2,4-Disubstituted pyridine derivatives are effective against intracellular and biofilm-forming tubercle bacilli.

It was recently reported that 4-substituted picolinohydrazonamides carrying hydrophilic cyclic amines, such as morpholine and pyrrolidine, at the end of their thiosemicarbazide chain have potent antimycobacterial activity in vitro at concentrations below 1 µg/ml. Here, two selected compounds, 2,4-disubstituted pyridine derivatives 11 and 15, revealed significant bactericidal activity against Mycobacterium tuberculosis localized intracellularly within human macrophages, as well as against biofilm-forming tubercle bacilli. Mutants were selected that were resistant to the investigated compounds at an efficiency similar to that identified in the presence of the first line antituberculosis drug rifampicin. The resistant mutants were viable in the presence of the tested compounds exclusively on solid media. Genome-wide sequencing of the mutants selected in the presence of compound 11 revealed the accumulation of nonsynonymous mutations in the mmpR5 gene encoding a transcriptional repressor of the MmpS5-MmpL5 efflux pump, whose upregulation has been associated with bedaquiline resistance. The depletion of MmpR5 in wild-type M. tuberculosis using CRISPR-Cas9 technology increased the resistance of this strain to compound 11. Mass spectrometry-based proteomics (LC-MS/MS) of wild-type tubercle bacilli growing in subinhibitory concentrations of compounds 11 or 15 revealed 15 overproduced proteins not detectable in the control cells, including virulence-related proteins.

[The paradigm change in medical thinking]. / Der Paradigmawechsel im medizinischen Denken.

Due to the rapid growth of basic knowledge in recent decades, a tremendous amount of superspecial scientific information is confronting us today. This overflow of new and often short-lived data is influencing in a considerable way the view and the management of all life sciences. On the basis of the change of paradigm in modern economic systems, also influencing management, we try to compare the particular components of these changes that occur in medical sciences, e.g. in pathophysiology, diagnostic investigations and therapy. Most of the paradigm components can be used for an analysis of the consequences of the rapid changes in the medical way of thinking. For this contemplation, selected cases of thyroid disorders have been chosen.

Fatty tissue visualization 18 hours after 133Xe lung ventilation study.

In order to check a new rebreathing unit for ventilation investigations of the lungs with radioactive gases, a 133Xe lung ventilation study was performed in a 56-year old healthy volunteer. The contamination check on the following day triggered a radiation warning caused by the retained xenon activity in the body. The whole-body scan performed 18 h after the inhalation showed clearly a faint delineation of the xenon activity, corresponding to the subcutaneous fatty tissue of the individual studied.

[Pseudopancreatitis in entero-invasive salmonellosis]. / "Pseudopankreatitis" bei enteroinvasiver Salmonellose.

The incidence of pancreatitis in bacterial enterocolitis is disputed. Two cases of young patients with S. enteritidis-induced enterocolitis and markedly elevated amylase and lipase blood levels are described. In both patients there were neither clinical nor ultrasonographic signs of pancreatitis. Furthermore, both had increased intestinal permeability for oral 51Cr-EDTA, a condition discussed as "leaky gut" in other publications. In one patient enzyme levels and 51Cr-EDTA resorption became rapidly normal, while in the other the values remained elevated after a 7-month interval with stool culture negative. Enhanced intestinal absorption of 51Cr-EDTA (mw 391) suggests--but does not definitely prove--an inflammatory response of the mucosa leading to increased intestinal permeability, which in turn may allow resorption of amylase (mw 62,000), lipase (43,000) or other macromolecules. Performance of a 51Cr-EDTA resorption test may be helpful in cases of clinical uncertainty.

In vitro and in vivo testing of the dopamine D1 ligand [123I]SCH 23982 with respect to its potential application in SPET investigations.

[123I]SCH 23982, a dopamine D1 ligand, was labelled in a large scale process and then tested in vitro for binding to rat brain sections and membranes. Because of the promising values of KD = 1.5 x 10(-10) M and Bmax = 0.7 x 10(-11) mol/g, in vivo evaluation was performed on rats and normal volunteers to test its possible usefulness for SPET imaging. In competition experiments, a higher binding in the presence of sulpiride was found while ketanserin displaced [123I]SCH 23982 only at a 10,000-fold excess. Differences between rats and men were seen with respect to their metabolism. SPET investigations failed because the washout of [123I]SCH 23982 was too rapid.

123I-SCH 23982 is not suitable for dopamine D1 receptor imaging in vivo in the human brain.

The tracer 123I-SCH 23982 was tested with regard to its ability to image dopamine D1 receptor in the human brain in vivo with single photon emission computed tomography (SPECT). The tracer did not reach equilibrium with regard to its binding to dopamine D1 receptors, presumably owing to fast metabolism to hydrophilic products and deiodination. It is concluded that 123I-SCH 23982 is not suitable for dopamine D1 receptor imaging with SPECT in the human brain.

Evaluation of a multicentre study with Iomazenil--a benzodiazepine receptor ligand.

After showing in an earlier publication that Iomazenil is a potent benzodiazepine receptor antagonist, the substance has been distributed to 11 clinical centres in Europe for further tests. The protocol asked for volunteers, epileptic cases and patients with Alzheimer's disease. Prior to the Iomazenil examination, flow images by perfusamine or HMPAO were required, and as comparative methods EEG, computed tomography (CT) and magnetic resonance imaging (MRI) were performed. The results allowed first the determination of the normal distribution of the benzodiazepine receptors in the human brain. The highest uptake was found in medial occipital cortex. Second, the evaluation of the epileptic cases shows a 100% positive prediction value for Iomazenil compared to 92% for flow images. Negative prediction values were calculated as 81% for Iomazenil and 54% for flow images. Furthermore, one group reported the successful diagnosis of Alzheimer's disease at an early stage. The visual image examination was tentatively compared to a more objective semiquantitative one based on quotients of corresponding left/right regions of interest. This semiquantitative method has not proved successful yet, but the problems have been identified. A more precise protocol for further studies is therefore proposed.

[The contribution of single-photon emission-computed tomography in cerebral function diagnosis]. / Der Beitrag der Single-Photon-Emissionscomputertomographie zur zerebralen Funktionsdiagnostik.

Single photon emission computed tomography (SPECT) makes it possible to visualize physiological and chemical processes in the cerebrum. In this technique, single photon emitting nuclides such as 99m technetium and 123 iodine, which are tagged to other compounds, or 133xenon, are used for the study of several clinical conditions. After injection of the radiopharmaceutic agent the radioactivity is measured by a rotating gamma-camera from numerous directions. Based on the measured values, its distribution within the brain can be computed and transformed in tomographic slices. We present our experience with the method in clinical practice using preferentially N-isopropyl-(123I)-p-iodoamphetamine (123I-IMP) and 99mTc hydroxymethyl-propylene-amine-oxime (99mTc-HMPAO). These substances are distributed in accordance with regional cerebral blood flow (rCBF). Hitherto, the application of the method has concentrated on the study of cerebrovascular disease and epilepsy. SPECT has contributed to a better understanding of the pathophysiological processes and their dynamics after ischemic infarction. The method also provides essential insights in epileptics. In partial epilepsy, a focus of reduced or enhanced tracer activity can be ascertained, dependent on the timing of the examination, in the interictal and ictal stage respectively. Even in the early course of senile dementia of Alzheimer type, zones of diminished neuronal activity in temporo-parietal and frontal cortex are demarcated. Preliminary results in psychiatric diseases and parkinsonism need further confirmation. In this connection future interest will focus especially upon the use of receptor ligands.

[Tumor scintigraphy with cobalt bleomycin in ORL tumors]. / Tumorszintigraphie mit Kobaltbleomycin bei den ORL-Tumoren.

Our experiences with cobalt bleomycin scintigraphy in the treatment planning of ORL tumors are described. 142 scintigrams taken from 127 patients have been examined. As is shown by our investigation, cobalt bleomycin scintigraphy is a good examination method, however, too much expenditure is needed to have the necessary data for therapy planning. To our opinion, the information obtained in oto-rhino-laryngology by an exact clinical examination is as good as that of cobalt bleomycin scintigraphy. Our treatment schemes had only to be revised in some exceptional cases.

[Semiquantitative display of regional cerebral blood flow and neuronal function using N-isopropyl-(123I)-p-iodoamphetamine (IMP) and emission tomography]. / Ein Beitrag zur semiquantitativen Darstellung der regionalen Hirndurchblutung und neuronalen Funktion mittels N-isopropyl-(123J)-p-Jodoamphetamin (IMP) und Emissionstomographie.

Between June 1983 and March 1985 197 patients were examined with 123I-IMP brain scintigraphy and ECT. They had various neurological diseases, the majority suffered from cerebrovascular affections. The reference for pathological findings was a group of 14 healthy volunteers. A visual interpretation of the ECT-slices alone is not reliable enough. A semiquantitative assessment of perfusion abnormalities seems to be very important, especially in diffuse or bilateral alterations. The proposed semiquantitative evaluation makes use of the total cerebral accumulation in the control group (35.6 +/- 4.3 cts/pixel/mCi/min) and right-left ratios of 14 paired and fixed regions of interest (ROI) in three ECT slices. The ROIs are related to the anatomical flow supply areas in the brain. The right-left ratios are around 1.0 with a physiological asymmetry of +/- less than 2% (standard deviation). The asymmetry is an important parameter in assessing presence and severity of disease. If pathological findings are diffuse or symmetric, the visual interpretation of scintigrams or the calculation of right-left ratios are often unsuccessful. Thus, the same ROI-data were separated for the right and left hemisphere and drawn as cts/ROI/pixel/mCi in diagrams as profile. The diagram demonstrates perfusion abnormalities semiquantitatively without using calculation of asymmetry, since asymmetry alone cannot differentiate between hypoperfusion of one and hyperperfusion of the contralateral side.

Regional quantitative noninvasive assessment of cerebral perfusion and function with N-isopropyl-[123I]p-iodoamphetamine.

Although several reports on the clinical usefulness of N-isopropyl-[123]p-iodoamphetamine (IMP) in the diagnosis of cerebral disease have appeared in the literature, quantitative, noninvasive measurements of regional cerebral blood flow with this method pose difficulties because cerebral IMP uptake not only depends on cerebral perfusion but also on cerebral function. Rather than trying to develop a method to measure cerebral perfusion with IMP, we have chosen to test a method to quantitatively evaluate planar and emission computed tomographic (ECT) studies by comparing the data obtained in patients with established pathology (n = 51, number of scans = 54) with the data obtained in a group of normal individuals (n = 10, number of scans = 11). Using this method, absolute cerebral IMP uptake (counts/pixel/mCi/min) and planar anterior right-left ratios were obtained. Also measured were right-left ratios obtained from 12 paired regions in three ECT slices. In the control group, we found an IMP uptake of 35.6 +/- 4.3 cts/pixel/mCi/min and right-left ratios around 1.00 (s.d. less than 2%). The evaluation of the patients cerebral IMP uptake asymmetries relative to the normal standard values is a useful adjunct to qualitative image analysis in assessing the presence and severity of disease, as qualitative analysis is prone to false-positive and negative results. Cerebral IMP uptake as measured in cts/pixel/mCi/min is abnormal only in severe cerebral disease and therefore generally a less helpful parameter.

131-Iodine capsules in thyroid therapy: an individually controlled study of their uptake kinetics as compared to liquid 131-iodine.

We investigated the uptake of therapeutic doses of 131-Iodine in capsular form which were given to 16 patients with benign thyroid disease, and compared it to the uptake of a diagnostic dose of liquid 131-Iodine given to the same patients. The aim of this study was to determine the additional radiation dose sustained by the gastric mucosa, and thus, to establish the safety of this galenic form of 131I. It was found that the average capsule-dissolution time was about 12 min, with a large standard deviation of about 7 min. Using these data and a theoretical radiation-dose calculation, we estimated that the maximum dose to the gastric mucosa was approximately 250 rad (250 cGy) for a therapeutic activity of 5 mCi (185 MBq), which is the maximum dose which may be given as single application to out-patients in Switzerland. Thus, 131I administered in capsular form is a safe galenic form for therapeutic use in patients with thyroid disease.

Suprasellar arachnoidal cyst as a cause of early puberty.

Puberty developed in a boy before age 12 years despite a marked delay in skeletal development. A large suprasellar arachnoidal cyst was found. Such cysts may be a cause of precocious puberty.

Polymyositis, myasthenic syndrome and thymoma in a patient with defective cell-mediated immunity.

We studied a 57-year old woman with severe myasthenic syndrome predominantly proximal. There was no therapeutic effect using cholinesterase inhibitors. Clinical findings, electromyography, whole body scanning and biopsy revealed polymyositis. Thirteen years before the patient was operated of a benign thymoma. The history of the patient showed numerous life threatening episodes of viral and fungal infections. Autoimmune anemia was diagnosed. Investigations of the immune system in vivo and in vitro revealed severe qualitative and quantitative defects in the lymphocyte population spontaneously forming rosettes with sheep red blood cells (SRBC). Thymoma, autoimmune disorder, such as polymyositis and myasthenia gravis, unspecifically elevated antibody titers, multiple severe viral and fungal infections and the defect of the cell-mediated immunity suggest a T-lymphocyte effector- and regulatory dysfunction in this patient.

[Difficulties in the differential diagnosis of a non-traumatic, active myositis ossificans during pregnancy (author's transl)]. / Differentialdiagnostische Schwierigkeiten bei einem fall von aktiver Myositis ossificans non traumatica in der Gravidität

A 28 year old patient complained of sensory disturbances and pain in the right upper arm during pregnancy. During the 32nd week of her pregnancy, a large painful mass developed in the flexor muscles which, radiographically, showed some calcification. A diagnosis of a parosseous sarcoma was made; biopsy, however, indicated a diagnosis of non-traumatic myositis ossificans. Since the histological appearances of active myositis may be vary difficult to distinguish from a juxtacortical sarcoma, a right brachial angiogram and scintiscan were obtained. The angiographic and scintigraphic findings were erroneously considered to suggest malignancy. Following delivery, the tumour was removed. Futher histology confirmed the diagnosis of localised, non-traumatic myositis ossificans. The value of radiology, biopsy, angiography and scintigraphy are discussed with reference to our experience.