The neutralization effect of montelukast on SARS-CoV-2 is shown by multiscale in silico simulations and combined in vitro studies

Small molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist montelukast as a novel agent that simultaneously targets two important drug targets of SARS-CoV-2. We initially demonstrated the dual inhibition profile of montelukast through multiscale molecular modeling studies. Next, we characterized its effect on both targets by different in vitro experiments including the enzyme (main protease) inhibition-based assay, surface plasmon resonance (SPR) spectroscopy, pseudovirus neutralization on HEK293T/hACE2+TMPRSS2, and virus neutralization assay using xCELLigence MP real-time cell analyzer. Our integrated in silico and in vitro results confirmed the dual potential effect of montelukast both on the main protease enzyme inhibition and virus entry into the host cell (spike/ACE2). The virus neutralization assay results showed that SARS-CoV-2 virus activity was delayed with montelukast for 20 h on the infected cells. The rapid use of new small molecules in the pandemic is very important today. Montelukast, whose pharmacokinetic and pharmacodynamic properties are very well characterized and has been widely used in the treatment of asthma since 1998, should urgently be completed in clinical phase studies and, if its effect is proved in clinical phase studies, it should be used against coronavirus disease 2019 (COVID-19).     

Bilateral carpal tunnel syndrome associated to familial Mediterranean fever

A unique case of bilateral severe carpal tunnel syndrome due to familial Mediterranean fever is reported. The syndrome was diagnosed by clinical examination and electrophysiological studies. Bilateral transverse carpal ligaments were released and the biopsy specimens revealed systemic type A amyloidosis. Up to our knowledge, the co-existence of bilateral carpal tunnel syndrome and familial Mediterranean fever has not been reported previously in the literature.     

Type 1 diabetes mellitus in a 3 1/2 year-old girl with Turner's syndrome

Turner's syndrome is associated with autoimmune disorders. Autoimmune endocrinopathy in Turner's syndrome seems to be limited to autoimmune thyroiditis. A small number of patients with Turner's syndrome has also been associated with celiac disease, inflammatory bowel disease and juvenile rheumatoid arthritis. Type 1 diabetes mellitus in Turner's syndrome has been rarely reported. We present here the youngest patient with Turner's syndrome who developed type 1 diabetes mellitus. At the age of 3.5 years she was hospitalized with diabetic ketoacidosis. Anti-islet cell and anti-insulin antibodies were positive and C-peptide level was low. When she was investigated for recurrent urinary tract infections, horseshoe kidney was detected by ultrasonography. Karyotype analysis revealed 45,XO. She has been followed for 2 years with an insulin dose of 0.9 U/kg per day. The prevalence of type 1 diabetes mellitus associated with Turner's syndrome is still unknown.     

The long-term efficacy and safety of botulinum toxin in refractory chronic tension-type headache

The objective of this study was to investigate the long-term efficacy and safety of botulinum toxin type-A (BoNT-A) for refractory chronic tension-type headache (CTTH). An open-label, prospective study was carried out in the Department of Neurology of Kirikkale University on 28 patients (8 males, 20 females), mean age 35.6 years, diagnosed with moderate/severe CTTH refractory to preventive medications. Each patient received BoNT-A injections once in pericranial muscles. Efficacy and safety data were analysed for 28 refractory CTTH patients who were receiving concomitant headache prophylactic medications at baseline and during the study. The main outcome parameters were reduction of headache frequency and intensity over 1 year. Both parameters were significantly decreased (p<0.05) by the end of the study. Sixty-four percent of patients reported complete headache relief at the final visit, compared to 7% CTTH persisted. BoNT-A also resulted in significant reductions in analgesic consumption (p<0.05). Adverse effects were transient and local. BoNT-A was found to be an effective and safe treatment for refractory CTTH patients with concomitant headache prophylactic medications, resulting in significant reductions in headache frequency, intensity and analgesic consumption which persisted up to 1 year.     

Risk factors of catheter-related bloodstream infections in parenteral nutrition catheterization

BACKGROUND: Intravascular catheters are integral to the practice of modern medicine. Potential risk factors for catheter-related bloodstream infection (CRBSI) include underlying disease, method of catheter insertion, and duration and purpose of catheterization. The administration of parenteral nutrition (PN) through intravascular catheters increases CRBSI risks. The purpose of this study was to evaluate the risk factors of CRBSI in patients with PN administration. METHODS: This study was conducted at the Karadeniz Technical University Hospital between October 2003 and November 2004. All the patients to whom PN was administered through intravascular catheters were prospectively monitored for the presence of CRBSI and risk factors. RESULTS: During the study period, 111 intravascular catheters through which PN was administered were monitored for a total of 1646 catheter-days. CRBSI was determined in 31 cases, a CRBSI rate of 18.8 per 1,000 catheter-days. When risk factors affecting CRBSI were investigated using logistic regression, an increase in APACHE II score (OR, 1.10; 95% CI, 1.01-1.21; p = .012), prolongation of catheterization (OR, 1.08; 95% CI, 1.02-1.14; p = .004), catheterization in emergent conditions (OR, 5.45; 95% CI, 1.20-24.82; p = .016), and poor patient hygiene (OR, 4.38; 95% CI, 1.39-13.78; p = .019) were all determined to be independent risk factors. Proper implementation of hand hygiene and maximal barrier precautions during the insertion of catheters reduced CRBSI levels (OR, 0.28; 95% CI, 0.09-0.88; p = .003 and OR, 0.26; 95% CI, 0.08-0.93; p = .017, respectively). CONCLUSIONS: It was concluded that the duration of catheterization should be shortened; that the intravascular catheter, which is inserted in urgent situations, should be removed as soon as possible; and that maximal sterile barrier precautions should be taken and due attention should be paid to hand hygiene.     

Novel mutations in epithelial sodium channel (ENaC) subunit genes and phenotypic expression of multisystem pseudohypoaldosteronism

OBJECTIVES: Multisystem pseudohypoaldosteronism (PHA) is a rare autosomal recessive aldosterone unresponsiveness syndrome that results from mutations in the genes encoding epithelial sodium channel (ENaC) subunits alpha, beta and gamma. In this study we examined three PHA patients to identify mutations responsible for PHA with different clinical presentations. PATIENTS: All three patients presented uniformly with symptoms of severe salt-loss during the first week of life and were hospitalized for up to a year. Beyond infancy, one of the patients showed mild renal salt loss and had no lower respiratory tract infections until 8 years of age, while the other patients continue with a severe course. RESULTS: We sequenced the complete coding regions and intron-exon junctions of the genes encoding alpha, beta and gamma subunits of ENaC for all patients. The results revealed that the mild case represents a novel compound heterozygote including a missense (Gly327Cys) mutation in the alphaENaC gene. Sequences of relatives over three generations confirmed that the missense mutation co-segregates with PHA. This mutation was not found in 60 control subjects. The other patients with severe PHA had two homozygous mutations, a novel deletion mutation in exon 8 of the alphaENaC gene and a splice site mutation in intron 12 of the betaENaC gene. Most of the PHA-causing mutations appear in the alphaENaC gene located on chromosome 12 rather than in the beta and gammaENaC genes located tandemly on chromosome 16. However, the frequency of sequence variants in patients and control subjects showed no difference between genes. CONCLUSIONS: Severe PHA cases are associated with mutations leading to absence of normal-length alpha, beta or gammaENaC, while a mild case has been found to be associated with a missense mutation in alphaENaC. The predominance of PHA-causing mutations in the alphaENaC gene may be related to the function of this subunit.     

Leukemia inhibitory factor (LIF) is immunohistochemically localized in tubal ectopic pregnancy

Leukemia inhibitory factor (LIF) is essential for implantation of the embryo in the endometrium. It is not clear whether the blastocyst requires expression of LIF for implantation into tissues other than endometrium. Immunohistochemical localization of LIF was performed in the fallopian tube of 20 women with ectopic pregnancies, 7 women with normal pregnancies and 20 healthy non-pregnant women. Fallopian tubes were evaluated from specimens taken during tubal ligation in normal pregnancies and non-pregnant fertile women or at operation for tubal surgery in ectopic pregnancies. Biopsies were assayed by immunohistochemistry. Semi-quantitative immunohistochemical reaction scores (IRS) were used for immunohistochemical analyses. Immunolabeling of LIF was detected in the surface epithelium and stroma of fallopian tubes in all subjects. IRS score in the epithelium and stroma of non-pregnant women and women with intrauterine pregnancy were similar (p>0.05). However, women with ectopic pregnancy had significantly increased labeling of LIF compared to others (p<0.05). Immunohistochemical labeling of LIF in the fallopian tube was found to be increased in ectopic pregnancies compared to non-pregnant and healthy pregnant controls. This may indicate a role of LIF in the ectopic implantation of embryos.