Sildenafil prevents chronic psychosocial stress-induced working memory impairment: Role of brain-derived neurotrophic factor.

Background: Psychosocial stress, a common feature in modern societies, impairs cognitive functions. It is suggested that stress hormones and elevated excitatory amino acids during stress are responsible for stress-induced cognitive deficits. Reduced brain-derived neurotrophic factor (BDNF) levels, increased oxidative stress, and alteration of synaptic plasticity biomarkers are also possible contributors to the negative impact of stress on learning and memory. Sildenafil citrate is a selective phosphodiesterase type 5 (PDE5) inhibitor and the first oral therapy for the treatment of erectile dysfunction. It has been shown that sildenafil improves learning and memory and possesses antioxidant properties. We hypothesized that administering sildenafil to stressed rats prevents the cognitive deficit induced by chronic psychosocial stress. Methods: Psychosocial stress was generated using the intruder model. Sildenafil 3 mg/kg/day was administered intraperitoneally to animals. Behavioral studies were conducted to test spatial learning and memory using the radial arm water maze. Then, the hippocampal BDNF level and several antioxidant markers were assessed. Results: This study revealed that chronic psychosocial stress impaired short-term but not long-term memory. The administration of sildenafil prevented this short-term memory impairment. Chronic psychosocial stress markedly reduced the level of hippocampal BDNF (P˂0.05), and this reduction in BDNF was normalized by sildenafil treatment. In addition, neither chronic psychosocial stress nor sildenafil significantly altered the activity of measured oxidative parameters (P > 0.05). Conclusion: Chronic psychosocial stress induces short-term memory impairment. The administration of sildenafil citrate prevented this impairment, possibly by normalizing the level of BDNF.

Sex differences in clinical features, utilization of oral anticoagulant agents, and 1-year outcome in Middle Eastern patients with atrial fibrillation.

OBJECTIVE: Studies have revealed that sex can predict differences in multiple aspects of atrial fibrillation (AF). These differences are underreported in the Middle East. This study aims to describe sex-specific differences in risk factors, symptomatology, management, and outcomes in Middle Eastern patients with AF. METHODS: The JoFib (Jordan-Atrial-Fibrillation) study is an observational, prospective, multicenter, nationwide registry in AF. Comparisons were made between female and male patients using Pearson chi-square and Mann-Whitney U tests. Multivariable regression models were constructed to investigate whether the female sex was predictive of any AF-related outcomes (all-cause death, cardiovascular death, ischemic stroke or systemic embolism [IS/SE], major bleeding, and clinically relevant non-major bleeding). RESULTS: Of 2,020 patients with AF, 54% (n = 1091) were females. Females with AF were older (median age 71 vs. 69, p <.001), but had less heart failure (20.9% vs. 27.2%, p = .001) and coronary artery disease (7.5% vs. 14.7%, p <.001). Females with AF were more symptomatic (74.7% vs. 66.5%, p <.001) and frequently received anticoagulant therapy (84.4% vs. 78.9%, p = .001). Rhythm control was pursued less frequently in females (23.4% vs. 27.3%, p = .04). All studied outcomes occurred with similar frequencies in females and males, and sex was not significantly predictive of any outcome. CONCLUSION: Females with AF are more symptomatic, yet they are treated less with rhythm control. Despite higher risk, females have similar risk-adjusted all-cause cardiovascular death and stroke rates compared to males. Future studies should explore how treatments and interventions can influence quality-of-life and cardiovascular outcomes in females with AF.

The Efficacy and Safety of Immune Checkpoint Inhibitors in Adrenocortical Carcinoma: A Systematic Review and Meta-Analysis.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of different malignancies. However, their efficacy in advanced adrenocortical carcinoma (ACC) remains uncertain. Thus, we conducted a systematic review and meta-analysis to summarize the efficacy and tolerability of ICIs in patients with advanced ACC. We searched PubMed, Scopus, and CENTRAL for studies that used ICIs in ACC. Studies with more than five patients were included in the meta-analysis of the objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and grade 3/4 adverse events. Twenty studies with 23 treatment arms and 250 patients were included. Single-agent anti-PD1 or anti-PD-L1 treatment was utilized in 13 treatment arms, whereas an anti-PD1 or anti-PD-L1 and anti-CTLA4 combination was used in 4 treatment arms. Other anti-PD1- or anti-PD-L1-based combinations were used in five treatment arms. The ORR was 14% (95% CI = 10-19%, I2 = 0%), and the DCR was 43% (95% CI = 37-50%, I2 = 13%). The combination anti-PD1- or anti-PD-L1-based treatment strategies did not correlate with higher responses compared with monotherapy. The median OS was 13.9 months (95% CI = 7.85-23.05), and the median PFS was 2.8 months (95% CI = 1.8-5.4). ICIs have a modest efficacy in advanced ACC but a good OS. Further studies are needed to investigate predictive biomarkers for ICI response and to compare ICI-based strategies with the current standard of care.

Cardiovascular medications used for comorbid diseases in patients with atrial fibrillation. The JoFib study.

PURPOSE: Many atrial fibrillation (AF) patients use cardiovascular medications for indications other than AF. These medications can affect morbidity and mortality. We aim to investigate the characteristics of AF patients who use different medication classes and their clinical course. METHODS: We collected data from the prospective, multicenter registry, JoFib study. We identified classes of non-AF medications (medications not used for rate control, rhythm control, or anticoagulation), described demographic and clinical characteristics, and investigated AF-related outcomes according to these medication classes. RESULTS: From a total of 2020 patients, five classes of cardiovascular non-AF medications were identified, aspirin, P2Y12 inhibitors, ACE inhibitors/ARBs, statins, and diuretics. The most commonly used non-AF medications were diuretics and ACE inhibitors/ARBs (39.2%, and 39%, respectively). 51% of AF patients took more than one non-AF medication. Multivariable Cox regression analysis demonstrated that ACE inhibitor/ARB therapy independently reduced the risks of all-cause mortality and cardiovascular mortality (aHR 0.50, 95%CI 0.37-0.68; aHR 0.51, 95%CI 0.34-0.75, respectively) and that statin therapy reduced the risk of cardiovascular mortality (aHR 0.68, 95%CI 0.48-0.98) in AF patients. Multivariable logistic regression analysis demonstrated a protective effect of statin therapy against the secondary outcome, clinically relevant non-major bleeding (CRNMB) (adjusted OR 0.62 95%CI 0.42-0.94). CONCLUSION: Our findings suggest a protective effect of ACE inhibitors/ARBs against all-cause and cardiovascular mortality, statins against cardiovascular mortality, and CRNMB in patients with AF. Accordingly, these medications should be encouraged in patients with AF when indicated. Additionally, future research should explore whether these medications should be offered to AF patients more routinely. The study was registered with Clinicaltrials.gov (unique identifier number: NCT03917992, Registration date:14/4/2019).

Clinical recurrence and antiplatelet drug resistance among patients with lower limb ischemia.

There is a high prevalence rate of peripheral artery disease worldwide, with estimated cases exceeding 200 million. Most patients are under-diagnosed and under-treated, and there is a lack of knowledge regarding the best therapeutic regimen and therapy duration, which leads to many cases of recurrence, complications, and amputations. This study aims to explore clinical recurrence, which was defined as the worsening of chronic peripheral artery disease requiring hospital admission, and its relationship with antiplatelet drug resistance among patients with lower limb ischemia. This cohort study includes both retrospective and prospective recruitment of patients with chronic lower limb ischemia. Platelet aggregation tests were offered to the patients. Between February 2018 and November 2020, 147 patients were recruited from King Abdullah University Hospital and followed up for at least 1 year. Platelet aggregation tests were done for 93 patients who agreed to participate in this part of the study. The prevalence of chronic lower limb ischemia was higher in young male patients who are current smokers with co-morbid diseases such as hypertension, diabetes mellitus, and/or dyslipidemia. There was a significant association only of clinical recurrence with younger age (P = .011) and with low platelets count in severe stages of the disease (P = .047). No significant association was found in terms of laboratory resistance. The clinical recurrence rates of chronic lower limb ischemia were higher in younger patients and among those with low platelet counts in the severe stages of the disease. Despite the laboratory responsiveness to anti-platelet therapy, we observed significant clinical resistance and increased recurrence rates.

Evaluation of Clinical, Echocardiographic, and Therapeutic Characteristics, and Prognostic Outcomes of Coexisting Heart Failure among Patients with Atrial Fibrillation: The Jordan Atrial Fibrillation (JoFib) Study.

BACKGROUND: Atrial fibrillation (AF) is the most commonly encountered cardiac arrhythmia in clinical practice. Heart failure (HF) can occur concurrently with AF. AIM: We compared different demographic, clinical, and echocardiographic characteristics between patients with AF+HF and patients with AF only. Furthermore, we explored whether concurrent HF independently predicts several outcomes (all-cause mortality, cardiovascular mortality, ischemic stroke/systemic embolism (IS/SE), major bleeding, and clinically relevant non-major bleeding (CRNMB)). MATERIALS AND METHODS: Comparisons between the AF+HF and the AF-only group were carried out. Multivariable Cox proportional hazard models were constructed for each outcome to assess whether HF was predictive of any of them while controlling for possible confounding factors. RESULTS: A total of 2020 patients were included in this study: 481 had AF+HF; 1539 had AF only. AF+HF patients were older, more commonly males, and had a higher prevalence of diabetes mellitus, dyslipidemia, coronary artery disease, and chronic kidney disease (p≤0.05). Furthermore, AF+HF patients more commonly had pulmonary hypertension and low ejection fraction (p≤0.001). Finally, HF was independently predictive of all-cause mortality (adjusted HR 2.17, 95% CI (1.66-2.85) and cardiovascular mortality (adjusted HR 2.37, 95% CI (1.68-3.36). CONCLUSION: Coexisting AF+HF was associated with a more labile and higher-risk population among Jordanian patients. Furthermore, coexisting HF independently predicted higher all-cause mortality and cardiovascular mortality. Efforts should be made to efficiently identify such cases early and treat them aggressively.

The risk of COVID-19 infection among nurses working with COVID-19 patients.

Working with 2019 coronavirus disease (COVID-19) patients is currently considered one of the main fears and challenges that face healthcare workers (HCWs), especially nurses. This challenge can jeopardize the quality of health care services for those patients and cause a serious mental burden to HCWs. To understand and estimate the risk of COVID-19 infection among HCWs who directly serve COVID-19 patients. Before the community spread of the disease, 270 nurses who worked with COVID-19 wards were followed for 11 weeks to report the COVID-19 cases. On the other hand, during the community spread of the disease, 981 registered nurses (300 worked in COVID-19 wards and 681 worked in non-COVID wards) were followed for up to 16 weeks to report the COVID-19 cases. Before the community spread of COVID-19, none of the nurses who worked with the COVID-19 patients got the infection. On the other hand, during the community spread of the COVID-19 infection, 30% of the 300 nurses who worked in the COVID-19 wards got the COVID-19 infection, while 64% of the 681 HCWs who worked in the non-COVID wards got the infection. The relative risk of getting COVID-19 infection among HCWs who worked in the COVID-19 wards was reduced to about half in comparison to other HCWs who worked in the non-COVID wards (RR = 0.469). HCWs should not fear working with COVID-19 patients. Considering appropriate personal protective measures and infection control standards, the risk of infection transmission from the community is higher than that of COVID-19 patients, if any.

Development and Evaluation of the Efficacy and Toxicity of a New Hybrid Antimicrobial Peptide MY8.

BACKGROUND: Antibiotics have led to significant advancements in medicine. Unfortunately, they were faced with the emergence of pathogen resistance. According to the World Health Organization, antimicrobial resistance has been declared one of humanity's top ten global public health threats. The risk of those bacteria is not only from their being resistant to multi-antibiotics but also from their ability to form biofilms, which can be 1,000 times more resistant than planktonic bacteria. METHOD: This study used rational design to hybridize two antimicrobial peptides, aiming to enhance their efficacy and stability with reduced toxicity. RESULTS: The MY8 novel peptide was designed from the parent peptides BMAP-27 and CAMP 211-225. Some amino acid modifications were introduced to the hybrid peptide to improve its physicochemical properties guided by several software. Its antimicrobial activity has been studied against gram-negative and gram-positive strains, which showed broad-spectrum activity with MIC values against planktonic bacteria ranging from 0.125 to 25 µM. In contrast, 25-200 µM were needed to eradicate biofilms. Moreover, the MY8 peptide showed synergism with four conventional antibiotics., It also showed reduced toxicity against mammalian cells and a slight hemolysis tendency towards erythrocytes. CONCLUSION: The design of the MY8 peptide was successful, resulting in a novel, potent, broad-spectrum antimicrobial peptide with reduced toxicity and possible synergism with conventional antibiotics.

Identifying psychosocial problems, needs, and coping mechanisms of adolescent Syrian refugees in Jordan.

Background: Refugees who have fled war zones are at a heightened risk of psychosocial problems that can impact their ability to function in day-to-day life and place a significant burden on the family structure. This study aimed to assess the psychosocial problems and needs and coping mechanisms of Adolescent Syrian refugees in Jordan. Methods: Between October and December 2018, we conducted a qualitative study using semi-structured interviews with a sample of key and individual informants. Our sample included 20 primary healthcare professionals, 20 schoolteachers, 20 Syrian parents, and 20 adolescents aged 12-17 years. All interviews were transcribed verbatim, and we utilized thematic analysis to group, categorize, and analyze the original Arabic language transcripts. To ensure thorough analysis, we adopted a bottom-up inductive approach that covered the six-phase iterative process proposed by Braun and Clarke. Results: The main psychosocial problems encountered by Syrian adolescents included stress, depression, loneliness, lack of a sense of security, isolation, aggressiveness, fear of war, and family disintegration. Almost all schoolteachers reported that they observed that Jordanian adolescents are more settled, self-confident, and financially stable relative to their Syrian peers. The Jordanian government and community were praised for their support, including education, recreational centers, health services, and awareness campaigns. Going to school, praying and reading the Holy Quran, listening to music, and talking to friends and engaging with them were reported as the main coping mechanisms. The majority of respondents said that more services are still needed for adolescents, including more places for entertainment, psychosocial support and psychological counseling, medical care, job creation, and providing health insurance. Conclusion: Syrian refugees are aware of the psychological aspects of their situation, but they are not always able to access clinic-based humanitarian assistance for mental health and psychosocial support. Stakeholders must interact with refugees to learn about their needs and develop services that are appropriate for their culture.

Design and in vitro assessment of chitosan nanocapsules for the pulmonary delivery of rifabutin.

Tuberculosis (TB) is a life-threatening disease and a main cause of death worldwide. It mainly affects the lungs, and it is attributed to the infection with Mycobacterium tuberculosis (MTB). Current treatments consist of the oral administration of combinations of antibiotics including rifabutin, in high doses and for long periods of time. These therapeutic regimens are associated with many side effects and high rates of drug resistance. To overcome these problems, this study aims at developing a nanosystem for the improved delivery of antibiotics, with potential application in pulmonary delivery. Chitosan-based nanomaterials are widely used in biomedical applications, due to their biodegradability and biocompatibility, as well as their potential antimicrobial effects and lack of toxicity. In addition, this polymer is particularly attractive for mucosal delivery due to its bioadhesive properties. Therefore, the structure of the proposed nanocarrier consists of a chitosan shell and a lipid core with a combination of different oils and surfactants to allow optimal association of the hydrophobic drug rifabutin. These nanocapsules were characterized in terms of size, polydispersity index, surface charge, morphology, encapsulation efficiency and biological stability. The release kinetics of the drug-loaded nanostructures was evaluated in simulated lung media. Moreover, in vitro studies in different cell models (A549 and Raw 264.7 cells) demonstrated the safety of the nanocapsules as well as their efficient internalization. An antimicrobial susceptibility test was performed to evaluate the efficacy of the rifabutin-loaded nanocapsules against Mycobacterium phlei. This study indicated complete inhibition for antibiotic concentrations within the expected susceptibility range of Mycobacterium (≤ 0.25-16 mg/L).

Validation of CHA2DS2 VASc Score Predictability of Stroke and Systemic Embolization in a Middle Eastern Population with AF: The Jordan Atrial Fibrillation (JoFib) Study.

Background and Purpose: CHA2DS2-VASc score is one of the most widely used scoring systems to assess the risk of systemic embolization and stroke in patients suffering from atrial fibrillation (Afib); furthermore, it is important in guiding their treatment. This study aimed to evaluate the predictivity of this score in the Jordanian population, build a deeper understanding of patients' demographic and risk factors, and assess the usefulness of anticoagulation as a preventive measure. Methods: A total of 2020 patients with Afib registered in the Jordanian Atrial Fibrillation (JoFib) registry were enrolled in this study. All patients were followed up for 1 year to assess their susceptibility to develop cerebrovascular accident (CVA) and systemic embolism (SE). The association between CHA2DS2-VASc score and risk of development of stroke or systemic embolization was analyzed based on bivariate and adjusted multivariate analyses. The ROC curve was used to assess the predictivity of the CHA2DS2-VASc score. Results: The mean age of the study population was 67.8 years; 45.8% were males, and 81.8% were on anticoagulants. And, 71.8% had a CHA2DS2-VASc score of ≥3. During the follow-up period of 1 year; 69 developed new CVA (mean age, 72.8 years), and 9 developed SE. A total of 276 patients died; 18 patients died (6.5% out of all deceased)% from CVA. A moderate predictive power of the CHA2DS2-VASc score was demonstrated through ROC curve analysis with C statistics of 0.689 CI (0.634 to 0.744) for predicting the development of SE or CVA at 1 year. Conclusion: CHA2DS2-VASc showed a moderate predictivity of stroke, SE, and all-cause mortality at 1 year. The study suggested disregarding gender differences in deciding to initiate anticoagulant therapy.

Thromboembolism and Major Bleeding in Patients with Atrial Fibrillation and EHRA Type 2 Valvular Heart Disease: The Jordan Atrial Fibrillation (JoFib) Study.

Aim: The risks of thromboembolism and major bleeding in atrial fibrillation (AF) patients were assessed according to the "Evaluated Heartvalves, Rheumatic or Artificial" (EHRA) classification. Additionally, the safety and efficacy of vitamin K antagonists (VKAs) and non-VKA oral anticoagulants (NOACs) were compared in AF patients with EHRA type 2 valvular heart disease (VHD) versus those with no VHD. Methods: AF patients enrolled in the "Jordan Atrial Fibrillation (JoFib)" study were followed up for thromboembolic events and major bleeding at 30, 180, and 365 days. Patients in the EHRA type 2 VHD and non-VHD groups were sub-grouped to compare different OACs. Results: 2020 AF patients were recruited. The thromboembolic risk was higher in EHRA type 2 VHD patients compared to non-VHD controls. Major bleeding also occurred at higher rates in EHRA type 2 patients. In addition, NOACs were more effective in preventing thromboembolic events than VKAs and non-anticoagulation in EHRA type 2 VHD patients. Furthermore, EHRA type 2 VHD patients taking rivaroxaban had significantly less thromboembolic risk than their non-anticoagulated counterparts. At the same time, apixaban and warfarin did not significantly lower the risk of thromboembolism compared to non-anticoagulation. Conclusion: AF patients with EHRA type 2 VHD are at significant risk of thromboembolism and major bleeding. Furthermore, NOACs were more effective than VKAs in preventing thromboembolic events in this group of patients without conferring an added risk of major bleeding. Moreover, rivaroxaban appears to be particularly efficacious.

Knowledge toward COVID-19 in children among undergraduate students at the beginning of COVID-19 era.

AIMS: To describe the level of knowledge of undergraduate students in Jordan toward COVID-19 in children in respect of the clinical signs of the disease, modes of transmission, protection measures against the disease and satisfaction with governmental measures. DESIGN: A cross-section was utilized in this study. METHODS: An online survey questionnaire was utilized in this research study. All undergraduate students in Jordan were able to take part. The size of the sample was 799. Knowledge toward COVID-19 among children was used to assess the participants' knowledge about COVID-19. RESULTS: The findings indicate that the students had a good understanding of the clinical signs, mode of transmission and protection measures and were satisfied with governmental measures. According to the students' responses, the resource they used the most was social media followed by news channels. Our study also found that medical specialty students had more knowledge toward COVID-19 than non-medical.

The Antimicrobial Effect Against Multi-drug Resistant Bacteria of the SK4 Peptide: A Novel Hybrid Peptide of Cecropin-A and BMAP-27.

BACKGROUND: Antibiotic-resistant is considered one of the critical health challenges in the management of infectious diseases. Resistant bacterial strains to different antibacterial agents have been spread worldwide. Anti-microbial peptides (AMPs), also called host defense peptides, have a broad spectrum of activity and targeting even to multi-drug resistant (MDR) bacteria, therefore, they have been extensively studied and developed as novel therapeutic antibacterial agents. OBJECTIVES: The study aims to design a novel SK4 hybrid peptide with improved characteristics compared with the BMAP-27 and Cecropin-A natural parents' peptides. METHODS: The bioinformatic analysis of the SK4 peptide compared with the parents BMAP-27 and Cecropin-A peptides was conducted and fully characterized using specialized software. The antimicrobial and antibiofilm activity of SK4 was tested, followed by a synergistic study with five conventional antibiotics (Levofloxacin, Rifampicin, Chloramphenicol, Doxycycline, and Ampicillin). Finally, the cytotoxicity against horse erythrocytes and mammalian cells was assessed. RESULTS: The SK4 peptide demonstrated broad-spectrum antimicrobial activity against both grampositive and gram-negative bacteria. The peptide also did not show any hemolytic activity even when used at concentrations ten folds higher than its MICs value. The SK4 peptide also showed a synergistic mode of action when combined with antibiotics, which resulted in a significant decrease in MIC values for both the peptide and the antibiotics. CONCLUSION: The SK4 peptide showed better activity, selectivity, and safety profile than the parent peptides, making it a novel potential treatment for MDR bacterial infections.

Factors Associated With University Students' Attitude Toward Euthanasia.

Although euthanasia has been practiced for thousands of years, a wide controversy still exists around it. This study aimed to assess the attitude of university students toward euthanasia and its associated factors. The study included an online self-administered survey. Survey questions consisted of demographic information, psychological condition, and attitude toward euthanasia. A total of 1,188 students participated in the study. Approximately only one-third of the respondents (34.1%) viewed euthanasia as a moral practice, and just one-quarter (25.3%) supported legalizing it. The main reason for not supporting euthanasia was religious considerations (72.2%), followed by moral considerations (46.5%). Factors that predicted a positive attitude toward euthanasia (p < .05) included undefined religion, being male, feeling lonely, or having suicidal thoughts. Conclusively, the negative attitude toward euthanasia is primarily driven by religious beliefs. Furthermore, gender and psychological status play critical roles in students' attitudes toward euthanasia.

Atrial resection for T4 non-small cell lung cancer with left atrium involvement: a systematic review and meta-analysis of survival.

PURPOSE: Extended resection for non-small cell lung cancer (NSCLC) with T4 left atrium involvement is controversial. We performed a systematic review and meta-analysis to evaluate the short- and long-term outcomes of this treatment strategy. METHODS: We searched the PubMed database for studies on atrial resection in NSCLC patients. The primary investigated outcome was the effectiveness of the surgery represented by survival data and the secondary outcomes were postoperative morbidity, mortality, and recurrence. RESULTS: Our search identified 18 eligible studies including a total of 483 patients. Eleven studies reported median overall survival and 17 studies reported overall survival rates. The estimated pooled 1, 3, 5-year overall survival rates were 69.1% (95% CI 61.7-76.0%), 21.5% (95% CI 12.3-32.3%), and 19.9% (95% CI 13.9-26.6%), respectively. The median overall survival was 24 months (95% CI 17.7-27 months). Most studies reported significant associations between better survival and N0/1 status, complete resection status, and neoadjuvant therapy. CONCLUSION: Extended lung resection, including the left atrium, for NSCLC is feasible with acceptable morbidity and mortality when complete resection is achieved. Lymph node N0/1 status coupled with the use of neoadjuvant therapies is associated with better outcomes.

Qualitative Comparison of Cryostat- versus Snap-Frozen Neurosurgical Intraoperative Consultations.

Background. Frozen sections (FS) are common in neurosurgery to address varied clinical concerns. Artifacts in central nervous system (CNS) FS can be severe and affect or hinder interpretation. We performed a case-control study using a semiquantitative scale: the Histologic Preservation Score (HPS), and a quantitative scale: the Ice Crystal Vacuolization Score (ICVS), to compare the histologic quality yielded by snap- versus cryostat freezing techniques. Material and Methods. All specimens were sectioned in 2 halves, one half was used for FS and the other for permanent evaluation. HPS assigns a distortion score to the FS sample using the non-frozen half as the comparator: 1 = minimal, 2 = slight, 3 = moderate, 4 & 5 = severe. The ICVS is the average size in µm of the 5 largest vacuoles/0.05 mm2, evaluated on digitized slides. Results. 86 CNS-FS were collected: 22 snap- and 64 cryostat-FS. Significant differences in HPS: 2.28 versus 2.84 (p <0.05) and ICVS 7.47 versus 14.56 (p < 0.001) were obtained for snap- versus cryostat-FS, respectively. HPS and ICVS showed a strong correlation: R2 = 0.63, p < 0.0001. Histologic distortion was worse for neuroglial than mesenchymal tissue by both methods; however, a significant difference was only observed in cryostat-FS: HPS: 3.23 versus 2.33, p < 0.001; ICVS: 16.86 µm versus 10.26 µm, p < 0.001. Conclusion. Snap-FS yields better histologic quality than cryostat-FS for CNS-FS, and the difference is more pronounced in neuroglial samples. HPS and ICVS correlate strongly, indicating that the histologic quality is inversely proportional to water-crystallization. These results may apply to other areas of surgical pathology.

Hydrolysis kinetics of the prodrug myristyl nicotinate.

Myristyl nicotinate is a prodrug of nicotinic acid. In this research, the kinetics of hydrolysis for myristyl nicotinate was studied in an aqueous phosphate buffer solution within a 5-10 pH range and constant ionic strength at a high temperature which was 80 °C to perform accelerated hydrolysis experiments. The effect of temperature, ionic strength, buffer concentrations, and buffer type was studied. The degradation was monitored using a validated HPLC method. The kinetics of hydrolysis of myristyl nicotinate was also studied in skin and liver homogenates. The hydrolysis was found to follow pseudo-first-order kinetics. The rate constant was calculated from the slope of a linear plot of Ln transformation (Ln) of the remaining parent prodrug concentration versus time. The hydrolysis was found pH- dependent, and a pH rate profile was constructed. Moreover, the hydrolysis rate of the prodrug was found to be buffer species dependent. Carbonate buffer has the most catalytic effect over borate and phosphate buffers. The effect of temperature on the kinetics of hydrolysis of myristyl nicotinate in phosphate buffer at pH 9 at 343, 348, 353, and 358°K was studied. The hydrolysis was found to follow the Arrhenius equation. From the Arrhenius plot, the half-life at 25 °C, and the activation energy were calculated and were found to be 466.5 days and 24.57 kcal mol-1, respectively. The hydrolysis of the prodrug was faster in liver and skin homogenates than those in aqueous buffer solutions. The pseudo-first-order rate constants were found to be 0.012, 0.028 min-1 for myristyl nicotinate in the liver, and skin homogenates, respectively.

Hydroxypropyl Beta Cyclodextrin as a Potential Surface Modifier for Paclitaxel Nanocrystals.

Paclitaxel (PTX) is a hydrophobic chemotherapeutic agent cytotoxic against many serious cancers. This study aimed at designing novel PTX nanocrystals (PTX-NCs) coated with the biocompatible and biodegradable hydroxypropyl-beta-cyclodextrin (HPßCD) polymer with specific characteristics through the formation of a non-inclusion complex. Briefly, PTX-NCs were prepared by the anti-solvent method followed by homogenization. Then, the surface of the prepared PTX-NCs was modified using the HPßCD coat (HPßCD-PTX-NCs). The prepared nanocrystals, both coated and uncoated, were characterized in terms of size, polydispersity index, charge, morphology, and stability. Moreover, the nanocrystals were investigated using powder X-ray diffraction (PXRD), differential scanning calorimeter (DSC), and Fourier transform infrared spectroscopy (FTIR). As well, the in vitro release of PTX from the nanocrystals was determined under conditions similar to the IV route of administration. Furthermore, the tendency of the nanocrystals to induce hemolysis was investigated. Results indicated that the size was about 241.4 and 310.5 nm, the polydispersity index was 0.14 and 0.21, and the zeta potential was about - 22.6 and - 16.4 mV for PTX-NCs and HPßCD-PTX-NCs, respectively. Additionally, the PXRD, FTIR, and DSC profiles can be explained by the NCs' integrity and coat formation. The SEM images showed that both PTX-NCs and HPßCD-PTX-NCs have rod-like structures. Moreover, HPßCD-PTX-NCs had significantly superior in vitro release than both PTX-NCs and PTX. Interestingly, the hemolytic assay showed that HPßCD-PTX-NCs had a more efficient and safer profile than PTX-NCs. This study emphasized that HPßCD could be an interesting candidate for the surface modification of PTX-NCs providing superior properties such as release and safety profiles.

Development of Self-Emulsifying Drug Delivery Systems (SEDDSs) Displaying Enhanced Permeation of the Intestinal Mucus Following Sustained Release of Prototype Thiol-Based Mucolytic Agent Load.

In this study, mucoactive self-emulsifying drug delivery systems (SEDDSs) based on sustained release of N-acetylcysteine (NAC) were developed for providing effective intestinal mucopermeation. Polymeric ionic complexes of NAC were formed with polyethyleneimine (PEI), Eudragit E 100, and Eudragit RS 100 and loaded into a novel SEDDS. The SEDDSs exhibited a stable average size of 75 ± 12 nm (polydispersity index (PDI) < 0.3) and showed a rise in the zeta potential from −17.31 mV to −7.72 mV. On Caco-2 cells, SEDDSs at 1−3% were non-cytotoxic. An average of 91.8 ± 5.4% NAC was released from SEDDSs containing Eudragit E 100 (p ≤ 0.05) and Eudragit RS 100 (p ≤ 0.001) complexes at a significantly slower rate within 80 min, whereas the SEDDS containing PEI released NAC in a matter of seconds. Similarly, the SEDDS complexes revealed a time-dependent reduction in mucus dynamic viscosity of 52.6 ± 19.9%. Consequently, as compared with a blank SEDDS, mucodiffusion revealed about 2- and 1.8-fold significantly greater mucopermeation of SEDDSs anchoring Eudragit E 100−NAC and RS 100−NAC complexes (p ≤ 0.05), respectively. The mucoactive SEDDSs, which steadily released NAC while permeating the mucus, were linked to a significantly increased mucopermeation in vitro as a result of optimal mucolytic targeting.