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Essentials Uncontrolled clot breakdown with active bleeding can be seen in advanced cirrhosis. A literature review found little information on optimal management. We report a case of successful treatment with tranexamic acid for persistent subdural hematoma in this setting. A 50‐year‐old woman with advanced cirrhosis presented with spontaneous subdural hematoma. She had a worsening clinical course following craniotomy despite administration of multiple blood products. With elevation in D‐dimer, persistently low fibrinogen and poor response to factor/fibrinogen replacement therapies, we had a suspicion for uncontrolled fibrinolysis. A literature review was conducted on treatment of hyperfibrinolysis in cirrhosis, finding 4 reports in which antifibrinolytics were used to control bleeding with different outcomes. The dose of tranexamic acid used in our patient was employed from previous experience in trauma patients. We transitioned from intravenous to oral administration based on expected pharmacokinetics. Our patient had a successful outcome with resolution of bleeding.

Background: Sickle cell anemia may be associated with cognitive dysfunction, and some complications of sickle cell anemia might affect those with sickle cell trait (SCT), so we hypothesized that SCT is a risk factor for cognitive impairment. Methods: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study enrolled a national cohort of 30,239 white and black Americans from 2003 to 7, who are followed every 6 months. Baseline and annual global cognitive function testing used the Six-Item Screener (SIS), a validated instrument (scores range 0–6; ≤4 indicates cognitive impairment). Participants with baseline cognitive impairment and whites were excluded. Logistic regression was used to calculate the association of SCT with incident cognitive impairment, adjusted for risk factors. Linear mixed models assessed multivariable-adjusted change in test scores on a biennially administered 3-test battery measuring learning, memory, and semantic and phonemic fluency. Findings: Among 7743 participants followed for a median of 7·1 years, 85 of 583 participants with SCT (14·6%) developed incident cognitive impairment compared to 902 of 7160 (12·6%) without SCT. In univariate analysis, the odds ratio (OR) of incident cognitive impairment was 1·18 (95% CI: 0·93, 1·51) for those with SCT vs. those without. Adjustment did not impact the OR. There was no difference in change on 3-test battery scores by SCT status (all p > 0·11). Interpretation: In this prospective cohort study of black Americans, SCT was not associated with incident cognitive impairment or decline in test scores of learning, memory and executive function. Funding: National Institutes of Health, American Society of Hematology. Keywords: Sickle cell trait, Cognitive dysfunction, Cognition, Prospective studies, Risk factors, Epidemiology

Acute myeloid leukaemia (AML) is a heterogeneous haematopoietic malignancy. Currently, treatment options offer a 5 year survival of60%. In elderly patients, where the incidence is highest, the survival is much lower. Current standard treatments have significant toxicity and are least well tolerated in older adults, where the need is greatest. Therefore, alternatives are required. Monoclonal antibodies (mAbs), due to the specific targeting to cell surface proteins (i.e. antigens), represent a promising strategy for drug delivery to malignant cells. This concept favours the therapeutic ratio simultaneously by reducing toxicity and increasing efficacy. Although delivery of chemotherapeutics, genes and imaging agents using multifunctional nanoparticles has been substantially explored in treating solid cancers, less information on this approach is available in the case of AML. This review describes the development of antibody-targeted nanoparticulate drug delivery systems, and discusses the barriers to clinical translation in the treatment of AML.

Retinoids are a family of signaling molecules derived from Vitamin A with well established roles in cellular differentiation. Physiologically active retinoids mediate transcriptional effects on cells through interactions with retinoic acid (RARs) and retinoid-X (RXR) receptors. Chromosomal translocations involving the RARα gene, which lead to impaired retinoid signaling, are implicated in acute promyelocytic leukemia (APL). All-trans-retinoic acid (ATRA), alone and in combination with arsenic trioxide (ATO), restores differentiation in APL cells and promotes degradation of the abnormal oncogenic fusion protein through several proteolytic mechanisms. RARα fusion-protein elimination is emerging as critical to obtaining sustained remission and long-term cure in APL. Autophagy is a degradative cellular pathway involved in protein turnover. Both ATRA and ATO also induce autophagy in APL cells. Enhancing autophagy may therefore be of therapeutic benefit in resistant APL and could broaden the application of differentiation therapy to other cancers. Here we discuss retinoid signaling in hematopoiesis, leukemogenesis, and APL treatment. We highlight autophagy as a potential important regulator in anti-leukemic strategies.

In 1998 new regulations [Misuse of Drugs (Supervision of Prescription and Supply of Methadone) Regulation, 1998; Government Publications, Dublin] obligated General Practitioners (GPs) in Ireland to have undergone a period of training before they could prescribe methadone and required collation of information about all patients treated on a Central Register. As a result of this new legislation patients who were previously being treated by private GPs, who were now no longer eligible to prescribe, were absorbed into the Health Authority's Addiction Services during the month of October 1998. Data were collected at entry and at three months follow-up on 464 of these patients. After three months the percentage on higher dose treatment (>90mg daily) dropped from 7% at entry to 2%; those positive for illicit opiates dropped from 64% to 28% (P < 0.001); and those positive for benzodiazepines dropped from 67% to 51% (P < 0.001). The introduction of new legislation regarding methadone treatment has underlined the need for a multi-disciplinary approach when treating opiate misuse. Since these regulations were introduced GPs can have access to training and support services.

The two recognized types of osteochondritis, juvenile osteochondritis dissecans (JOCD), and adult osteochondritis dissecans (OCD), differ in several ways. A painful malady found most frequently in the femoral condyles of children, JOCD occurs before the closure of the distal femoral physis, whereas OCD is seen when the physis is closed. The prognosis for healing is much worse for OCD than for JOCD. The pathologic tissue of JOCD resides in the subchondral bone of the afflicted femoral condyles of children, especially active young athletes. If the condition is allowed to continue, the lesion usually will detach. Surgical attempts to repair these detachments seldom restore the articular surface to opticity. This results in early onset of gonarthrosis. On the other hand, when JOCD is diagnosed early, conservative treatment can often result in healing of the lesions. If healing occurs, the child can expect a normal adult knee. There is also a recognized subtype of JOCD, once called asymptomatic JOCD. After joint scintigraphy of a symptomatic JOCD knee, there is often an abnormal scintigram in the opposite, asymptomatic, knee. This JOCD subtype is discussed further in the section on OCD classification. Possibly the first recorded evidence of JOCD was in 1840, when Ambrose Pare reported his finding of a “stone” in the human knee. 11 The stone also might have been a product of degenerative joint disease, and not JOCD or OCD at all. It was not until 1887, in Konig's paper on OCD, that factual information was published that these were not all joint mice or stones. 8 This speculation forced Konig to give this newly described phenomenon a proper christening, thus, he may not have pondered this task for long. The eponym Konig selected was osteochondritis dissecans , literally “dry inflamed bone.” Konig believed that these lesions were the result of inflammation. Subsequent re-examination of these lesions by other surgeons and Konig himself revealed that, in reality, there was no visible sign of inflammation. Ironically, a definitive cause is still not agreed on. The current literature on JOCD is limited largely to the surgical aspects, especially internal fixation of these pernicious lesions. Although there is literature that discusses conservative treatment, there currently is none available focusing on the important role of compliance in successful outcomes, or the interdependent roles of the parents, patient, and the physician—a group we will refer to as the “compliance triad.” The incidence of JOCD has increased during the past 40 to 50 years. 6 This escalation is thought to be related to the increasing exercise dose to which young athletes are subjected. Given the increased incidence of JOCD-related presentations and the explosive growth of intensive, year-round sports for children of both sexes, we believe that it is critical for any physician working with children to be knowledgeable about this condition. Because of the minimal information available on conservative treatment, and the complete lack of articles on the complex roles of the individuals involved in the compliance triad, we believe a need exists to address these issues. This article describes the essence of conservative JOCD treatment, including how to develop compliance in the triad, the importance of early diagnosis, and the results of conservative treatment. This article refers to the knee as the affected joint, because most JOCD cases occur there, and presents only the authors' experience with JOCD.

We describe an enzyme-linked immunosorbent assay (ELISA) for quantifying relative amounts of active caspase 3 in apoptotic cells. Covalent modification of caspase 3 active sites with a biotinylated inhibitor differentiates active from latent caspases. Capture on an ELISA plate with an antibody specific for caspase 3 makes the assay specific for caspase 3. Detection is with horseradish peroxidase (HRP)-conjugated streptavidin that binds to the biotinylated inhibitor covalently bound to caspase 3. Using the assay we detected 6.6 ng active caspase 3 per 10(6) apoptotic staurosporine-treated Jurkat cells. Specificity of the assay for caspase 3 was demonstrated by lack of signal with purified caspases 2, 7, 8, and 10 that were modified by a biotinylated inhibitor. Specificity was also demonstrated by lack of signal with apoptotic MCF-7 cells which do not express caspase 3. The ability to discriminate between active and latent caspase 3 was shown by Western blotting with HRP-streptavidin and anti-caspase 3. Although latent caspase 3 was captured it was not covalently modified with the biotinylated inhibitor. The basic principle of using a covalent inhibitor to identify active enzymes and an antibody to differentiate between enzymes with similar activities has potential for quantifying active members of many classes of enzymes.

Eruption is a highly localized process during which the bone resorption and formation that occur on opposite sides of the tooth are dependent upon the surrounding soft tissues, the true dental follicle externally and the enamel organ internally. To examine the ability of the enamel organ to cause eruption the external layer (dental follicle) was removed just prior to and up to 4 weeks before eruption in 13 mandibular premolars in dogs and eruption followed clinically, radiographically and histologically. None of the teeth without dental follicles erupted but three teeth from which the follicle was separated then replaced did erupt. These data indicate that the enamel organ without the dental follicle cannot support tooth eruption and provide indirect evidence for the central role of the dental follicle, alone or in combination with the enamel organ, in eruption.

Purpose : In an attempt to intensify conditioning therapy for bone marrow transplantation of hematologic malignancies, a retrospective three center evaluation of escalating doses of etoposide added to cyclophosphamide and either total body irradiation or busulfan was undertaken. Methods and Materials : Seventy-six patients who received etoposide (25–65 mg/kg) added to cyclophosphamide (60–120 mg/kg) and either total body irradiation (12.0–13.2 Gy) or busulfan (12–16 mg/kg) were evaluable for toxicity. Fifty-one of the evaluable patients received allogeneic transplants, while twenty-six received autologous transplants. A comparative analysis of toxicities according to conditioning regimen, donor source and etoposide dose was made. Results : Similar toxicities were observed among the treatment groups with the exception of more frequent skin (p = 0.003) and life threatening hepatic toxicities (p = 0.01) in the busulfan treated patients. Life threatening or fatal toxicities were not influenced by donor source, either when analyzed by treatment group or etoposide dose. Etoposide at a dose of 60–65 mg/kg in combination with TBI and cyclophosphamide was associated with a significantly increased incidence of life threatening or fatal toxicities compared with a combination using a dose of 25–50 mg/kg (15 of 24 vs. 5 of 20; p = 0.013). The maximally tolerated dose of etoposide in combination with busulfan and cyclophosphamide cannot be definitively established in this analysis in part due to the heterogeneity of the patient population and treatment schemes. Conclusion : Although toxicities with bone marrow transplant preparative regimens containing etoposide in combination with cyclophosphamide and total body irradiation or busulfan were frequently severe, treatment related mortality risk was believed to be acceptably low.

C/EBPalpha (42 kDa) is commonly dysregulated in acute myeloid leukaemia (AML) by mutation or via the action of AML oncogenes, which can increase the 30 kDa protein oncogenic form of C/EBPalpha (p30). The Trib2 oncogene is associated with dysregulated C/EBPalpha in human AML and leads to the degradation of p42, leaving p30 intact. Indeed there exists a novel paradigm whereby an E2F1-p30-Trib2 positive regulatory loop and an E2F1-p42-Trib2 negative feedback loop plays a key role in Trib2 expression, essential for AML cell proliferation and survival. Thus, it is important to understand the Trib2-C/EBPalpha relationship in the context of p42 degradation and/or C/EBPalpha mutation in AML. Using mouse genetics our data reveals that in the absence of C/EBPalpha (-/-) Trib2 was unable to induce AML whereas in the presence of p42 and mutant p30 (L/+), Trib2 and p30 cooperate to decrease the latency of AML disease. In the situation where p30 is expressed in the absence of p42, which alone can lead to AML (L/L), Trib2 does not lead to a more aggressive disease than that caused by p30 itself. These data show that the modulation of p42 rather than the expression of p30 is a key driver in Trib2 AML. Peptide array analysis showed the site-specific direct interaction between Trib2 and p42, and mutational analysis showed that these site-specific interactions were required for the K48-specific ubiquitin-dependent proteasomal degradation of p42. A C-terminal lysine residue of C/EBPalpha commonly found duplicated in AML patients was critical for Trib2-mediated p42 ubiquitination and proteasomal degradation. Proteasome inhibition using bortezomib induced cell death in Trib2 positive AML cell lines and AML patient samples in vitro and in vivo. Knockdown and overexpression of Trib2 in AML cells followed by transplantation in NSG mice and treated with bortezomib selectively killed Trib2 positive AML. Our data show the mechanism required for oncogene function centres on p42 degradation.

Deregulation of the transcription factor E2F1 occurs in AML, and it has been shown to induce both cell cycle progression and apoptosis. In normal granulopoiesis, proliferation arrest and differentiation mediated by C/EBPalpha involves repression of E2F1 target genes. Elevated Trib2 expression has been linked with a subset of human AML and dysregulated C/EBPalpha. Using promoter assays, mutational analyses and chromatin immunoprecipitation experiments, we show that E2F1 (and E2F2, E2F3, but not E2F4 or E2F5) are bound directly to the DNA on site-specific regions on the Trib2 promoter in leukaemic cells. Trib2 expression is decreased following siRNA-mediated knockdown of E2F1, and in E2F1 knockout cells as compared to wild type cells. The reintroduction of E2F1 rescued Trib2 expression showing that E2F1 is regulating the expression of endogenous Trib2. Further analyses revealed that this activation of Trib2 by E2F1 is repressed by wild type C/EBPalpha consistent with C/EBPalpha having a negative regulatory role on E2F1, and in normal GMP cells we detect C/EBPalpha bound to the Trib2 promoter. Conversely there was synergistic activation upon coexpression of the oncogenic C/EBPalpha truncated mutant, and Trib2 expression levels were elevated in GMPs from preleukaemic mutant C/EBPalpha mice compared to wild type GMPs. Indeed a positive correlation between Trib2 and E2F1 expression in AML datasets support these findings. Finally, inhibition of the cell cycle pathway in leukaemia cells expressing high endogenous levels of Trib2 protein resulted in G1 arrest with a reduction in E2F1 levels and Trib2 protein levels. Our work indicates that the cell cycle regulator E2F1 plays a key role in the control of Trib2 expression important for the control of cell proliferation and may have important implications for normal and malignant haematopoiesis.

This uncommon syndrome is caused by compression of the posterior humeral circumflex artery and axillary nerve or one of its major branches in the quadrilateral space. Forward flexion and/or abduction and external rotation of the humerus aggravate the symptoms. Discrete point tenderness is always found posteriorly in the quadrilateral space. Patients with appropriate history and physical findings should have a subclavian arteriogram done by the Seldinger technique. A positive arteriogram reveals occlusion of the posterior humeral circumflex artery with the arm in abduction and external rotation. Patients with sufficient symptoms not responding to conservative treatment and having a positive subclavian arteriogram and local tenderness over the quadrilateral space should be considered for surgical decompression. A posterior approach is recommended. Of the 18 patients operated on, eight have had dramatic and complete relief, eight have been improved, and two have shown no improvement.

The effect of electronegativity of α substituents on geminal coupling constants is discussed with particular reference to a recent paper by Anteunis, Swaelens and Gelan.

A series of substituted morpholin-2-ones has been synthesized, and their 1H NMR spectra interpreted in terms of a half-chair conformation. The effect of different solvents on the spectra is discussed.

Further values of geminal coupling constants ( J ) in CH 2 groups α to heteroatoms confirm established trends in the variation of J with molecular environment; in addition, J is quoted for new systems not described in Part I, and the exceptions to the general trends are discussed.