Probing milk extracellular vesicles for intestinal delivery of RNA therapies.

BACKGROUND: Oral delivery remains unattainable for nucleic acid therapies. Many nanoparticle-based drug delivery systems have been investigated for this, but most suffer from poor gut stability, poor mucus diffusion and/or inefficient epithelial uptake. Extracellular vesicles from bovine milk (mEVs) possess desirable characteristics for oral delivery of nucleic acid therapies since they both survive digestion and traverse the intestinal mucosa. RESULTS: Using novel tools, we comprehensively examine the intestinal delivery of mEVs, probing whether they could be used as, or inform the design of, nanoparticles for oral nucleic acid therapies. We show that mEVs efficiently translocate across the Caco-2 intestinal model, which is not compromised by treatment with simulated intestinal fluids. For the first time, we also demonstrate transport of mEVs in novel 3D 'apical-out' and monolayer-based human intestinal epithelial organoids (IEOs). Importantly, mEVs loaded with small interfering RNA (siRNA) induced (glyceraldehyde 3-phosphate dehydrogenase, GAPDH) gene silencing in macrophages. Using inflammatory bowel disease (IBD) as an example application, we show that administration of anti-tumour necrosis factor alpha (TNFα) siRNA-loaded mEVs reduced inflammation in a IBD rat model. CONCLUSIONS: Together, this work demonstrates that mEVs could either act as natural and safe systems for oral delivery or nucleic acid therapies, or inform the design of synthetic systems for such application.

Assessment of In Vitro Airway Smooth Muscle Relaxant Activity of Rhus coriaria L. Fruit Ethanolic Extract and Its Possible Mechanisms.

Rhus coriaria L. (Anacardiaceae), also known as Sumac, is commonly used as a spice, flavoring agent, and as a traditional medicinal herb. This includes also the traditional use for treating asthma, catarrh, and common colds. The accumulating evidence supports its cardioprotective, antidiabetic, neuroprotective, anticancer, gastroprotective, antibacterial, anti-inflammatory, antiviral, antioxidant, and respiratory effects. However, there are no previous studies that have shown its effects and mechanism in the airway smooth muscle tone, and therefore, the aim of our study was to investigate the in vitro pharmacological action of R. coriaria L. extract (RCE) on the rat isolated tracheal and bronchial preparations by exploring its relaxant activity and mechanism of action. The direct relaxant effect of RCE (0.1-0.7 mg/mL) was tested in the rat bronchi and trachea rings precontracted by carbachol (CCh). In addition, the pretreatment with RCE (1 mg/mL) was tested on the bronchial and tracheal reactivity induced by CCh, potassium chloride (KCl), or CaCl2. In addition, the cyclooxygenase inhibitor indomethacin and the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME), respectively, were used for exploring the mechanisms of RCE-induced relaxation and reduction of reactivity. Our findings demonstrated that RCE induced a concentration-dependent relaxation and a significant reduction of reactivity, significantly reduced with either indomethacin or L-NAME. In addition, RCE decreased the responsiveness to KCl and affected the extracellular Ca2+-induced contraction in the tissues with added CCh or KCl in Ca2+-free Krebs-Henseleit solution. In summary, we have shown that RCE displayed relaxant activities in the in vitro airway smooth muscles, and the possible mechanisms seems to involve the prostaglandin, nitric oxide, and Ca2+ pathways. Taken together, our findings indicate the potential role of RCE in the treatment of respiratory diseases with limited airflow, or obstructive respiratory diseases, and could justify its traditional use in the respiratory diseases.

Incidence rate of injury and injury sites in European and Swiss karate competitions: a prospective epidemiological study of 2404 fights.

Objectives: To compare the rates and injury sites among competitors in European and Swiss karate tournaments and to identify differences in these incidence rates by sex and age. Methods: This prospective cohort study collected data from two European and four national tournaments in Switzerland between 2011 and 2019. The on-site medical staff completed an anonymised report sheet with demographic data and injury characteristics in all injuries requiring medical treatment. The incidence rates per 1000 exposed athletes (AoE) and 1000 min of exposition (MoE) were analysed. Furthermore, the relative risk of injury related to sex and age was calculated and compared. Results: In total, 228 injuries were observed in 2404 fights, for an incidence rate of 47.4 per 1000 AoE (95% CI 41.5 to 54.0) or 22.5 injuries per 1000 MoE (95% CI 19.7 to 25.6), respectively. The oldest age group (senior) of both sexes had a 3.6-fold (95% CI 2.7 to 4.8) significantly higher relative risk of injury than younger participants. Furthermore, there was a 2.9-fold (95% CI 1.6 to 5.6) statistically higher risk of injury for males in the senior age group compared with senior females. The most injured body part was the head, followed by the lower extremity, trunk and upper extremity. Conclusion: Senior athletes, especially senior males, had significantly more injuries compared with younger and female senior competitors. Medical staff should be aware of the increased propensity for injury among this age and sex group to facilitate injury prevention and intervention.

5-HT7 receptors mediate dilation of rat cremaster muscle arterioles in vivo.

OBJECTIVE: Serotonin (5-HT) infusion in vivo causes hypotension and a fall in total peripheral resistance. However, the vascular segment and the receptors that mediate this response remain in question. We hypothesized that 5-HT7 receptors mediate arteriolar dilation to 5-HT in skeletal muscle microcirculation. METHODS: Cremaster muscles of isoflurane-anesthetized male Sprague-Dawley rats were prepared for in vivo microscopy of third- and fourth-order arterioles and superfused with physiological salt solution at 34°C. Quantitative real-time PCR (RT-PCR) was applied to pooled samples of first- to third-order cremaster arterioles (2-4 rats/sample) to evaluate 5-HT7 receptor expression. RESULTS: Topical 5-HT (1-10 nmols) or the 5-HT1/7 receptor agonist, 5-carboxamidotryptamine (10-30 nM), dilated third- and fourth-order arterioles, responses that were abolished by 1 µM SB269970, a selective 5-HT7 receptor antagonist. In contrast, dilation induced by the muscarinic agonist, methacholine (100 nmols) was not inhibited by SB269970. Serotonin (10 nmols) failed to dilate cremaster arterioles in 5-HT7 receptor knockout rats whereas arterioles in wild-type litter mates dilated to 1 nmol 5-HT, a response blocked by 1 µM SB269970. Quantitative RT-PCR revealed that cremaster arterioles expressed mRNA for 5-HT7 receptors. CONCLUSIONS: 5-HT7 receptors mediate dilation of small arterioles in skeletal muscle and likely contribute to 5-HT-induced hypotension, in vivo.

Comparison of systemic inflammatory responses of proximal femoral nail versus dynamic hip screw after treatment of patients with pertrochanteric fractures: A prospective comparative study.

OBJECTIVE: The aim of this study was to investigate the differences between the induction of early postoperative inflammatory response and muscle tissue injury biomarkers after treatment of pertrochanteric fractures by dynamic hip screw (DHS) or proximal femoral nail (PFN). METHODS: In this prospective comparative study, 40 patients with AO-Müller/Orthopaedic Trauma Association (AO/OTA) 31. A1-31.A2 pertrochanteric fractures were enrolled and allocated one of the two groups based on the treatment type: group DHS, (n =20,mean age = 78.4 ± 6.9 years) and group PFN (n = 20, mean age = 77.75 ± 7.0 years). Operation time was recorded in both groups. In each patient, circulating levels of high sensitivity interleukin-6 (hs-IL-6), C-reactive protein (CRP), and creatine kinase (CK), and erythrocyte sedimentation rate (ESR)weremeasured fromblood samples collected 1 hour preoperatively and 24 hours postoperatively. RESULTS: The operation time was slightly shorter in group PFN than in group DHS (51.9 ± 21.1 and 38 ± 15.2 min, respectively; P = 0.02). DHS and PFN both increased hs-IL-6 (143.81 ± 89.12 and 94.13 ± 67.14, respectively), CRP (98.84 ± 31.81 and 104.4 ± 31.80, respectively), and CK (400.8 ± 31.81 and 250.7 ± 31.80, respectively) 24 hours postoperatively. However, PFN compared to DHS resulted in a lesser increase from baseline to 24 hours postoperatively only in hs IL-6 (58.91 ± 59.02 vs 113.30 ± 76.24, respectively; P = 0.0016) and CK (163.6 ± 123.3 vs 310.0 ± 198.3, respectively; P < 0.0001).Moreover, there was a positive correlation of CK levels' surgery time in DHS (r = 0.38, P = 0.0065) and PFN (r = 0.45, P = 0.0013). CONCLUSION: The results of this study have shown that PFN can induce a lower early postoperative inflammatory response and muscle tissue injury based on the assessment of hs-IL-6 and CK levels, compared to DHS in after the treatment patients pertrochanteric fractures. LEVEL OF EVIDENCE: Level II, Therapeutic Study.

Role of omega-3 polyunsaturated fatty acids in gestational diabetes, maternal and fetal insights: current use and future directions.

ω-3-Polyunsaturated fatty acids (ω-3 PUFAs) are widely used during pregnancy and gestational diabetes mellitus (GDM). ω-3 PUFAs are beneficial in the regulation of maternal and fetal metabolic function, inflammation, immunity, macrosomia (MAC), oxidative stress, preeclampsia, intrauterine growth, preterm birth, offspring metabolic function, and neurodevelopment. Dietary counseling is vital for improving therapeutic outcomes in patients with GDM. In maternal circulation, ω-3 PUFAs are transported via transporters, synthesis enzymes, and intracellular proteins, which activate nuclear receptors and play central roles in the cellular metabolic processes of placental trophoblasts. In patients with GDM, this process is compromised due to abnormal functioning of the placenta, which disrupts the normal mother to fetus transport. This results in reduced fetal levels of ω-3 PUFAs, which contributes negatively to fetal growth, metabolic function, and development. Dietary counseling and nutritional assessment remain challenging in the prevention and alleviation of GDM. Therefore, personalized approaches, including measurement of the ω-3 index, pharmacogenetic implementation strategies, and appropriate supplementation with ω-3 PUFAs are used to achieve sufficient distribution in the maternal and fetal fluids during the entire pregnancy period. Developing new dosing guidelines and personalized approaches, determining the mechanisms of ω-3 PUFAs in the placenta, and examining the pharmacodynamic and pharmacokinetics interactions involving ω-3 PUFAs will lead to better management and increase the quality of life of patients with GDM and their offspring. Moreover, different strategies for supplementing with ω-3 PUFAs, improving their placental transport, and pharmacological exploration of the maternal-fetal interactions will help to further elucidate the role of ω-3 PUFAs in women with GDM. In this review, we summarize the current information on the potential therapeutic benefits and clinical applicability of ω-3 PUFAs in patients with GDM and their offspring, highlighting recent progress and future perspectives in this field. Studies investigating the mechanisms of ω-3 PUFA transport to targeted tissues have spurred an interest in personalized treatment strategies for patients with GDM and their offspring. To implement such therapies, we need to clarify the index/ratio of ω-3 PUFAs in maternal and fetal fluids, delineate the ω-3 PUFA transport pathways, and establish the guidelines for FA profiling prepregnancy and during pregnancy-associated weight gain. Such therapies also need to take into account the gender of the fetus, and whether the patient is obese.

Rivaroxaban improves vascular response in LPS-induced acute inflammation in experimental models.

Rivaroxaban (RVX) was suggested to possess anti-inflammatory and vascular tone modulatory effects. The goal of this study was to investigate whether RVX impacts lipopolysaccharide (LPS)-induced acute vascular inflammatory response. Male rats were treated with 5 mg/kg RVX (oral gavage) followed by 10 mg/kg LPS i.p injection. Circulating levels of IL-6, MCP-1, VCAM-1, and ICAM-1 were measured in plasma 6 and 24 hours after LPS injection, while isolated aorta was used for gene expression analysis, immunohistochemistry, and vascular tone evaluation. RVX pre-treatment significantly reduced LPS mediated increase after 6h and 24h for IL-6 (4.4±2.2 and 2.8±1.7 fold), MCP-1 (1.4±1.5 and 1.3±1.4 fold) VCAM-1 (1.8±2.0 and 1.7±2.1 fold). A similar trend was observed in the aorta for iNOS (5.5±3.3 and 3.3±1.9 folds reduction, P<0.01 and P<0.001, respectively), VCAM-1 (1.3±1.2 and 1.4±1.3 fold reduction, P<0.05), and MCP-1 (3.9±2.2 and 1.9±1.6 fold reduction, P<0.01). Moreover, RVX pre-treatment, improved LPS-induced PE contractile dysfunction in aortic rings (Control vs LPS, Emax reduction = 35.4 and 31.19%, P<0.001; Control vs LPS+RVX, Emax reduction = 10.83 and 11.48%, P>0.05, respectively), resulting in 24.5% and 19.7% change in maximal constriction in LPS and LPS+RVX respectively. These data indicate that RVX pre-treatment attenuates LPS-induced acute vascular inflammation and contractile dysfunction.

The use of remdesivir outside of clinical trials during the COVID-19 pandemic.

With a scientific background from filoviruses, paramyxoviruses, SARS-CoV, and MERS-CoV, remdesivir entered into the COVID-19 battle to become one of the favorable therapeutic candidates with potential antiviral activity in the treatment of this disease. Globally, remdesivir was accessed and investigated through clinical research (clinical trials) and clinical practice (compassionate use, expanded access, early access scheme, and emergency use). Currently, remdesivir approval status differs between states. This paper aims to review and analyze regulatory approaches for accessing and investigating remdesivir, by communicating regulatory variability between countries in terms of terminology, modalities, and protocols.

Clinical and Regulatory Concerns of Biosimilars: A Review of Literature.

Although biosimilars have been part of clinical practice for more than a decade, healthcare professionals (HCPs) do not fully accept them. This is because of the perception that biosimilars may not be like their originators in terms of quality, safety, and efficacy. This study aims to evaluate the current knowledge and attitudes of healthcare professionals toward biosimilar prescription, and to elaborate on their concerns. We reviewed the literature using PubMed, Cochrane Library, and Science Direct electronic databases in the period from 2018 to 2020. The knowledge and confidence of healthcare professionals vary between countries, between clinical profiles and between studies. Although most of the healthcare professionals had a positive attitude to prescribing biosimilars, they would still prefer to prescribe them in initial treatment. Generally, HCPs were against multiple switches and substitution of biosimilars at the pharmacy level. HCP's key concern was interchangeability, with eventual consequences on the clinical outcome of patients. HCPs still approach biosimilars with caution and stigma. HCPs need to have an unbiased coherent understanding of biosimilars at clinical, molecular and regulatory levels. It was also observed that most of their concerns are more theoretical than science-based. Physicians are in an excellent position to accept biosimilars, but they need the additional support of regulatory authorities to approve and take into consideration the available scientific data regarding biosimilars.

Effect of omega-3 polyunsaturated fatty acids in modulation of vascular tone under physiological and pathological conditions.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are mainly found in marine fish oils and commercially available fish oil supplements. Several studies have documented that n-3 PUFAs can reduce the risk of cardiovascular diseases through anti-inflammatory, anti-thrombotic, and anti-atherosclerotic properties. Notably, regulation of vascular tone is one of the most important bases of cardiovascular health and especially for maintaining blood pressure within optimal physiological ranges. Recent clinical and animal studies indicate an association between n-3 PUFAs and vascular functions. In this regard, many clinical trials and basic experimental studies have been conducted so far to investigate the influence of n-3 PUFAs on vascular tone. In this review, we have summarized the results obtained from both clinical and basic studies that evaluated the effect of n-3 PUFAs under physiological and pathological conditions. Moreover, we also focus on verifying the underlying basic molecular mechanism of n-3 PUFAs on the vascular system.

Tuberculosis drug safety and pharmacovigilance in health system of Kosova: A cross-sectional analysis.

BACKGROUND: Tuberculosis (TB) remains a significant worldwide social and life-threatening epidemiological problem. Because this disease requires multiple drug treatment and prolonged therapy for several months, followed by a high probability of adverse effects (AEs), we assessed AE monitoring for anti-TB drugs in the Health Care System of Kosova. METHODS: This survey was a cross-sectional analysis performed at the primary, secondary and tertiary health care levels in Kosova. We included 930 registered tuberculosis patients within three levels of this health system in our study. Furthermore, we interviewed 62 physicians and 71 nurses at TB health facilities. Data were collected from official TB registers and personal contact with patients for 12 months. RESULTS: The representative age group was 19 to 29 years (30.49%), followed by a group of patients aged >60 years (23.23%). Among 930 patients treated with TB drugs, the total incidence of adverse AEs was 29.03%. Female TB patients had a higher rate of AEs than did male patients (33.56% vs 28.84%, respectively). The highest incidence of registered AEs was recorded in the gastrointestinal system (270, 80.83%), followed by the central nervous system (CNS, 7.50%) and was lower in other organ systems. The reporting of anti-TB drug effects by medical staff (TB medical doctor and TB medical nurse) at different levels of TB medical settings occurred among 62.90% of medical doctors and 81.69% of nurses. Only 53.23% of medical doctors and 46.48% of nurses completed pharmacovigilance training. CONCLUSION: The pharmacovigilance approach in Health System of Kosova is not comprehensible and not systematic. The relatively low incidence of AEs among TB patients is due under reporting of these by medical staff. The knowledge, attitudes, and adherence of medical staff reveal low awareness for pharmacovigilance activities, and this concern should be addressed to reinforce this important issue for the safe treatment of TB patients.

Current regulatory approaches for accessing potential COVID-19 therapies.

This commentary aims to elaborate challenges in the regulatory approaches for accessing and investigating COVID-19 potential therapies either with off-label use, compassionate use, emergency use or for clinical trials. Since no therapies have been formally approved and completely effective and safe to date, the best clinical choice is acquired only after consistent and fair communication and collaboration between licensed clinicians, researchers, regulatory authorities, manufacturers and patients.

In Vitro Effects of Eicosapentaenoic and Docosahexaenoic Acid on the Vascular Tone of a Human Saphenous Vein: Influence of Precontractile Agents.

BACKGROUND: Cardiovascular effects of omega-3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been widely reported. However, there are limited studies concerning their effects on human blood vessels. Therefore, the aim of this study was to investigate the direct vascular effects of EPA and DHA on the human saphenous vein (SV) precontracted with either prostaglandin F2α (PGF2α), or thromboxane A2 analogue (U46619), or norepinephrine (NE). Moreover, we aimed to investigate the protein expression of free fatty acid receptor 4 (FFAR4) in human SV. METHODS: Pretreatment of human SV rings with EPA and DHA (100 µM, 30 min) was tested on vascular reactivity induced by PGF2α (10 nM to 5 µM), NE (10 nM to 100 µM), and U46619 (1 nM to 100 nM). In addition, direct relaxant effects of EPA/DHA (1-100 µM) were tested in human SV rings precontracted by PGF2α, NE, and U46619. Furthermore, the involvement of potassium channels on their vascular effects was investigated in the presence of the nonselective K+ channel inhibitor tetraethylammonium chloride. RESULTS: Pretreatment with EPA and DHA resulted in a significant decrease in vascular reactivity induced by U46619 and PGF2α compared to NE. In the presence of TEA, the relaxant effects of EPA and DHA were significantly decreased in SV preparations precontracted by U46619 and PGF2α for DHA. Furthermore, FFAR-4 protein was expressed in tissue extracts of human SV. CONCLUSIONS: Our study demonstrates that both EPA and DHA reduce the increased vascular tone elicited by contractile agents on the human SV and that the direct vasorelaxant effect is likely to involve potassium channels.

Antibiotic utilisation in adult and children patients in Kosovo hospitals.

OBJECTIVES: There are no reliable data on antibiotic use in Kosovo hospitals. The aim of this survey was to monitor volumes and patterns of antibiotic use in hospitalised patients in order to identify targets for quality improvement. METHODS: Data on antimicrobial use were collected from seven hospitals in Kosovo during 2013 using the standardised point prevalence survey (PPS) methodology as developed by the ESAC (European Surveillance of Antimicrobial Consumption) and ARPEC (Antibiotic Resistance and Prescribing in European Children). The survey included all inpatients receiving an antimicrobial agent on the day of the PPS. RESULTS: Overall, 1667 patients were included in the study: adults 1345 (81%) and children 322 (19%). Of the hospital inpatients, 579/1345 (43%) adults and 188/322 (58%) children received at least one antibiotic during a hospital stay. The top three antibacterial subgroups (ATC level 3) were ß-lactam antibiotics, cephalosporins and aminoglycosides. In all hospital centres, the most commonly prescribed antibiotic was ceftriaxone (39% for adult and 36% for children). Antibiotics were administered mainly parenterally in 74% of adults and 94% of children. Empirical prescribing was higher in adults 498/579 (86%) and children 181/188 (96%), compared with targeted treatment based on susceptibility testing-81 (14%) and 8 (4%), respectively. CONCLUSIONS: Antibiotic use in Kosovo's hospitals is very high. Gathered data will be an important tool to identify targets for quality improvement and will support preparation of guidelines and protocols for the prudent use of antibiotics.

Role of the Angiotensin Pathway and its Target Therapy in Epilepsy Management.

Despite extensive research on epileptogenesis, there is still a need to investigate new pathways and targeted therapeutic approaches in this complex process. Inflammation, oxidative stress, neurotoxicity, neural cell death, gliosis, and blood⁻brain barrier (BBB) dysfunction are the most common causes of epileptogenesis. Moreover, the renin⁻angiotensin system (RAS) affects the brain's physiological and pathological conditions, including epilepsy and its consequences. While there are a variety of available pharmacotherapeutic approaches, information on new pathways is in high demand and the achievement of treatment goals is greatly desired. Therefore, targeting the RAS presents an interesting opportunity to better understand this process. This has been supported by preclinical studies, primarily based on RAS enzyme, receptor-inhibition, and selective agonists, which are characterized by pleiotropic properties. Although there are some antiepileptic drugs (AEDs) that interfere with RAS, the main targeted therapy of this pathway contributes in synergy with AEDs. However, the RAS-targeted treatment alone, or in combination with AEDs, requires clinical studies to contribute to, and clarify, the evidence on epilepsy management. There is also a genetic association between RAS and epilepsy, and an involvement of pharmacogenetics in RAS, so there are possibilities for the development of new diagnostic and personalized treatments for epilepsy.

Pharmacotherapy Evaluation and Utilization in Coronary Artery Bypass Grafting Patients in Kosovo during the Period 2016-2017.

BACKGROUND: Coronary Artery Bypass Grafting (CABG) is realised in patients with critical or advanced disease of coronary arteries. There are different pharmacotherapeutic approaches which are used as management, treatment and preventive therapy in cardiovascular disease or related comorbidities. Performing a successful surgery, pharmacotherapy, and increase of bypass patency rate remains a serious challenge. AIM: This study aims to analyse the patient characteristics undergoing CABG and evaluation of their drug utilisation rate and daily dosages in the perioperative period. MATERIAL AND METHODS: Data were collected from 102 patients in the period 2016-2017 and detailed therapeutic prescription and dosages, patient characteristics were analysed before the operation, after the operation and visit after operation in the Clinic of Cardiac surgery-University Clinical Center of Kosovo. RESULTS: Our findings had shown that patients provided to have normal biochemical parameters in the clinic before the operation, and were related to cardiovascular diseases and comorbidities and risk factors with mainly elective intervention. The, however, higher utilisation of cardiovascular drugs such as beta blockers, diuretics, anticoagulants, statins and lower calcium blockers, ACEi, ARBs, hydrochlorothiazide, amiodarone were founded. ARBs, beta blockers, statins, nitrates and nadroparin utilisation decreased after operation and visit after the operation, whereas amiodarone only in the visit after the operation. Diuretics are increased after the operation which decreases in the visit after the operation. Regarding the daily dosage, only metoprolol was increased in the visit after operation (P < 0.001) and visit after operation (P < 0.05) whereas losartan and furosemide were increased (P < 0.01) and (P < 0.05) respectively. CONCLUSION: The study showed that beta blockers, statins, aspirin, nitrates (before the operation), furosemide and spironolactone are the most utilised drugs. However, we found low utilisation rate for ACEi, ARBs, clopidogrel, nadroparin, warfarin, xanthines, amiodarone, calcium blockers. Daily dosages were different compared to before CABG only in metoprolol, losartan, and furosemide.

Microperforated Hymen Presenting Spontaneous Pregnancy with Cesarean Delivery and Hymenotomy Surgery: A Case Report.

BACKGROUND: Female genital tract anomalies including imperforate hymen affect sexual life and fertility. CASE PRESENTATION: In the present case, we describe a pregnant woman diagnosed with imperforate hymen which never had penetrative vaginal sex. A 27-year-old married patient with 2 months of amenorrhea presented in a clinic without any other complications. Her history of difficult intercourse and prolonged menstrual flow were reported, and subsequent vaginal examination confirmed the diagnosis of imperforate hymen even though she claims to made pinhole surgery in hymen during puberty. Her urine pregnancy test was positive, and an ultrasound examination revealed 8.3 weeks pregnant. The pregnancy was followed up to 39.5 weeks when she entered in cesarean delivery in urgency. Due to perioperative complications in our study, a concomitant hymenotomy was successfully performed. The patient was discharged with the baby, and vaginal anatomy was restored. CONCLUSIONS: This case study suggests that even though as microperforated hymen surgery in puberty can permit pregnancy and intervention with cesarean section and hymenotomy is a good option to reduce the resulting perioperative complications which indirectly affect the increase of the fertilisation and improvement of later sexual life.

Individualizing Treatment Approaches for Epileptic Patients with Glucose Transporter Type1 (GLUT-1) Deficiency.

Monogenic and polygenic mutations are important contributors in patients suffering from epilepsy, including metabolic epilepsies which are inborn errors of metabolism with a good respond to specific dietetic treatments. Heterozygous variation in solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1) and mutations of the GLUT1/SLC2A2 gene results in the failure of glucose transport, which is related with a glucose type-1 transporter (GLUT1) deficiency syndrome (GLUT1DS). GLUT1 deficiency syndrome is a treatable disorder of glucose transport into the brain caused by a variety of mutations in the SLC2A1 gene which are the cause of different neurological disorders also with different types of epilepsy and related clinical phenotypes. Since patients continue to experience seizures due to a pharmacoresistance, an early clinical diagnosis associated with specific genetic testing in SLC2A1 pathogenic variants in clinical phenotypes could predict pure drug response and might improve safety and efficacy of treatment with the initiation of an alternative energy source including ketogenic or analog diets in such patients providing individualized strategy approaches.

Tuberculosis Treatment Adherence of Patients in Kosovo.

SETTING: The poor patient adherence in tuberculosis (TB) treatment is considered to be one of the most serious challenges which reflect the decrease of treatment success and emerging of the Multidrug Resistance-TB (MDR-TB). To our knowledge, the data about patients' adherence to anti-TB treatment in our country are missing. OBJECTIVE: This study was aimed to investigate the anti-TB treatment adherence rate and to identify factors related to eventual nonadherence among Kosovo TB patients. DESIGN: This study was conducted during 12 months, and the survey was a descriptive study using the standardized questionnaires with total 324 patients. RESULTS: The overall nonadherence for TB patient cohort was 14.5%, 95% CI (0.109-0.188). Age and place of residence are shown to have an effect on treatment adherence. Moreover, the knowledge of the treatment prognosis, daily dosage, side effects, and length of treatment also play a role. This was also reflected in knowledge regarding compliance with regular administration of TB drugs, satisfaction with the treatment, interruption of TB therapy, and the professional monitoring in the administration of TB drugs. CONCLUSION: The level of nonadherence TB treatment in Kosovar patients is not satisfying, and more health care worker's commitments need to be addressed for improvement.

Omega-3 polyunsaturated fatty acids reduce vascular tone and inflammation in human saphenous vein.

Dietary intake of omega-3 polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), has been reported to have beneficial cardiovascular effects. However, little is known about the effect of EPA and DHA on human vascular tone. Therefore, the aim of this study is to evaluate the effect of EPA and DHA on vascular tone of the human saphenous vein (SV) obtained from patients undergoing coronary bypass operation under normal and inflammatory conditions. Moreover, we aimed to investigate the effect of EPA and DHA on the release of inflammatory mediators from SV. Pretreatment of SV with EPA and DHA (100µM, 18h) decreased the contractile response of SV to norepinephrine (NE) under normal and inflammatory conditions. Moreover, EPA and DHA pretreatment diminished increased Monocyte Chemoattractant Protein-1 (MCP-1) and Tumor Necrosis Factor-alpha (TNF-α) release from SV under inflammatory conditions. In conclusion, our results suggest that EPA and DHA pretreatment may be beneficial to counteract graft vasospasm and vascular inflammation in SV which are important factors in graft failure development. Therefore, dietary intake of EPA and DHA may have potential clinical applications in improving coronary bypass graft patency.