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Pharmacogenomics: sex Differences and Application in Pediatrics
No full textPharmacogenomics is a promising field which increasingly influences medicine and biomedical research in many areas. The aim of this article is to review recent advancements in the understanding of genetic polymorphisms and their influence on interindividual variability in drug response. Also, the main variabilities in drug response according to sex differences will be discussed. The translation of pharmacogenomics into the clinical routine as well as the challenges of achieving the goal of personalized medicine are also discussed. The role of pharmacogenetic tests in pediatrics has not been well defined yet, but it is clear that those tests could help in resolving some issues regarding the administration of drugs to children. At the conclusion, the foremost ethical, social and regulatory issues regarding the translation of pharmacogenomics into clinical practice and future perspectives in the field will be discussed
Coronary Microcirculatory Dysfunction in Human Cardiomyopathies: a Pathologic and Pathophysiologic Review
No full textCardiomyopathies are a heterogeneous group of diseases of the myocardium. The term cardiomyopathy involves a wide range of pathogenic mechanisms that affect the structural and functional states of cardiomyocytes, extravascular tissues, and coronary vasculature, including both epicardial coronary arteries and the microcirculation. In the developed phase, cardiomyopathies present with various clinical symptoms: dyspnea, chest pain, palpitations, swelling of the extremities, arrhythmias, and sudden cardiac death. Due to the heterogeneity of cardiomyopathic patterns and symptoms, their diagnosis and therapies are great challenges. Despite extensive research, the relation between the structural and functional abnormalities of the myocardium and the coronary circulation are still not well understood in the various forms of cardiomyopathy. The main pathological characteristics of cardiomyopathies and the coronary microcirculation develop in a progressive manner due to (1) genetic-immunologic-systemic factors; (2) comorbidities with endothelial, myogenic, metabolic, and inflammatory changes; (3) aging-induced arteriosclerosis; and (4) myocardial fibrosis. The aim of this review is to summarize the most important common pathological features and/or adaptations of the coronary microcirculation in various types of cardiomyopathies and to integrate the present understanding of the underlying pathophysiological mechanisms responsible for the development of various types of cardiomyopathies. Although microvascular dysfunction is present and contributes to cardiac dysfunction and the potential outcome of disease, the current therapeutic approaches are not specific for the given types of cardiomyopathy
Cochlear Potential Difference Between Endolymph Fluid and the hair Cell's Interior: a Retold Interpretation Based on the Goldman Equation
No full textReported cochlear potential values of near 150 mV are often attributed to endolymph itself, although membrane potentials result from ion fluxes across the adjacent semipermeable membranes due to concentration gradients. Since any two fluids separated by a semipermeable membrane develop potential due to differences in solute concentrations, a proposed interpretation here is that positive potential emanates from the Reissner membrane due to small influx of sodium from perilymph to endolymph. Basolateral hair cell membranes leak potassium into the interstitial fluid and this negative potential inside hair cells further augments the electric gradient of cochlear potential. Taken together as a sum, these two potentials are near the reported values of cochlear potential. This is based on reported data for cochlear fluids used for the calculation of Nernst and Goldman potentials. The reported positive potential of Reissner membrane can be explained almost entirely by the traffic of Na+ that enters endolymph through this membrane. At the apical membrane of hair cells, acoustic stimulation modulates stereocillia permeability to potassium. Potassium concentration gradients on the apical membrane are low (the calculated Nernst value is <+3 mV), suggesting that the potassium current is not caused by the local potassium concentration gradient, but an electric field between the positive sodium generated potential on the Reissner membrane and negative inside hair cells. Potassium is forced by this overall electric field to enter hair cells when stereocilia are permeable due to mechanical bending
The Importance of Assessing the Quality of Life in Patients with Chronic Obstructive Pulmonary Disease
No full textU kliničkim studijama, kao i u svakodnevnoj kliničkoj praksi, bolesnici s kroničnom opstruktivnom plućnom bolešću (KOPB-om) imaju bitno smanjenu kvalitetu života. Brojne studije pokazale su da je prognoza bolesnika s KOPB-om izravno povezana s kvalitetom njihova života. Egzacerbacije i pridružene bolesti uvelike utječu na pogoršanje kvalitete života bolesnika s KOPB-om. Među simptomima te bolesti za smanjenu kvalitetu života najodgovornija je dispneja koju obično imaju teži bolesnici. Međutim, smanjena kvaliteta života prisutna je u bolesnika s KOPB-om svih stupnjeva težine prema GOLD-u, pa i u onih s blagom opstrukcijom dišnih putova. Stoga je osim plućne funkcije uvijek potrebno procjenjivati i bolesnikove simptome. U smjernicama Global Initiative for Chronic Obstructive Lung Disease (GOLD) od 2011. g. pa nadalje simptomi su uključeni u kombiniranu procjenu težine i prognoze bolesti, a poboljšanje zdravstvenog stanja odnosno kvalitete života postalo je jedan od važnih ciljeva liječenja. Kvaliteta života mjeri se upitnicima za procjenu utjecaja bolesti na zdravstveno stanje bolesnika. Upitnici se dijele u dvije osnovne skupine: 1. generičke i 2. upitnike specifične za bolest. U KOPB-u se najčešće upotrebljavaju generički upitnici SF-36 (The Short Form 36 health survey questionnaire) i oni specifični za bolest SGRQ (St. George’s Respiratory Questionnaire). Osim navedenih u kliničkim istraživanjima KOPB-a rabi se velik broj drugih upitnika za procjenu kvalitete života koji nisu primjenjivi u svakodnevnoj kliničkoj praksi. Za procjenu kvalitete života u svakodnevnom radu kliničara osmišljen je jednostavniji upitnik CAT (COPD Assessment Test) koji omogućuje brzu procjenu i praćenje bolesnika te odlično korelira sa znatno složenijim SGRQ-om.Both clinical studies and daily clinical practice have shown that patients suffering from COPD have a significantly lower quality of life. Numerous studies have demonstrated that the prognosis for COPD patients is directly linked to their quality of life, which is significantly affected by exacerbations and related diseases. In that regard the most obvious symptom is dyspnoea, and usually patients with severe form of the disease suffer from it. However, reduced quality of life is present in all groups of patients categorised using the GOLD guidelines, including those with mild air passages obstruction. It is therefore necessary to assess not only the pulmonary function, but other symptoms as well. The GOLD guidelines from 2011 onward suggest including symptoms in the combination of the assessed severity and risk of the disease. Improving health and life quality in general has become one of the goals of treatment. The quality of life is evaluated using questionnaires to assess the impact of the disease on patient’s general condition. Questionnaires are divided into generic and disease-specific ones. For COPB generic SF-36 questionnaires (The Short-Form 36-item health survey questionnaire) are usually used, as well as the disease specific one SGRQ (St. George’s Respiratory Questionnaire). In addition, COPD clinical trials use a number of other questionnaires which cannot be applied in daily clinical practice. For this purpose a simpler CAT questionnaire (COPD Assessment Test) has been created, enabling a fast evaluation and monitoring, and it correlates well with a more complex SGRQ
Plasminogen Activator Inhibitor-1 Concentrations and Bone Mineral Density in Postmenopausal Women with Type 2 Diabetes Mellitus
No full textBackground: Women with type 2 diabetes mellitus (T2DM) have a higher risk of fractures despite increased bone mineral density (BMD). In experimental studies a potential role of plasminogen activator inhibitor-1 (PAI-1) in bone remodeling is suggested but studies in humans are lacking. This is a first study in humans investigating whether circulated levels of PAI-1 in postmenopausal women with T2DM are related to BMD and adiposity.
Methods: Anthropometric variables, PAI-1 and insulin levels, serum lipids and bone turnover markers were measured in 127 postmenopausal women with T2DM. A total of 117 female patients were divided according to lumbar spine BMD measurements via dual-energy x-ray absorptiometry in three groups: 47 with osteopenia, 21 with osteoporosis and 49 with normal BMD.
Results: Diabetic patients with normal BMD had significantly higher BMI, greater waist circumference and lower bone
turnover markers than diabetics with osteopenia and osteoporosis. PAI-1 was lower in diabetics with osteoporosis and
osteopenia compared with diabetics with normal BMD. Multiple regression analysis revealed insulin, triglycerides levels,
pyrilinks and beta blocker therapy to be the strongest predictors of PAI-1 levels. PAI-1 levels correlated with both L-BMD and hip BMD, but after adjustment for age and BMI association was no longer significant.
Conclusion: Our findings suggest that elevated PAI-1 levels are associated with higher BMD in obese diabetic patients but the possible implications of this finding and underlying mechanisms still remain unclear. Obviously, metabolic parameters, may affect both BMD and PAI-levels, and association of PAI-1 and BMD could be indirect. However, as pyrilinks is also independently and significantly negatively correlated to PAI-1 its direct involvement in bone metabolism is also plausible. Further investigations are needed to elucidate the nature of interaction of this matrix modulator in relation to energy and bone metabolism in humans
Structural and Electronic Determinants of Flavonoid Binding to Human Serum Albumin: an Extensive Ligand-based Study
No full textFlavonoids are ubiquitous plant metabolites that interfere with different biological processes in the human organism. After absorption they bind to human serum albumin (HSA), the most abundant carrier protein in the blood which also binds various hormones and drugs. Binding of flavonoids to HSA may impact their distribution, influencing the active concentration in the blood. To determine the most prominent features responsible for binding of 20 different flavonoid aglycones to the IIA region of HSA, in vitro fluorescence measurements and density functional theory (DFT) calculations were conducted. These results were then integrated to elucidate structure–affinity relationships. The presented results reveal that flavones and flavonoles bind most strongly to the IIA region of HSA. There are several electronic and structural determinants associated with flavonoid binding to this HSA region: high C3 nucleophilicity and partial charge of O4, high HOMO and LUMO energies, and coplanarity of AC and B rings. Both steric and electronic characteristics of flavonoids have a great impact on their binding to HSA, with hydrogen donor and acceptor properties and coplanarity being the most prominent
Total hip Endoprotesis in Femoral Neck Dislocation Fracture in a Young Person: Case Study
No full textPrijelomi kuka najučestaliji su među starijom populacijom kao posljedica pada u razini, dok je u osoba mlađe životne dobi ovaj tip prijeloma rijedak s incidencijom manjom od 10%, a u najvećem broju slučajeva uzrokovan je traumom visokog intenziteta. Povezuju se s velikim rizikom razvoja avaskularne nekroze glave femura, nesraštanjem, te značajnim skraćenje ekstremiteta. Prikazujemo slučaj 20-godišnjeg pacijenta s prijelomom proksimalnog dijela femura, te pregled recentne literature o principima i smjernicama operativnog liječenja prijeloma kuka u mlađih osoba.The majority of hip fractures occur in elderly patients and are considered extremely rare in young patients. They are caused by high energy trauma in most of the cases and the incidence is less than 10%. They are associated with avascular necrosis of the femoral head, malunion and significant limb shortening. We report a case of a 20-year-old patient with a hip fracture and a review of the recent literature considering the guidelines for operative treatment of hip fractures in young patients
Związek między stanem odżywienia a stosowaniem inhibitorów pompy protonowej u pacjentów poddawanych rehabilitacji kardiologicznej po leczeniu niedokrwiennej i zastawkowej choroby serca
No full textBACKGROUND: Multiple and yet uncertain connections exist between cardiovascular diseases and the nutritional status of patients, particularly in relation to cardiovascular treatments. Proton pump inhibitors (PPI) are among the most commonly used group of drugs.
AIM: To analyse utilisation of PPI in association with nutritional risk of patients scheduled for rehabilitation after treatment for ischaemic and valvular heart disease.
METHODS: Retrospective analyses on a consecutive sample of patients, which included drug utilisation of PPI and nutritional risk screening, using a standardised NRS-2002 tool. The patients (n = 536) were divided into groups based on previous cardiovascular treatments and use of PPI.
RESULTS: Nearly half of the patients (244, 46.1%) had PPI in their chronic therapy despite the clinically negligible prevalence of conditions that are their fundamental indications. The odds for using PPI in patients with increased nutritional risk, estimated by logistic regression, were 3.34 (95% confidence intervals [CI] 2.26-4.94), p 3: positive likelihood-ratio (LR) 2.35 (95% CI 2.10-2.60); negative LR 0.46 (95% CI 0.4-0.6); area under the curve (AUC) 0.720; p 6.36% (positive LR 2.22 [95% CI 2.00-2.50]; negative LR 0.41 [95% CI 0.30-0.50]; AUC 0.707; p < 0.001).
CONCLUSIONS: Utilisation of PPI was found to be of relatively high prevalence and significantly associated with parameters of nutritional risk screening. Furthermore, it was in correlation with the age of patients and the existence of chronic kidney disease, which are well-established predispositions for poor nutritional status. Nutritional risk seems to be additionally negatively challenged by utilisation of PPI due to gastric malabsorption and anaemia.Wstęp: Istnieją liczne i nieustalone w pełni powiązania między chorobami sercowo-naczyniowymi a stanem odżywienia
chorych, zwłaszcza w przypadku stosowania leków działających na układ sercowo-naczyniowy. Do grupy najczęściej wykorzystywanych preparatów należą inhibitory pompy protonowej (PPI).
Cel: Celem badania było przeanalizowanie zależności między stosowaniem PPI a ryzykiem związanym ze stanem odżywienia pacjentów poddawanych rehabilitacji kardiologicznej po leczeniu choroby niedokrwiennej i zastawkowej serca.
Metody: Przeprowadzono retrospektywną analizę kolejnych prób chorych obejmującą stosowanie PPI i badanie przesiewowe w kierunku ryzyka związanego ze stanem odżywienia, wykorzystując wystandaryzowane narzędzie NRS-2002. Pacjentów (n = 536) podzielono na grupy w zależności od wcześniejszego leczenia chorób sercowo-naczyniowych i stosowania PPI.
Wyniki: Prawie połowa chorych (244 osoby, 46,1%) przyjmowała PPI w ramach długookresowej terapii, mimo że zaburzenia
stanowiące podstawowe wskazania do ich stosowania występowały u niewielkiego (nieistotnego klinicznie) odsetka badanych. Prawdopodobieństwo stosowania PPI u chorych obciążonych zwiększonym ryzykiem związanym ze stanem odżywienia oszacowane metodą regresji logistycznej wynosiło 3,34 (95% przedział ufności [CI] 2,26–4,94), p 3: iloraz prawdopodobieństwa (LR) otrzymania wyniku dodatniego: 2,35 (95% CI 2,10–2,60); LR otrzymania wyniku ujemnego: 0,46 (95% CI 0,4–0,6); pole pod krzywą (AUC): 0,720; p 6,36% (LR wyniku dodatniego: 2,22 [95% CI 2,00–2,50]; LR wyniku ujemnego: 0,41 [95% CI 0,30–0,50]; AUC: 0,707; p < 0,001.
Wnioski: Stwierdzono, że leki z grupy PPI były wykorzystywane stosunkowo często. Terapia tymi preparatami wiązała się
istotnie z parametrami oceny ryzyka związanego ze stanem odżywienia, a także korelowała z wiekiem pacjentów i obecnością przewlekłej choroby nerek, będących uznanymi czynnikami predysponującymi do złego stanu odżywienia. Wydaje się, że stosowanie PPI dodatkowo zwiększa ryzyko związane ze stanem odżywienia ze względu na zmniejszenie wchłaniania w żołądku i niedokrwistość
Cultured Circulating Tumor Cells and Their Derived Xenografts for Personalized Oncology
No full textRecent cancer research has demonstrated the existence of circulating tumor cells (CTCs) in cancer patient's blood. Once identified, CTC biomarkers will be invaluable tools for clinical diagnosis, prognosis and treatment. In this review, we propose ex vivo culture as a rational strategy for large scale amplification of the limited numbers of CTCs from a patient sample, to derive enough CTCs for accurate and reproducible characterization of the biophysical, biochemical, gene expressional and behavioral properties of the harvested cells. Because of tumor cell heterogeneity, it is important to amplify all the CTCs in a blood sample for a comprehensive understanding of their role in cancer metastasis. By analyzing critical steps and technical issues in ex vivo CTC culture, we developed a cost-effective and reproducible protocol directly culturing whole peripheral blood mononuclear cells, relying on an assumed survival advantage in CTCs and CTC-like cells over the normal cells to amplify this specified cluster of cancer cells
Histopatološke promjene trahealne sluznice nakon totalne laringektomije
No full textThe aim of this study was to determine the long term histopathologic changes in tracheal mucosa after a total laryngectomy,
and to fi nd out the relationship between the progression of histopathologic changes in tracheal mucosa and the duration of breathing through the tracheostomy. Tracheal mucosal biopsies were taken from a total of 35 patients, of both sexes, who underwent a total laryngectomy for laryngeal carcinoma at least one year prior. Histologic specimens of tracheal mucosa were stained with hematoxylin and eosin and examined under light microscopy. Almost all of the patients demonstrated histopathologic changes or abnormalities. Based on the results, histological fi ndings were grouped into seven categories: normal respiratory epithelium, mild, moderate and advanced basal cell hyperplasia, squamous metaplasia, and slight and moderate and dysplasia. The time elapsed since surgery was calculated for each histopathological change separately. In laryngeal carcinoma patients, after a total laryngectomy histopathologic changes occur in tracheal mucosa. The mildest histopathological changes are found in the patients who had a longer period between the operation and the examination.Cilj ovog istraživanja bio je utvrditi kasne histopatološke promjene sluznice traheje nakon totalne laringektomije, te usporediti stupanj progresije histoloških promjena sluznice traheje u odnosu na vrijeme trajanja disanja kroz traheostomu. Bioptički uzorci sluznice traheje uzeti su od ukupno 35 ispitanika oba spola, kojima je zbog karcinoma larinksa učinjena totalna laringektomija najmanje godinu dana prije istraživanja. Histološki preparati obojeni su hemalaun - eozinom i pregledani svjetlosnim mikroskopom. Gotovo u svih ispitanika došlo je do histopatoloških promjena ili abnormalnosti. Temeljem dobivenih rezultata, histološki nalaz sluznice traheje grupiran je u sedam kategorija: normalni respiratorni epitel, blaga, umjerena i jaka hiperplazija bazalnih stanica, pločasta metaplazija i blaga i umjerena displazija. Vrijeme proteklo od operacije izračunato je za svaku patohistološku promjenu posebno. Kod bolesnika oboljelih od karcinoma larinksa, nakon totalne laringektomije dolazi do histopatoloških promjena sluznice traheje. Najblaže histopatološke promjene nađene su u bolesnika kod kojih je prošlo duže vremensko razdoblje između operacije i istraživanja