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Objective: To reveal the profile and practice in patients with acute stroke who received intravenous tissue plasminogen activator (IV tPA) and/or neuro-interventional therapy in Türkiye. Materials and Methods: On World Stroke Awareness Day, May 10, 2018, 1,790 patients hospitalized in 87 neurology units spread over 30 health regions were evaluated retrospectively and prospectively. Results: Intravenous tPA was administered to 12% of 859 cases of acute ischemic stroke in 45 units participating in the study. In the same period, 8.3% of the cases received neurointerventional treatment. The rate of good prognosis [modified Rankin score (mRS) 0–2] at discharge was 46% in 83 patients who received only IV tPA [age: 67 +- 12 years; National Institutes of Health Stroke Scale (NIHSS): 12 +- 6; hospital stay, 24 +- 29 days]; 35% in 51 patients who underwent thrombectomy (MT) alone (age: 64 +- 13 years; NIHSS: 14.1 +- 6.5; length of hospital stay, 33 +- 31 days), 19% in those who received combined treatment (age: 66 +- 14 years; NIHSS: 15.6 +- 5.4; length of hospital stay, 26 +- 35 days), and 56% of 695 patients who did not receive treatment for revascularization (age: 70 +- 13 years; NIHSS: 7.6 +- 7.2; length of hospital stay, 21 +- 28 days). The symptom-to-door time was 87 +- 53 minutes in the IV treatment group and 200 +- 26 minutes in the neurointerventional group. The average door-to-needle time was 66 +- 49 minutes in the IV tPA group. In the neurothrombectomy group, the door-to-groin time was 103 +- 90 minutes, and the TICI 2b-3 rate was 70.3%. In 103 patients who received IV tPA, the discharge mRS 0–2 was 41%, while the rate of mRS 0–1 was 28%. In 71 patients who underwent neurothrombectomy, the mRS 0–2 was 31% and mRS 0–1 was 18%. The door-to-groin time was approximately 30 minutes longer if IV tPA was received (125 +- 107 and 95 +- 83 minutes, respectively). Symptomatic bleeding rates were 4.8% in IV recipients, 17.6% among those who received only MT, and 15% in combined therapy. Globally, the hemorrhage rate was 6.8% in patients receiving IV tPA and 16.9% in MT. Conclusion: IV thrombolytic and neurointerventional treatment applications in acute ischemic stroke in Türkiye can provide the anticipated results. Heterogeneity has begun to be reduced in our country with the dissemination of the system indicated by the 'Directive on Health Services to be Provided to Patients with Acute Stroke.'

Objective: Atrial fibrillation (AF) is the most common directly preventable cause of ischemic stroke. There is no dependable neurology-based data on the spectrum of stroke caused by AF in our country. Within the scope of NeuroTek-Turkey, hospital-based data on acute stroke patients with AF were collected to contribute to the creation of acute stroke algorithms. Materials and Methods: Atrial fibrillation (AF) is the most common directly preventable cause of ischemic stroke. There is no dependable neurology-based data on the spectrum of stroke caused by AF in Türkiye. Within the scope of NöroTek-Türkiye (TR), hospital-based data on acute stroke patients with AF were collected to contribute to the creation of acute-stroke algorithms. Results: The rate of AF in patients hospitalized for ischemic stroke/TIA was 29.8%, of which 65% were known before stroke, 5% were paroxysmal, and 30% were diagnosed after hospital admission. The proportion of patients with AF who received 'effective' treatment [international normalization ratio ≥2.0 warfarin or non-vitamin K antagonist oral anticoagulants (NOACs) at a guideline dose] was 25.3%, and, either no medication or only antiplatelet was used in 42.5% of the cases. The low dose rate was 50% in 42 patients who had a stroke while taking NOACs. Anticoagulant was prescribed to the patient at discharge at a rate of 94.6%; low molecular weight or unfractionated heparin was prescribed in 28.1%, warfarin in 32.5%, and NOACs in 31%. The dose was in the low category in 22% of the cases discharged with NOACs, and half of the cases, who received NOACs at admission, were discharged with the same drug. Conclusion: NöroTekTR revealed the high but expected frequency of AF in acute stroke in Türkiye, as well as the aspects that could be improved in the management of secondary prophylaxis. AF is found in approximately one-third of hospitalized acute stroke cases in Türkiye. Effective anticoagulant therapy was not used in three-quarters of acute stroke cases with known AF. In AF, heparin, warfarin, and NOACs are planned at a similar frequency (one-third) within the scope of stroke secondary prophylaxis, and the prescribed NOAC dose is subtherapeutic in a quarter of the cases. Non-medical and medical education appears necessary to prevent stroke caused by AF.

Objective: Nutritional status assessment, dysphagia evaluation and enteral feeding decision are important determinants of prognosis in acute neurovascular diseases. Materials and Methods: NöroTek is a point prevalence study conducted with the participation of 87 hospitals spread across all health sub regions of Turkey conducted on 10-May-2018 (World Stroke Awareness Day). A total of 972 hospitalized neurovascular patients [female: 53%, age: 69+-14; acute ischemic stroke in 845; intracerebral hematoma (ICH) in 119 and post-resuscitation encephalopathy (PRE) in 8] with complete data were included in this sub-study. Results: Gastrostomy was inserted in 10.7% of the patients with ischemic stroke, 10.1% of the patients with ICH and in 50% of the patients with PRE. Independent predictors of percutaneous endoscopic gastrostomy (PEG) administration were The National Institutes of Health Stroke Scale score at admission [exp (β): 1.09 95% confidence interval (CI): 1.05-1.14, per point] in ischemic stroke; and mechanical ventilation in ischemic [exp (β): 6.18 (95% CI: 3.16-12.09)] and hemorrhagic strokes [exp (β): 26.48 (95% CI: 1.36-515.8)]. PEG was found to be a significant negative indicator of favorable (modified Rankin's scale score 0-2) functional outcome [exp (β): 0.032 (95% CI: 0.004-0.251)] but not of in-hospital mortality [exp (β): 1.731 (95% CI: 0.785-3.829)]. Nutritional and swallowing assessments were performed in approximately two-thirds of patients. Of the nutritional assessments 69% and 76% of dysphagia assessments were completed within the first 2 days. Tube feeding was performed in 39% of the patients. In 83.5% of them, tube was inserted in the first 2 days; 28% of the patients with feeding tube had PEG later. Conclusion: The NöroTek study provided the first reliable and large-scale data on key quality metrics of nutrition practice in acute stroke in Turkey. In terms of being economical and accurate it makes sense to use the point prevalence method.

Sphingosine 1-phosphate (S1P) lyase (SPL, Sgpl1) is an ER-associated enzyme that irreversibly degrades the bioactive lipid, S1P, and thereby regulates multiple cellular functions attributed to S1P. Biallelic mutations in the human Sglp1 gene lead to a severe form of a particular steroid-resistant nephrotic syndrome, suggesting that the SPL is critically involved in maintaining the glomerular ultrafiltration barrier, which is mainly built by glomerular podocytes. In this study, we have investigated the molecular effects of SPL knockdown (kd) in human podocytes to better understand the mechanism underlying nephrotic syndrome in patients. A stable SPL-kd cell line of human podocytes was generated by the lentiviral shRNA transduction method and was characterized for reduced SPL mRNA and protein levels and increased S1P levels. This cell line was further studied for changes in those podocyte-specific proteins that are known to regulate the ultrafiltration barrier. We show here that SPL-kd leads to the downregulation of the nephrin protein and mRNA expression, as well as the Wilms tumor suppressor gene 1 (WT1), which is a key transcription factor regulating nephrin expression. Mechanistically, SPL-kd resulted in increased total cellular protein kinase C (PKC) activity, while the stable downregulation of PKCδ revealed increased nephrin expression. Furthermore, the pro-inflammatory cytokine, interleukin 6 (IL-6), also reduced WT1 and nephrin expression. In addition, IL-6 caused increased PKCδ Thr505 phosphorylation, suggesting enzyme activation. Altogether, these data demonstrate that nephrin is a critical factor downregulated by the loss of SPL, which may directly cause podocyte foot process effacement as observed in mice and humans, leading to albuminuria, a hallmark of nephrotic syndrome. Furthermore, our in vitro data suggest that PKCδ could represent a new possible pharmacological target for the treatment of a nephrotic syndrome induced by SPL mutations.

Erythropoietin (Epo) is a crucial hormone regulating red blood cell number and consequently the hematocrit. Epo is mainly produced in the kidney by interstitial fibroblast-like cells. Previously, we have shown that in cultures of the immortalized mouse renal fibroblast-like cell line FAIK F3-5, sphingosine 1-phosphate (S1P), by activating S1P1 and S1P3 receptors, can stabilize hypoxia-inducible factor (HIF)-2α and upregulate Epo mRNA and protein synthesis. In this study, we have addressed the role of intracellular iS1P derived from sphingosine kinases (Sphk) 1 and 2 on Epo synthesis in F3-5 cells and in mouse primary cultures of renal fibroblasts. We show that stable knockdown of Sphk2 in F3-5 cells increases HIF-2α protein and Epo mRNA and protein levels, while Sphk1 knockdown leads to a reduction of hypoxia-stimulated HIF-2α and Epo protein. A similar effect was obtained using primary cultures of renal fibroblasts isolated from wildtype mice, Sphk1−/−, or Sphk2−/− mice. Furthermore, selective Sphk2 inhibitors mimicked the effect of genetic Sphk2 depletion and also upregulated HIF-2α and Epo protein levels. The combined blockade of Sphk1 and Sphk2, using Sphk2−/− renal fibroblasts treated with the Sphk1 inhibitor PF543, resulted in reduced HIF-2α and Epo compared to the untreated Sphk2−/− cells. Exogenous sphingosine (Sph) enhanced HIF-2α and Epo, and this was abolished by the combined treatment with the selective S1P1 and S1P3 antagonists NIBR-0213 and TY52156, suggesting that Sph was taken up by cells and converted to iS1P and exported to then act in an autocrine manner through S1P1 and S1P3. The upregulation of HIF-2α and Epo synthesis by Sphk2 knockdown was confirmed in the human hepatoma cell line Hep3B, which is well-established to upregulate Epo production under hypoxia. In summary, these data show that sphingolipids have diverse effects on Epo synthesis. While accumulation of intracellular Sph reduces Epo synthesis, iS1P will be exported to act through S1P1+3 to enhance Epo synthesis. Furthermore, these data suggest that selective inhibition of Sphk2 is an attractive new option to enhance Epo synthesis and thereby to reduce anemia development in chronic kidney disease.

sinir üzerine etkisinin değerlendirilmesi amaçlanmıştır.Gereç ve Yöntem: Katılımcılar akıllı telefon kullanımı fazla olanlar (Akıllı telefon bağımllık ölçeği (SAS) skoru 71 üzerinde olanlar), az kullanımı olanlar (71'nin altındakiler) ve klasik cep telefonu kullananlar olarak 3 gruba ayrılarak değerlendirildi. Katılımcıların görsel analog skala (VAS), kol, omuz ve elin hızlı yetersizlikleri (qDASH) değerleri ve median sinir iletileri değerlendirildi. Bulgular: Akıllı telefonu az kullanan grupta diğer 2 gruba göre anlamlı derecede median sinir latanslarının daha kısa ve hızlarının yüksek olduğu gözlendi. Ancak, akıllı telefonu fazla kullananlar ile klasik cep telefonu kullananlar arasında median sinir iletileri açısından anlamlı fark gözlenmedi. VAS ve qDASH değerlerinde gruplar arasında anlamlı fark gözlenmedi.Sonuç: Aşırı akıllı telefon kullanımı karpal tünel sendromu ve buna bağlı median sinirin etkilenmesine neden olabilir. Akıllı telefonların yaygınlaştığı hatta bağımlılık düzeyinde kullanımının olduğu günümüzde telefon tasarımlarında bu durumlar akılda tutulmalı belki de sesli komut uygulamalarında daha çok yer verilmelidir. Ayrıca akıllı telefon bağımlılığı olan hastalarda median sinir iletilerinin elektrofizyolojik olarak takip edilmesi faydalı olabilir.

Erythropoietin (Epo) is the critical hormone for erythropoiesis. In adults, Epo is mainly produced by a subset of interstitial fibroblasts in the kidney, with minor amounts being produced in the liver and the brain. In this study, we used the immortalized renal interstitial fibroblast cell line FAIK F3-5 to investigate the ability of the bioactive sphingolipid sphingosine 1-phosphate (S1P) to stimulate Epo production and to reveal the mechanism involved. Stimulation of cells with exogenous S1P under normoxic conditions (21% O2) led to a dose-dependent increase in Epo mRNA and protein levels and subsequent release of Epo into the medium. S1P also enhanced the stabilization of HIF-2α, a key transcription factor for Epo expression. S1P-stimulated Epo mRNA and protein expression was abolished by HIF-2α mRNA knockdown or by the HIF-2 inhibitor compound 2. Furthermore, the approved S1P receptor modulator FTY720, and its active form FTY720-phosphate, both exerted a similar effect on Epo expression as S1P. The effect of S1P on Epo was antagonized by the selective S1P1 and S1P3 antagonists NIBR-0213 and TY-52156, but not by the S1P2 antagonist JTE-013. Moreover, inhibitors of the classical MAPK/ERK, the p38-MAPK, and inhibitors of protein kinase (PK) C and D all blocked the effect of S1P on Epo expression. Finally, the S1P and FTY720 effects were recapitulated in the Epo-producing human neuroblastoma cell line Kelly, suggesting that S1P receptor-dependent Epo synthesis is of general relevance and not species-specific. In summary, these data suggest that, in renal interstitial fibroblasts, which are the primary source of plasma Epo, S1P1 and 3 receptor activation upregulates Epo under normoxic conditions. This may have a therapeutic impact on disease situations such as chronic kidney disease, where Epo production is impaired, causing anemia, but it may also have therapeutic value as Epo can mediate additional tissue-protective effects in various organs.

Sphingosine 1-phosphate (S1P) is an extensively studied signaling molecule that contributes to cell proliferation, survival, migration and other functions through binding to specific S1P receptors. The cycle of S1P1 internalization upon S1P binding and recycling to the cell surface when local S1P concentrations are low drives T cell trafficking. S1P1 modulators, such as fingolimod, disrupt this recycling by inducing persistent S1P1 internalization and receptor degradation, which results in blocked egress of T cells from the secondary lymphoid tissues. The approval of these compounds for the treatment of multiple sclerosis has placed the development of S1PR modulators in the focus of pharmacological research, mostly for autoimmune indications. Here, we report on a novel anellated bismorpholino derivative of oxy-fingolimod, named ST-2191, which exerts selective S1P1 agonist and functional antagonist potency. ST-2191 is also effective in reducing the lymphocyte number in mice, and this effect is not dependent on phosphorylation by sphingosine kinase 2 for activity. These data show that ST-2191 is a novel S1P1 modulator, but further experiments are needed to analyze the therapeutic impact of ST-2191 in animal models of autoimmune diseases.

Lafora disease (LD) is a progressive myoclonus epilepsy with autosomal recessive inheritance. Clinical course is progressive and includes myoclonic, cerebellar, and extrapyramidal signs, generalized tonic-clonic seizures, and cognitive decline. Valproic acid, zonisamide, levetiracetam, clonazepam, and piracetam are among the treatment options. Carbamazepine (CBZ), oxcarbazepine, phenytoin, and lamotrigine (LM) should be avoided to prevent worsening of symptoms. Though evidence is limited, perampanel is the only drug to achieve sustained improvement in frequency of seizures, and effective control of neurological and cognitive decline in patients with LD. Described in the present report is a case of typical LD with clinical worsening on CBZ and LM treatment. Electroencephalographic and pathologic findings are reported.

Cardaria draba is considered as one of the most fundamental plants that have wide diversity in medical uses, other researches had shown that this plant has a strong antioxidant activity for this reason the idea came to look for the cytotoxicity of this plant extract against different carcinogenic cell lines after subjection of this plant to methanolic extraction method.Result declared strong cytotoxicity against those carcinogenic cell line with a variable values of IC50 and the best effect was seen against HepG2 cell line, then we looked for the reason behind this reduction in viability of the cells via performing Caspase 9 assay which is used to check the induction of apoptosis and the expression of the TNF-α as a strong transcription factor which is activated in tumor cell lines. Interestingly, our finding suggested that the plant extract produced a positive effect in the induction of Caspase 9 which led to induce early apoptosis, regarding TNF-α expression; the result explained a significant reduction in expression of those genes which were correlated with induction of tumor. This meant that the reduction in cell viability resulted in the induction of apoptosis and reduction of TNF-α transcription genes.

The corpus callosum is the biggest commissural structure located in two brain hemispheres and it ensures the connection between cortical and subcortical neurons. The agenesis of the corpus callosum is generally diagnosed in the prenatal period or childhood. It is observed along with congenital abnormalities such as mental and motor retardation, seizures, myelomeningocele. In this article, we reported a case of colpocephaly and corpus callosum agenesis with no symptoms that diagnosed incidentally. [Cukurova Med J 2016; 41(3.000): 564-566]

Possible synergistic effect of tamoxifen (2 μM) and hydrazinyldiene-chroman-2,4-diones (10-100 μM) was examined with an aim to create more effective treatment for ER+ breast cancer. Anti-breast cancer effect has been evaluated on the proliferation of MCF-7 breast adenocarcinoma cells using MTT and alamarBlue assays. Cell viability was evaluated after 48h-treatment and the ICs50 of the coumarin derivatives were determined. The apoptotic effect was evaluated by detection of PARP cleavage and reduced activity of the survival kinase Akt. The results demonstrated dose-dependent activity, with a percent of growth inhibition after combination treatment being significantly higher (53% to 79%, 10 μM and 100 μM, respectively) than the one in the cell lines treated with tamoxifen (29% to 37%) and the synthesized coumarin derivatives alone (11% to 68%, 10 μM and 100 μM, respectively). The ICs50 of the synthesized compounds significantly decreased in synergy with tamoxifen (33% to 51%). Coumarin derivative having thiazole moiety with additional methyl groups attached to the carbons at positions 5 and 4 in the thiazole ring showed to be the most potent, with IC50 20 µM when administered alone and 10 µM in synergy with tamoxifen. The levels of phospho-Thr308 Akt were down-regulated by the combination treatment, pointing to tyrosine kinase phosphorylation inhibition. In conclusion, the novel coumarin derivatives enhance the activity of tamoxifen and this combination may be suitable for prevention of ER+ breast cancer or development of related compounds. Further studies are needed to elucidate precisely the type of receptor involved in the activity and the mechanism of action.

Diyabetik üremik hastalarda akut bilateral bazal gangliyon oluşumu ile ilişkili sendromlar yaygın değildir. Üremik ensefalopati tipik olarak kortikal tutulum gösterir. Konfüzyon, nöbetler, tremor ve myoklonik nöbetler görülür. Bazal gangliyonlar anatomik olarak tutulursa kore dahil hareket bozuklukları görülür. Biz bu vakada koreye neden olan, bazal gangliyon tutulumlu üremik diyabetik hastayı nadir görülmesi nedeniyle sunduk.

Syndromes associated with acute bilateral lesions of the basal ganglia in diabetic uremic patients are uncommon. Uremic encephalopathy is typical of patients showing cortical involvement, with symptoms including confusion, seizures, tremors, or myoclonus. Whenever basal ganglia are anatomically involved, movement disorders arise, including chorea. In this article we present a case with basal ganglia involvement in a uremic diabetic patient causes chorea because of rare presentation. [Cukurova Med J 2014; 39(2.000): 353-356]

Cluster headache (CH) is one of the most severe types of headache, characterized by periods of recurrent attacks of sudden and intense pain, localized in the orbital or temporal region, and associated with ipsilateral autonomic symptoms and signs. The mean age of onset of CH is in the late third decade. Only few cases of childhood-onset ( [Med-Science 2014; 3(1.000): 1136-9]

Genetic factors are associated with susceptibility to many infectious diseases and may be determinants of clinical progression. Gene copy number variation (CNV) has been shown to be associated with phenotypes of numerous diseases, including malaria. We quantified gene copy numbers of the pyruvate kinase, liver, and red blood cell (PKLR) gene as well as of the Fcγ receptor 2A and Fcγ receptor 2C (FCGR2A, FCGR2C) and Fcγ receptor 3 (FCGR3) genes using real-time quantitative polymerase chain reaction (RT-qPCR) assays in Gabonese children with severe (n = 184) or and mild (n = 189) malaria and in healthy Gabonese and white individuals (n = 76 each). The means of PKLR, FCGR2A, FCGR2C, and FCGR3 copy numbers were significantly higher among children with severe malaria compared to those with mild malaria (P < .002), indicating that a surplus of copies of those genes is significantly associated with malaria severity. Copy numbers of the FCGR2A and FCGR2C genes were significantly lower (P = .005) in Gabonese individuals compared with white individuals. In conclusion, CNV of the PKLR, FCGR2A, FCGR2C, and FCGR3 genes is associated with malaria severity, and our results provide evidence for a role of CNV in host responses to malaria., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Ficolin-2 coded by FCN2 gene is a soluble serum protein that plays an important role in innate immunity. In this study, we analyzed five functional polymorphisms of the FCN2 gene for their possible association with cutaneous leishmaniasis., Methods: Initially we screened 40 Syrian Arabs for the entire FCN2 gene. We investigated the contribution of FCN2 functional variants in 226 patients with cutaneous leishmaniasis and 286 healthy controls from Syria. Polymorphisms in the promoter regions (-986G/A, -602G/A, -4A/G) of the FCN2 gene were assessed by TaqMan real time PCR, whereas polymorphisms in exon8 (+6359C/T and +6424G/T) were assessed by DNA sequencing. We also measured serum ficolin-2 levels in 70 control Syrian Arabs and correlated the serum concentrations to FCN2 genotypes and haplotypes respectively., Results: Nine new FCN2 variants including two with non synonymous substitutions in exon6 and exon8 were observed. The homozygous genotypes +6424T/T were distributed more in controls and none in patients (P = 0.04). The AGACG haplotype were observed more in patients than in controls (OR = 2.0, 95%CI 1.2-3.4, P = 0.006). The serum ficolin-2 levels were significantly distributed among the reconstructed ficolin-2 haplotypes (P<0.008) and the haplotype AGACG was observed with higher ficolin-2 levels in 70 control individuals., Conclusion: Our results demonstrate a significant association of FCN2 AGACG haplotype with cutaneous leishmaniasis in a Syrian Arab population. These first results provide a basis for a future study that could confirm or disprove possible relationships between FCN2 gene polymorphisms with cutaneous leishmaniasis.

Human ficolin-2 (L-ficolin; FCN2) is a serum protein binding to sugar moieties of different human micro-pathogens forcing phagocytosis. Here, we investigate the clinical significance of FCN2 in African children with either mild or severe malaria (n = 130 and n = 108, respectively) from Gabon by analyzing three promoter SNPs (-986G>A, -602G>A, and -4A>G) and one single nucleotide polymorphisms (SNP) in exon 8 (+6424G>T) using quantitative TaqMan, real-time polymerase chain reaction (PCR). In addition, we measured the ficolin-2 plasma levels at two time points: on admission (t(0), acute disease) and 4 weeks after treatment (t(1), healthy phase). Comparison of ficolin-2 plasma levels shows that ficolin-2 concentration is highest during acute severe disease. In addition, we determined polymorphisms in the promoter and all coding regions of FCN2 in 40 Gabonese. Linkage disequilibrium data revealed polymorphic allelic combination patterns in the FCN2 promoter region; strong allelic combinations at -986 and -4, and -557 and -64 were found. No FCN2 promoter haplotypes were significantly distributed between mild and severe cases., (Copyright © 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

In this group we would like to answer the question why people show a different response against certain pathogens. In many infections the course of the disease can range from asymptomatic carriage to the severest forms even death. In the past we have analysed candidate genes and their role in the course of malaria and could detect some polymorphisms influencing infectious diseases in the genes encoding NOS2, MBL2, IFNa, FCN2, and receptors for IFNg and IFNa. Having worked initially mainly on malaria we broadened our spectrum also to other infectious diseases like hepatitis B, Leprosy, schistosomiasis. Here we give a short overview about ongoing projects.

In humans, infections contribute highly to mortality and morbidity rates worldwide. Malaria tropica is one of the major infectious diseases globally and is caused by the protozoan parasite Plasmodium falciparum. Plasmodia have accompanied human beings since the emergence of humankind. Due to its pathogenicity, malaria is a powerful selective force on the human genome. Genetic epidemiology approaches such as family and twin studies, candidate gene studies, and disease-association studies have identified a number of genes that mediate relative protection against the severest forms of the disease. New molecular approaches, including genome-wide association studies, have recently been performed to expand our knowledge on the functional effect of human variation in malaria. For the future, a systematic determination of gene-dosage effects and expression profiles of protective genes might unveil the functional impact of structural alterations in these genes on either side of the host-parasite interaction.

Objectives: We studied the role of the regulatory T cells CD4+CD25+ (Treg) and activated CD4+CD30+ cells in the pathogenesis of asthma and their association with apoptosis and NF-kappaB in patients with mild intermittent asthma (MA), severe persistent asthma (SA), and healthy volunteers (HV)., Methods: Peripheral blood lymphocytes (PBL) were extracted from asthmatic patients during exacerbations, and CD4+ cells were separated using Dynal beads. Immunostaining of whole PBL for NF-kappaB, Bax, and Bcl-2, and immunostaining of CD4+ cells for CD25+ and CD30+ cells were performed using immunocytochemistry., Results: Treg cells were expressed at higher levels in MA than in HV and SA (P < .05), while CD30+ T cells were expressed at higher levels in both SA and MA than in HV (P < .05), although there was no remarkable difference between SA and MA (P>.05). Levels of NF-kappaB, Bcl-2, and Bcl-2/Bax increased, whereas those of Bax decreased, progressively, from MA to SA (P < .05). NF-kappaB levels correlated directly with the Bcl-2/Bax ratio and with CD4+CD30+ cells in SA and MA, whereas CD4+CD30+ cells correlated inversely with the Bcl-2/Bax ratio., Conclusions: Unregulated Treg cells probably return inflammatory responses to normal values during exacerbations in MA; however, expression of Treg cells was extensively diminished in SA, leading to probable loss of suppressive control over underlying immune reactions. CD4+CD30+ cells were associated with the pathogenesis of asthma but not with severity. NF-kappaB seems to be the central inflammatory factor in SA, with a remarkable loss of PBL apoptosis, diminished Treg levels, and high CD30+ cell levels that probably induce NF-kappaB, which in turn blocks the proapoptotic potential of CD30 induction itself.

In the context of drug eluting stent, we present two-dimensional numerical models of mass transport of the drug in the wall and in the lumen to study the effect of the drug diffusion coefficients in the three principal media (blood, vascular wall, and polymer coating treated as a three-compartment problem) and the impact of different strut apposition configurations (fully embedded, half embedded, and not embedded). The different conditions were analyzed in terms of their consequence on the drug concentration distribution in the arterial wall. We apply the concept of the therapeutic window to the targeted vascular wall region and derive simple metrics to assess the efficiency of the various stent configurations. Although most of the drug is dispersed in the lumen, variations in the blood flow rate within the physiological range of coronary blood flow and the diffusivity of the drug molecule in the blood were shown to have a negligible effect on the amount of drug in the wall. Our results reveal that the amount of drug cumulated in the wall depends essentially on the relative values of the diffusion coefficients in the polymer coating and in the wall. Concerning the strut apposition, it is shown that the fully embedded strut configuration would provide a better concentration distribution.

Stenting is becoming the major interventional cardiology procedure worldwide. However restenosis remains a major limitation to the effectiveness of stents. Alterations to the local hemodynamics in the stented segment of the artery could be a potential factor in the development of in-stent restenosis. The characterization of wall shear stress and of blood flow patterns in a stented artery is therefore necessary for a good understanding of the role of hemodynamics in the development of in-stent restenosis. We have used a time-dependent 3D numerical model of a stented coronary artery to study the characteristics of the blood flow and the shear stress distribution. Our results show that the presence of the stent produces significant secondary flow that is limited to an annulus in the near wall region. Low shear stress zones were localized in the vicinity of the struts while the tips of the struts exhibited high values of shear stress. These results support the hypothesis that local hemodynamics may affect the development of in-stent restenosis and could influence the choice of stent geometries for future stent designs.

One of the principal therapies considered for the control of in-stent restenosis is the use of drug loaded polymer-coated stents for local delivery. We present two-dimensional and three-dimensional numerical models to study local delivery of drug eluting stents. The impact of various stent and flow parameters on the concentration distribution in the wall are investigated including the effect of the strut size, coating thickness, strut inter-distance and strut embedment in the vascular wall, blood flowing speed and the respective diffusion coefficients in the blood, wall and polymer. We also present criteria to assess the drug delivery efficiency based of the concept of the therapeutic window which aims at an spatial homogeneous concentration distribution and we introduce the variables to assess the amount of drug delivered in the wall. The results suggest that advection have a much stronger effect compared to diffusion in the blood media and that drug diffusivity in the arterial wall and in the polymer coating significantly affects the drug distribution. It is also shown that fully-embedded struts provide better spatial drug concentration uniformity after a short period of time and the half-embedded struts have a better temporal uniformity.