Priming of human neutrophils with N-formyl-methionyl-leucyl- phenylalanine by a calcium-independent, pertussis toxin-insensitive pathway

Resting neutrophils may be "primed" to augmented effector function, eg, superoxide (O2-) production in the respiratory burst, upon a second stimulation with a variety of soluble agonists including formylated methionyl-leucyl-phenylalanine (FMLP) and phorbol myristate acetate (PMA). At priming concentrations of FMLP (5 x 10(-9) mol/L) that did not initiate O2- generation, two metabolic activities were noted: (1) approximately a threefold increase in the baseline intracellular calcium (Ca++i) level, that was not dependent on extracellular Ca++, and (2) a rapid rise in intracellular pH that was blocked by 5-(N,N- dimethyl) amiloride (DA), that had no effect on the Ca++i response to priming. Furthermore, there were no significant increases in inositol metabolites in cells primed and stimulated with FMLP compared with cells receiving the stimulating dose of FMLP alone and pretreatment with pertussis toxin (PT) (before the addition of the priming -5 x 10(- 9) mol/L dose of FMLP), whereas abolishing the response to FMLP during the second stage of stimulation, had (1) no effect on FMLP-primed cells subsequently stimulated with PMA, and (2) only partially ablated the rise in Ca++i initiated with FMLP. That FMLP priming involved distinctive processes to those of the well characterized FMLP-coupled Ca++-dependent activation cascade was shown by the full priming effect attained in a Ca++-free buffer, which did not sustain an O2- response to a second-stage FMLP stimulation, but sustained a primed response to PMA. These data demonstrate that FMLP primes human neutrophils by a Ca++-independent and PT-insensitive pathway, offering a functional model for studying heterogeneous FMLP receptor-coupled reactions.     

Life-sustaining treatment. A prospective study of patients with DNR orders in a teaching hospital

We conducted a prospective survey of attending, resident, and intern physicians who had written a "do not resuscitate" (DNR) order for 93 patients in their care. After writing a DNR order, 11% of respondents would still use chest compression if their patient experienced a cardiopulmonary arrest. Many physicians did not plan to withdraw therapy except intensive care, but most physicians planned to withhold a spectrum of life-sustaining therapies, from hemodialysis (86%) to intravenous fluids (21%). Attending and house-staff physicians generally agreed on whether to withdraw a given therapy or not but frequently disagreed on whether to withhold a therapy or not. After patient discharge or death, 88 charts were reviewed. None of the 88 patients was coded. Physicians initiated 68 life sustaining therapies in 43 patients and discontinued 64 therapies in 34 patients; there was no change in management in 31 patients. We conclude that individual physicians interpret the DNR order differently. These orders often are associated with the discontinuation or noninitiation of life-sustaining therapies other than emergency CPR.     

Effect of estradiol on insulin secreting INS-1 cells overexpressing estrogen receptors

BACKGROUND: Estrogen has been shown to have profound effects on insulin and glucose metabolism in vivo. Indeed, estrogens were recently shown to modulate ion channel and secretory activities in endocrine cells. DESIGN AND METHODS: To investigate whether estrogenic influences are caused by direct effects on pancreatic beta-cells, we equipped INS-1 insulinoma cells with estrogen receptors and monitored insulin content and Ca(2+) fluxes as well as basal and stimulated insulin secretion upon different stimuli including glucose, the Ca(2+) ionophore ionomycin, the Ca(2+) channel agonist BayK8644, the protein kinase C activator TPA, and the adenylate cyclase activator forskolin. RESULTS AND CONCLUSION: Our data reveal that estradiol has no significant direct effect on proliferation rate, insulin content, basal and stimulated insulin output as well as Ca(2+) fluxes of insulin secreting cells in vitro, indicating that in vivo responses to estrogen on insulin and glucose metabolism result from indirect betacytotropic effects.     

Management guidelines for uninvestigated and functional dyspepsia in the Asia-Pacific region: First Asian Pacific working party on functional dyspepsia

Dyspepsia is most optimally defined as pain or discomfort centred in the upper abdomen. The symptom complex may be caused by peptic ulcer disease, gastro-oesophageal reflux, or gastric cancer but is most often due to functional (or non-ulcer) dyspepsia. While upper endoscopy is the method of choice to determine the underlying cause of dyspepsia, it is expensive. A more pragmatic approach is needed in the Asia-Pacific region where health services are limited. A detailed treatment algorithm is given for managing patients presenting with new-onset dyspepsia and documented functional dyspepsia after endoscopy, and evidence to support this approach is reviewed. Prompt endoscopy is recommended for patients with alarm features. In patients without alarm features, treatment for 2–4 weeks with an empirical anti-secretory or prokinetic agent, followed by investigation using non-invasive Helicobacter pylori testing and treatment for patients who do not respond or relapse, is recommended. Trials of management strategies are now needed to establish the efficacy and cost-effectiveness of the approaches recommended.     

Early results of a prospective study on the pyrolytic carbon (pyrocarbon) Amandys? for osteoarthritis of the wrist

INTRODUCTION

The preliminary results of a pyrocarbon interpositional radiocarpal implant in a small cohort of patients were reviewed. As it is currently only a limited release product, we describe to potential users early complications and negative outcomes.

METHODS

Patients were assessed using pain levels, ranges of motion, grip strength, type of and time to return to work as well as pre-operative and post-operative DASH (Disabilities of the Arm, Shoulder and Hand) scores. Radiographs were taken and patient satisfaction was recorded.

RESULTS

All six patients were contacted. One was not satisfied. Three had reduced motion. None experienced squeaking. There were no immediate or late post-operative complications. There was one early volar displacement of an implant.

CONCLUSIONS

Although our early results are somewhat encouraging, further and longer studies are warranted before supporting the use of this particular pyrocarbon implant as a primary procedure.     

Potentiating Functional Antigen-specific CD8+ T Cell Immunity by a Novel PD1 Isoform-based Fusion DNA Vaccine

Understanding and identifying new ways of mounting an effective CD8⁺ T cell immune response is important for eliminating infectious pathogens. Although upregulated programmed death-1 (PD1) in chronic infections (such as HIV-1 and tuberculosis) impedes T cell responses, blocking this PD1/PD-L pathway could functionally rescue the “exhausted” T cells. However, there exists a number of PD1 spliced variants with unknown biological function. Here, we identified a new isoform of human PD1 (Δ42PD1) that contains a 42-nucleotide in-frame deletion located at exon 2 domain found expressed in peripheral blood mononuclear cells (PBMCs). Δ42PD1 appears to function distinctly from PD1, as it does not engage PD-L1/PD-L2 but its recombinant form could induce proinflammatory cytokines. We utilized Δ42PD1 as an intramolecular adjuvant to develop a fusion DNA vaccine with HIV-1 Gag p24 antigen to immunize mice, which elicited a significantly enhanced level of anti-p24 IgG1/IgG2a antibody titers, and important p24-specific and tetramer⁺CD8⁺ T cells responses that lasted for ≥7.5 months. Furthermore, p24-specific CD8⁺ T cells remain functionally improved in proliferative and cytolytic capacities. Importantly, the enhanced antigen-specific immunity protected mice against pathogenic viral challenge and tumor growth. Thus, this newly identified PD1 variant (Δ42PD1) amplifies the generation of antigen-specific CD8⁺ T cell immunity when used in a DNA vaccine.     

Association between home working and mental health by key worker status during the Covid-19 pandemic. Evidence from four British longitudinal studies

Little is known about the relationship between homeworking and mental health during the Covid-19 pandemic and how it might differ by keyworker status. To understand this relationship, we use longitudinal data collected over three time points during the pandemic from three British cohort studies born in 1958 (National Child Development Study), 1970 (British Cohort Study) and 1989–90 (Next Step) as well as from a population-based study stratified by four age groups (Understanding Society). We estimate the association between life satisfaction, anxiety, depression, and psychological distress and homeworking by key worker status using mixed effects models with maximum likelihood estimation to account for repeated measurements across the pandemic, allowing intercepts to vary across individuals after controlling for a set of covariates including pre-pandemic home working propensities and loneliness. Results show that key workers working from home showed the greatest decline in mental health outcomes relative to other groups. Pre-pandemic homeworking did not significantly change the nature of such a relationship and loneliness slightly attenuated some of the effects. Finally, mental health outcomes varied across age-groups and time points. The discussion emphasises the need to pay attention to key workers when assessing the relationship between mental health and homeworking.     

亚太地区炎症性肠病处理共识意见(一)

虽然目前亚太地区尚无炎症性肠病（IBD）的大规模流行病学资料，但一系列研究显示其发病率和患病率呈上升趋势。与西方国家相比仍呈滞后现象。溃疡性结肠炎（UC）的发病率仍较克罗恩病（CD）高。除地域差异外。在一些多民族国家中，IBD尚可见种族差异。亚太地区IBD的遗传背景有异于西方国家。如据报道该地区CD患者未检出NOD2／CARDI5变异。一般而言，该地区IBD患者的临床过程似不如西方国家严重。 亚太地区IBD的诊断存在一些特殊问题。如缺乏IBD诊断金标准。存在多种小肠结肠炎，与IBD临床表现相似，使鉴别诊断特别困难。迄今为止，亚太地区IBD的诊断标准多采用西方国家的诊断标准。诊断必须逐步排除非IBD的小肠结肠炎。确诊应有典型的组织学表现。某些患者需借助随访和诊断性治疗才能确诊。进一步研究IBD发病机制将有助于开发更好的诊断标记物。 亚太地区IBD的治疗亦存在特殊问题。由于诊断困难。IBD患者常未能及时接受适当的药物治疗，但该地区仍广泛采用药物治疗方案。结合西方指南和本地经验可制定类似的处理原则。以利诱导缓解和维持缓解。提倡逐级使用基于病变范围、活动性和严重度的阶梯式治疗方案。对不同病例采用综合性、个体化的方法。随着对IBD发病机制和亚太地区IBD独特性的深入理解。合理、实用的药物治疗指南和应用生物制剂治疗将改善该地区IBD的治疗前景。