The efficacy and tolerability of MK-0633, a 5-lipoxygenase inhibitor, in chronic asthma

Leukotriene B4 (LTB(4)) is a potent inflammatory mediator in asthma, and is increased in more severe asthma. Targeting LTB(4), in addition to cysteinyl leukotrienes, could be beneficial in asthma. This was a randomized, double-blind trial of once-daily MK-0633, a potent 5-lypoxygenase inhibitor, 10?mg, 50?mg, and 100?mg, and placebo in patients 18-70 years with a history of chronic asthma, and FEV(1) ≥45 and ≤85% predicted. There was a 6-week main period and optional 18-week and 34-week periods (52 weeks total), the latter two comparing only MK-0633 100?mg and placebo. The primary endpoint was the change from baseline in FEV(1) over the last 4 weeks of the 6-week primary treatment period. Secondary endpoints included symptom scores, β-agonist use, peak expiratory flow (PEF), asthma quality of life questionnaire (AQLQ), asthma control questionnaire (ACQ), asthma attacks, exacerbations, days with asthma control, post-β-agonist FEV(1), and blood eosinophils. MK-0633 100?mg was significantly more effective than placebo for the change from baseline in FEV(1) (0.20?L vs. 0.13?L; p?=?0.004). The other MK-0633 doses were not significantly more effective than placebo. MK-0633 (at various doses) was also more effective than placebo for β-agonist use, AQLQ, AM and PM PEFR, ACQ, and post-β-agonist FEV(1) (p?相似文献   

α-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson’s disease and multiple system atrophy?

We report a British family with young-onset Parkinson’s disease (PD) and a G51D SNCA mutation that segregates with the disease. Family history was consistent with autosomal dominant inheritance as both the father and sister of the proband developed levodopa-responsive parkinsonism with onset in their late thirties. Clinical features show similarity to those seen in families with SNCA triplication and to cases of A53T SNCA mutation. Post-mortem brain examination of the proband revealed atrophy affecting frontal and temporal lobes in addition to the caudate, putamen, globus pallidus and amygdala. There was severe loss of pigmentation in the substantia nigra and pallor of the locus coeruleus. Neuronal loss was most marked in frontal and temporal cortices, hippocampal CA2/3 subregions, substantia nigra, locus coeruleus and dorsal motor nucleus of the vagus. The cellular pathology included widespread and frequent neuronal α-synuclein immunoreactive inclusions of variable morphology and oligodendroglial inclusions similar to the glial cytoplasmic inclusions of multiple system atrophy (MSA). Both inclusion types were ubiquitin and p62 positive and were labelled with phosphorylation-dependent anti-α-synuclein antibodies In addition, TDP-43 immunoreactive inclusions were observed in limbic regions and in the striatum. Together the data show clinical and neuropathological similarities to both the A53T SNCA mutation and multiplication cases. The cellular neuropathological features of this case share some characteristics of both PD and MSA with additional unique striatal and neocortical pathology. Greater understanding of the disease mechanism underlying the G51D mutation could aid in understanding of α-synuclein biology and its impact on disease phenotype.     

The promise of urethral pressure reflectometry: an update

Introduction and hypothesis

The urethral closure mechanism in women is incompletely understood. Measuring closure function in a collapsed urethral tube without distending the tube and changing its natural shape is impossible with conventional methods. Over the last decade, studies with urethral pressure reflectometry (UPR), a method that measures pressure and the corresponding cross-sectional area along the entire length of the urethra continuously by means of acoustic reflectometry, have been performed. The studies have mainly been performed on patients with stress urinary incontinence (SUI).

Methods

Our aim was to provide an overview of the studies conducted with UPR, establishing whether the method may be used in clinical practice. We reviewed all literature published on UPR.

Results

Urethral pressure reflectometry is easily performed with limited bother for the patient. The catheter consists of a 45-cm-long PVC tube connected to a thin and highly flexible polyurethane bag, which is placed in the urethra. When inserted, the bag only occupies 0.4 mm² of the urethra, respecting the natural shape and orientation of the urethra and, most importantly; respecting the laws of physics when measuring urethral pressure. UPR can discriminate patients with SUI from continent women and separate assessment of the sphincter function and support system is possible. Also, UPR has revealed statistically significant differences in urethral pressures after drug therapy for SUI.

Conclusions

We conclude that UPR has a place in clinical practice. The method has shown groundbreaking potential in the understanding of urethral dysfunction in SUI patients.

     

High levels of the p53 inhibitor MDM4 in head and neck squamous carcinomas

The p53 tumor suppressor is mutated in most human tumors. MDM2, a well-known inhibitor of p53, is overexpressed in a large number of tumors, suggesting that increased levels of MDM2 also contribute to tumorigenesis. A novel p53 inhibitor, MDM4, was more recently identified. The role of MDM4 in cancer development is not well understood. We set out to examine the levels of MDM4 by immunohistochemistry in head and neck squamous carcinomas (HNSC) to ask whether high MDM4 levels could contribute to its development and progression. In addition, MDM2 and p53 levels were examined to identify overlapping expression patterns. MDM4 is present at high levels in 50% of HNSC. In addition, overexpression of MDM2 was detected in 80% of tumors, many of which were also positive for MDM4. A subset of tumors displayed high levels of all 3 proteins. Sequencing of the p53 gene revealed that tumors with positive immunoreactivity for MDM2 or MDM4, some of which also had high levels of p53, did not carry mutations in this gene. Thus, the detection of p53 by immunohistochemistry was not synonymous with the presence of p53 mutations. Expression of both MDM2 and MDM4 in tumors without p53 mutations strongly suggests that MDM2 and MDM4 inhibit the activity of this tumor suppressor in HNSC.     

Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid

To maintain immune homeostasis, the intestinal immune system has evolved redundant regulatory strategies. In this regard, the gut is home to a large number of regulatory T (T reg) cells, including the Foxp3(+) T reg cell. Therefore, we hypothesized that the gut environment preferentially supports extrathymic T reg cell development. We show that peripheral conversion of CD4(+) T cells to T reg cells occurs primarily in gut-associated lymphoid tissue (GALT) after oral exposure to antigen and in a lymphopenic environment. Dendritic cells (DCs) purified from the lamina propria (Lp; LpDCs) of the small intestine were found to promote a high level of T reg cell conversion relative to lymphoid organ-derived DCs. This enhanced conversion by LpDCs was dependent on TGF-beta and retinoic acid (RA), which is a vitamin A metabolite highly expressed in GALT. Together, these data demonstrate that the intestinal immune system has evolved a self-contained strategy to promote T reg cell neoconversion.     

Der Weg zum Kompetenzzentrum für Adipositas und metabolische Chirurgie – Erfahrungen aus 2 verschiedenen Kliniken

Die Chirurgie - Bei hoher Prävalenz, stetig steigender Inzidenz der Adipositas und nachgewiesener Wirksamkeit adipositaschirurgischer Operationen (Ops) nehmen die Anzahl dieser OPs und die...     

Nurses are research leaders in skin and wound care

The World Health Assembly declared 2020, the International Year of the Nurse and the Midwife. Recent editorials and commentaries support the leading role of nurses and midwives as frontline caregivers emphasizing the need to invest in the nursing workforce worldwide to meet global health needs. Today nurses are also leaders in research and one example is skin and wound care. In order to reflect on the contribution of nurses as researchers we conducted a systematic review of published articles in five international leading wound care journals in the years 1998, 2008 and 2018. We aimed to determine the type of research publication and percentage of nurses as first, second or senior authors. The place in the authorship was selected as indicative of leadership as it implies responsibility and accountability for the published work. Across the years 1998, 2008 and 2018, 988 articles were published. The overall proportion of nurse‐led articles was 29% (n = 286). The total numbers of articles increased over time and so too did the nurse‐led contributions. Nurse‐led research was strongest in the design categories ''cohort studies'' (46%, n = 44), ''systematic reviews'' (46%, n = 19), and ''critically appraised literature and evidence‐based guidelines'' (47%, n = 55).Results of this review indicate that, in addition to the crucial clinical roles, nurses also have a substantial impact on academia and development of the evidence base to guide clinical practice. Our results suggest that nurse led contributions were particularly strong in research summarizing research to guide skin and wound care practice.