Multidimensional severity assessment in bronchiectasis: an analysis of seven European cohorts.

INTRODUCTION: Bronchiectasis is a multidimensional disease associated with substantial morbidity and mortality. Two disease-specific clinical prediction tools have been developed, the Bronchiectasis Severity Index (BSI) and the FACED score, both of which stratify patients into severity risk categories to predict the probability of mortality. METHODS: We aimed to compare the predictive utility of BSI and FACED in assessing clinically relevant disease outcomes across seven European cohorts independent of their original validation studies. RESULTS: The combined cohorts totalled 1612. Pooled analysis showed that both scores had a good discriminatory predictive value for mortality (pooled area under the curve (AUC) 0.76, 95% CI 0.74 to 0.78 for both scores) with the BSI demonstrating a higher sensitivity (65% vs 28%) but lower specificity (70% vs 93%) compared with the FACED score. Calibration analysis suggested that the BSI performed consistently well across all cohorts, while FACED consistently overestimated mortality in 'severe' patients (pooled OR 0.33 (0.23 to 0.48), p<0.0001). The BSI accurately predicted hospitalisations (pooled AUC 0.82, 95% CI 0.78 to 0.84), exacerbations, quality of life (QoL) and respiratory symptoms across all risk categories. FACED had poor discrimination for hospital admissions (pooled AUC 0.65, 95% CI 0.63 to 0.67) with low sensitivity at 16% and did not consistently predict future risk of exacerbations, QoL or respiratory symptoms. No association was observed with FACED and 6 min walk distance (6MWD) or lung function decline. CONCLUSION: The BSI accurately predicts mortality, hospital admissions, exacerbations, QoL, respiratory symptoms, 6MWD and lung function decline in bronchiectasis, providing a clinically relevant evaluation of disease severity.

The Brief Repeatable Battery: psychometrics and normative values with age, education and gender corrections in a Serbian population.

Cognitive impairment is present in up to 65 % of multiple sclerosis (MS) patients. The Brief Repeatable Battery of neuropsychological tests (BRB) is one of the most used neuropsychological tools for cognitive assessment in MS. However, relative lack of normative data limits its application in research and clinical practice. In order to obtain normative data for a Serbian population, we administered the BRB version A to 140 healthy subjects and assessed the influence of demographic factors such as gender, age, and education on the tests' scores. We also calculated corrections for these factors. Higher education was associated with better performance on all the tests. Age influenced all the tests, except the word list generation, higher age being associated with worse performance on all other tests. Women performed worse on the paced auditory serial addition test 2, no other gender differences were observed. Our data obtained for the Serbian population could further improve use of the BRB in clinical practice and for the research purposes, establishing cognitive evaluation as a part of standard neurological examination of MS patients.

Retention mechanisms of imidazoline and piperazine-related compounds in non-aqueous hydrophilic interaction and supercritical fluid chromatography based on chemometric design and analysis.

The experimental design methodology based on central composite design of experiments was applied to compare the retention mechanisms in supercritical fluid chromatography (SFC) and non-aqueous hydrophilic interaction liquid chromatography (NA-HILIC). The selected set consists of 26 compounds that belong to imidazoline and serotonin receptor ligands. The different chemometric tools (multiple linear regression, principal component analysis, parallel factor analysis) were used to examine the retention, as well as to identify the most significant retention mechanisms. The retention mechanism was investigated on two different stationary phases (diol, and mixed-mode diol). In NA-HILIC, the mobile phase contains acetonitrile as a main component, and methanolic solution of ammonium formate (+ 0.1% of formic acid) as a modifier. The same mobile phase modifier was used in SFC, with a difference in the main component of the mobile phase which was CO2. The retention behaviour differs significantly between HILIC and SFC conditions. The retention pattern in HILIC mode was more partition-like, while in SFC the solute-sorbent interactions allowed retention. The retention mechanism between mixed-mode diol and the diol phases varies depending on the applied chromatographic mode, e.g., in HILIC the type of stationary phase significantly affects the elution order, while in SFC this was not the case. The HILIC retention behaviour was influenced by the number of tertiary amines-aliphatic, and N atom-centred fragments in tested compounds. On the other hand, the number of pyrrole and pyridine rings in the structure of the compound showed correlation with their SFC retention, simultaneously increasing the molecular weight and rapid elution of larger compounds. It was found that temperature surprisingly plays a major role in SFC mode. The increase in temperature reduces the relative contribution of enthalpy factors to total retention, so the separation in SFC was more entropy-controlled. For further pharmaceutical research and optimization, the SFC would be considered more beneficial compared to HILIC since it gives good selectivity in separation of chosen impurities.

Neuropsychological deficits after bithalamic hemorrhages.

Strategic lesions of the thalamus interfere with cognitive functions and produce complex neuropsychological symptoms. Bilateral, simultaneous thalamic hemorrhages are unusual causes of thalamic dementia. We present clinical, neuropsychological and structural neuroimaging data of a 12-month follow-up period of a patient with bilateral thalamic hemorrhages. After the operation of pancreatitis acuta hemorrhagico-necroticans, the patient developed coma. Computed tomography (CT) and magnetic resonance (MR) of the brain showed medially situated bithalamic hematomas. During the follow-up period, patient's level of consciousness has improved. Moderate dementia (MMSE 20/30) was found with severe temporal and spatial disorientation. Neuropsychological tests showed that attention and concentration were prominently impaired; there were severe verbal and less prominent, visual memory deficits, with anterograde and retrograde amnesia, accompanied by confabulations. Loss of cognitive flexibility and dysexecutive syndrome were also demonstrated. Dynamic apraxia, visual organization and visual construction deficit and impairment of categorial and phonemic fluency were noted. Language was only moderately impaired (anomia). A year later, neuropsychological profile was similar with moderate improvement of retrograde amnesia, whereas anterograde deficits persisted. Neuropsychological syndrome in our patient with bilateral thalamic hemorrhages was characteristic for subcortico-cortical cognitive deficit and was caused by disruption of the cortico-thalamic circuitry.

Use of biopartitioning micellar chromatography and RP-HPLC for the determination of blood-brain barrier penetration of α-adrenergic/imidazoline receptor ligands, and QSPR analysis.

For this study, 31 compounds, including 16 imidazoline/α-adrenergic receptor (IRs/α-ARs) ligands and 15 central nervous system (CNS) drugs, were characterized in terms of the retention factors (k) obtained using biopartitioning micellar and classical reversed phase chromatography (log kBMC and log kwRP, respectively). Based on the retention factor (log kwRP) and slope of the linear curve (S) the isocratic parameter (φ0) was calculated. Obtained retention factors were correlated with experimental log BB values for the group of examined compounds. High correlations were obtained between logarithm of biopartitioning micellar chromatography (BMC) retention factor and effective permeability (r(log kBMC/log BB): 0.77), while for RP-HPLC system the correlations were lower (r(log kwRP/log BB): 0.58; r(S/log BB): -0.50; r(φ0/Pe): 0.61). Based on the log kBMC retention data and calculated molecular parameters of the examined compounds, quantitative structure-permeability relationship (QSPR) models were developed using partial least squares, stepwise multiple linear regression, support vector machine and artificial neural network methodologies. A high degree of structural diversity of the analysed IRs/α-ARs ligands and CNS drugs provides wide applicability domain of the QSPR models for estimation of blood-brain barrier penetration of the related compounds.

Cancer of the cervix stage Ib and IIa: survival related to treatment and histopathological risk factors.

Forty-five patients with carcinoma of the cervix stage Ib or IIa underwent primary radical surgery. The patho-histological examination of the surgical specimens showed, that pelvic lymph node metastases, tumour volume, depth of tumour invasion, lymphatic or vascular permeation and parametrial involvement were significant bad prognostic factors. The histological types of squamous cell carcinomas and local lymphoplasmocytic stromal reaction to the tumour had no statistical prognostic significance. A simple and objective method of assessing tumour volume is described. A 5-year actuarial survival rate for patients with metastatic pelvic lymph nodes (33% of the patients in this study) treated by surgery and additional postoperative external whole pelvis radiotherapy was 55%. This is significantly lower than the 86% 5-year actuarial survival rate of patients without pelvic lymph node metastases treated by surgery alone (P less than 0.05). The postoperative radiotherapy of carcinoma of the cervix with bad prognostic factors including pelvic lymph node metastases seems to improve local tumour control and perhaps survival in a subgroup of node negative tumours presenting other histopathological risk factors.

Mesothelial paracrystalline inclusions in continuous ambulatory peritoneal dialysis patients.

OBJECTIVE: Uremia is known to be followed by changes in the serous membranes of pleura, pericardium, and peritoneum. During continuous ambulatory peritoneal dialysis (CAPD), the peritoneum is exposed to altered body conditions as well as to the influence of dialysate. The aim of the present study was to examine the ultrastructure of the mesothelial cells in CAPD patients, and to compare the findings with those from studies of the peritoneum in uremic controls. Paracrystalline intracytoplasmic inclusions in mesothelial cells were objects of special interest. METHODS: Biopsies of human parietal peritoneum were studied. These were taken from 12 uremic patients during catheter implantation before the start of CAPD, and from 7 CAPD patients during catheter removal for infection or malfunction. The samples were prepared in the standard way to be studied by transmission electron microscopy (TEM). RESULTS: Paracrystalline intracytoplasmic inclusions were seen in mesothelial cells only by TEM. They appear as filamentous structures at the outer part of the inclusions, and as pearl-like structures at the core of the inclusions. Sacculate dilatations of rough endoplasmic reticulum cisternae with partly destroyed membranes and only few ribosomes were also seen, with and without densely osmiophilic filaments within the cisternae. We have found paracrystalline intracytoplasmic inclusions in mesothelial cells from uremic and CAPD patients both. According to the literature, these changes are present in one third of biopsies from uremic patients. Until now, however, they have not been mentioned in CAPD patients.

Fine-needle aspiration in the diagnosis of head and neck growths: is it necessary?

The results of fine-needle aspiration cytology performed on 150 patients at the Geneva Clinic of Otolaryngology were analyzed. The accuracy rate was 80%. The study was nondiagnostic in 10% of the cases and falsely negative in another 10%. These results are similar to those in other centers. Nevertheless, several recent reports attest to the accuracy of fine-needle aspirations cytology, and in some clinics it is now part of the initial workup of every patient with a growth in the head and neck. On the basis of our own retrospective analysis, we believe fine-needle aspiration is a useful study only in patients with a previously treated malignancy and who have a new lump in the neck suspected to be a recurrence.

On-line training of recurrent neural networks with continuous topology adaptation.

This paper presents an online procedure for training dynamic neural networks with input-output recurrences whose topology is continuously adjusted to the complexity of the target system dynamics. This is accomplished by changing the number of the elements of the network hidden layer whenever the existing topology cannot capture the dynamics presented by the new data. The training mechanism is based on the suitably altered extended Kalman filter (EKF) algorithm which is simultaneously used for the network parameter adjustment and for its state estimation. The network consists of a single hidden layer with Gaussian radial basis functions (GRBF), and a linear output layer. The choice of the GRBF is induced by the requirements of the online learning. The latter implies the network architecture which permits only local influence of the new data point in order not to forget the previously learned dynamics. The continuous topology adaptation is implemented in our algorithm to avoid memory and computational problems of using a regular grid of GRBF'S which covers the network input space. Furthermore, we show that the resulting parameter increase can be handled "smoothly" without interfering with the already acquired information. If the target system dynamics are changing over time, we show that a suitable forgetting factor can be used to "unlearn" the no longer-relevant dynamics. The quality of the recurrent network training algorithm is demonstrated on the identification of nonlinear dynamic systems.

Ultrastructural changes of peritoneal lining cells in uremia.

Some thirty years ago, peritoneal dialysis (PD) became a respectable modality of renal replacement therapy. That is why peritoneal membrane attracted the interest of investigators. Uremia is followed by changes in the morphology of serous membranes (uremic serositis). Uremic effects on pleura and pericardia have been studied for a long time, but the peritoneum is affected as well. The aim of our study was to examine the morphology of the peritoneum in uremic patients before the start of PD and to compare the findings with those from examinations of peritoneum in healthy controls. We examined 12 uremic patients and 10 healthy controls (kidney donors). Biopsies were taken from parietal peritoneum. The samples were prepared in the standard way for study by transmission electron microscopy (TEM). Certain pathological changes--deformation of mesothelial cells, their detachment from the basement membrane, and unusual bulging of apical surface--were identified at the light microscopy level on semi-fine sections. Paracrystalline intracytoplasmic inclusions were seen in mesothelial cells only by TEM. We hypothesize that the inclusions were causing deformation of the mesothelial cells and detachment of those cells from the basement membrane. Sacculate dilatations of rough endoplasmic reticulum (RER) cisternae with partly destroyed membranes and few ribosomes were also seen, with and without densely osmiophilic filaments within cisternae. Although these changes are mentioned in the literature, the exact reason for their appearance remains unknown.

Optimization of PCR in application of hot start Taq DNA polymerase for detection of Erwinia amylovora with primers FER1-F and FER1-R.

There are two approaches in detection of bacterium Erwinia amylovora by PCR. One is based on detection of plasmid pEA29 and the other is based on detection of a chromosomal DNA sequence, specific for E. amylovora, in a sample. Since pathogenic strains without pEA29 have been isolated from the environment, methods based on this plasmid have been compromised and PCR methods based on chromosomal DNA species specific sequences became only reliable methods. PCR method with chromosomal primers FER1-F and FER1-R is currently the most reliable method due to its high sensitivity and specificity. The goal of this research is to make a significant improvement of the method by optimization of PCR in application of hot start DNA Taq polymerase, instead of wax, to obtain a hot start reaction. This enzyme, which is currently widely applied, can provide simpler achievement of hot start, saving labor and time and decreasing possibility of cross contamination of samples. Experiments showed that simple replacement of a regular recombinant Taq DNA polymerase by a hot start Taq DNA polymerase leads to complete failure of the reaction. Many optimization experiments had to be carried out to obtain an operational and reliable PCR which simultaneously has high sensitivity and specificity. Content of the reaction mixture, as well as temperature and time parameters of PCR, were significantly changed to achieve proper optimization.

Detection of Erwinia amylovora by novel chromosomal polymerase chain reaction primers.

A new sensitive and specific method for the detection of Erwinia amylovora was developed. The method is based on the detection of a chromosomal DNA sequence specific for this bacterial species and enables the detection of E. amylovora pathogenic strains, including the recent isolates that lack plasmid pEA29 and thus cannot be detected by the previously popular PCR methods based on the detection of this plasmid. Species-specific random amplified polymorphic DNA (RAPD) marker was identified, cloned, and sequenced, and sequence characterized amplified region (SCAR) primers for specific PCR were developed. The E. amylovora specific sequence, 1269 bp long, was amplified in polymerase chain reaction and detected with electrophoresis in agarose gel stained with ethidium bromide. Amplification with other bacterial species did not produce any PCR product detectable by electrophoresis. Belonging of the E. amylovora specific sequence to chromosomal DNA was confirmed by computer analysis of the E. amylovora genome. A consistent sensitivity limit of the method was 3 CFU/reaction, and in some cases it was possible to detect 0.6 CFU/reaction. Due to its high sensitivity and specificity, our method of E. amylovora detection is currently the most reliable, taking into account that the reliability of PCR methods based on plasmid pEA29 has been compromised by the isolation of pathogenic E. amylovora strains that lack this plasmid.

[Serotonin immunoreactivity in the adrenal medullar in hypoxia]. / Serotoninska imunoreaktivnost medule nadbubrezne zlezde u hipoksiji.

Laboratory rats were exposed to influence of intermittent hypoxia every other day during the period of 11 days. Conditions similar to those of 7000 meters above sea level were imitated. Using the method of indirect immunofluorescence the state of serotonin immunoreactivity of the adrenal glands medulla was analyzed. After exposure of animals to influence of hypoxia serotonin decreased in the adrenal glands medulla, which is in harmony with the realization concerning adrenomedullar regulatory mechanisms as a response to hypoxia.

[Immunoreactivity in the adrenal medulla in hypoxia]. / Imunoreaktivnost medule nadbubrezne zlezde u hipoksiji.

Laboratory rats were exposed to influence of intermittent hypoxia every other day during the period of 11 days. Conditions similar to those of 7000 meters above sea level were imitated. Using the method of indirect immunofluorescence the state of noradrenal, adrenal and serotonin immunoreactivity of adrenal glands medulla were analyzed. After exposure of animals to influence of hypoxia adrenalin and serotonin are decreased in adrenal glands medulla, while noradrenal cells get totally emptied. The decrease of adrenal and noradrenal contents in the adrenal glands is in harmony with the knowledge about involvement of sympathoadrenal regulatory mechanisms as a response to hypoxia. The finding of decreased serotonin is explained by its simultaneous release with adrenalin from of adrenal glands medulla.

Information maximization and independent component analysis; is there a difference?

This article provides a detailed and rigorous analysis of the two commonly used methods for redundancy reduction: linear independent component analysis (ICA) posed as a direct minimization of a suitably chosen redundancy measure and information maximization (InfoMax) of a continuous stochastic signal transmitted through an appropriate nonlinear network. The article shows analytically that ICA based on the Kullback-Leibler information as a redundancy measure and InfoMax lead to the same solution if the parameterization of the output nonlinear functions in the latter method is sufficiently rich. Furthermore, this work discusses the alternative redundancy measures not based on the Kullback-Leibler information distance. The practical issues of applying ICA and InfoMax are also discussed and illustrated on the problem of extracting statistically independent factors from a linear, pixel-by-pixel mixture of images.

[Membranous lesions and histochemical changes in cardiac muscle cells during hypoxia in white rats]. / Membranska ostecenja i histohemijske promene u misicnih celija srca belog pacova u hipoksiji.

The authors of this paper have explored the effects of intermittent hypoxia on the cell membrane and histochemical changes in the muscle cardiac tissue of the white rat. The animals have been exposed to the experimental conditions characteristic of 7.000 m of height above sea level and divided in three groups. The first one consisted of animals sacrificed immediately after the final exposition (first experimental group), in the second one there were animals sacrificed 24 hours after (the second experimental group), and the third group made animals sacrificed 7 days after the final exposition (the third experimental group). The hypoxial stress elicited the vacuolation in the cardiac muscle fibers of the subendocardial layer of miocard which persisted, and did not reduce its intensity and extensity in all the three groups of animals, while in fuxinorrhagia the intensity and extensity falls to the half of the animals sacrificed 24 hours after the experiment, and completely disappeared in those sacrificed 7 days after the final exposure. Glycogen as well as the activity of succinat-dehydrogenase were preserved in all the three experimental groups of animals. It could be concluded that hypoxia elicites ischemical changes in the sense of vacuolation of muscle tissue which does not disappear or its disappearance is slower than is the case with fuxinorrhagia which leaves a clear evidence, too, that the permeability of cytoplasmatic membrane affected by hypoxia was disturbed.

[Standardization of liver dimensions for the local population]. / Prilog standardizaciji dimenzija jetre domace populacije.

A retrospective and consecutive analysis of the autopsy records for a statistical group of 298 cases revealed 138 pathohistological states of cyanopathies and liver steatoses of the first and second degree i.e. liver conditions which scarcely disturb the dimensions and weight of the liver. Statistical processing of the exactly monitored parameters (length, thickness, height and weight) of the liver in 109 males and 78 females point to a homogenous group of cases without statistically significant differences between male and female subjects. The average liver length in males of the regional population is 26 cm, while in females it is 25 cm, average liver thickness in males of the regional population is 22 cm and 21 cm in females, and the average liver height both in male and female subjects is 7 cm. Average liver weight in males of the regional population is 1700 g and in females it is 1600 g. The values of the established liver parameters can be considered as valid and normal features of the regional population.