Repeated Baclofen treatment ameliorates motor dysfunction,suppresses reflex activity and decreases the expression of signaling proteins in reticular nuclei and lumbar motoneurons after spinal trauma in rats

The interruption of supraspinal input to the spinal cord leads to motor dysfunction and the development of spasticity. Clinical studies have shown that Baclofen (a GABA_B agonist), while effective in modulating spasticity is associated with side-effects and the development of tolerance. The aim of the present study was to assess if discontinued Baclofen treatment and its repeated application leads antispasticity effects, and whether such changes affect neuronal nitric oxide synthase (nNOS) in the brainstem, nNOS and parvalbumin (PV) in lumbar α-motoneurons and glial fibrillary acidic protein in the ventral horn of the spinal cord. Adult male Wistar rats were exposed to Th9 spinal cord transection. Baclofen (30 mg/b.w.) diluted in drinking water, was administered for 6 days, starting at week 1 after injury and then repeated till week 4 after injury. The behavior of the animals was tested (tail-flick test, BBB locomotor score) from 1 to 8 weeks. Our results clearly indicate the role of nitric oxide, produced by nNOS in the initiation and the maintenance of spasticity states 1, 6 and 8 weeks after spinal trauma. A considerable decrease of nNOS staining after Baclofen treatment correlates with improvement of motor dysfunction. The findings also show that parvalbumin and astrocytes participate in the regulation of ion concentrations in the sub-acute phase after the injury.     

Iron status in patients with pyruvate kinase deficiency: neonatal hyperferritinaemia associated with a novel frameshift deletion in the PKLR gene (p.Arg518fs), and low hepcidin to ferritin ratios

Pyruvate kinase (PK) deficiency is an iron‐loading anaemia characterized by chronic haemolysis, ineffective erythropoiesis and a requirement for blood transfusion in most cases. We studied 11 patients from 10 unrelated families and found nine different disease‐causing PKLR mutations. Two of these mutations ‐ the point mutation c.878A>T (p.Asp293Val) and the frameshift deletion c.1553delG (p.(Arg518Leufs*12)) ‐ have not been previously described in the literature. This frameshift deletion was associated with an unusually severe phenotype involving neonatal hyperferritinaemia that is not typical of PK deficiency. No disease‐causing mutations in genes associated with haemochromatosis could be found. Inappropriately low levels of hepcidin with respect to iron loading were detected in all PK‐deficient patients with increased ferritin, confirming the predominant effect of accelerated erythropoiesis on hepcidin production. Although the levels of a putative hepcidin suppressor, growth differentiation factor‐15, were increased in PK‐deficient patients, no negative correlation with hepcidin was found. This result indicates the existence of another as‐yet unidentified erythroid regulator of hepcidin synthesis in PK deficiency.     

NT-proBNP levels on admission predicts pulmonary hypertension persistence in patients with acute pulmonary embolism

BackgroundChronic thromboembolic pulmonary hypertension (CTEPH) is a rare, but due to its unfavorable prognosis, feared complication of thromboembolic disease. We assessed the incidence and risk factors for pulmonary hypertension (PH) in a cohort of consecutive patients admitted with pulmonary embolism to the tertiary University Hospital.MethodsIn our cohort of 120 consecutive patients with proved pulmonary embolism (PE) we studied the course of biochemical and echocardiographic parameters with regard to risk factors predicting pulmonary hypertension at the end of hospitalization.ResultsEchocardiographic signs of pulmonary hypertension were present at the time of discharge in more than one half (50.8%) of patients admitted with pulmonary embolism. Predictors of persisting pulmonary hypertension were initial pulmonary hypertension, high initial NT-proBNP levels and age.ConclusionResidual pulmonary hypertension at discharge was present in 50.8% cases, at this time there was a strong relationship between PH and elevated NT-proBNP on admission. The patients will be followed-up and possible development of CTPEH will be evaluated at 6, 12 and 24-month period.     

Hybrid myocardial revascularization—the cardiologist's view

This article summarizes current knowledge on the mutual position of surgical and interventional treatment of patients with multivessel coronary artery disease. It focuses on the possibilities of their combined use – so called hybrid myocardial revascularization. The use of minimally invasive surgery combined with current technologies of coronary interventions offers new opportunities, taking advantages of both procedures and eliminating some of their disadvantages. This previously rarely used technique could improve the clinical outcomes and treatment comfort in selected groups of patients.     

Selfish supernumerary chromosome reveals its origin as a mosaic of host genome and organellar sequences

Supernumerary B chromosomes are optional additions to the basic set of A chromosomes, and occur in all eukaryotic groups. They differ from the basic complement in morphology, pairing behavior, and inheritance and are not required for normal growth and development. The current view is that B chromosomes are parasitic elements comparable to selfish DNA, like transposons. In contrast to transposons, they are autonomously inherited independent of the host genome and have their own mechanisms of mitotic or meiotic drive. Although B chromosomes were first described a century ago, little is known about their origin and molecular makeup. The widely accepted view is that they are derived from fragments of A chromosomes and/or generated in response to interspecific hybridization. Through next-generation sequencing of sorted A and B chromosomes, we show that B chromosomes of rye are rich in gene-derived sequences, allowing us to trace their origin to fragments of A chromosomes, with the largest parts corresponding to rye chromosomes 3R and 7R. Compared with A chromosomes, B chromosomes were also found to accumulate large amounts of specific repeats and insertions of organellar DNA. The origin of rye B chromosomes occurred an estimated ～1.1-1.3 Mya, overlapping in time with the onset of the genus Secale (1.7 Mya). We propose a comprehensive model of B chromosome evolution, including its origin by recombination of several A chromosomes followed by capturing of additional A-derived and organellar sequences and amplification of B-specific repeats.     

The effects of repeated delivery of angiotensin II AT(1) receptor antisense on distinct vasoactive systems in Ren-2 transgenic rats: young vs. adult animals

Although Ren-2 transgenic rat (TGR) is defined as a model of angiotensin II-dependent hypertension, we studied whether the renin-angiotensin system (RAS) is really the main contributor to blood pressure (BP) elevation in hetero- and homozygous TGRs. Moreover, we examined whether repeated antisense (AS) therapy against AT(1) receptors would have a similar effect on the BP and the contribution of the principle vasoconstrictor/vasodilator systems to BP regulation in young and adult TGRs. From the age of 30 (young) and 100 (adult) days, rats were injected with AS for 40 days in 10-day intervals. After 10 and 40 days of AS therapy, the basal BP and acute BP responses to the sequential blockade of the RAS, sympathetic nervous (SNS) and nitric oxide systems were determined in conscious rats. The RAS system was the major system maintaining elevated BP in young homozygous animals, whereas there was an increasing contribution of the SNS in heterozygous TGR with age. The AS therapy in the young TGR had a transient BP-lowering effect that was associated with reduced cardiac hypertrophy; the AS therapy was most effective in young homozygous TGR, causing a substantial reduction of angiotensin-dependent vasoconstriction. In heterozygous rats, AS therapy at earlier stages was related to an inhibition of sympathetic vasoconstriction, whereas to RAS inhibition in established hypertension. In conclusion, repeated AS therapy had transient antihypertensive effects exclusively in young TGR. The contribution of the RAS to BP maintenance is highly important only in homozygous TGRs, whereas it is surpassed by SNS in heterozygous TGR.     

Profile of thrombin generation in children with acute lymphoblastic leukemia treated by Berlin-Frankfurt-Münster (BFM) protocols

Treatment with L-asparaginase is associated with coagulation disturbances with deep venous thrombosis being the most common clinical consequence. Use of the calibrated automated thrombogram allows precise estimation of thrombin generated in vitro. We show the first data on thrombin generation, measured by calibrated automated thrombography (CAT), in children with acute lymphoblastic leukemia treated with L-asparaginase. Thrombin generation was measured by means of CAT in 23 children treated for acute lymphoblastic leukemia. Samples were obtained at predefined time points during the induction and reinduction phase of acute lymphoblastic leukemia-intercontinental Berlin-Frankfurt-Münster (BFM) 2000 or Associazione Italiana Ematologica Oncologia Pedaitrica Interim BFM 2000 protocols. Antihrombin and fibrinogen were measured on the same sample. Twenty-eight sets of thrombin generation measurements were collected from 23 patients. We observed no significant effect of antithrombin deficiency and/or hypofibrinogenemia on thrombin generation. Endogenous thrombin generation and peak thrombin were significantly higher during induction than in the reinduction phase (P?相似文献   

Minimal residual disease detectable by quantitative assessment of WT1 gene before allogeneic stem cell transplantation in patients in first remission of acute myeloid leukemia has an impact on their future prognosis

Overall 42 patients (pts) transplanted in hematological CR1 were retrospectively analyzed. Median follow‐up was 15 months (range 2–77). The expression of WT1 gene was measured according to the European Leukaemia Net recommendations. At the time of allogeneic stem cell transplantation (allo‐SCT) 29 pts were WT1‐negative and 13 pts were WT1‐positive. In the univariate analysis, significantly better results were observed in the group of WT1 neg in terms of progression‐free survival (in three yr 77% vs. 27%, p = 0.001). In multivariate analysis, the only significant feature in terms of better OS was WT1 negativity (p = 0.029). Our results show that minimal residual disease status measured by quantitative assessment of WT1 gene in acute myeloid leukemia pts in CR1 significantly affects their future prognosis after allo‐SCT.     

C‐type natriuretic peptide slows down wound healing but promotes angiogenesis in SKH1‐hr hairless mice

C‐type natriuretic peptide (CNP) is known to increase growth rate of endothelial cells in vitro. In addition, gene transfer of CNP into ischaemic muscle was shown to induce angiogenesis. So far, no study has addressed the effect of CNP on dermal wound healing. The ear wound model in mice was used in this study. The first group was treated with dsRed‐CNP plasmid, whereas the second group was transfected with the empty dsRed‐sine plasmid, lacking sequence coding for CNP. The third group was sham operated and treated with saline to serve as second control. Wound size was measured on days 0, 1, 3, 5, 7, 9, 11 and 14. On days 7 and 14 capillary density was analysed. Wound closure rate was significantly reduced in mice treated with CNP [dsRed‐CNP 73·3 ± 3·2% versus dsRed‐sine 94·5 ± 2·4% versus saline 92·1 ± 2·4%, n = 8 per group, analysis of variance (ANOVA) P < 0·001] at day 7 postop. Capillary density was found to be significantly higher in CNP‐treated mice (dsRed‐CNP 18·7 ± 3·9 versus dsRed‐sine 12·3 ± 2·7 versus control 10·1 ± 4·7, CD31⁺ capillaries per microscope field, ANOVA P = 0·018) at day 14 postoperative. CNP significantly reduces wound closure rate in hairless mice but promotes the development of new blood vessels. A possible explanation is the dual effect of CNP, inhibiting growth of fibromyoblasts but stimulating growth of endothelial cells. Thus, CNP may serve as a therapeutic approach to diseases caused by hyperfibrosis.