Structure-activity relationships of actively FhuE transported rifabutin derivatives with potent activity against Acinetobacter baumannii.

Hospital-acquired infections are on the rise and represent both, a clinical and financial burden. With resistance emerging and an ever-dwindling armamentarium at hand, infections caused by Acinetobacter baumannii are particularly problematic, since these bacteria have a high level of resistance and resilience to traditional and even last-resort antibiotics. The antibiotic rifabutin was recently found to show potent in vitro and in vivo activity against extensively drug resistant A. baumannii. Building on this discovery, we report on the synthesis and activity of rifabutin analogs, with a focus on N-functionalization of the piperidine ring. The antimicrobial testing uncovered structure activity relationships (SAR) for A. baumannii that were not reflected in Staphylococcus aureus. The cellular activity did not correlate with cell-free transcription inhibition, but with bacterial intracellular compound accumulation. Mass spectrometry-based accumulation studies confirmed the involvement of the siderophore receptor FhuE in active compound translocation at low concentrations, and they showed a strong impact of the culture medium on the accumulation of rifabutin. Overall, the study underlines the structural feature required for strong accumulation of rifabutin in A. baumannii and identifies analogs as or more potent than rifabutin against A. baumannii.

Increased right amygdala volume in lithium-treated patients with bipolar I disorder.

OBJECTIVE: The amygdala plays a major role in processing emotional stimuli. Fourteen studies using structural magnetic resonance imaging (MRI) have examined the amygdala volume in paediatric and adult patients with bipolar disorder (BD) compared with healthy controls (HC) and reported inconsistent findings. Lithium has been found to increase grey matter volume, and first evidence points towards an effect on regional brain volume such as the amygdala. METHOD: We examined the amygdala volume of euthymic patients with BD treated with lithium (n = 15), without lithium (n = 24) and HC (n = 41) using structural MRI. RESULTS: Patients treated with lithium exhibited in comparison to HC a larger right absolute (+17.9%, P = 0.015) and relative (+18%, P = 0.017) amygdala volume. There was no significant difference in amygdala volume between patients without lithium treatment and HC. CONCLUSION: Lithium appears to have a sustained effect on a central core region of emotional processing and should therefore be considered in studies examining BD.

Assessment of determinants for osteoporosis in elderly men.

SUMMARY: The aim of this cross-sectional study was to determine and quantify some determinants associated to low bone mineral density (BMD) in elderly men. This study showed that ageing, a lower body mass index (BMI), a higher blood level of C-terminal cross-linking telopeptides of type I collagen (CTX-1), family history of osteoporosis, and/or fracture and prior fracture were associated with bone mineral density. INTRODUCTION: Our aims were to identify some determinants associated to low bone mineral density in men and to develop a simple algorithm to predict osteoporosis. METHODS: A sample of 1,004 men aged 60 years and older was recruited. Biometrical, serological, clinical, and lifestyle determinants were collected. Univariate, multivariate, and logistic regression analyses were performed. Receiver operating characteristic analysis was used to assess the discriminant performance of the algorithm. RESULTS: In the multiple regression analysis, only age, BMI, CTX-1, and family history of osteoporosis and/or fracture were able to predict the femoral neck T-score. When running the procedure with the total hip T-score, prior fracture also appeared to be significant. With the lumbar spine T-score, only age, BMI, and CTX-1 were retained. The best algorithm was based on age, BMI, family history, and CTX-1. A cut-off point of 0.25 yielded a sensibility of 78%, a specificity of 59% with an area under the curve of 0.73 in the development and validation cohorts. CONCLUSION: Ageing, a lower BMI, higher CTX-1, family history, and prior fracture were associated with T-score. Our algorithm is a simple approach to identify men at risk for osteoporosis.

Neurocognitive functions in euthymic bipolar patients.

OBJECTIVE: Meta-analytic findings support the hypothesis of specific neurocognitive deficits for bipolar patients in the domains of attention, processing speed, memory and executive functions. This study aims to show neurocognitive impairment in euthymic patients with bipolar I disorder compared with healthy controls while detailing the impact of medication side-effects or illness characteristics on neuropsychological test performance. METHOD: Forty euthymic patients with bipolar I disorder were compared with 40 healthy controls in a cross-sectional design. Clinical features and neuropsychological measures of IQ, psychomotor speed, verbal fluency, learning and memory, executive functions and attention were assessed. RESULTS: Patients without antipsychotic drug use did not differ significantly from healthy controls in any neuropsychological measure. Yet patients treated with antipsychotics showed significant underperformance in the domains of semantic fluency, verbal learning and recognition memory as well as executive functions related to planning abilities, even when clinical features were controlled for. CONCLUSION: The impact of antipsychotic medication needs to be further clarified for euthymic bipolar patients and should be considered when neuropsychological test performance is interpreted.

Neurochemical pathology in hippocampus in euthymic patients with bipolar I disorder.

OBJECTIVE: Subcortical regions such as hippocampus, thalamus and ventral putamen are assumed to be involved in the pathophysiology of mood regulation. Disturbed hippocampal neuronal function indicated by reduced N-acetyl-aspartate (NAA) levels in bipolar patients was shown by several studies. Results in thalamus and putamen are inconsistent. METHOD: N-acetyl-aspartate, choline (Cho), creatine (Cr) and myo-inositol (Ins) were measured in left hippocampus, left thalamus and left putamen using proton magnetic resonance spectroscopy in 13 euthymic patients with bipolar I disorder and 13 pairwise matched healthy control subjects. Metabolic ratios NAA/Cr, NAA/Cho, Cho/Cr and Ins/Cr were calculated. RESULTS: Patients with bipolar I disorder demonstrated significantly reduced NAA/Cr in the left hippocampus compared with healthy control subjects. No alterations were found in thalamus or putamen. CONCLUSION: We hypothesize that this NAA/Cr reduction might reflect neuronal dysfunction in the left hippocampus in patients with bipolar disorder.

Specificity of human antibodies to intracytoplasmic type-A particles of the murine mammary tumor virus.

Large-scale studies showed that antibodies previously detectable in women with proliferating mastopathy or breast cancer were directed to intracytoplasmic type-A particles (iAp) of mouse mammary tumor virus. Immunofluorescence revealed the human antibodies to be bound only by those tumors producing a certain amount of iAp clusters visible by light microscopy. The intensity of the reaction corresponded to the iAp content of every tumor tested as revealed by electron microscopy and rabbit antisera to iAp. The fluorescence patterns obtained with positive human sera were similar to those obtained with rabbit antisera specific for iAp and resembled the tissue distribution patterns of iAp inclusions stained by acid fuchsin. The reaction with human sera was entirely blocked by rabbit antisera to iAp and, less so, by rabbit or mouse antisera to B particles. The human antibody activity was exhaustively absorbed by purified iAp or purified and disrupted B particles, which indicated that the human antibodies were directed to antigenic components shared by iAp and B particles. Preliminary immunoperoxidase studies supported the assumption that the human antibodies were bound to the iAp membrane; technical details might have accounted for the finding that the human antibodies reacted with the iAp but not with B particles in situ.

Effects of p-chlorophenoxyisobutyric acid (CPIB) on the human liver.

Serial liver biopsies were carried out in 67 patients with HLP and/or fatty liver before, during short- and long-term therapy with CPIB and after termination of therapy. Results (1) Decrease of liver glycogen from 4.17% to 2.69% (wet weight, P less than 0.02). (2) Insignificant changes of liver triglyceride content. (3) Significant decrease of manganese, while the concentrations of zinc and copper in the liver biopsy specimens remained unchanged. (4) No signs of liver intoxication or cancerogeneous effects of light-microscopic pictures. (5) Significant increases in numbers of mitochondria and cristae as well as a hypertrophy of endoplasmic reticulum with longer lasting therapy. (6) Striking focal proliferation of cristae mitochondriales in 3 cases on longterm treatment. (7) Regression of the mitochondrial alterations after termination of the CPIB therapy. Our findings suggest that an increased number of mitochondria and of their inner membranes in the liver cells induced by CPIB could play an important role in the hypolipidemic action of the drug.

Abbreviated antibiotic therapy for the treatment of postpartum endometritis.

Standard antimicrobial therapy for postpartum endometritis usually consists of several days of intravenous antibiotics followed by up to ten days of oral therapy. In an effort to decrease the length of hospitalization and duration of antibiotic use, 54 patients were placed on an abbreviated antibiotic protocol. Therapy consisted of intravenous gentamicin and clindamycin until the patient's temperature remained lower than 99.5F for 24 hours, at which time intravenous antibiotics were discontinued and the patient was discharged immediately without oral medication. No morbidity secondary to the abbreviated regimen was observed. Further, the duration of hospitalization and antibiotic therapy of the study group were significantly shorter than similar data from a group of historic controls. These observations suggest that an abbreviated course of antibiotics, based upon the patient's "therapeutic response," may be a safe and cost-effective alternative to the currently practiced therapeutic regimen.

Image processing in pathology. IV. Internal structure of mitochondria.

For extensive recording of mitochondrial membrane lengths hitherto statistical methods were applied which only provide mean values. Conventional measurements of the lengths by means of curvimetry or by intersection counts are required for estimating size distributions and secondary parameters. The former method requires expenditure in time, the latter yields only very rough values for single organelles. Automatic image processing is a possible way to obtain more informations. A method for an automatic definition of the internal mitochondria structure is given in this paper and preliminary results are discussed.

[Morphometry and densitometry with the aid of automatic image analysis]. / Morphometrie und Densitometrie mit Hilfe der automatischen Bildverarbeitung.

Method and effectiveness of recording primary morphometrical and densitometrical data by picture processing are compared with classical test point methods. The advantages of picture processing are demonstrated by measing of mitochondria.

[Radiation pneumonitis. Morphology and pathogenesis]. / Die Strahlenpneumonitis. Morphologisches Bild und Pathogenese.

Radiation-induced pulmonary damage is an inflammatory process which progresses in stages. The quantity rather than quality of pulmonary reactions depends on the given radiation dose. Damage to endothelial cells of capillaries and of respiratory epithelium is the initial event in the development of radiation pneumonitis. Release or activation of cytogenic and serum-derived mediators, increased permeability of the capillary wall, and damage to pneumocytes II are the most important factors in pathogenesis. There is no morphological latent stage. The latency between exposure to irradiation and manifestation of clinical symptoms of pneumonitis may be explained by the morphologic findings. Several non-radiation-induced lung diseases are predisposing factors. There is a tendency to bacterial, viral or mycological superinfections in patients with radiation pneumonitis. Radiotherapy leaves behind a latent pulmonary lesion with continuously changing reactions to most various irritations.

[Ultrastructural results in liver biopsies of patients with hyperlipoproteinaemia (author's transl)]. / Ultrastrukturelle Befunde an Leberpunktaten von Patienten mit Hyperlipoproteinämien.

Electron microscopic investigations were performed on liver biopsies of 24 patients with endogenous hyperlipoproteinaemia (HLP) of the types IIa--V, classified by lipid- and lipoprotein-fractions, as to Frederickson et al. (4), as well as on biopsy specimens of 6 control persons without histological alterations, and on 7 biopsies with staetosis hepatis. In type IIa we found a typical proliferation of the smooth endoplasmic reticulum and a slight alteration of the mitochondria. Types IIb--V are characterized by increasing fatty degeneration of the liver cells as well as by quantitative and qualitative alteration of the endoplasmic reticulum and the Golgi areas. Giant mitochondria, organelles with atypical membrane structures and paracrystalline matrix inclusions occur more frequently, especially in patients with additional diabetes mellitus. There are scarcely differences between steatosis hepatis without HLP and steatosis with combined HLP, resp., except the more distinct alterations of mitochondria, endoplasmic reticulum, and Golgi areas in the latter. The morphological changes are especially restricted to those liver cell structures, involved in the metabolic disregulation.

[Comparative light and electron microscopic study on liver cell inclusions in chronic alcoholic liver damage (author's transl)]. / Vergleichende licht- und elektronenmikroskopische Untersuchungen über Leberzelleinschlüsse bei chronischer alkoholischer Leberschädigung

Liver cell inclusions in chronic alcoholic liver damage observed by means of the ligth microscope proved by correlated electron microscopy to be bile depositions, autophagic vacuoles, megamitochondria, alcoholic hyalin or accumulation of ribosomes. These liver cell inclusions are usually identifiable at the light microscopical level. The bile depositions undergo a lysosomal degradation. Thereby, they are converted into a pale brownish pigment and lose the property of reacting with histochemical bile tests. Owing to this brownish pigmentation bile depositions are distinguishable from the other mentioned liver cell inclusions under the light microscope. Autophagic vacuoles appear as eosinophilic inclusions and are PAS positive before as well as after the diastase treatment. On the contrary to these, the likewise eosinophilic megamitochondria are PAS negative, in the same way as alcoholic hyaline. With the procedure according to Goldner megamitochondria mostly strain red, whereas alcoholic hyalin lacks this property. Moreover, alcoholic hyalin is usually distinguishable from megamitochondria by its shape. Accumulations of ribosomes represent basophilic cytoplasm areas in light microscopy and are frequently located in he pericanalicular regions of liver epithelium.

Demonstration of mouse mammary tumour virus (MuMTV) antigenicity in human milk by means of immunodiffusion technique.

Using the micro-Ouchterlony immunodiffusion technique, we were able to demonstrate mouse mammary tumour virus (MuMTV) antigenicity in the 1.26-1.28 g/ml density fraction prepared from pooled human milk samples after treatment with detergents and ether. The cross-reacting antigen(s) was precipitated by rabbit antisera to MuMTV-B particles prepared from murine milk and intracytoplasmic A particles (iAp) isolated from mouse mammary tumour tissue. By confluence of precipitin lines, the human milk "core" antigen(s) was shown to be identical with the main antigen(s) of iAp which are known to share antigenicity with the MuMTV-B particle cores. Electron microscopy of the human "core" fraction revealed abundant particulate structures of 40-70 nm in diameter. However, the structural entities bearing the cross-reactive antigen(s) remain to be identified.

Electron microscopic investigations of intracytoplasmic A particles in mouse mammary tumours.

Mouse mammary tumour cells were investigated with special regard to intracytoplasmic A particles using ultrahistochemical techniques, especially for the detection of DNA. The findings are discussed in connection with biochemical and immunological results, previously reported by several groups.

[Correlation between the production of mature mammary tumour virus particles and the histomorphological differentiation of murine mammary tumours]. / Korrelation zwischen der Produktion reifer Viruspartikel und der histo-morphologischen Differenzierung virusinduzierter muriner Mammakarzinome

The mammary tumour virus (MTV) contents of mammary tumours (MT's) of various mouse strains were investigated by means of the indirect immunofluorescence technique and the electron microscopy. Only in acinus-forming, well differentiated MT's MTV-B particles could be observed in high quantity. The release of B particles seems to be correlated with the degree of structural ripeness of the tumor tissue. As to intracytoplasmic A particles such a strong relationship could not be found out. Many A particles were seen in mature adenocarcinomas as well as in acinus-free tumours. Some mammary carcinomas of an extreme low degree of histomorphological differentiation were free of any detectable virus production. The indirect immunofluorescence test was confirmed as a sensitive method for the detection of MTV antigens in MT slices. Using polyvalent anti-MTV sera, obtained after immunization of rabbits with ether-disrupted B particles from tumour tissue or milk, the test system allowed the distinction of A and B particle antigens. Accumulations of B particles were seen as an intercellular fluorescence reaction while clusters of A particles were represented by a granular paranuclear reaction within the tumor cells.

Image processing in pathology. X. Electron microscopic morphometric analysis of human lymphocyte subpopulations.

In the present paper, methods of automatic image processing were used for a fine structural differentiation of lymphocyte subpopulations in purified non-labelled lymphocyte suspensions from peripheral blood. It was found that lymphocyte subpopulations differ in several morphological features which have been generated from the whole cell as well as from the nucleus. In general, these differences are greater than those attributed to individual deviations as well as as to influences from the preparation. As found by immunological methods, the composition of morphologically determined subpopulations corresponds to T- and non- T-cells. A preliminary functional interpretation fo the morphological differences is discussed.

[Amyotrophic lateral sclerosis with myoclonic bodies (Lafora bodies) (author's transl)]. / Amyotrophe Lateralsklerose mit Myoklonuskörpern

In the present investigation 2 sporadic cases of amyotrophic lateral sclerosis with the occurrence of myoclonic bodies (Lafora bodies) in the CNS are reported. The patients died after about 14 respectively 8 months lasting disease at the age of 41 and 43, respectively under the clinical signs of an ALS. Morphology, staining qualities, and the distribution of the myoclonic bodies in our cases correspond to the adult form of the myoclonic body disease (type Lundborg). In the literature we found further 6 cases of neurogenic muscle atrophy with the occurrence of myoclonic bodies in the CNS so that one might suppose a syntropy of these two affections. The possible pathophysiological relations of neurogenic muscle atrophy to the occurrence of myoclonic body disease in adults are briefly discussed.