[Neuropsychiatric aspects of long COVID]. / Neuropsychiatrische aspecten van long COVID.

BACKGROUND: Persistent symptoms after COVID-19 are a global problem, and it is becoming increasingly clear that they include neuropsychiatric symptoms. AIM: To provide an overview of current knowledge on clinical presentation, risk factors, prevention and treatment of neuropsychiatric symptoms and disorders after COVID-19. METHOD: PRISMA literature search. RESULTS: Anxiety, depression and posttraumatic stress symptoms are common after COVID-19. Cognitive symptoms are also very common and appear to be persistent, while data on risk factors to develop these symptoms is scarce. Women and patients after ICU admission, delirium or with somatic comorbidities have a higher risk of developing post COVID psychiatric symptoms. Vaccination may have a protective effect. Furthermore, there is a lack of evidence on effective treatment strategies for COVID-19-related neurocognitive symptoms. CONCLUSION: More research on risk factors, identification and especially effective treatment options for neuropsychiatric symptoms after COVID-19 is needed. In the meantime, guidelines on disorders with a similar clinical presentation could potentially play a role in the diagnosis and treatment of persistent neuropsychiatric symptoms after COVID-19.

Spectroscopic interactions of non-insulin-dependent diabetes mellitus with levocetirizine.

Non insulin dependent diabetes mellitus (NIDDM) drugs such as glibenclamide and metformin is employed to heterogeneous disorder characterized by alteration in production of glucose due to impairment of both insulin secretion and insulin action. These patients might suffer with allergic rhinitis and in this case, there is a possibility to maintain patient on levocetirizine, an anti-allergic drug commonly used in rhinitis. The object of the present study is to detect possible interaction between glibenclamide or metformin with levocetirizine Current study was performed using UV spectroscopic technique sing simultaneous equation in pH simulated to gastric juice (pH 1), pH 4, pH 7.4 and in pH 9. All drugs followed Beer Lambert's Law. Results showed that glibenclamide and metformin can increase or decrease availability of levocetirizine and in the same way levocetirizine can alter availabilities of glibenclamide and metformin in different pH. Hence, drug interaction between glibenclamide or metformin with levocetirizne occurred. This may be due to his may be due to the charge transfer or binding capabilities of these drugs which resulted in significantly changed availability of NIDDIM as well as levocetirizine. Therefore, co-administration of these drugs should be avoided and furtherinvestigations at clinical and pre-clinical levels should be done.

Hepatotoxicity induced by chronic suppurative otitis media in rats and effects of ceftazidime and amikacin on it.

Chronic suppurative otitis media (CSOM) is the chronic inflammation with perforation of middle ear. If CSOM is not treated, it may cause secondary inflammation of liver with elevated liver enzymes and histological changes. Present study is aimed to observe the hepatotoxic effects due chronic suppurative otitis media (CSOM) in CSOM induced rats and alsoto observe the effects of ceftazidime and amikacin to attenuate hepatotoxicity due to CSOM. Liver enzyme tests and histological examinations were performed on rats divided into different groups as G1 (negative control), G2 (positive control), G3 ceftizidime (15mg/kgintraperitonelly) and G4 amikacin (15mg/kg). One-way ANOVA showed that liver enzymes were significantly increased (p=0.000 and F value 6.899) except gamma glutamic transferase in G2 (rats with CSOM without treatment) from G1 (negative control without CSOM) with histological damage of liver. These hepatotoxic effects were attenuated or recover with proper treatment with potent antibiotics (ceftazidime and amikacin). Therefore, study showed that chronic suppurative otitis media can induce hepatic toxicity including elevated liver enzymes level and inflammation, aggregation or infiltration in liver cells in rat model with reversible hepatic damage. If CSOM is treated with adult dose of ceftazidime or amikacin, it may attenuate the damage and prevent risk of liver damage.

Spectroscopic interaction studies of H2 receptor antagonists with levocetirizine.

Patients with allergic rhinitis may also suffer abdominal pain, gastritis or peptic ulcer. In this condition patient may use levocetirizine with famotidine or ranitidine. These drugs have potential to interact with another drug and form complex. The aim of the present study is to evaluate the possible drug drug interaction with each other which may cause increase or decrease of therapeutic effects. For this purpose, validity of Beer Lambert law was checked, lone availability of famotidine (20gm), ranitidine (150gm) and levocetirizine (5mg) were studied in pH simulated to gastric juice (pH 1), pH 4, pH 7.4 and in pH 9 and finally percent availabilities of these drugs were calculated with the help of simultaneous equation. Results showed high percentage of levocetirizine in all pH as 300.32%, 514.41%, 173.38% and 220.68% in presence of famotidine but very low availability of famotidine as 5.36%, 35.38%, 51.87% and 10.89% in presence of levocetirizine. In the case of levocetirizine and ranitidine interaction, zero percent levocetirizine was available at pH 1and 9, 56.28% in pH 4 and 191.1% in pH 7.4. On the other hand, ranitidine was available as 95.36%, 127.93%, 41.47% and 144.3%. These results showed that percentage of all drugs were altered in presence of each other due to drug-drug interaction. This may be due to the charge transfer binding capabilities of the drugs which resulted in significantly changed availability of famotidine, ranitidine as well as levocetirizine.

Exploration of clinical management system: Career ladders, working model and reforms; a cross sectional estimate from Karachi, Pakistan.

Clinical and hospital pharmacy services are not just medical and pharmaceutical sciences but also occupy significant placement in healthcare system. Pakistan is a developing state with a huge prerequisite for changes in the general wellbeing framework, specially hospital and clinical aspect of pharmaceutical services. The principal intention of this study is to analyze the services offered by different pharmacies in hospitals of Karachi in terms of infrastructure and personnel service qualities. The study was conducted in a cross sectional way that included stratified sampling technique. Reactions were broken down utilizing descriptive and inferential insights of measurements. The fundamental result procedures incorporated the scope of hospital pharmacy services, the general recruitment of clinical drug specialists (pharmacist), the product and equipment used in hospital pharmacy services, the background of staff (educational), acquisition of proficient training mode, practical involvement and experience. The clinical pharmacy facilities coverage mutually on the departmental scale (median =22.43%) and patient scale (median =17.25%) do not comply the 100% coverage that is obligatory for standard practices. In addition, 48.65% of the pooled hospitals data has shown absence of distinct administration rules for hospital and clinical pharmacists, and 45.33% lacks the use of rational drug software. It is concluded that important parameters like drug monitoring, medication records keeping; appropriate drug information software's and quality assurance in hospitals still need attention for better patient outcomes.

Pharmacological inhibition of ß-catenin/BCL9 interaction overcomes resistance to immune checkpoint blockades by modulating Treg cells.

The Wnt/ß-catenin (ß-cat) pathway plays a critical role in cancer. Using hydrocarbon-stapled peptide technologies, we aim to develop potent, selective inhibitors targeting this pathway by disrupting the interaction of ß-cat with its coactivators B-cell lymphoma 9 (BCL9) and B-cell lymphoma 9-like (B9L). We identified a set of peptides, including hsBCL9CT-24, that robustly inhibits the activity of ß-cat and suppresses cancer cell growth. In animal models, these peptides exhibit potent anti-tumor effects, favorable pharmacokinetic profiles, and minimal toxicities. Markedly, these peptides promote intratumoral infiltration of cytotoxic T cells by reducing regulatory T cells (Treg) and increasing dendritic cells (DCs), therefore sensitizing cancer cells to PD-1 inhibitors. Given the strong correlation between Treg infiltration and APC mutation in colorectal cancers, it indicates our peptides can reactivate anti-cancer immune response suppressed by the oncogenic Wnt pathway. In summary, we report a promising strategy for cancer therapy by pharmacological inhibition of the Wnt/ß-cat signaling.

Platelet count and platelet indices in women with preeclampsia.

BACKGROUND: Although the exact pathophysiology of preeclampsia is not completely understood, the utility of different platelets indices can be utilized to predict preeclampsia. OBJECTIVE: To compare platelet indices, namely platelet count (PC), mean platelet volume (MPV), platelet distribution width (PDW), and PC to MPV ratio in women with preeclampsia compared with healthy controls. SETTING: Qassim Hospital, Kingdom of Saudi Arabia. DESIGN: A case-control study. Sixty preeclamptic women were the cases and an equal number of healthy pregnant women were the controls. RESULTS: There was no significant difference in age, parity, and body mass index between the study groups. Sixteen and 44 of the cases were severe and mild preeclampsia, respectively. There was no significant difference in PDW and MPV between the preeclamptic and control women. Both PC and PC to MPV ratios were significantly lower in the women with preeclampsia compared with the controls. There was no significant difference in the PC, PDW, MPV, and PC to MPV ratio when women with mild and severe preeclampsia were compared. Using receiver operating characteristic (ROC) curves, the PC cutoff was 248.0×103/µL for diagnosis of pre-eclampsia (P=0.019; the area under the ROC curve was 62.4%). Binary regression suggests that women with PC <248.010×103/µL were at higher risk of preeclampsia (odds ratio =2.2, 95% confidence interval =1.08-4.6, P=0.03). The PC/MPV cutoff was 31.2 for diagnosis of preeclampsia (P=0.035, the area under the ROC curve was 62.2%). CONCLUSION: PC <248.010×103/µL and PC to MPV ratio 31.2 are valid predictors of preeclampsia.

Formulation development and evaluation of zolmitriptan oral soluble films using 22 factorial designs.

OBJECTIVE: The present investigation involves the development of zolmitriptan oral soluble film (OSF) formulations and optimization with quality by design (QBD) using natural polymers and evaluation. MATERIALS AND METHODS: Initially, various natural polymers such as sodium alginate, pectin, and gelatin were screened by casting films using solvent casting technique and the prepared films were evaluated. Based on the physical and mechanical properties, sodium alginate was selected as best film former and zolmitriptan-loaded films were casted. The formulation was optimized with the help of 22 factorial experimental designs (QBD) in which sodium alginate concentration and plasticizer concentrations were used as factors and at two levels. The drug-loaded films were evaluated for various mechanical, physicochemical properties, and in vitro drug release properties. Factor effects were interpreted by calculating the main factor effects and by plotting the interaction plots. RESULTS: Thickness of the films, disintegration time, and percent drug loading efficiency were in the range of 0.698 ± 0.13-1.318 ± 0.22 mm, 175 ± 3.1-280 ± 1.7 s, and 68.34 ± 0.5-94.70 ± 0.7% w/v, respectively. Cumulative percent drug released was 61.8 ± 2.6-94.7 ± 4.1% after 30 min. Polymer concentration at two levels of plasticizer had statistically significant effect on drug loading efficiency and in vitro drug release rate. X2 formulation was found to be excellent in drug loading efficiency and in vitro drug release profiles; hence, drug excipient compatibility studies using Fourier transform infrared spectroscopy and stability studies for 60 days were carried out for X2 formulation and found to be stable. CONCLUSION: Sodium alginate OSFs containing zolmitriptan was successfully prepared, optimized, and evaluated.

Saracatinib as a metastasis inhibitor in metastatic castration-resistant prostate cancer: A University of Chicago Phase 2 Consortium and DOD/PCF Prostate Cancer Clinical Trials Consortium Study.

BACKGROUND: Fyn is a kinase that is upregulated in a subset of metastatic castration-resistant prostate cancer. Saracatinib potently inhibits Fyn activation. We have noted a relationship between Fyn expression and directional motility, a cellular process related to metastasis. As such we hypothesized that treatment with saracatinib would increase the time required to develop new metastatic lesions. METHODS: Patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel were eligible for enrollment. This study was executed as a randomized discontinuation trial. During a lead-in phase of two 28-Day cycles, all patients received saracatinib. Afterward, patients with radiographically stable disease were randomized to either saracatinib or placebo. Patients continued treatment until evidence of new metastasis. RESULTS: Thirty-one patients were treated. Only 26% of patients had stable disease after 8 weeks and thus proceeded to randomization. This required early termination of the study for futility. The 70% of patients who progressed after the lead-in phase exhibited expansion of existing lesions or decompensation due to clinical progression without new metastatic lesions. Fatigue was reported in more than 25% of patients (all grades) with only two patients experiencing grade 3 toxicity. Other grade 3 adverse events included dehydration, thrombocytopenia, and weakness. CONCLUSIONS: This study was unable to determine if saracatinib had potential as metastasis inhibitor. Metastasis inhibition by saracatinib may still be viable in an earlier time in the disease history.

Subclassification of prostate cancer circulating tumor cells by nuclear size reveals very small nuclear circulating tumor cells in patients with visceral metastases.

BACKGROUND: Although enumeration of circulating tumor cells (CTCs) has shown some clinical value, the pool of CTCs contains a mixture of cells that contains additional information that can be extracted. The authors subclassified CTCs by shape features focusing on nuclear size and related this with clinical information. METHODS: A total of 148 blood samples were obtained from 57 patients with prostate cancer across the spectrum of metastatic states: no metastasis, nonvisceral metastasis, and visceral metastasis. CTCs captured and enumerated on NanoVelcro Chips (CytoLumina, Los Angeles, Calif) were subjected to pathologic review including nuclear size. The distribution of nuclear size was analyzed using a Gaussian mixture model. Correlations were made between CTC subpopulations and metastatic status. RESULTS: Statistical modeling of nuclear size distribution revealed 3 distinct subpopulations: large nuclear CTCs, small nuclear CTCs, and very small nuclear CTCs (vsnCTCs). Small nuclear CTCs and vsnCTC identified those patients with metastatic disease. However, vsnCTC counts alone were found to be elevated in patients with visceral metastases when compared with those without (0.36 ± 0.69 vs 1.95 ± 3.77 cells/mL blood; P<.001). Serial enumeration studies suggested the emergence of vsnCTCs occurred before the detection of visceral metastases. CONCLUSIONS: There are morphologic subsets of CTCs that can be identified by fundamental pathologic approaches, such as nuclear size measurement. The results of this observational study strongly suggest that CTCs contain relevant information regarding disease status. In particular, the detection of vsnCTCs was found to be correlated with the presence of visceral metastases and should be formally explored as a putative blood-borne biomarker to identify patients at risk of developing this clinical evolution of prostate cancer.

Obesity in haemophilia patients: effect on bleeding frequency, clotting factor concentrate usage, and haemostatic and fibrinolytic parameters.

The prevalence of obesity in patients with haemophilia (PWH) is increasing. We investigated the effect of obesity on bleeding frequency and clotting factor concentrate (CFC) usage in PWH and assessed whether prothrombotic changes observed in obesity differ between controls and PWH. Number of bleeds and CFC usage were compared between obese (N = 51) and non-obese (N = 46) haemophilia A patients. Markers of haemostasis and fibrinolysis were compared between PWH, and gender-, age- and body mass index (BMI)-matched non-haemophilic controls (N = 91). Median number of bleeds/patient-month was comparable between obese and non-obese patients with severe haemophilia (P = 0.791). Obese patients with severe haemophilia used 1.4 times more CFC/patient-month than non-obese patients (P = 0.036). When adjusting for weight this difference disappeared (P = 0.451). von Willebrand factor plasma concentration (VWF:Ag), factor VIII activity and endogenous thrombin potential were higher in obese than in non-obese controls. Obesity did not influence these markers in PWH. Plasminogen activator inhibitor type 1 levels were higher in obese vs. non-obese PWH (P < 0.001), whereas levels were comparable between PWH and controls (P = 0.912). Plasmin-α2-antiplasmin complex (PAP) levels appeared to be lower in obese vs. non-obese subjects, both within controls (P = 0.011) and PWH (P = 0.008). However, in PWH, PAP levels were higher than in controls (P < 0.001). Obesity is associated with an increase in net CFC usage in PWH, but has no effect on bleeding frequency. In addition, obesity attenuates hyperfibrinolysis in PWH. Future research investigating whether obese PWH need CFC treatment dosed on weight or whether a lower dosage would suffice to prevent and treat bleedings is needed.

Urinary prothrombin fragment 1+2 in patients with venous thrombosis and myocardial infarction.

Patients with venous-thromboembolism (VTE) and myocardial infarction (MI) have elevated prothrombin fragment 1+2 (F1+2) levels. In patients with postoperative VTE, urinary F1+2 (uF1+2) was higher than in individuals without VTE. To explore the relationship between plasma and uF1+2 we performed a pilot study in patients with thrombotic events and healthy controls. In 40 patients with VTE or MI, and 25 age- and sex-matched healthy controls, F1+2 and D-dimer levels were measured in urine and plasma within 48 h after diagnosis. In addition, in all subjects renal function was assessed. Plasma and uF1+2 levels were positively correlated. Compared to controls, patients with VTE had higher levels of both plasma F1+2 (271 vs 160 pmol L(-1), p < 0.05) and uF1+2 levels (38 vs 28 pmol L(-1)), the latter, however, was not statistically significant. Patients with acute MI had similar F1+2 levels as controls in both plasma and urine. Differences in urinary F1+2 levels could not be attributed to differences in concentrations of creatinine or albumin in spot urine samples. Overall, D-dimer and F1+2 levels in urine were extremely low in all groups.

Polymorphisms and evolutionary history of retrotransposon insertions in rice promoters.

Retrotransposons are ubiquitous in higher plant genomes. The presence or absence of retrotransposons in whole genome and high throughput genomic sequence (HTGS) from cultivated and wild rice was investigated to understand the organization and evolution of retrotransposon insertions in promoter regions. Approximately half of the Oryza sativa subsp. japonica 'Nipponbare' promoters with retrotransposons conserved in Oryza sativa subsp. indica '93-11' and four wild rice species showed higher sequence conservation in retrotransposon than nonretrotransposon regions. We further investigated, in detail, the evolutionary dynamics of five retrotransposons in the promoter regions of 95 rice genotypes. Our data suggest that four of five insertions (Rp2-Rp5) occurred in the ancestor of AA genome, while the other insertion (Rp1) predates the ancestral divergence of Oryza officinalis (CC genome). Four retrotransposons (Rp2-Rp5) were present in 52% (Rp2), 29% (Rp3), 53% (Rp4), and 43% (Rp5) of the rice genotypes with AA genome type, and the fifth retrotransposon (Rp1) was present in 95% of the rice genotypes with AA, BBCC, or CC genome types. Furthermore, most of these retrotransposons were found to evolve slower than flanking promoter regions, suggesting a role in promoter function for regulating downstream genes.

The impairment in daily life of obese haemophiliacs.

Obesity is a major health concern not only in the general population but also in patients with haemophilia. Little is known about the consequences of obesity for haemophilia patients. As obesity is an important risk factor for osteoarthritis, these effects may be even more pronounced in haemophilia patients who are prone to joint damage. The association between obesity and limitations in daily activities as well as the frequency of bleeds and use of factor VIII (FVIII) concentrate in obese and normal weight haemophilia patients was assessed. Fifteen obese (BMI ≥ 30 kg m(-2)) and fifteen normal weight (BMI ≤ 25 kg m(-2)) haemophilia A patients matched for severity and age were analysed. The Hemophilia Activities List (HAL) was used to assess the impairment in daily activities. Compared with the normal weight haemophilia patients, obese haemophiliacs had a significantly lower sum score (88/100 and 98/100, respectively, P = 0.02), which was mainly caused by an impaired lower limb function. All other components of the HAL also showed lower scores in the obese patients, but did not reach statistical significance. A higher frequency of bleeds requiring treatment with FVIII concentrate occurred in the obese haemophiliacs (17 bleeds in eight individuals) compared with the controls (three bleeds in three individuals) (P = 0.045). Compared with non-obese haemophilia patients, obese haemophiliacs had more joint bleeds and a lower overall HAL score, which was driven by a lower limb function score. Prevention of overweight and weight reduction requires special attention from physicians treating haemophilia patients.

Subcutaneous temporal browlift under local anesthesia: a useful technique for periorbital rejuvenation.

BACKGROUND: Various techniques have been described for periorbital rejuvenation and correction of the ptotic brow, including the coronal brow lift, the endoscopic brow lift, anterior hairline foreheadplasty in the subgaleal, subperiosteal, or subcutaneous planes, and the subcutaneous temporal brow lift. OBJECTIVES: The authors present results from a series of 28 patients treated with subcutaneous temporal brow lift over nearly four years. METHODS: A retrospective chart review was conducted of 28 patients who were treated with subcutaneous temporal brow lift by the senior author (JDF) between July 2003 and January 2007. All patients underwent the same subcutaneous temporal brow lift procedure under local anesthesia in an office-based setting. No combined procedures were performed on any of the patients in this series. RESULTS: Of the 28 patients, 27 were female and one was male; mean age was 54 years. Five patients underwent a unilateral brow lift for asymmetry and 23 patients underwent a bilateral procedure. The mean length of follow-up was 10.8 months. Scarring was minimal and rated as "good" or "excellent" by both patients and surgeon. The effectiveness of the browlift was also rated as "good" or "excellent" by all but one patient. Two patients underwent revision-one for scar revision and the other for a greater degree of lift. There were no incidences of hematoma, infection, numbness, or excessive scarring. CONCLUSIONS: The subcutaneous temporal brow lift is an effective, reproducible, and inexpensive technique that can be performed safely under local anesthesia.

The effect of haemophilia and von Willebrand disease on arterial thrombosis: a systematic review.

BACKGROUND: Patients with haemophilia and von Willebrand disease (VWD) may have a reduced cardiovascular mortality, due to a hypocoagulable state or decreased atherogenesis. We performed a systematic review to assess the association between haemophilia and VWD, and fatal and nonfatal arterial thrombosis and asymptomatic atherosclerosis. METHODS: Medline and PubMed were searched to identify studies that assessed the incidence of cardiovascular mortality and morbidity in haemophilia and VWD, and that measured asymptomatic atherosclerosis with intima media thickness (IMT) of the carotid and femoral arteries, or flow-mediated dilatation (FMD) of the brachial artery. Weighted standardised mortality ratios (SMR) and mean differences (WMD) were calculated and pooled using a random effects model. RESULTS: 15 longitudinal and cross-sectional studies consisting of 19,242 patients were included. Mortality due to arterial thrombosis was nonsignificantly reduced in patients with haemophilia compared with healthy controls (SMR 0.51, 95% CI 0.24 to 1.09). Haemophilia reduced nonfatal coronary events, and severe haemophilia offered better protection, but these results were based on a single study. No results were available for VWD. Although IMT of the carotid and femoral arteries was similar between VWD and haemophilia patients and healthy controls, atherosclerotic plaques of the large arteries were less prevalent in haemophilia patients. Only two studies assessed FMD and the results were inconsistent. CONCLUSION: Haemophilia may reduce arterial thrombosis, but this association should be further studied in haemophilia patients with a higher prevalence of cardiovascular risk factors.

Intrabiliary rupture of hepatic hydatid cyst: role of ERCP.

We report a case of hepatic hydatid cyst presenting with obstructive jaundice following cholecystectomy. ERCP showed intrabiliary cyst rupture with biliary obstruction due to cyst remnants. Endoscopic sphincterotomy was performed and cyst debris removed with complete resolution of symptoms.

Fluroquinolone resistance in typhoidal Salmonella and its detection by nalidixic acid disc diffusion.

OBJECTIVE: To determine the presence of fluoroquinolone resistance in Typhoidal salmonellae at Rawalpindi and the role of nalidixic acid in predicting the resistance against fluoroquinolones in Microbiology Laboratory, Department of Pathology, Army Medical College, Rawalpindi. METHODS: One hundred consecutive clinical isolates of Typhoidal salmonellae isolated from blood culture samples were studied. The organisms were identified biochemically and serologically by standard technique. Sensitivity testing was carried out against nalidixic acid and ciprofloxacin by modified Kirby bauer disc diffusion method and minimum inhibitory concentration (MICs) were determined by E-test. RESULTS: Seventeen percent of the isolates were resistant to nalidixic acid. Nalidixic acid disc diffusion and MIC estimation by E-test were 100% comparable. All isolates were sensitive to ciprofloxacin but the isolates which were resistant to nalidixic acid had raised MIC values against ciprofloxacin. CONCLUSION: Typhoidal salmonellae have not shown an overt in vitro resistance against fluoroquinolones in our set up but a significant population has emerged with raised MIC values. Nalidixic acid susceptibility test can be used an indirect evidence of resistance to quinolones.