A battery of tandem mass spectrometry assays with stable isotope-dilution for the quantification of 15 anti-tuberculosis drugs and two metabolites in patients with susceptible-, multidrug-resistant- and extensively drug-resistant tuberculosis.

OBJECTIVE: Anti-tuberculosis (antiTB) drugs are characterized by an important inter-interindividual pharmacokinetic variability poorly predictable from individual patients' characteristics. Therapeutic drug monitoring (TDM) may therefore be beneficial for patients with Mycobacterium tuberculosis infection, especially for the management of multidrug/extensively drug resistant- (MDR/XDR)-TB. Our objective was to develop robust HPLC-MS/MS methods for plasma quantification of 15 antiTB drugs and 2 metabolites, namely rifampicin, isoniazid plus N-acetyl-isoniazid, pyrazinamide, ethambutol (the conventional quadritherapy for susceptible TB) as well as combination of agents against MDR/XDR-TB: bedaquiline, clofazimine, delamanid and its metabolite M1, levofloxacin, linezolid, moxifloxacin, pretomanid, rifabutin, rifapentine, sutezolid, and cycloserine. METHODS: Plasma protein precipitation was used for all analytes except cycloserine, which was analyzed separately after derivatization with benzoyl chloride. AntiTB quadritherapy drugs (Pool1) were separated by Hydrophilic Interaction Liquid Chromatography (column Xbridge BEH Amide, 2.1 × 150 mm, 2.5 µm, Waters®) while MDR/XDR-TB agents (Pool 2) and cycloserine (as benzoyl derivative) were analyzed by reverse phase chromatography on a column XSelect HSS T3, 2.1 × 75 mm, 3.5 µm (Waters®). All runs last <7 min. Quantification was performed by selected reaction monitoring electrospray tandem mass spectrometry, using stable isotopically labelled internal standards. RESULTS: The method covers the clinically relevant plasma levels and was extensively validated based on FDA recommendations, with intra- and inter-assay precision (CV) < 15% over the validated ranges. Application of the method is illustrated by examples of TDM for two patients treated for drug-susceptible- and MDR-TB. CONCLUSION: Such convenient extraction methods and the use of stable isotope-labelled drugs as internal standards provide an accurate and precise quantification of plasma concentrations of all major clinically-used antiTB drugs regimens and is optimally suited for clinically efficient TDM against tuberculosis.

[The Pathogenesis of Pulmonary Emphysema - Laennec was right!] / Die Pathophysiologie des Lungenemphysems ­ Laënnec (1781­1826) hatte Recht!

Pulmonary emphysema is characterised by irreversible destruction and enlargement of alveolar structure distal to terminal bronchioles. Small conducting airways < 2 mm in diameter are the major site of chronic airway inflammation and obstruction in COPD patients. 80 - 90 % of the last generation of small conducting airways, the terminal bronchioles, are destroyed in patients with very severe COPD. Recent data showing, that small airways disease is also a pathological feature in patients with COPD GOLD stage 1 and 2. Although 40 % of terminal and 60 % of transitional bronchioles were destroyed, there was no sign for emphysema. Only a significant loss of terminal and respiratory bronchioles seems to be able to induce pulmonary emphysema and respiratory symptoms.

[Are Small Airways the Key to Understanding Pathophysiology and Treatment Efficacy in Chronic Obstructive Pulmonary Diseases?] / Sind die "kleinen Atemwege" der Schlüssel zum Verständnis von Pathophysiologie und Therapieeffizienz chronisch obstruktiver Atemwegserkrankungen?

This review presents updated information on small airways in the pathogenesis of chronic obstructive respiratory diseases. The lungs have a branching structure, segmentally divided from trachea down to the alveoli (generations 1 - 23). Airways can be divided into a conducting (generations 1 - 16) and a respiratory zone (generations 17 - 23). Conducting zone is mainly for air transportation, respiratory zone for gas exchange. Increasing attention has been directed to the role of small airways in chronic obstructive respiratory diseases. The small conducting airways < 2 mm in diameter are the major site of airway inflammation and obstruction in COPD. It has been shown that the last generation of small conducting airways, the terminal bronchioles, are significantly destroyed in patients with very severe COPD. At what stage in the development of COPD the loss of small airways occurs is not exactly known. The small airways represent the most important target for deposition of inhaled therapeutic particles. Currently there is no gold standard for detecting small airway dysfunction. Techniques such as spirometry and body plethysmography can provide information on air trapping. High-resolution CT enables the diagnosis of pulmonary emphysema and diseases of the large airways. Only micro-CT imaging offers the option to describe microstructure of terminal bronchioles. Impulse oscillometry, gas washout techniques and analysis of exhaled nitric oxide are diagnostic tools which have to be validated for diagnosis and treatment response of small airway diseases.

[Asthma Control in Adults and Children Must be Improved!] / Die Asthmakontrolle bei Erwachsenen und Kindern muss optimiert werden!

Medication management of asthma is based on level of asthma control. GINA defined criteria for asthma control include asking about daytime symptoms, limitation of activity, nocturnal symptoms/awakenings and need for reliever treatment. Effective asthma control is necessary for preventing exacerbations and worsening of lung function. Standardized and validated questionnaires such as asthma control test (ACT) help to assess the level of asthma control. Asthma control is classified as controlled, partially controlled or uncontrolled. Multicenter studies like REALISE and AIRE give health care professionals information about effectiveness and adherence to medication over nearly 15 years. Asthma is still poorly controlled in more than 50 % of patients despite the availability of very effective drugs. Low adherence to the treatment, fear of systemic side effects related to long term treatment with inhaled corticosteroids, inadequate knowledge of the disease may be responsible factors for bad asthma control. Optimized tools for disease management and intensified education are necessary for therapeutic success.

Erectile dysfunction after radical prostatectomy: the impact of nerve-sparing status and surgical approach.

The core question of the study was whether the nerve-sparing status and surgical approach affected the patients' sexual life in the first year after surgery. In addition, determinants of erectile function (EF) and the extent of sexual activity were investigated. We conducted a multicentric, longitudinal study in seven German hospitals before, 3, 6 and 12 months after radical prostatectomy (RP). A total of 329 patients were asked to self-assess the symptoms associated with erectile dysfunction (ED). These symptoms were assessed using the International Index of Erectile Function and EORTC QLQ-PR25 questionnaires. A multiple regression model was used to test the influence of clinical, socio-demographic and quality-of-life-associated variables on the patients' EF 1 year after RP. Before surgery, 39% of patients had a severe ED (complete impotence). At 3, 6 and 12 months after surgery, it was 80, 79 and 71%, respectively. Although the surgical approach had no significant effect on EF, patients who had undergone nerve-sparing surgery had significantly lower ED rates. Nevertheless, 1 year after RP, 66% of these patients had severe ED. Age, nerve-sparing status and the burden of urinary symptoms had the greatest impact on the patients' EF. Regardless of nerve-sparing status and surgical approach, postsurgical improvement of EF does not mean a full convalescence of presurgical EF. Instead, it may rather reduce the degree of postsurgical ED in time. Consequently, urologists should disclose to the patient that ED is a likely side effect of RP.

[Neonatal screening for congenital hypothyreoidism in Germany. The development of concerned children in retrospect analysis using the federal state "Hessen"]. / Neugeborenenhypothyreosescreening in Deutschland. Retrospektive Analyse der Entwicklung von betroffenen Kindern am Beispiel des Bundeslandes Hessen.

BACKGROUND: Since widespread screenings for hypothyreosis were started in 1981 in Germany, the numbers of mental and physical handicaps due to hypothyroidism are reduced markedly. The aim of this study is to evaluate the actual efficiency of the newborn screenings in Germany using in the federal state "Hessen". METHODS/SUBJECTS: All children born between 1988 and 1992 with suspicions laboratory results in the screening examination were contacted personally and statements concerning the screening itself and the physical and mental development were gathered from their parents, doctors and teachers. RESULTS: 99.1% of all hessian newborns born between 1988 and 1992 were included into the screening for hypothyreosis. The incidence of congenital hypothyreosis in general was 1:3 313. An etiological classification was possible in 77% of the patients which is divided as follows: 40% athyreosis, 24% hypoplasia of the thyroid, 8% dyshormonogenesis, 5% ektopia of the thyroid. In 67% of the cases hormone substitution was initiated during the first 14 days of life. In 23.9% it was started in the third week, in 6.8% in the fourth week and only in 2.3% of the patients treatment was started later on. The physical development of the children with congenital hypothyreosis can be regarded as widely normal. The school achievement was moderately retarded even when treatment was started in the early neonatal period. CONCLUSIONS: The screening for hypothyreosis is well established in Hessen concerning tracking, organisation and analysis. There are short comings concerning the follow ups of children with suspicions findings, which shall be overcome by creating a new position. The long-term-follow-up according to the guidelines of the "Arbeitsgemeinschaft Pädiatrische Endokrinologie" is of central interest. Furthermore compliance is improved by regular personal counselling with the parents.

An analysis of the electrocardiogram QT interval

No reports testing the efficacy of the use of the QT/RR ratio <1/2 for detecting a normal QTc interval were found in the literature. The objective of the present study was to determine if a QT/RR ratio <=1/2 can be considered to be equal to the normal QTc and to compare the QT and QTc measured and calculated clinically and by a computerized electrocardiograph. Ratios (140 QT/RR) of 28 successive electrocardiograms obtained from 28 consecutive patients in a tertiary level teaching hospital were analyzed clinically by 5 independent observers and by a computerized electrocardiograph. The QT/RR ratio provided 56 percent sensitivity and 78 percent specificity, with an area under the receiver operator characteristic curve of 75.8 percent (95 percentCI: 0.68 to 0.84). The divergence in QT and QTc interval measurements between clinical and computerized evaluation were 0.01 ± 0.03 s (95 percentCI: 0.04-0.02) and 0.01 ± 0.04 s (95 percentCI: -0.05-0.03), respectively. The QT and QTc values measured clinically and by a computerized electrocardiograph were similar. The QT/RR ratio <=1/2 was not a satisfactory index for QTc evaluation because it could not predict a normal QTc value.

An analysis of the electrocardiogram QT interval.

No reports testing the efficacy of the use of the QT/RR ratio <1/2 for detecting a normal QTc interval were found in the literature. The objective of the present study was to determine if a QT/RR ratio < or =1/2 can be considered to be equal to the normal QTc and to compare the QT and QTc measured and calculated clinically and by a computerized electrocardiograph. Ratios (140 QT/RR) of 28 successive electrocardiograms obtained from 28 consecutive patients in a tertiary level teaching hospital were analyzed clinically by 5 independent observers and by a computerized electrocardiograph. The QT/RR ratio provided 56% sensitivity and 78% specificity, with an area under the receiver operator characteristic curve of 75.8% (95%CI: 0.68 to 0.84). The divergence in QT and QTc interval measurements between clinical and computerized evaluation were 0.01 +/- 0.03 s (95%CI: 0.04-0.02) and 0.01 +/- 0.04 s (95%CI: -0.05-0.03), respectively. The QT and QTc values measured clinically and by a computerized electrocardiograph were similar. The QT/RR ratio < or =1/2 was not a satisfactory index for QTc evaluation because it could not predict a normal QTc value.

Serial blood pressure measurements

The objective of the present investigation was to study the effects of a 60-s interval of venous congestion between two noninvasive measurements of arterial blood pressure (ABP) on the fluctuation of ABP, assessed by the standard deviation of the differences between two readings. ABP was measured in 345 successive patients, at rest, four times each. For 269 participants, one pair of readings was obtained with a 60-s interval and the other pair without an interval. For 76 patients, the first pair was read at the same interval, and the second pair had venous congestion interposed and there was no waiting interval. There was no increased ABP oscillation, either when there was no interval between ABP readings, or when venous congestion was interposed compared to pairs of ABP measurements performed with a 60-s interval. There was no increase in ABP oscillations when successive ABP readings were taken without an interval or even with venous congestion interposed. Contrary to the present belief, there seems to be no loss of reliability when blood pressure recordings are taken immediately one after another, in the clinical setting

Analysis of the effects of the continuous electrode paste band on precordial leads of the electrocardiogram.

OBJECTIVE: To determine if the application of a continuous electrode paste band on precordial leads results in alteration of the electrocardiographic tracing as compared with an adequate amount of electrode paste, and if the former condition does not cause uniform morphologies from V1 to V6. METHODS: The amplitude and morphology of the electrocardiographic waves on the precordial leads in electrocardiographic tracings, which were performed with standard (control group) or excessive (continuous band) application of the electrode paste, were compared. RESULTS: None of the 106 patients studied showed uniformity of the QRS morphology from V1 to V6. The electrocardiographic alterations identified in the tracings performed with a continuous electrode paste band that showed statistical significance in relation to the control group were the following: inversion of the P wave in V1; inversion of the T wave in V1, V2, and V3; appearance of R' waves in V1 and V2; disappearance of S waves in V1; appearance of S waves in V5 and V6; alterations in the amplitude of almost all waves, in all leads. CONCLUSION: Application of a continuous electrode paste band in the precordial leads may cause significant alterations in the electrocardiographic tracing obtained.

The antibody repertoire in experimental allergic neuritis: evidence for PMP-22 as a novel neuritogen.

Experimental allergic neuritis (EAN) is an autoimmune disease that serves as an animal model for the Guillain-Barré syndrome (GBS). In both disorders there is still great uncertainty as to the significance and diversity of autoantibodies involved. We focused on the characterization of serum antibody production in response to various peripheral nervous system (PNS) myelin proteins during the course of actively induced EAN in Lewis rats. These data were compared with EAN induced by adoptive transfer of P2-specific CD4+ T cells (AT-EAN) and with inoculation with complete Freund's adjuvant (CFA) alone. Semiquantitative Western blotting was applied to measure serum IgM and IgG titers against specific myelin proteins, including P2, P0, myelin basic protein (MBP), myelin-associated glycoprotein (MAG) and PMP-22. Considerable differences in the dynamics of antibody titers against individual myelin proteins were observed in active EAN and after inoculation with CFA alone. Our data suggest a pathogenic role of IgM antibodies against HNK adhesion carbohydrate epitope expressing PNS proteins P0, MAG and PMP-22. Among these, PMP-22, a novel candidate neuritogen may be of particular relevance. Thus, we provide evidence for the involvement of antibody-mediated immune response in actively induced EAN and a basis for similar studies on related human disorders such as GBS or other demyelinating neuropathies.

[Etiology of left bundle branch block in Porto Alegre]. / Estudo da etiologia do bloqueio do Ramo Esquerdo em Porto Alegre.

PURPOSE: To determine the type of cardiac disease causing left bundle branch block (LBBB) in Porto Alegre, Brazil, and to assess the role of associated left axis deviation (-30 degrees or more in the frontal plane) in order to identify a specific etiology of LBBB. METHODS: Through reports from the assistant physicians or through examination of the patients, the underlying heart disease in 264 cases of LBBB was assessed. The chi-square test was used to determine a possible association between left anterior hemiblock LBBB and one or more specific type of underlying heart disease. RESULTS: Systemic arterial hypertension (30.7%), ischemic heart disease (30.3%), valvar heart disease (8.7%), cardiomyopathies (7.5%), idiopathic degenerative disease of the conduction system (1.6%) and miscellaneous heart diseases (1.2%) were the underlying heart diseases. The presence of LBBB did not indicate any specific type of cardiac disease. CONCLUSION: The causes of LBBB in Porto Alegre are the same as reported in the international medical literature. Upward and leftward deviation (> or = -30 degrees) of QRS axis in the frontal plane did not show statistical significant association with any type of underlying cardiac disease.

[Evaluation of QRS voltage in 12 derivations and Cornell criteria in the diagnosis of left ventricular hypertrophy]. / Estudo da voltagem do QRS em 12 derivações e do critério Cornell na detecção de hipertrofia ventricular esquerda.

PURPOSE: To search for the existence and degree of correlation between total 12 lead ECG amplitude and the sum of RaVL + SV3 > 28 mm (for men) or > 20mm (for women) and left ventricular hypertrophy (LV mass calculated by echocardiography > 215g for both sexes). METHODS: ECG and echocardiograms of 227 consecutive patients were examined and submitted to statistical analysis searching for correlation between total 12 lead ECG amplitude and Cornell criteria and LV mass (ASE formula modified by Devereux). RESULTS: Patients had ischemic heart disease, hypertension, valvular disease, cardiomyopathy or other less common heart diseases, or had no cardiac illness at all. There was statistically significant association of total 12 lead amplitude > 120mm and Cornell criteria with LV mass > 215g (p = 0.02 and p = 0.01 respectively). Total ECG amplitude showed 74.3% sensitivity, 42.6% specificity, and 52.4% accuracy. Cornell criteria showed values of 37.8%, 82.7% and 68.7% respectively. CONCLUSION: Total 12-lead amplitude presented limited diagnostic performance for detecting LV hypertrophy, as well as did ECG Cornell criteria, although the latter was more specific and more accurate.

[Changes in electrocardiogram in V1 by precordial electrode malposition]. / Alterações do eletrocardiograma em V1 por malposição do eletrodo precordial.

PURPOSE: To evaluate changes in the electrocardiogram (ECG) with incorrect positioning of the chest lead for V1, placed in the second and third right intercostal spaces. METHODS: Two hundred and five patients were studied after a conventional ECG, with the record of tracings where the chest electrode for V1 was placed at the second and third right intercostal spaces at the right sternal border. These tracings were then compared with the former one and changes observed in the P wave, QRS complex and T wave registered and submitted to statistical analysis. Patients age ranged from 6 to 89 years, mean 46. Whites comprised 79%, black 6% and mulattos 15%. Women totalized 62% and men 38% of the sample. Clinical diagnosis were arterial hypertension (50%), no apparent cardiac disease (41%), coronary atherosclerotic heart disease (4%), mitral valve prolapse and other organic heart disease (5%). RESULTS: Negativation or accentuation of negative terminal forces of P wave were present in 84% of the patients, alterations in the QRS complex in 75% of the cases, and in the T wave in 66% of the cases, with confidence intervals of 0.7898 to 0.8901; 0.6907 to 0.8092; and 0.6163 to 0.7437, respectively. CONCLUSION: Important changes in the ECG record may occur with high probability if the chest electrode for lead V1 is placed above the standard place.

[Left arterial overload. Electro-echocardiographic correlations]. / Sobrecarga atrial esquerda. Correlação eletro-ecocardiográfica.

PURPOSE: To compare the accuracy of left atrial enlargement (LAE) diagnosis made by electrocardiographic criteria with those obtained using M-mode echocardiography. METHODS: We studied 273 patients age 17 to 87 (mean 49) years, 115 men, white 95.5%, black 3.5% mulattos 1%, with or without heart disease of different etiologies. The ECG criteria studied were: a) P terminal force in V1 > or = 0.04 mmx s; b) Pt force in V1 duration > 0.04s; c) Pt force in V1 depth > or = 1 mm; d) P wave notching in D2 with interpeak distance > or = 40ms; f) presence of atrial fibrillation. The gold-standard for LAE was left atrial dimension > 40 mm obtained by echocardiography. RESULTS: The percentage of correct diagnosis were: atrial fibrillation (88%), Morris index (75%), PtfV1 negativity > or = 1 mm (74%), notched P wave in D2 with interpeak distance > or = 0.04 s (70%), PtfV1 with duration > 0.04 s (64%) and P wave duration in D2 > 0.11s (46%). CONCLUSION: Conventional ECG has limited value for detecting LAE. A higher correlation was found between atrial fibrillation and changes in P wave in V1 and the echocardiographic LAE.

An unusual cardiomelic syndrome.

We report on a patient with pre- and postnatal growth retardation, bilateral symmetrical ulnar agenesis with monodactyly, atrial septal defect, two ventricular septal defects, Wolff-Parkinson-White conduction abnormality, and abnormal configuration of the pancreas. Although she had some facial features reminiscent of the Brachmann-de Lange syndrome, relatively normal head size and motor development indicate a distinct syndrome.