Comparative assessment of high-risk cardiovascular medication knowledge between practising and student nurses: a descriptive multi-centre study.

Aim To examine unexplored knowledge of cardiovascular highrisk medications and perception thereof among practising nurses and students in the Kingdom of Saudi Arabia (KSA). Methods The multicentre cross-sectional quantitative study used an online survey dichotomised into a knowledge test (true/false and multiple choice questions) and a perception assessment (closed-ended questions). Four hundred and eighteen nurses participated in the study. Results In the knowledge test, 19 (4.5%) participants scored high (≥71%), while 83 (19.8%) and 316 (75.5%) demonstrated moderate (score ≥51-70%) and poor performance (score ≤50%), respectively. In a comparative analysis, the knowledge level of staff nurses was significantly higher than the students but not the other nurses' cohort. Nurses' specialty and region of KSA were strongly associated with the knowledge level. Emergency room nurses and those belonging to the eastern region of KSA exhibited higher knowledge levels than other subgroups. A vast majority of nurses, 128 (30.6 %), rated their knowledge of medicines as somewhat sufficient, while quoting insufficient knowledge 226 (54.1%) as the major cause of medication errors. Three hundred and sixteen (75%) nurses expressed interest in undergoing specialised training in high-alert medication-based therapy preferably in a classroom setting by 279 (66.7%). Conclusion This study revealed a marked knowledge deficit in high-risk cardiovascular drugs among nurses. The pharmacological curriculum in nursing schools should be tailored to be clinically oriented and reinforced with problem-based learning. Continued pharmacology education focusing on high-risk drugs should be implemented among nurses to safeguard patient lives by mitigating the risks of medication error.

Current trends and prospects of multiple sclerosis research in Arab countries.

Background: Multiple sclerosis is a complex and intractable neurological disease associated with substantial morbidity, healthcare utilization, management cost, and loss of productivity. There has been an alarming increase in the number of multiple sclerosis cases in Arab countries in recent years, which has spurred an increase in local research. Aims: To analyse the multiple sclerosis research profile in Arab countries. Methods: A total of 781 publications focusing on multiple sclerosis research in Arab countries from 1983 to 2021 were extracted from the Web of Science database and analysed using bibliometric techniques. Results: Publication on multiple sclerosis research increased sharply in the last decade, globally and in the Arab countries. However, Arab countries have only contributed 0.8% of the overall number of publications. Keyword pattern analysis showed that magnetic resonance imaging, optical coherence tomography, expanded disability status, demyelination, and epidemiology were the major themes of multiple sclerosis research in Arab countries. Case-control, cohort, and descriptive studies were the most prevalent study designs. However, there was a notable paucity of meta-analyses, randomized controlled trials, and clinical trials. Conclusion: Arab countries can improve their regional expertise and add a wealth of knowledge to global multiple sclerosis resources by diversifying their current research initiatives, and tracking recent advances in pathogenesis, diagnosis, and management of multiple sclerosis.

A literature analysis of scientific research on gender incongruence in Muslim nations.

This study aims to chart and review the unexplored transgender research portfolio of Muslim countries using bibliometric method. Data retrieved from the Scopus database were analyzed using CiteSpace, VOSviewer, Biblioshiny, and ScientoPy software. It was found that barring Turkey and Iran, transgender research has been minimal in most Muslim countries. The collective productivity is gradually but surely rising. Around 84% of the publications have been collaborative efforts. The keyword analysis revealed that gender dysphoria, human immunodeficiency virus, LGBT, and vaginoplasty were the most frequently used keywords. The socio-economic circumstances of the transgender community are generally deplorable in most Muslim nations. Overall, there is a dire need for high-quality multifaceted transgender research in the Muslim world to raise general awareness. Resolving disputes on gender dysphoria or sex reassignment surgeries and reinstating the social rights of the transgender community should be the utmost priority of future research in Muslim countries.

Gender Dysphoria: A Medical and Ethical Perplexity as Distinct from Reality and the Rational Approach for Muslim Young People.

Gender dysphoria (GD), a conflict between one's self-perceived gender identity and the biological sex has been a wholly enigma and a source of contention between experts of various disciplines since long. This is a narrative review of the medical literature utilizing PubMed, Scopus, and Web of science databases, on the social status of GD patients, their therapeutic options, as well as the medical and ethical debate on GD that are of especial interest to the Muslim readers. Gender dysphoric patients or transgender people have a long history of social discrimination, marginalization, abuse, and neglect all around the world. Currently, large scale social developments supporting of transgender rights are rapidly underway in the west. Clinical evidence-based guidelines have also been published and are available for the management of GD, albeit with some medical and ethical concerns. On the other hand, the transgender community is continued to suffer profoundly in the developing and majority of Muslim nations, due to generalized unawareness, neglect, cultural and religious boundaries on this issue. Currently, Muslim youth or young adults are showing passionate interest in GD and are actively seeking information to comprehend its complexities, but they face more dilemma on this matter than the people in the West. This article addresses and discusses key transgender issues and controversies and provides a logical explanation that demonstrates that GD is real medical condition needing attention and that its treatment guidelines are justified. We hope this article will stimulate a new and broader perspective in minds of young Muslims and will urge them to take pragmatic steps in alleviating the travails of long-suffering and neglected transgender community.

The extracellular domain of myelin oligodendrocyte glycoprotein elicits atypical experimental autoimmune encephalomyelitis in rat and Macaque species.

Atypical models of experimental autoimmune encephalomyelitis (EAE) are advantageous in that the heterogeneity of clinical signs appears more reflective of those in multiple sclerosis (MS). Conversely, models of classical EAE feature stereotypic progression of an ascending flaccid paralysis that is not a characteristic of MS. The study of atypical EAE however has been limited due to the relative lack of suitable models that feature reliable disease incidence and severity, excepting mice deficient in gamma-interferon signaling pathways. In this study, atypical EAE was induced in Lewis rats, and a related approach was effective for induction of an unusual neurologic syndrome in a cynomolgus macaque. Lewis rats were immunized with the rat immunoglobulin variable (IgV)-related extracellular domain of myelin oligodendrocyte glycoprotein (IgV-MOG) in complete Freund's adjuvant (CFA) followed by one or more injections of rat IgV-MOG in incomplete Freund's adjuvant (IFA). The resulting disease was marked by torticollis, unilateral rigid paralysis, forelimb weakness, and high titers of anti-MOG antibody against conformational epitopes of MOG, as well as other signs of atypical EAE. A similar strategy elicited a distinct atypical form of EAE in a cynomolgus macaque. By day 36 in the monkey, titers of IgG against conformational epitopes of extracellular MOG were evident, and on day 201, the macaque had an abrupt onset of an unusual form of EAE that included a pronounced arousal-dependent, transient myotonia. The disease persisted for 6-7 weeks and was marked by a gradual, consistent improvement and an eventual full recovery without recurrence. These data indicate that one or more boosters of IgV-MOG in IFA represent a key variable for induction of atypical or unusual forms of EAE in rat and Macaca species. These studies also reveal a close correlation between humoral immunity against conformational epitopes of MOG, extended confluent demyelinating plaques in spinal cord and brainstem, and atypical disease induction.

GM-CSF-neuroantigen fusion proteins reverse experimental autoimmune encephalomyelitis and mediate tolerogenic activity in adjuvant-primed environments: association with inflammation-dependent, inhibitory antigen presentation.

Single-chain fusion proteins comprised of GM-CSF and neuroantigen (NAg) are potent, NAg-specific inhibitors of experimental autoimmune encephalomyelitis (EAE). An important question was whether GMCSF-NAg tolerogenic vaccines retained inhibitory activity within inflammatory environments or were contingent upon steady-state conditions. GM-CSF fused to the myelin oligodendrocyte glycoprotein MOG35-55 peptide (GMCSF-MOG) reversed established paralytic disease in both passive and active models of EAE in C57BL/6 mice. The fusion protein also reversed EAE in CD4-deficient and B cell-deficient mice. Notably, GMCSF-MOG inhibited EAE when coinjected adjacent to the MOG35-55/CFA emulsion. GMCSF-MOG also retained dominant inhibitory activity when directly emulsified with MOG35-55 in the CFA emulsion in both C57BL/6 or B cell-deficient models of EAE. Likewise, when combined with proteolipid protein 139-151 in CFA, GM-CSF fused to proteolipid protein 139-151 peptide inhibited EAE in SJL mice. When deliberately emulsified in CFA with the NAg, GMCSF-NAg inhibited EAE even though NAg was present at >30-fold molar excess. In vitro studies revealed that the GM-CSF domain of GMCSF-MOG stimulated growth and differentiation of inflammatory dendritic cells (DC) and simultaneously targeted the MOG35-55 domain for enhanced presentation by these DC. These inflammatory DC presented MOG35-55 to MOG-specific T cells by an inhibitory mechanism that was mediated in part by IFN-γ signaling and NO production. In conclusion, GMCSF-NAg was tolerogenic in CFA-primed proinflammatory environments by a mechanism associated with targeted Ag presentation by inflammatory DC and an inhibitory IFN-γ/NO pathway. The inhibitory activity of GMCSF-NAg in CFA-primed lymphatics distinguishes GMCSF-NAg fusion proteins as a unique class of inflammation-dependent tolerogens that are mechanistically distinct from naked peptide or protein-based tolerogens.

The role of nicotinic acetylcholine receptor (nAChR) α7 subtype in the functional interaction between nicotine and ethanol in mouse cerebellum.

BACKGROUND: Many epidemiological studies report that alcoholics overwhelmingly smoke tobacco and vice versa, which suggests a possible functional interaction between ethanol and nicotine. Although nicotine-ethanol interaction is well documented within the central nervous system, the mechanism is not well understood. Therefore, it is important from a public health standpoint to understand the mechanisms involved in nicotine and ethanol functional interaction. The intracerebellar (ICB) administration of nicotine significantly attenuates ethanol ataxia through nicotinic acetylcholine receptor (nAChR) α(4)ß(2) subtype. This study, an extension of earlier work, was intended to investigate the possible role of nAChR subtype α(7) in mitigating ethanol ataxia. METHODS: The effect of ICB injection of PNU-282987 (α(7) agonist; 25 ng to 2.5 µg) and the antagonist methyllycaconitine was evaluated on ethanol (2 g/kg; i.p.)-induced ataxia with a Rotorod. Cerebellar nitric oxide was determined fluorometrically in the presence of ethanol and/or PNU-282987. RESULTS: Attenuation of ethanol-induced ataxia following PNU-282987 microinfusion was dose-dependent suggesting the participation of α(7) subtype in nicotine and ethanol interaction. Intracerebellar pretreatment with methyllycaconitine (α(7) -selective antagonist; 6 ng) virtually abolished the attenuating effect of PNU-282987 as well as the effect of nicotine, but not of RJR-2403 (α(4)ß(2) -selective agonist; 125 ng) on ethanol-induced ataxia. Finally, ethanol administration significantly decreased cerebellar NO(x), whereas ICB PNU-282987 significantly increased and/or opposed ethanol-induced decrease in NO(x). These results were functionally in agreement with our Rotorod data. CONCLUSIONS: These observations confirmed the following: (i) α(7) participation in nicotine-ethanol interaction and (ii) α(7) selectivity of methyllycaconitine. Overall, the results demonstrate the role of cerebellar nAChR α(7) subtype in nicotine-induced attenuation of ethanol-induced ataxia in cerebellar NO(x)-sensitive manner.

Role of mouse cerebellar nicotinic acetylcholine receptor (nAChR) α(4)ß(2)- and α(7) subtypes in the behavioral cross-tolerance between nicotine and ethanol-induced ataxia.

We have demonstrated that nicotine attenuated ethanol-induced ataxia via nicotinic-acetylcholine-receptor (nAChR) subtypes α(4)ß(2) and α(7). In the present study, ethanol (2g/kg; i.p.)-induced ataxia was assessed by Rotorod performance following repeated intracerebellar infusion of α(4)ß(2)- and α(7)-selective agonists. Localization of α(4)ß(2) and α(7) nAChRs was confirmed immunohistochemically. Cerebellar NO(x) (nitrite+nitrate) was determined flurometrically. Repeated intracerebellar microinfusion of the α(4)ß(2)-selective agonist, RJR-2403 (for 1, 2, 3, 5 or 7 days) or the α(7)-selective agonist, PNU-282987 (1, 2, 3 or 5 days), dose-dependently attenuated ethanol-induced ataxia. These results suggest the development of cross-tolerance between ethanol-induced ataxia and α(4)ß(2) and α(7) nAChR agonists. With RJR-2403, the cross-tolerance was maximal after a 5-day treatment and lasted 48h. Cross-tolerance was maximal after a 1-day treatment with PNU-282987 and lasted 72h. Pretreatment with α(4)ß(2)- and α(7)-selective antagonists, dihydro-ß-erythroidine and methyllycaconitine, respectively, prevented the development of cross-tolerance confirming α(4)ß(2) and α(7) involvement. Repeated agonist infusions elevated cerebellar NO(x) 16h after the last treatment while acute ethanol exposure decreased it. Pretreatment with repeated RJR-2403 or PNU-282987 reversed ethanol-induced decrease in NOx. The NO(x) data suggests the involvement of the nitric oxide (NO)-cGMP signaling pathway in the cross-tolerance that develops between α(4)ß(2)- and α(7)-selective agonists and ethanol ataxia. Both α(4)ß(2) and α(7) subtypes exhibited high immunoreactivity in Purkinje but sparse expression in molecular and granular cell layers. Our results support a role for α(4)ß(2) and α(7) nAChR subtypes in the development of cross-tolerance between nicotine and ethanol with the NO signaling pathway as a potential mechanism.

Neuroantigen-specific, tolerogenic vaccines: GM-CSF is a fusion partner that facilitates tolerance rather than immunity to dominant self-epitopes of myelin in murine models of experimental autoimmune encephalomyelitis (EAE).

BACKGROUND: Vaccination strategies that elicit antigen-specific tolerance are needed as therapies for autoimmune disease. This study focused on whether cytokine-neuroantigen (NAg) fusion proteins could inhibit disease in chronic murine models of experimental autoimmune encephalomyelitis (EAE) and thus serve as potential therapeutic modalities for multiple sclerosis. RESULTS: A fusion protein comprised of murine GM-CSF as the N-terminal domain and the encephalitogenic MOG35-55 peptide as the C-terminal domain was tested as a tolerogenic, therapeutic vaccine (TTV) in the C57BL/6 model of EAE. Administration of GMCSF-MOG before active induction of EAE, or alternatively, at the onset of EAE blocked the development and progression of EAE. Covalent linkage of the GM-CSF and MOG35-55 domains was required for tolerogenic activity. Likewise, a TTV comprised of GM-CSF and PLP139-151 was a tolerogen in the SJL model of EAE. CONCLUSION: These data indicated that fusion proteins containing GM-CSF coupled to myelin auto-antigens elicit tolerance rather than immunity.

Protein kinase C- and reactive oxygen species-dependent stimulation of intracellular cAMP in human eosinophils. The role of extracellular signal-regulated protein kinases.

OBJECTIVE: The objective of this study was to investigate the role of the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in the signalling pathway of the novel protein kinase C (PKC)- and reactive oxygen species (ROS)-dependent stimulation of intracellular adenosine 3',5'-cyclic monophosphate (cAMP) production in human eosinophils. MATERIALS AND METHODS: Immunomagnetically purified human eosinophils were stimulated in vitro with a PKC activator, phorbol myristate acetate (PMA), and the cAMP response in the presence of a phosphodiesterase inhibitor, rolipram, was determined. The role of ERK1/2 phosphorylation was investigated using specific inhibitors and Western blot analysis. RESULTS: The PMA-stimulated eosinophils responded with a profound increase in intracellular levels of cAMP that was dependent on both PKC and ROS, as confirmed by the use of specific inhibitors: Ro 31-8220 for PKC and diphenyleneiodonium (DPI) for the ROS-generating enzyme NADPH oxidase. Pre-treatment of cells with the ERK1/2 inhibitor PD 98059, but not the p38-MAPK inhibitor SB203580, nor the PI3 kinase inhibitor, wortmannin, abolished the response. PMA treatment induced the phosphorylation of ERK1/2 with a time course that is consistent with a role in the cAMP response. The ERK1/2 phosphorylation was abolished by the ERK1/2 inhibitor PD 98059 and the PKC inhibitor Ro 31-8220, but not the NADPH oxidase inhibitor DPI. CONCLUSION: These results reveal the involvement of ERK1/2 in the signalling mechanism of PMA-stimulated, PKC- and ROS-dependent stimulation of cAMP production in human eosinophils, and show that ERK1/2 phosphorylation is upstream of ROS production in the signalling pathway.

Reactive oxygen species mediate phorbol ester-stimulated cAMP response in human eosinophils.

Recently, we showed that phorbol 12-myristate 13-acetate (PMA) can cause a direct, PKC-dependent, stimulation of intracellular cAMP in human eosinophils. Since PMA also stimulates the release of reactive oxygen species in these cells, we have investigated whether reactive oxygen species are involved in the cAMP response. Provided eosinophils were incubated for <20 min at 37 degrees C before stimulation, PMA potently stimulated cAMP generation that surpassed that of histamine. Pre-treatment of the cells with the NADPH oxidase inhibitors, diphenyleneiodonium (DPI) and apocynin, strongly inhibited the cAMP production induced by PMA, but not that induced by histamine. This treatment also strongly inhibited the release of superoxide anions (O(2)(-)). The cAMP response was also inhibited by pre-treatment with the specific peroxide scavenger, ebselen, but not superoxide dismutase, or NG-nitro-l-arginine methyl ester (L-NAME), thus, suggesting the possible involvement of a peroxide rather than O(2)(-) or nitric oxide (NO). These results reveal a novel involvement of intracellular reactive oxygen species in protein kinase C (PKC)-dependent stimulation of cAMP production in human eosinophils.

Protein kinase C activation inhibits eosinophil degranulation through stimulation of intracellular cAMP production.

The mechanism of inhibition of eosinophil degranulation by protein kinase C (PKC) was investigated in complement C5a (C5a)-stimulated degranulation of highly purified human eosinophils using the specific PKC activator - phorbol 12-myristate 13-acetate (PMA). C5a-induced release of eosinophil peroxidase and eosinophil cationic protein was potently inhibited in a concentration-dependent manner by PMA (IC(50): 3 and 5 nM, respectively). The inhibition by PMA, but not histamine, was significantly reversed by the specific, but isoform nonselective, PKC inhibitor Ro 31-8220 (1 microM). In the presence of phosphodiesterase inhibitor rolipram (5 microM), PMA stimulated a pronounced concentration-dependent increase in intracellular cAMP, with a potency 400 times that of histamine (EC(50): 55 nM vs 22.5 microM). The inactive PMA analogue, 4alpha-PMA, had no such effect. The cAMP production by PMA, but not histamine, was significantly reversed by Ro 31-8220 (1 microM) and the selective inhibitor of the novel PKCdelta, rottlerin (1-3 microM), but not the selective inhibitor of the classical PKC isoforms, Gö 6976 (0.01-0.1 microM). Western blot analysis revealed the presence of six PKC isoforms (alpha, betaI, betaII, delta, iota and zeta) in isolated eosinophils. Chelation of internal or external calcium had no effect on PMA-induced cAMP response, but abolished that induced by histamine. There was a good correlation between increase in intracellular cAMP and inhibition of degranulation. These results show, for the first time, that in human eosinophils, PMA, via activation of PKCdelta isoform, can stimulate cAMP production, and that this may be the basis for its potent anti-degranulatory effect.