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OBJECTIVES: To compare a new low-dose warfarin induction regimen with the Fennerty regimen in elderly inpatients. DESIGN: Age-stratified, randomized prospective study. SUBJECTS: 120 age-stratified elderly inpatients. INTERVENTIONS: Each patient was randomized to either the new induction regimen or to a modified Fennerty regimen. MAIN OUTCOMES MEASURES: Days to therapeutic International Normalized Ratio (INR >2); days in the therapeutic range (INR 2-3) during induction; number of patients with INR >4.5; ability of day 4 INR to predict day 8 warfarin dose. RESULTS: The mean time to therapeutic INR was longer for the new induction regimen than modified Fennerty regimen in patients aged 65-75 years [4.6 (mean) +/- 1.6 (SD) days vs 3.8 +/- 0.8 days; P = 0.03] and in patients aged >75 years (4.5 +/- 1.4 days vs 3.5 +/- 0.7 days; P = 0.003). Patients spent more time in the therapeutic INR range with the new induction regimen [3.0 +/- 1.3 days vs 2.7 +/- 1.3 days (P = 0.03) for those aged 65-75 years and 2.9 +/- 1.1 days vs 2.4 +/- 1.3 days (P = 0.04 for those aged >75 years]. Fewer patients using the new regimen had INRs >4.5 in the first 8 days [1 (3%) vs 6 (20%) for 65-75 years (P < 0.05) and 1 (3%) vs 11 (37%) for >75 years (P < 0.01)]. The ability to predict the maintenance dose to within 1 mg was 55% for both regimens. CONCLUSION: The low-dose regimen has important clinical advantages over the Fennerty regimen for anticoagulating elderly inpatients. [ABSTRACT FROM AUTHOR]

Memory and cognitive decline are the product of numerous physiological changes within the aging brain. Multiple theories have focused on the oxidative, calcium, cholinergic, vascular, and inflammation hypotheses of brain aging, with recent evidence suggesting that reductions in insulin signaling may also contribute. Specifically, a reduction in insulin receptor density and mRNA levels has been implicated, however, overcoming these changes remains a challenge. While increasing insulin receptor occupation has been successful in offsetting cognitive decline, alternative molecular approaches should be considered as they could bypass the need for brain insulin delivery. Moreover, this approach may be favorable to test the impact of continued insulin receptor signaling on neuronal function. Here we used hippocampal cultures infected with lentivirus with or without IRβ, a constitutively active, truncated form of the human insulin receptor, to characterize the impact continued insulin receptor signaling on voltage-gated calcium channels. Infected cultures were harvested between DIV 13 and 17 (48 h after infection) for Western blot analysis on pAKT and AKT. These results were complemented with whole-cell patch-clamp recordings of individual pyramidal neurons starting 96 h post-infection. Results indicate that while a significant increase in neuronal pAKT/AKT ratio was seen at the time point tested, effects on voltage-gated calcium channels were not detected. These results suggest that there is a significant difference between constitutively active insulin receptors and the actions of insulin on an intact receptor, highlighting potential alternate mechanisms of neuronal insulin resistance and mode of activation.

The insulin receptor (IR) is a ligand-activated receptor tyrosine kinase that has a key role in metabolism, cellular survival, and proliferation. Progesterone receptor membrane component 1 (PGRMC1) promotes cellular signaling via receptor trafficking and is essential for some elements of tumor growth and metastasis. In the present study, we demonstrate that PGRMC1 coprecipitates with IR. Furthermore, we show that PGRMC1 increases plasma membrane IR levels in multiple cell lines and decreases insulin binding at the cell surface. The findings have therapeutic applications because a small-molecule PGRMC1 ligand, AG205, also decreases plasma membrane IR levels. However, PGRMC1 knockdown via short hairpin RNA expression and AG205 treatment potentiated insulin-mediated phosphorylation of the IR signaling mediator AKT. Finally, PGRMC1 also increased plasma membrane levels of two key glucose transporters, GLUT-4 and GLUT-1. Our data support a role for PGRMC1 maintaining plasma membrane pools of the receptor, modulating IR signaling and function., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

Point-of-care ultrasonography has been recognized as a relevant and versatile tool in Special Operations Forces (SOF) medicine. The Special Operator Level Clinical Ultrasound (SOLCUS) program has been developed specifically for SOF Medics. A number of challenges, including skill sustainment, high-volume training, and quality assurance, have been identified. Potential solutions, including changes to content delivery methods and application of tele-ultrasound, are described in this article. Given the shift in operational context toward extended care in austere environments, a curriculum adjustment for the SOLCUS program is also proposed., (2016.)

Cancer is one of the leading causes of death in America, and there is an urgent need for new therapeutic approaches. The progesterone receptor membrane component 1 (PGRMC1) is a cytoch-rome b 5 related protein that binds heme and is associated with signaling, apoptotic suppression and autophagy. PGRMC1 is essential for tumor formation, invasion and metastasis, and is upregulated in breast, colon, lung and thyroid tumors. In the present study, we have analyzed PGRMC1 levels in over 600 tumor sections, including a larger cohort of lung tumors than in previous studies, and report the first clinical analysis of PGRMC1 levels in human oral cavity and ovarian tumors compared to corresponding nonmalignant tissues. PGRMC1 was highly expressed in lung and ovarian cancers and correlated with patient survival. PGRMC1 has been previously associated with drug resistance, a characteristic of cancer stem cells. The stem cell theory proposes that a subset of cancerous stem cells contribute to drug resistance and tumor maintenance, and PGRMC1 was detected in lung-tumor derived stem cells. Drug treatment with a PGRMC1 inhibitor, AG-205, triggered stem cell death whereas treatment with erlotinib and the ERK inhibitor, PD98059, did not, suggesting a specific role for PGRMC1 in cancer stem cell viability. Together, our data demonstrate PGRMC1 as a potential tumor biomarker across a variety of tumors, as well as a therapeutic target for cancer stem cells.

EGFR (epidermal growth factor receptor) is activated through changes in expression or mutations in a number of tumors and is a driving force in cancer progression. EGFR is targeted by numerous inhibitors, including chimeric antibodies targeting the extracellular domain and small molecule kinase domain inhibitors. The kinase domain inhibitors are particularly active against mutant forms of the receptor, and subsequent mutations drive resistance to the inhibitors. Here, we review recent developments on the trafficking of wild-type and mutant EGFR, focusing on the roles of MIG6, SPRY2, ITSN, SHP2, S2R(PGRMC1) and RAK. Some classes of EGFR regulators affect wild-type and mutant EGFR equally, while others are specific for either the wild-type or mutant form of the receptor. Below we summarize multiple signaling-associated pathways that are important in trafficking wild-type and mutant EGFR with the goal being stimulation of new approaches for targeting the distinct forms of the receptor.

Major surgery in persons with haemophilia A and inhibitors is increasingly being performed. Both recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (APCC) are used to cover surgery but it remains unclear what the optimal dosing schedules are. We describe the use of a hybrid regimen in four inhibitor patients undergoing eight major surgical procedures using rFVIIa in the initial 2-6 postoperative days followed by FEIBA for the remaining period. All patients were also treated with tranexamic acid while receiving rFVIIa. We performed six major orthopaedic procedures, one emergency orchidectomy and one open appendectomy. The dosing schedules were at the higher end of those described in the literature but within the recommendations of the summary of product characteristics. Despite this, we encountered non-surgical bleeding in four of eight episodes. Three of these occurred in one individual suggesting a patient factor. The overall outcome was good for all episodes. The hybrid regimen combines flexibility of dose and dosing frequency of rFVIIa in the immediate postoperative setting with the advantage of a reduced dosing frequency with FEIBA in the subsequent days. This study also emphasizes that surgical procedures in this patient group remain a challenge., (© 2014 John Wiley & Sons Ltd.)

Background. Molecular markers for prostate cancer (PCa) risks are currently lacking. Here we address the potential association of a dinucleotide polymorphism (DNP) in exon 2 of the p73 gene with PCa risk/progression and discern any disruption of p73 protein isoforms levels in cells harboring a p73 DNP allele. Methods. We investigated the association between p73 DNP genotype and PCa risk/aggressiveness and survival by fitting logistic regression models in 1,292 incident cases and 682 controls. Results. Although we detected no association between p73 DNP and PCa risk, a significant inverse relationship between p73 DNP and PCa aggressiveness (AT/AT + GC/AT versus GC/GC, OR = 0.55, 95%Cl = 0.31-0.99) was detected. Also, p73 DNP is marginally associated with overall death (dominant model, HR = 0.76, 95%Cl = 0.57-1.00, P = 0.053) as well as PCa specific death (HR = 0.69, 95%Cl = 0.45-1.06, P = 0.09). Western blot analyses for p73 protein isoforms indicate that cells heterozygous for the p73 DNP have lower levels of ∆Np73 relative to TAp73 (P < 0.001). Conclusions. Our findings are consistent with an association between p73 DNP and low risk for PCa aggressiveness by increasing the expressed TAp73/∆Np73 protein isoform ratio.

Background: Life threatening bleeding and emergency procedures in patients on vitamin K antagonists are indications for urgent reversal with prothrombin complex concentrate and vitamin K. Rapid reversal in these situations is emphasized in the literature and guidelines, but only very limited information is available on its real life use, especially on the timing of treatment in relation to presentation., Materials and Methods: We retrospectively audited emergency warfarin reversal in 131 consecutive patients. We studied the indication, use of vitamin K, time between presentation and administration of vitamin K and PCC, effectiveness in INR reduction and clinical outcome., Results: The median PCC dose was 26.8 IU/kg. The median INR was reduced from 3.1 to 1.2. Vitamin K (5 mg) was given in 91.6% of evaluable patients. We found significant delays in administration of PCC and vitamin K. The median time between presentation and administration of vitamin K/PCC was 3.6 and 5.2 hours respectively. The times in intracranial haemorrhage were 2.7 and 3.0 hours and in emergency procedures 17.4 and 15.9 hours respectively. Mortality related to bleeding was 7.6% overall but in patients with intracranial haemorrhage 22.8%. The thrombotic rate within 7 days of reversal was 1.5%., Discussion: The local protocol for reversal with PCC and vitamin K was adhered to well but the delay in pre-procedural patients, suggests that intravenous vitamin K alone may be sufficient in many cases and PCC administration can be avoided by better planning. Intracranial haemorrhage in warfarinised patients carries a high mortality. Treatment delays should be avoided by making PCC stocks available within emergency departments, simple dosing structures independent of INR and administering PCC without waiting for INR and CT scan results in those with strong suspicion of intracranial haemorrhage and clear trauma. Future reports and studies should always include the time from presentation to PCC treatment.

Low molecular weight heparins (LMWHs) are frequently used in the prophylaxis or treatment of venous thrombosis, acute coronary syndromes and peri-operative bridging. Major bleeding occurs in 1-4% depending on dose and underlying condition. Protamine is recommended for reversal but only partially reverses the anti-Xa activity and there are very limited data on clinical effectiveness. We retrospectively studied the effect of emergency reversal of LMWH with protamine in actively bleeding patients and patients requiring emergency surgery in our institution. Eighteen patients were identified through haematology referral/pharmacy records of protamine prescriptions between 1998 and 2009. Case notes were checked for the reversal indication, type/dose of LMWH, dose and clinical response to protamine, timing in relation to the last dose of LMWH and anti-Xa levels before and after protamine. All but one patient received enoxaparin. Fourteen were actively bleeding, three required emergency surgery without active bleeding and one had an accidental overdose without bleeding. The three patients requiring surgery had an uneventful procedure. In 12 of 14 patients with active bleeding, protamine could be evaluated. Bleeding stopped in eight. In the four with continuing bleeding, one had an additional coagulopathy. Protamine only partially affected anti-Xa levels. Protamine may be of use in reversing bleeding associated with LMWH but not in all patients. Anti-Xa levels were useful to assess the amount of anticoagulation before protamine administration but unhelpful in assessing its effect. Better reversal agents and methods to monitor LMWH therapy are required.

Introduction: An isolated prolongation to the activated partial thromboplastin time (APTT) can be caused by the presence of the lupus anticoagulant or an intrinsic or contact factor deficiency, of which only deficiencies of factors VIII, IX or XI are associated with bleeding. Our local protocol states that further investigation of a prolonged APTT by specific assays of FVIII, FIX and FXI should only be undertaken where the APTT with one reagent (Synthasil) is more than 3 s prolonged, and further investigation by an APTT with a second reagent (Actin FS) is also prolonged, unless there is a history of bleeding in the patient, in which case assays are indicated irrespective of the APTT., Methods: We retrospectively reviewed the results of all APTTs performed over a 36-month period to evaluate whether strictly applying our protocol would reduce the number of unnecessary clotting factor assays performed, without leaving patients with potentially significant bleeding disorders undiagnosed., Results: Of a total number of 587 samples tested for coagulation factors VIII, IX and XI, only 117 samples yielded an abnormal result. Thus, 80% of all the assays requested in the 3-year period audited gave a result within the reference range for factors VIII, FIX and XI. Three quarters of the abnormal results revealed mild FXI deficiency., Conclusion: This review has demonstrated that no significant coagulation factor deficiency would be left undiagnosed if the protocol was followed. This would have considerably reduced the cost and time spent performing these assays., (© 2010 Blackwell Publishing Ltd.)

Background: Severe FX deficiency is a rare disorder with a variable bleeding tendency but spontaneous life threatening haemorrhage can occur. Treatment for invasive procedures and spontaneous bleeding is with prothrombin complex concentrates (PCC). When used in large or repetitive doses these are associated with a thrombotic tendency. FX:C levels of 0.15 - 0.30 IU/ mL are thought to be haemostatic during surgery . There is only limited information on the outcome and management of pregnancy in severe FX deficiency. Caesarean section is suggested as delivery mode to reduce the risk of intracranial/abdominal neonatal haemorrhage, but successful vaginal deliveries are also described. The calibrated automated thrombin generation assay (CAT) is a global coagulation test that measures the time course of thrombin generation. It has been reported to correlate with prothrombotic states and the severity of bleeding in rare coagulation disorders. The variability in phenotype, the uncertainty of the minimal haemostatic FX:C concentration and the association of PCC's with thrombosis make thrombin generation of interest in the management of FX deficient patients., Patient: We describe the use of CAT as a possible means to monitor treatment with PCC (Beriplex) in a patient with severe FX deficiency (FX:C < 0.01 IU/mL) during successful vaginal delivery and epidural anaesthesia., Results: Thrombin generation was normal at FX:C 0.80 IU/mL but only borderline normal at FX:C 0.25 IU/mL. Repetitive doses over 3 days increased thrombin generation to the upper limit of normal at FX:C 0.25 IU/mL consistent with a prothrombotic tendency after multiple doses. The increase in thrombin generation was not related to prothrombin levels., Conclusion: The data suggest that CAT may be used to monitor treatment with PCC in FX deficiency. Higher levels than previously thought may be needed to normalize thrombin generation. Further studies into the correlation with bleeding or thrombosis are needed before the approach can be accepted in clinical practice.

This eighth best practice review examines four series of common primary care questions in laboratory medicine: (i) sodium abnormalities; (ii) faecal occult blood testing; (iii) warfarin management; and (iv) sputum cytology in diagnosis of bronchopulmonary malignancy. The review is presented in question-answer format, referenced for each question series. The recommendations represent a précis of guidance found using a standardised literature search of national and international guidance notes, consensus statements, health policy documents and evidence-based medicine reviews, supplemented by Medline Embase searches to identify relevant primary research documents. They are not standards but form a guide to be set in the clinical context. Most are consensus rather than evidence-based. They will be updated periodically to take account of new information.

Haemoperitoneum secondary to ruptured corpus luteum is a rare complication for women on anticoagulants and with certain congenital bleeding disorders. A surgical approach is often taken, leading to oophorectomy in many cases. We describe three patients presenting with haemoperitoneum in association with factor VII deficiency, factor X deficiency and sitosterolaemia. In two of the patients, recurrent episodes occurred prior to introduction of the oral contraceptive pill. Conservative management with blood product and factor concentrate support was successful in avoiding surgery in three of the five episodes of bleeding. These cases demonstrate that preservation of ovarian function is possible with a conservative approach and recurrent episodes may be prevented by suppression of ovulation.