as to generate anti-Angptl4 mAbs with pharmacological activity. Angptl4 -/- mice had lower triglyceride (TG) levels resulting both from increased very low-density lipoprotein (VLDL) clearance and decreased VLDL production and had modestly lower cholesterol levels. Also, both Angptl4 -/- suckling mice and adult mice fed a high-fat diet showed reduced viability associated with lipogranulomatous lesions of the intestines and their draining lymphatics and mesenteric lymph nodes. Treating C57BL/6J, ApoE -/-, LDLr -/-, and db/db mice with the anti-Angptl4 mAb 14D12 recapitulated the lipid and histopathologic phenotypes noted in Angptl4 -/- mice. This demonstrates that the knockout phenotype reflects not only the physiologic function of the Angptl4 gene but also predicts the pharmacologic consequences of Angptl4 protein inhibition with a neutralizing antibody in relevant models of human disease.

The aim of this study was to develop a saturated transcript map of the region encompassing the HPC1 locus to identify the susceptibility genes involved in hereditary prostate cancer (OMIM 176807) and hyperparathyroidism-jaw tumor syndrome (OMIM 145001). We previously reported the generation of a 6-Mb BAC/PAC contig of the candidate region and employed various strategies, such as database searching, exon-trapping, direct cDNA hybridization, and sample sequencing of BACs, to identify all potential transcripts. These efforts led to the identification and precise localization on the BAC contig of 59 transcripts representing 22 known genes and 37 potential transcripts represented by ESTs and exon traps. Here we report the detailed characterization of these ESTs into full-length transcript sequences, their expression pattern in various tissues, their genomic organization, and their homology to known genes. We have also identified an Alu insertion polymorphism in the intron of one of the transcripts. Overall, data on 13 novel transcripts and the human RGS8 gene (homologue of the rat RGS8 gene) are presented in this paper. Ten of the 13 novel transcripts are expressed in prostate tissue and represent positional candidates for HPC1., (Copyright 2001 Academic Press.)

The PKD1 gene accounts for 85% of autosomal dominant polycystic kidney disease (ADPKD), the most common human genetic disorder. Rats with a germline inactivation of one allele of the Tsc2 tumor suppressor gene developed early onset severe bilateral polycystic kidney disease, with similarities to the human contiguous gene syndrome caused by germline codeletion of PKD1 and TSC2 genes. Polycystic rat renal cells retained two normal Pkd1 alleles but were null for Tsc2 and exhibited loss of lateral membrane-localized polycystin-1. In tuberin-deficient cells, intracellular trafficking of polycystin-1 was disrupted, resulting in sequestration of polycystin-1 within the Golgi and reexpression of Tsc2 restored correct polycystin-1 membrane localization. These data identify tuberin as a determinant of polycystin-1 functional localization and, potentially, ADPKD severity.