Objectives: Because physicians may have difficulty distinguishing accidental fractures from those that are caused by abuse, abusive fractures may be at risk for delayed recognition; therefore, the primary objective of this study was to determine how frequently abusive fractures were missed by physicians during previous examinations. A secondary objective was to determine clinical predictors that are associated with unrecognized abuse. Methods: Children who were younger than 3 years and presented to a large academic children's hospital from January 1993 to December 2007 and received a diagnosis of abusive fractures by a multidisciplinary child protective team were included in this retrospective review. The main outcome measures included the proportion of children who had abusive fractures and had at least 1 previous physician visit with diagnosis of abuse not identified and predictors that were independently associated with missed abuse. Results: Of 258 patients with abusive fractures, 54 (20.9%) had at least 1 previous physician visit at which abuse was missed. The median time to correct diagnosis from the first visit was 8 days (minimum: 1; maximum: 160). Independent predictors of missed abuse were male gender, extremity versus axially located fracture, and presentation to a primary care setting versus pediatric emergency department or to a general versus pediatric emergency department. Conclusions: One fifth of children with abuse-related fractures are missed during the initial medical visit. In particular, boys who present to a primary care or a general emergency department setting with an extremity fracture are at a particularly high risk for delayed diagnosis.

BACKGROUND: Gastric cancer is a disease with different management approaches in different regions, especially between Western and Asian countries. Surgery is the mainstay of treatment for non-metastatic disease. Perioperative chemotherapy or adjuvant radio-chemotherapy is recommended, since recurrences are common after curative resection. Unfortunately, advanced or metastatic gastric cancer constitutes the majority of patients in clinical practice. For these patients systemic chemotherapy is the standard treatment, to provide palliation and prolong survival; however, prognosis remains poor. Several molecular targeting agents are under evaluation in international randomized studies. OBJECTIVE: To review chemotherapy and targeted therapies for gastric cancer, chemical and pharmacological characteristics of trastuzumab, and evidence for its clinical use in gastric cancer. METHODS: Examination of relevant literature. RESULTS/CONCLUSIONS: HER-2 is overexpressed/amplified in approximately 22% of gastric cancer patients. Trastuzumab, a recombinant humanized anti-HER-2 monoclonal antibody, is, to our knowledge, the first biological therapy that has showed a survival improvement by nearly 3 months (reduced risk of death by 26%), thus trastuzumab in combination with chemotherapy is a treatment option for patients with HER2-positive advanced gastric cancer. Trastuzumab's role in curative gastric cancer treatment needs to be studied, as well as monotherapy, maintenance therapy and second line treatment in the palliative setting.

Cisplatin is one of the most widely used antineoplastic agents in the treatment of solid tumour and haematological malignancies, including cancers of the testes, ovary, bladder, head and neck, oesophagus, stomach and lung, as well as lymphoma and osteosarcoma. Its non-specific targeting commonly results in adverse effects and toxicities affecting the gastrointestinal, renal, neurological and haematological systems even when administered at standard doses. Since cisplatin-related toxicities are dose-dependent, these may be more pronounced in the setting of a cisplatin overdose, resulting in significant morbidity and/or mortality. The incidence of cisplatin overdoses is unknown; however, early-phase clinical trials utilizing high-dose cisplatin, and case reports in the overdose setting have characterized the clinical features associated with cisplatin overdoses, highlighting some therapeutic strategies for consideration. To date, no published guidelines exist for managing a cisplatin overdose. The major toxicities of a cisplatin overdose include nausea and vomiting, renal insufficiency, electrolyte abnormalities, myelosuppression, ototoxicity, peripheral neuropathy, hepatotoxicity and retinopathy. Diarrhoea, pancreatitis, seizures and respiratory failure have also been reported. No specific antidote for cisplatin exists. Key management principles and strategies to lessen toxicities include renoprotection and enhancing drug elimination with aggressive intravenous hydration with or without the use of an osmotic diuretic, and avoidance of nephrotoxic medications. Sodium thiosulfate and plasmapheresis, with or without haemodialysis support, should be strongly considered. Close monitoring of clinical and laboratory parameters, and institution of supportive therapies, including antiemetics and haematopoietic colony stimulating factor support, are warranted. Based on the current literature, experimental therapies such as amifostine, ditiocarb sodium (diethyldithiocarbamate), acetylcysteine, fosfomycin and colestipol are of limited clinical effectiveness and remain investigational. This review serves to highlight the clinical spectrum of toxicities resulting from a cisplatin overdose, to critically appraise the available literature and to present a suggested algorithmic approach for the initial management of a cisplatin overdose.

The dicistrovirus is a positive-strand ssRNA virus which possesses two internal ribosome entry sites (IRES) that direct translation of distinct open reading frames encoding the viral structural and non-structural proteins. Through an unusual mechanism, the intergenic region (IGR) IRES responsible for viral structural protein expression mimics a tRNA to directly recruit the ribosome and set the ribosome into translational elongation. In this study, we explored the mechanism of host translational shutoff in Drosophila S2 cells infected by the dicistrovirus, Cricket paralysis virus (CrPV). CrPV infection of S2 cells results in host translational shutoff concomitant with an increase in viral protein synthesis. CrPV infection resulted in the dissociation of eIF4G and eIF4E early in infection and the induction of deIF2alpha phosphorylation at 3 hours post infection, which lags after the initial inhibition of host translation. Forced dephosphorylation of deIF2alpha by overexpression of dGADD34, which activates protein phosphatase I, did not prevent translational shutoff nor alter virus production, demonstrating that deIF2alpha phosphorylation is dispensable for host translational shutoff. However, premature induction of deIF2alpha phosphorylation by thapsigargin treatment early in infection reduced viral protein synthesis and replication. Finally, translation mediated by the 5' untranslated region (5'UTR) and the IGR IRESs were resistant to impairment of eIF4F or eIF2 in translation extracts. These results support a model by which the alteration of the deIF4F complex contribute to the shutoff of host translation during CrPV infection, thereby promoting viral protein synthesis via the CrPV 5'UTR and IGR IRESs.

BACKGROUND Precise sperm-oocyte interaction is a critical event for successful fertilization. However, the identity of molecules involved in this process in humans remains largely unknown. This report describes the identification and characterization of a novel cell-surface protein and its potential role in human sperm-oocyte interaction. METHODS AND RESULTS We previously identified an orphan guanylyl cyclase receptor (mouse GC-G) highly enriched in mouse testis and involved in sperm activation. By using a comparative genomic approach, we found the homologue gene in human (hGC-G) composed of 21 exons, spanning a minimum of 48 kb on chromosome 10q25. Real-time RT-PCR analysis revealed hGC-G mRNA selectively expressed in testis but with low or no expression in all other tissues examined. Compared with mGC-G, the hGC-G transcript contains three 1-bp deletions and two in-frame termination codons, which results in a short putative receptor-like polypeptide. Western blot analysis with an anti-hGC-G-specific antibody confirmed the protein expression of hGC-G in human sperm lysate. Flow cytometry and confocal immunofluorescence analysis demonstrated the localization of hGC-G protein on the acrosome cap and equatorial segment of mature human sperm. In addition, an integrin-binding Arg-Gly-Asp (RGD) motif was found in the extracellular domain of hGC-G. Pre-incubation of the hGC-G RGD peptide with zona pellucida-free oocytes greatly decreased the binding of human sperm to hamster oocytes, which suggests a role for hGC-G role in sperm-oocyte interaction. CONCLUSIONS hGC-G is a novel surface protein on human sperm and potentially mediates sperm-oocyte interaction through its RGD-containing motif.

Background The National Cancer Institute of Canada Clinical Trials Group CO.17 study showed that patients with advanced colorectal cancer had improved overall survival when cetuximab, an epidermal growth factor receptor-targeting antibody, was given in addition to best supportive care. We conducted a cost-effectiveness analysis using prospectively collected resource utilization and health utility data for patients in the CO.17 study who received cetuximab plus best supportive care (N = 283) or best supportive care alone (N = 274). Methods Direct medical resource utilization data were collected, including medications, physician visits, toxicity management, blood products, emergency department visits, and hospitalizations. Mean survival times for the study arms were calculated for the entire population and for the subset of patients with wild-type KRAS tumors over an 18- to 19-month period. All costs were presented in 2007 Canadian dollars. One-way and probabilistic sensitivity analysis was used to determine the robustness of the results. Cost-effectiveness acceptability curves were determined. The 95% confidence intervals (CIs) for the incremental cost-effectiveness ratios and the incremental cost-utility ratios were estimated by use of a nonparametric bootstrapping method (with 1000 iterations). Results For the entire study population, the mean improvement in overall and quality-adjusted survival with cetuximab was 0.12 years and 0.08 quality-adjusted life-years (QALYs), respectively. The incremental cost with cetuximab compared with best supportive care was $23 969. The incremental cost-effectiveness ratio was $199 742 per life-year gained (95% CI =$125 973 to $652 492 per life-year gained) and the incremental cost-utility ratio was $299 613 per QALY gained (95% CI =$187 440 to $898 201 per QALY gained). For patients with wild-type KRAS tumors, the incremental cost with cetuximab was $33 617 and mean gains in overall and quality-adjusted survival were 0.28 years and 0.18 QALYs, respectively. The incremental cost-effectiveness ratio was $120 061 per life-year gained (95% CI =$88 679 to $207 075 per life-year gained) and the incremental cost-utility ratio was $186 761 per QALY gained (95% CI =$130 326 to $334 940 per QALY gained). In a sensitivity analysis, cetuximab cost and patient survival were the only variables that influenced cost-effectiveness. Conclusions The incremental cost-effectiveness ratio of cetuximab over best supportive care alone in unselected advanced colorectal cancer patients is high and sensitive to drug cost. Incremental cost-effectiveness ratios were lower when the analysis was limited to patients with wild-type KRAS tumors.

Several cases in which uteruses have been preserved in women with placenta percreta have been reported. We herein report a 38-year-old woman with a history of previous cesarean section who was admitted with lower abdominal pain and vaginal bleeding at 31 weeks of gestation. An urgent exploratory laparotomy revealed active bleeding from the uterine rupture on the posterior uterine wall. A female infant weighing 1560 g, with Apgar scores of 1, 1, and 3 at 1, 5, and 10 min, respectively, was delivered, and the placenta was removed. We performed bilateral uterine vessel occlusion, followed by wedge resection of the ruptured uterine wall with the aid of an intrauterine muscle injection of 20 IU oxytocin, a local injection of diluted vasopressin (1:60) into the myometrium around and into the rupture site, and an intramuscular injection of 0.2 mg methylergonovine, primary repair of the defect, and an additional 24-h postoperative oxytocin infusion (30 IU in 5% dextrose 500 mL) to preserve the uterus successfully. Although the overall blood loss was 3700 mL, no disseminated intravascular coagulopathy occurred after the patient had received adequate blood transfusion. The postoperative pathological diagnosis was placenta percreta with uterine rupture. The patient and her baby were discharged uneventfully. In some cases of spontaneous uterine rupture secondary to placenta percreta, we can preserve the uterus by performing bilateral uterine vessel occlusion and wedge resection of the ruptured uterine wall.

OBJECTIVE:: To determine the association between type of previous delivery (vaginal compared with cesarean) on the success of medical abortion with mifepristone-misoprostol in early pregnancy. METHODS:: The records of 879 women with intrauterine pregnancies at or before 56 days of gestation who underwent medical abortions were reviewed. Medical treatment consisted of 600 mg mifepristone orally followed 48 hours later with oral misoprostol. An ultrasound examination was performed 14-21 days after treatment, and a successful medical abortion was defined as an empty uterus without surgical intervention. Univariable and multivariable logistic regressions were used to determine risk factors for failure of medical abortion. RESULTS:: A total of 797 (90.7%) women had successful medical abortions; 82 (9.3%) had failed medical abortions. Multivariable logistic regression indicated that women with gestational ages greater than 42 days (odds ratio [OR] 2.53, 95% confidence interval [CI] 1.55-4.05) had higher odds of failed abortion compared with a gestational age less than 43 days. Parous women (OR>/=3.94, 95% CI 1.83-8.53) and those with prior cesarean delivery (OR 9.59, 95% CI 4.30-21.39) were more likely to have failed abortions compared with nulliparous women. Among 523 parous women (68 had failed abortion), those with gestational ages greater than 42 days (OR 2.07, 95% CI 1.22-3.50) and prior cesarean delivery (OR 3.33, 95% CI 1.95-5.69) were more likely to have failed abortions compared with those with gestational ages less than 43 days or with prior vaginal delivery. CONCLUSION:: Parous women are at increased risk for failed medical abortion in comparison with nulliparous women. Prior cesarean delivery is significantly associated with failed medical abortion. LEVEL OF EVIDENCE:: II.

PURPOSE: National Cancer Institute of Canada Clinical Trials Group CO.17 demonstrated the antiepidermal growth factor receptor (anti-EGFR) monoclonal antibody cetuximab improves overall and progression-free survival in patients with advanced, chemotherapy-refractory colorectal cancer (CRC), particularly in patients with wild-type KRAS tumors. This article reports the health-related quality-of-life (HRQL) outcomes from CO.17. PATIENTS AND METHODS: Patients (N = 572) with pretreated EGFR-detectable advanced CRC were randomly assigned to cetuximab and best supportive care (BSC) or to BSC alone. HRQL primary end points assessed by the EORTC QLQ-C30 were physical function (PF) and global health status (GHS); mean changes from baseline to 8 and 16 weeks were assessed. Post hoc analysis by KRAS mutation status was performed. RESULTS: Questionnaire compliance was 94% at baseline, but it declined differentially (67% v 47% for cetuximab v BSC at 16 weeks). PF change scores were -3.9 for cetuximab and -8.6 for BSC (P =.046) at 8 weeks and were -5.9 and -12.5 for cetuximab and BSC, respectively,(P =.027) at 16 weeks. GHS change scores were -0.5 and -7.1 (P =.008) at 8 weeks and were -3.6 and -15.2 (P =.008) at 16 weeks for cetuximab and BSC, respectively. In patients who had tumors with wild-type KRAS status, cetuximab resulted in less PF deterioration at 8 weeks (-0.7 v -7.2; P =.11) and 16 weeks (-3.4 v -13.8; P =.008) compared with BSC. Patients with wild-type status who received cetuximab experienced improved GHS at 8 weeks, whereas patients who received BSC alone deteriorated (3.2 v -7.7; P =.002). Cetuximab preserved GHS at 16 weeks (-0.2 v -18.1; P <.001). No significant differences were noted between study arms for patients with mutated KRAS tumors. CONCLUSION: Cetuximab offers important HRQL and survival benefits for pretreated patients with advanced, wild-type KRAS CRC.