The association of V249I and T280M fractalkine receptor haplotypes with disease course of multiple sclerosis

We investigated the association of CX3CR1 genotypes/haplotypes with MS and performed the prediction analysis of protein sequence variants' effects on CX3CL1/CX3CR1 interaction. We found no association of CX3CR1 with MS susceptibility. Frequency of I(249)T(280) haplotype was significantly lower in SP compared to RR patients (RR>10 years, OR=0.30, 95%CI=0.11-0.79, p=0.01; OR=0.53, 95%CI=0.18-1.56, p=0.2, in SP<10 years vs. RR>10 years). Prediction analysis showed that I249 T280 protein variant would significantly affect CX3CL1/CX3CR1 interaction. Our results suggest that CX3CR1 I???T??? haplotype could have protective effect for switch to SP MS. Further research is warranted to validate and replicate currently observed results.     

Low frequency of NRAS and KRAS2 gene mutations in childhood myelodysplastic syndromes

In children, myelodysplastic syndromes (MDS) represent less then 10% of all hematological malignancies; consequently, molecular genetic studies dealing with this group of patients are scarce. We have analyzed 35 archival bone marrow samples of children with MDS for the presence of mutations in the first and second exons of the NRAS and KRAS2 genes. Mutations were detected with single-strand conformation polymorphism analysis in three patients. One patient harbored a mutation in the second exon of NRAS and two patients in the second exon of KRAS2. Sequencing was performed in two samples and novel mutations were found in both. One patient had a missense mutation in codon 45 of NRAS; the other had a silent mutation in codon 53 and a missense mutation in codon 55 of KRAS2.     

Postantibiotic effect of colistin alone and combined with vancomycin or meropenem against Acinetobacter spp. with well defined resistance mechanisms

Previous studies found short postantibiotic effect of colistin on Acinetobacter baumannii. Many studies have evaluated the potential for synergy between colistin and other antibiotics against A. baumannii. The aim of this study was to determine in vitro synergy and postantibiotic effect (PAE) of colistin alone and combined with other antibiotics (vancomycin or meropenem) against eight carbapenem-non-susceptible Acinetobacter spp. strains with defined resistance mechanisms. It was hypothesised that vancomycin or meropenem would prologue the PAE of colistin since it was previously found that they exert synergism with colistin in time-kill kinetics and chequerboard analysis. After exposure of 1?hour colistin alone exhibited the negative (???0.07?hour) (OXA-143), short (0.2–1.82?hours) (OXA-24, OXA-58, OXA-72, VIM-1+OXA-23, OXA-58+NDM-1, ISAba1/OXA-69) or moderate PAE (3.2?hours) for OXA-23 positive strain. When combined with vancomycin, the PAE was moderate (1.7–4?hours) with OXA-23, OXA-23+VIM-1, OXA-72 and OXA-24 positive strains while with OXA-58, OXA-143, OXA-58/NDM-1 and ISAba1/OXA-69 positive strains, it was not possible to calculate mean duration of PAE because there was no regrowth after exposure to antibiotics or it was longer than 5?hours. The combination with meropenem resulted in short (0.2?hours) (OXA-143), moderate (2.4–3.73?hours) (OXA-24, OXA-58, OXA-23, OXA-23+VIM-1), long PAE of 5?hours (OXA-23) or longer than 5?hours (OXA-58+VIM-1, ISAba1/OXA-69). From the clinical point of view, the prolongation of colistin PAE when combined with other antibiotics could provide a rationale for the modification of the dosing interval and could be important for the optimization of the treatment regimen and the minimization of drug-induced side effects.     

The impact of primary packaging on the quality of parenteral products

The unique approach in manufacturing of pharmaceutical dosage forms of active substances known to be unstable in aqueous solution is the introduction of lyophilization process. Nevertheless, these products must be reconstituted using the diluent from a separate container before application. The possible solution for this problem is the application of dual chamber vials comprising the freeze-dried product in a lower compartment of the vial and the solution for reconstitution in the upper chamber. The main issue in development of such product is the choice of contact packaging (rubber closures, glass vials and the container closure system as a whole). The most important parameter used for evaluation of the influence of contact material on product quality was the pH value. The results have shown that the type of vials (moulded or tubular glass) has no impact on pH shift of the solution for reconstitution (tested solution-TS), while significant differences in pH value of the TS were observed depending on the rubber closures formulation used (with some formulations, the pH shift during the test was 6.5-9.14). Benzyl alcohol assay during the tests remained unchanged. Integrity tests of the container closure system (CCS) have demonstrated the adequacy of the selected packaging system. The quality of the CCS of choice was confirmed in the course of stability studies, only parameters directly influenced by CCS being presented in this work: loss on drying and pH value. On the basis of these results, no changes in loss on drying were connected to CCS, and the pH value of the reconstituted solution remains unchanged in samples tested both ex-tempore and after in-use period of 48 h.     

Effect of potassium channel opener pinacidil on the contractions elicited electrically or by noradrenaline in the human radial artery

In order to discover an agent that can prevent spasm of the human radial artery, the aim of our study was to evaluate the effect of the K⁺ channel opener, pinacidil, on contractions in the radial artery. Contractions of the radial artery were evoked by exogenously applied noradrenaline or by electrical field stimulation (EFS, 20 Hz, neurogenic). Pinacidil induced concentration-dependent inhibition of both EFS- and noradrenaline-evoked contractions of the radial artery. Glibenclamide, a selective blocker of ATP-sensitive K⁺ channels (Kir6.x containing subunit) antagonized in the same manner the pinacidil-induced inhibition of neurogenic contractions and contractions evoked by exogenous noradrenaline. The inhibition of pinacidil relaxation by tetraethylammonium (TEA), a blocker of Ca-sensitive K⁺ (K_Ca) channels, was more pronounced in EFS-contracted preparations. A blocker of voltage-sensitive K⁺ (K_V) channels, 4-aminopyridine (4-AP), inhibited pinacidil relaxation only in EFS-contracted preparations. In order to test the presence of different K⁺ channels, immunohistochemistry of K⁺ channels expression in the radial artery was performed. The vascular wall of the human radial artery showed variable positivity with the following applied antibodies: Kv1.2, Kv1.3, Kir6.1, and K_Ca1.1. The antibodies against Kv1.6, Kv2.1, and Kir6.2 channel subunits were completely negative. These results suggest that the inhibitory effect of pinacidil on contractions of the human radial artery might be postsynaptic and associated with opening of smooth muscle Kir6.1-containing K_ATP channels. TEA- and 4-AP-sensitive K⁺ channels may also contribute to pinacidil effect in the human radial artery.     

Early diagnosis of asymptomatic neurocutaneous melanosis (60 month follow‐up)

Neurocutaneous melanosis (NCM) is a rare, sporadic, congenital neuroectodermal dysplasia. Large congenital melanocytic nevi (CMN) can evolve in a certain percentage of patients to NCM. Meningeal deposits are benign, but can be prone to malignant transformation in some cases. We describe the case of an infant with asymptomatic NCM, and typical magnetic resonance imaging (MRI) findings. The diagnosis was established shortly after delivery, and the patient was followed for 60 months. At that time, the girl did not have any neurologic symptoms; she reached normal developmental milestones and did not show mental retardation and did not develop malignant melanoma; further follow‐up will be needed, although there are no reliable guidelines as to the time range of follow up of asymptomatic NCM in the literature. We report the typical MRI signal abnormalities of the brain, and present a review of the literature regarding this rare and mysterious congenital disorder.     

Primary leiomyosarcoma of the thyroid gland with prior malignancy and radiotherapy:A case report and review of literature

BACKGROUND Leiomyosarcoma(LMS) of the thyroid gland is a rarely presented tumor that offers poor prognosis. To the best of the authors' knowledge, there currently exist only 28 known cases described in the literature(limited to English).CASE SUMMARY Herein a case is reported of a 60-year-old female patient who had an LMS of the thyroid, which was accompanied by periodic dysphonia and breathing disorder as well as the feeling of pressure in the chest and neck. At the time the disease was diagnosed, no metastases were detected. Prior to the diagnosis, the patient experienced a uterine adenocarcinoma that had been treated by surgical procedure and radiotherapy. For the LMS, a total thyroidectomy was performed,followed by radiotherapy. Since metastases were also discovered in the lungs,sternum, and femur, chemotherapy was administered as well.Immunohistochemically, the tumor cells in the thyroid indicated positively for alpha smooth muscle actin, calponin, and H-caldesmon, but were negative for CD34, p63, estrogen receptor, progesterone receptor, and Epstein-Barr virus.CONCLUSION Although the etiology of the LMS is as of yet unknown, prior malignancy and radiation should be considered as risk factors.     

Gefitinib plus cisplatin and radiotherapy in previously untreated head and neck squamous cell carcinoma: A phase II, randomized, double-blind, placebo-controlled study

Background and purpose

To assess the efficacy and safety of gefitinib given concomitantly and/or as maintenance therapy to standard cisplatin/radiotherapy for previously untreated, unresected, stage III/IV non-metastatic SCCHN.

Materials and methods

In this phase II, double-blind, study, 226 patients were randomized to gefitinib 250 mg/day, 500 mg/day or placebo in two phases: a concomitant phase (gefitinib or placebo with chemoradiotherapy), followed by a maintenance phase (gefitinib or placebo alone). Primary endpoint was local disease control rate (LDCR) at 2 years; secondary endpoints were LDCR at 1 year, objective response rate, progression-free survival, overall survival, and safety and tolerability.

Results

Gefitinib (250 and 500 mg/day) did not improve 2-year LDCR compared with placebo either when given concomitantly with chemoradiotherapy (32.7% vs. 33.6%, respectively; OR 0.921, 95% CI 0.508, 1.670 [1-sided p = 0.607]) or as maintenance therapy (28.8% vs. 37.4%, respectively; OR 0.684, 95% CI 0.377, 1.241 [1-sided p = 0.894]). Secondary efficacy outcomes were broadly consistent with the 2-year LDCR results. In both doses, gefitinib was well-tolerated and did not adversely affect the safety and tolerability of concomitant chemoradiotherapy.

Conclusion

Gefitinib was well-tolerated, but did not improve efficacy compared with placebo when given concomitantly with chemoradiotherapy, or as maintenance therapy alone.     

Magnetic resonance imaging in the evaluation of uterus didelphys with obstructed hemivagina and renal agenesis: a case report

Uterus didelphys with obstructed hemivagina and ipsilateral renal agenesis usually presents after menarche with progressive abdominal pain during menses secondary to hematocolpos. Initially, the anomaly remains unrecognized, while patients most frequently referred to surgeons for assistance. The method of choice for diagnosis is magnetic resonance imaging. A greater awareness of the syndrome of uterus didelphys, obstructed hemivagina and ipsilateral renal agenesis should lead to its prompt diagnosis, allowing for early and appropriate surgical treatment as well as decreased long-term morbidity. Transvaginal excision of the septum is the appropriate mode of treatment.