Developmental regulation of SMN expression: pathophysiological implications and perspectives for therapy development in spinal muscular atrophy.

Spinal muscular atrophy (SMA), the predominant form of motoneuron disease in children and young adults is caused by loss of function of the SMN protein. On the basis of a disrupted splice acceptor site in exon 7, transcripts from a second SMN gene in humans called SMN2 cannot give rise to SMN protein at sufficient levels for maintaining function of motoneurons and motor circuits. First clinical trials with Spinraza/Nusinersen, a drug that counteracts disrupted splicing of SMN2 transcripts, have shown that elevating SMN levels can successfully interfere with motoneuron dysfunction. This review summarizes current knowledge about the pathophysiological alterations in Smn-deficient motoneurons, which lead to defective neuromuscular transmission and altered spinal circuit formation. Both pathological mechanisms are important targets for therapeutic intervention. However, the developmental time window when therapeutic interventions ideally should start is not known. Endogenous SMN expression both from SMN1 and SMN2 genes is high at early developmental stages and declines progressively in humans and mice. Thus, therapeutic SMN upregulation should start just before SMN declines below a critical threshold, and before irreversible defects occur at neuromuscular junctions and in spinal circuits. Previous results indicate that loss of Smn function leads to synaptic dysfunction during a stage of neuromuscular development when synaptic strength determines which synapses are maintained or not. This time window appears as an important target for therapy, which possibly could be supported by additional strategies that strengthen synaptic transmission.

Stiff person syndrome associated anti-amphiphysin antibodies reduce GABA associated [Ca(2+)]i rise in embryonic motoneurons.

Autoantibodies to the synaptic protein amphiphysin play a crucial pathogenic role in paraneoplastic stiff-person syndrome. Impairment of GABAergic inhibition is the presumed pathophysiological mechanism by which these autoantibodies become pathogenic. Here we used calcium imaging on rat embryonic motor neurons to investigate whether antibodies to amphiphysin directly hinder GABAergic signaling. We found that the immunoglobulin G fraction from a patient with stiff-person syndrome, containing high titer antibodies to amphiphysin and inducing stiffness in rats upon passive transfer, reduced GABA-induced calcium influx in embryonic motor neurons. Depletion of the anti-amphiphysin fraction from the patient's IgG by selective affinity chromatography abolished this effect, showing its specificity for amphiphysin. Quantification of the surface expression of the Na(+)/K(+)/2Cl(2-) cotransporter revealed a reduction after incubation with anti-amphiphysin IgG, which is concordant with a lower intracellular chloride concentration and thus impairment of GABA mediated calcium influx. Thus, anti-amphiphysin antibodies exert a direct effect on GABA signaling, which is likely to contribute to the pathogenesis of SPS.

Principles of induction chemotherapy for non-small cell lung cancer.

The results of lung cancer treatment have not significantly improved for many years. About 35% of patients with non-small cell lung cancer (NSCLC) are in clinical stage IIIA. Clinically asymptomatic distant metastases occur in the majority of these patients. In such cases only combined treatment offers a chance of cure. In the Chest Surgery Center in Lublin a clinical trial was carried out aimed to assess late results of combined treatment in patients with IIIA NSCLC. Over 700 patients were enrolled in the study. The results of the trial disclosed, that neoadjuvant chemotherapy prolonged life of the operated patients and improved their life quality. However, a question of qualification for this complex treatment and complexity of assessment criteria, still remain to be answered.

The role of SMN in spinal muscular atrophy.

Childhood spinal muscular atrophy (SMA) is a common autosomal recessive disorder which is characterized by muscle weakness due to degeneration of motoneurons in the spinal cord and brainstem nuclei. Positional cloning strategies have revealed several gene candidates including the genes for the survival motoneuron (SMN) and the neuronal apoptosis inhibitory protein (NAIP). Both genes are duplicated on chromosome 5. Homozygous deletions/mutations of the telomeric SMN gene, which is expressed from both copies on human chromosome 5, are associated with the disease. Recent reports suggest involvement of the SMN protein in the formation of spliceosomal particles in the cytoplasm and in the regeneration of spliceosomes in the nucleus. These data put spinal muscular atrophy into a growing group of disorders of RNA metabolism which also include fragile-X syndrome and myotonic dystrophy. Relevance of these previous data for the pathogenesis of the disease are discussed in this review.

[Surgical treatment of advanced lung emphysema. Does it really improve treatment results?]. / Chirurgiczne leczenie zaawansowanej rozedmy pluc. Czyzby nowa nadzieja na poprawe wyników leczenia?

Lung emphysema may be one of the components of chronic obstructive pulmonary disease (COPD). Nearly 60% of patients with advanced chronic respiratory insufficiency with FEV1 < 30% expected, aged > 65 years die within the first 2 years of the disease. The treatment of COPD includes oxygen therapy, lung transplantation and/or lung volume reduction (LVR). The study presents qualification criteria for LVR in reference to oxygen therapy and lung transplantation. Crucial diagnostic features include: CT of the chest with densitometric analysis and lung perfusion scans. Patients with severe but limited dyspnea, disseminated emphysema lesions with fairly untouched areas of normal lung tissue, FEV1% < 30-35%, DLCO < 25% expected, PaCO2 < or = 50 mmHg and PaO2 < or = 50-55 mmHg, appear to be the best candidates for LVR. The results of the study indicate, that in Poland, patients with advanced emphysema, who are treated with oxygen therapy or soon will be qualified this therapy or await lung transplantation might be candidates for LVR. The early results of lung volume reduction are promising and include: decrease in total lung capacity, residual volume and breathing frequency. LVR has been in use for about 3 years and majority of authors still do not possess clinical observations long enough to obtain statistically significant comparison with other methods of treatment. Limited morbidity and low perioperative mortality enable application of LVR even in patients with severe respiratory insufficiency and/or requiring constant oxygen therapy. In conclusion considering all positive aspects of LVR it is necessary to emphasise that for overall assessment of this method a broader clinical material is required including data on duration of clinical improvement.

[Lung neoplasms in patients under 40 years of age. Treatment results in patients qualifying for surgical treatment]. / Rak pluca u chorych przed 40 rokiem zycia. Wyniki leczenia chorych kwalifikowanych do leczenia operacyjnego.

In last decades an increase of new cases of lung cancer has been observed. The global prognosis based on the analysis of the increase rate of new cases envisages that total number of lung cancer patients will reach 2 millions at the end of the XXth century. In Poland alone, the number of new cases can come up to 50,000 a year in the second decade of the XXIst century. Respectively, the number of surgically treated patients with lung cancer increases. In literature, controversial opinions on the results of surgical therapy of patients with lung cancer younger than 40 years can be found. Some authors report unsatisfactory results. The others do not confirm differences due to the age of operated patients. We present our observations based on the clinical analysis of 46 patients below 40 years of age treated surgically because of lung cancer. The aim of this analysis is the evaluation of the long-term results of surgical therapy in this group of patients. This is the first Polish report on this problem.

Relationships between divisions of the lingular bronchus and vascularization patterns in the lingula.

In 100 left human lungs the main bronchus, the pulmonary artery and the pulmonary veins were injected with 65% methyl methacrylate (Duracryl) and then digested in sulphuric acid. The resulting specimens were studied concerning the divisions of the lingular bronchus and the types of arterial and venous vascularization of the lingula. As a rule the lingular bronchus divided into two segmental bronchi. A single lingular artery was found in 80% of the cases and a single lingular vein in 58%. Atypical bronchial divisions were almost always associated with unusual types of vascularization. Patterns of bronchial division showed complete concordance with those of arterial vascularization of the lingula in 64% of the lungs and consistency with venous drainage patterns in 54%.

[The effect of ambroxol on peroxidative processes in dog lung mitochondria]. / Wplyw ambroksolu na procesy peroksydacyjne w mitochondriach pluc psa.

The influence of Ambroxol on the Fe3+ (ADP) dihydroxyfumarate-induced peroxidation of mitochondrial lipids in dog lung was investigated. It was shown that changes in mitochondrial lipid composition include great decrease in phosphatidylcholine and phosphatidylethanolamine content, with concomitant increase in lysophosphoglyceride content. Addition of Ambroxol (5 mM and 10 mM) to the incubation medium decreases these changes in dose-dependent manner. The malondialdehyde production was greatly reduced in the presence of Ambroxol. The mode of Ambroxol action was comparable to that of other free radical scavengers.