Introduction
Emicizumab has been shown to be safe and effective for prevention of bleeds in patients with severe haemophilia A (SHA), both with and without inhibitors. The subcutaneous administration ...and long half‐life make emicizumab an attractive option for prophylaxis in infants with SHA, however data to inform treatment decisions in this younger age group are almost absent.
Aim
The aim of this report is to share real world experience to illustrate how the availability of emicizumab has shifted the prophylaxis paradigm in the management of infants with SHA.
Method
We selected four cases from our own cohort of infants with SHA to outline the rationale for emicizumab prophylaxis in a range of scenarios familiar to paediatric haemophilia treaters.
Results
In Case 1 emicizumab was commenced at 7 days following initial treatment of neonatal ICH with a FVIII infusion. In Case 2 emicizumab was commenced at 5 weeks due to parental anxiety regarding the potential for ICH during infancy. Case 3 commenced emicizumab at 15 months in lieu of standard primary prophylaxis. Case 4 switched to emicizumab prophylaxis at 14 months after a period of primary prophylaxis with FVIII concentrates to alleviate parental anxiety regarding future inhibitor development. No patient had any bleeding events after commencement of emicizumab (median follow up 12 months), and no drug‐related adverse effects were observed.
Conclusion
Despite the paucity of data in infants with SHA the potential role of emicizumab prophylaxis should be discussed with families when clinically relevant, with decisions tailored to individual need.
There is limited literature on associations between inflammatory tone and response to sequential pharmacotherapies in major depressive disorder (MDD).
In a 16-week open-label clinical trial, 211 ...participants with MDD were treated with escitalopram 10-20 mg daily for 8 weeks. Responders continued escitalopram while non-responders received adjunctive aripiprazole 2-10 mg daily for 8 weeks. Plasma levels of pro-inflammatory markers-C-reactive protein, interleukin (IL)-1β, IL-6, IL-17, interferon-gamma (IFN)-Γ, tumor necrosis factor (TNF)-α, and Chemokine C-C motif ligand-2 (CCL-2)-measured at baseline, and after 2, 8 and 16 weeks were included in logistic regression analyzes to assess associations between inflammatory markers and treatment response.
Pre-treatment IFN-Γ and CCL-2 levels were significantly associated with a lower of odds of response to escitalopram at 8 weeks. Increases in CCL-2 levels from weeks 8 to 16 in escitalopram non-responders were significantly associated with higher odds of non-response to adjunctive aripiprazole at week 16.
Higher pre-treatment levels of IFN-Γ and CCL-2 were associated with non-response to escitalopram. Increasing levels of these pro-inflammatory markers may be associated with non-response to adjunctive aripiprazole. These findings require validation in independent clinical populations.
Association of urinary arsenic concentration with incident diabetes was examined in American Indians from Arizona who have a high prevalence of type 2 diabetes and were screened for diabetes between ...1982 and 2007. The population resides where drinking water contains arsenic at concentrations above federally recommended limits. A total of 150 nondiabetic subjects aged ≥25 years who subsequently developed type 2 diabetes were matched by year of examination and sex to 150 controls who remained nondiabetic for ≥10 years. Total urinary arsenic concentration, adjusted for urinary creatinine level, ranged from 6.6 µg/L to 123.1 µg/L, and inorganic arsenic concentration ranged from 0.1 µg/L to 36.0 µg/L. In logistic regression models adjusted for age, sex, body mass index, and urinary creatinine level, the odds ratios for incident diabetes were 1.11 (95% confidence interval (CI): 0.79, 1.57) and 1.16 (95% CI: 0.89, 1.53) for a 2-fold increase in total arsenic and inorganic arsenic, respectively. Categorical analyses suggested a positive relationship between quartiles of inorganic arsenic and incident diabetes (P = 0.056); post-hoc comparison of quartiles 2-4 with quartile 1 revealed 2-fold higher odds of diabetes in the upper quartiles (OR = 2.14, 95% CI: 1.19, 3.85). Modestly elevated exposure to inorganic arsenic may predict type 2 diabetes in American Indians. Larger studies that include measures of speciated arsenic are required for confirmation.
From the death of James III to the execution of Mary, Queen of Scots, Jane Dawson tells story of Scotland from the perspective of its regions and of individual Scots, as well as incorporating the ...view from the royal court. Scotland Re-formed shows how the country was re-formed as the relationship between church and crown changed, with these two institutions converging, merging and diverging, thereby permanently altering the nature of Scottish governance. Society was also transformed, especially by the feuars, new landholders who became the backbone of rural Scotland. The Reformation Crisis of 1559-60 brought the establishment of a Protestant Kirk, an institution influencing the lives of Scots for many centuries, and a diplomatic revolution that discarded the 'auld alliance' and locked Scotland's future into the British Isles.
Although the disappearance of the pre-Reformation church left a patronage deficit with disastrous effects for Scottish music and art, new forms of cultural expression arose that reflected Protestant sensibilities or were transposed to secular settings. Alongside the dramatic events and slow transformations of cultural, social, economic, political and religious life, in 1587 much remained as it had been in 1488, with Scots deeply rooted in their country through their abiding sense of people and place.
Key Features
Distinctive regional approach brings a fresh perspective to the century's political and religious eventsCompelling new interpretation based upon the complex inter-relationship of crown and church, helps students make sense of the upheavals brought to Scotland by the Renaissance and ReformationCareful integration of visual, artistic and material culture enlivens and enriches students' understanding of Scottish life
The modification of reduced cysteines of proteins by nitric oxide alters protein function, structure, and potentially, interactions with downstream signaling targets. We assessed the effect of the ...S-nitroso compounds S-nitrosoglutathione and S-nitroso-N-acetyl-penicillamine, the NO donor 2-(N,N-diethylamino)-diazenolate 2-oxide, and the nitroxyl donor Angeli’s salt on the cysteines of the abundant cytoskeletal protein, tubulin. Total cysteine modification by each compound was quantitated and compared to peroxynitrite anion, an oxidant that we have studied previously. Angeli’s salt was most effective at modifying the cysteines of tubulin and at inducing the formation of tubulin interchain disulfide bonds followed by peroxynitrite anion, S-nitrosoglutathione, S-nitroso-N-acetyl-penicillamine, and 2-(N,N-diethylamino)-diazenolate 2-oxide. S-nitrosation of tubulin by S-nitrosoglutathione and S-nitroso-N-acetyl-penicillamine was detected by the Saville assay. Our data show that tubulin interchain disulfide bond formation by these molecules correlated with inhibition of tubulin polymerization. Closer examination of the reaction of tubulin with S-nitrosoglutathione showed a concentration-dependent shift in the type of cysteine modification detected. More tubulin disulfides were detected at lower concentrations of S-nitrosoglutathione than at higher concentrations, suggesting that reduced glutathione, generated by the reaction of S-nitrosoglutathione with tubulin cysteines, reduced disulfides initially formed by S-nitrosoglutathione.
The biotin switch assay was developed to aid in the identification of
S-nitrosylated proteins in different cell types. However, our work with microtubule proteins including tubulin and its associated ...proteins tau and microtubule-associated protein-2 shows that ascorbic acid is not a selective reductant of protein
S-nitrosothiols as described in the biotin switch assay. Herein we show that ascorbic acid reduces protein disulfides in tubulin, tau, and microtubule-associated protein-2 that are formed by peroxynitrite anion. Reduction of microtubule-associated protein disulfides by ascorbic acid following peroxynitrite treatment restores microtubule polymerization kinetics to control levels. We also show that ascorbic acid reduces the disulfide dithiobis(2-nitrobenzoic acid), a reagent commonly used to detect protein thiols. Not only do we describe a new reactivity of ascorbic acid with microtubule proteins but we expose an important limitation when using the biotin switch assay to detect protein S-nitrosylation.
OBJECTIVE
To report a phase‐1 study of patients with recurrent superficial bladder cancer treated with photodynamic therapy (PDT) using sequential mitomycin C and 5‐aminolaevulinic acid (ALA).
...PATIENTS AND METHODS
Twenty‐four patients were treated, the primary endpoint being the safety and tolerability of combined therapy at increasing doses of ALA and light.
RESULTS
Mitomycin C instillation was followed by ALA concentrations of 6%, 8% or 10%; there was no effect on toxicity. The light dose, at a wavelength of 635 nm, was increased from zero to 25 J/cm2, with the upper fluences producing transient symptoms. There were no episodes of skin photosensitivity or systemic toxicity. A total fluence of 25 J/cm2 represented the upper light dose for the tolerability of this procedure by patients. There were no persistently high urinary symptom scores or reduction in functional bladder capacity up to ≥24 months of follow‐up. In this group, cumulative tumour recurrences were none at 4, two at 8, six at 12, nine at 18 and 11 at 24 months after PDT, respectively.
CONCLUSION
Sequential mitomycin C and ALA‐PDT is a safe and well tolerated treatment, with potential for managing difficult‐to‐control superficial transitional cell carcinoma and carcinoma in situ of the bladder.
T cell activation and the resultant production of interleukin (IL‐2) is a central response of the adaptive immune system to pathogens, such as hepatitis C virus (HCV). HCV uses several mechanisms to ...evade both the innate and adaptive arms of the immune response. Here we demonstrate that liver biopsy specimens from individuals infected with HCV had significantly lower levels of IL‐2 compared with those with other inflammatory liver diseases. Cell culture–grown HCV particles inhibited the production of IL‐2 by normal peripheral blood mononuclear cells, as did serum from HCV‐infected patients. This process was mediated by the interaction of HCV envelope protein E2 with tetraspanin CD81 coreceptor. HCV E2 attenuated IL‐2 production at the level of secretion and not transcription by targeting the translocation of protein kinase C beta (PKCβ), which is essential for IL‐2 secretion, to lipid raft microdomains. The lipid raft disruptor methyl‐β‐cyclodextrin reversed HCV E2‐mediated inhibition of IL‐2 secretion, but not in the presence of a PKCβ‐selective inhibitor. HCV E2 further inhibited the secretion of other cytokines, including interferon‐γ. Conclusion: These data suggest that HCV E2–mediated disruption of the association of PKCβ with the cellular secretory machinery represents a novel mechanism for HCV to evade the human immune response and to establish persistent infection. (HEPATOLOGY 2011;)
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