Paracetamol (acetaminophen) is the most commonly used drug in the world, with a long record of use in acute and chronic pain. In recent years, the benefits of paracetamol use in chronic conditions ...has been questioned, notably in the areas of osteoarthritis and lower back pain. Over the same period, concerns over the long‐term adverse effects of paracetamol use have increased, initially in the field of hypertension, but more recently in other areas as well. The evidence base for the adverse effects of chronic paracetamol use consists of many cohort and observational studies, with few randomized controlled trials, many of which contradict each other, so these studies must be interpreted with caution. Nevertheless, there are some areas where the evidence for harm is more robust, and if a clinician is starting paracetamol with the expectation of chronic use it might be advisable to discuss these side effects with patients beforehand. In particular, an increased risk of gastrointestinal bleeding and a small (~4 mmHg) increase in systolic blood pressure are adverse effects for which the evidence is particularly strong, and which show a degree of dose dependence. As our estimation of the benefits decreases, an accurate assessment of the harms is ever more important. The present review summarizes the current evidence on the harms associated with chronic paracetamol use, focusing on cardiovascular disease, asthma and renal injury, and the effects of in utero exposure.
The development of antibodies against infused factor VIII (FVIII) in patients with haemophilia A is a serious complication leading to poorly controlled bleeding and increased morbidity. No treatment ...has been proven to reduce high titre antibodies in patients who fail immune tolerance induction or are not candidates for it. The Rituximab for the Treatment of Inhibitors in Congenital Hemophilia A (RICH) study was a phase II trial to assess whether rituximab can reduce anamnestic FVIII antibody (inhibitor) titres. Male subjects with severe congenital haemophilia A and an inhibitor titre ≥5 Bethesda Units/ml (BU) following a FVIII challenge infusion received rituximab 375 mg/m² weekly for weeks 1 through 4. Post-rituximab inhibitor titres were measured monthly from week 6 through week 22 to assess treatment response. Of 16 subjects who received at least one dose of rituximab, three (18.8%) met the criteria for a major response, defined as a fall in inhibitor titre to <5 BU, persisting after FVIII re-challenge. One subject had a minor response, defined as a fall in inhibitor titre to <5 BU, increasing to 5-10 BU after FVIII re-challenge, but <50% of the original peak inhibitor titre. Rituximab is useful in lowering inhibitor levels in patients, but its effect as a solo treatment strategy is modest. Future studies are indicated to determine the role of rituximab as an adjunctive therapy in immune tolerisation strategies.
Two tandem cellulosome-associated genes were identified in the cellulolytic rumen bacterium, Ruminococcus flavefaciens. The deduced gene products represent multimodular scaffoldin-related proteins ...(termed ScaA and ScaB), both of which include several copies of explicit cellulosome signature sequences. The scaB gene was completely sequenced, and its upstream neighbor scaA was partially sequenced. The sequenced portion of scaA contains repeating cohesin modules and a C-terminal dockerin domain. ScaB contains seven relatively divergent cohesin modules, two extremely long T-rich linkers, and a C-terminal domain of unknown function. Collectively, the cohesins of ScaA and ScaB are phylogenetically distinct from the previously described type I and type II cohesins, and we propose that they define a new group, which we designated here type III cohesins. Selected modules from both genes were overexpressed in Escherichia coli, and the recombinant proteins were used as probes in affinity-blotting experiments. The results strongly indicate that ScaA serves as a cellulosomal scaffoldin-like protein for several R. flavefaciens enzymes. The data are supported by the direct interaction of a recombinant ScaA cohesin with an expressed dockerin-containing enzyme construct from the same bacterium. The evidence also demonstrates that the ScaA dockerin binds to a specialized cohesin(s) on ScaB, suggesting that ScaB may act as an anchoring protein, linked either directly or indirectly to the bacterial cell surface. This study is the first direct demonstration in a cellulolytic rumen bacterium of a cellulosome system, mediated by distinctive cohesin-dockerin interactions.
ABSTRACT
We previously reported that the binding of two‐chain high molecular weight kininogen (HKa) to endothelial cells may occur through interactions with endothelial urokinase receptors. Since the ...binding of urokinase to urokinase receptors activates signaling responses and may stimulate mitogenesis, we assessed the effect of HKa binding on endothelial cell proliferation. Unexpectedly, HKa inhibited proliferation in response to several growth factors, with 50% inhibition caused by ~10 nM HKa. This activity was Zn2+ dependent and not shared by either single‐chain high molecular weight kininogen (HK) or low molecular weight kininogen. HKa selectively inhibited the proliferation of human umbilical vein and dermal microvascular endothelial cells, but did not affect that of umbilical vein or human aortic smooth muscle cells, trophoblasts, fibroblasts, or carcinoma cells. Inhibition of endothelial proliferation by HKa was associated with endothelial cell apoptosis and unaffected by antibodies that block the binding of HK or HKa to any of their known endothelial receptors. Recombinant HK domain 5 displayed activity similar to that of HKa. In vivo, HKainhibited neovascularization of subcutaneously implanted Matrigel plugs, as well as rat corneal angiogenesis. These results demonstrate that HKa is a novel inhibitor of angiogenesis, whose activity is dependent on the unique conformation of the two‐chain molecule.—Zhang, J.‐C., Claffey, K., Sakthivel, R., Darzynkiewicz, Z., Shaw, D. E., Leal, J., Wang, Y.‐C., Lu, F. M., McCrae, K. R. Two‐chain high molecular weight kininogen induces endothelial cell apoptosis and inhibits angiogenesis: partial activity within domain 5. The FASEB J. 14, 2589–2600 (2000)
Policy makers and funders working to address best practices for residential care and treatment require evidence for the effectiveness of residential interventions, particularly related to maintenance ...of effects post-discharge. With support from the Substance Abuse and Mental Health Services Administration of the US Department of Health and Human Services, the Building Bridges Initiative and providers of residential interventions partnered with Chapin Hall to study the feasibility of a method for collecting follow-up data on the functioning of young people who were recently discharged from residential treatment. This paper describes the implementation and findings regarding the feasibility of (1) identifying the location of youth 6 months post-discharge, (2) contacting the caregivers of these youth for the purpose of administering a follow-up survey, and (3) administering a brief (10-min) survey inquiring about youth functioning in key domains. The results of this research provide guidance for measuring youth progress and outcomes after residential interventions. This study also lays the groundwork for a larger post-discharge outcomes study that includes linkage to administrative data, baseline data on youth functioning, and assessment of the services received in the context of residential interventions. Data and information obtained from the feasibility study provide evidence for the viability of a brief, telephone-administered post-discharge survey with caregivers.
Abstract
Introduction
More than half of heavy-drinking young adults report symptoms of insomnia, which have been associated with alcohol-related problems. This study examined improvement in insomnia ...(via Cognitive Behavioral Therapy for Insomnia; CBT-I) as a mechanism for improvement in alcohol-related problems.
Methods
Fifty-six heavy-drinking young adults with insomnia (ages 18-30y) were randomized to CBT-I (n=28) or single-session sleep hygiene control (SH; n=28). Of those, 43 (77%) completed post-treatment (24 SH, 19 CBT-I) and 48 (86%) completed 1-month follow-up (25 SH, 23 CBT-I). Multiple imputation was used to estimate missing data. Treatment outcomes were assessed using multilevel models. Mediation was tested using bootstrapped confidence intervals for indirect effects in the PROCESS macro.
Results
CBT-I participants reported greater decreases in insomnia severity than those in the sleep hygiene group group X time interaction, F(2,59)=11.29, p<.001, both post-treatment and at 1-month follow-up. Both groups decreased significantly in diary-assessed sleep quality time, F(2,55)=40.30, p<.001, with a marginally significant interaction in favor of the CBT-I group F(2,55)=2.69, p=.08. There were no significant group by time interactions in the prediction of actigraphy-assessed sleep variables, although again, there was a marginally significant interaction in the prediction of actigraphy-assessed sleep efficiency F(2,66)=2.75, p=.07. Both groups reported significant decreases in drinking quantity over time time, F(2,58=13.88, p<.001. However, CBT-I participants reported greater decreases in alcohol-related consequences than those in the sleep hygiene group F(2,67)=4.13, p=.02. In the mediation model, CBT-I did not have a direct effect on change in alcohol-related consequences (B=1.49, SE=1.06, 95%CI=-0.65, 3.62); however, it influenced change in 1-month alcohol-related consequences indirectly through its influence on post-treatment insomnia symptoms (B=-1.09, SE=0.57, 95%CI=-2.30, -0.05).
Conclusion
CBT-I is effective in treating insomnia among heavy-drinking young adults and may be associated with reductions in alcohol-related problems due to its impact on insomnia symptoms.
Support
This work was supported by funding from the University of Missouri System Research Board Office (PI Miller). Mary Beth Miller’s contribution to this project was also supported by the National Institute on Alcohol Abuse and Alcoholism grant number K23AA026895.
Histidine-proline-rich glycoprotein (HPRG) is an abundant multidomain plasma protein evolutionarily related to high-molecular-weight kininogen. The cleaved form of high-molecular-weight kininogen has ...recently been demonstrated to exhibit antiangiogenic activities in vitro (J. C. Zhang et al., FASEB J., 14: 2589-2600, 2000), mediated primarily through domain 5. HPRG contains a histidine-proline-rich (H/P) domain with sequence and functional similarities to HKa-D5. We hypothesized that HPRG may also have antiangiogenic properties, localized within its H/P domain. The H/P domain is highly conserved among species, and because rabbit H/P domain is more resistant to internal proteolytic cleavage than the human domain, the rabbit HPRG (rbHPRG) was primarily used to assess the antiangiogenic activity of HPRG. Rabbit HPRG inhibited human umbilical vein endothelial cell (HUVEC) tube formation stimulated by fibroblast growth factor-2 (FGF-2) or vascular endothelial growth factor on a Matrigel surface as well as cell proliferation of FGF-2 stimulated HUVECs. The antiangiogenic activity of rbHPRG was localized to the H/P domain by use of proteolytic fragments of rbHPRG and was further confirmed and characterized in two in vivo models of angiogenesis: the chorioallantoic membrane of the chick assay and the mouse Matrigel plug assay. Caspase-3 activation was observed in HUVECs stimulated with FGF-2 in the presence of rbHPRG, suggesting that apoptosis of activated endothelial cells may be one of the mechanisms underlying its antiangiogenic activity. Finally, the H/P domain of rbHPRG reduced tumor cell number when tumor cells were co-inoculated in the Matrigel plug assay. In conclusion, the H/P domain within HPRG induces the apoptosis of activated endothelial cells leading to potent antiangiogenic effects.
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