Whole-genome sequencing disproves two suspected transmission events of blaNDM between Pseudomonas aeruginosa and Enterobacterales in hospitalized patients.

New Delhi metallo-ß-lactamase (blaNDM) acquisition by Gram-negative bacteria is a primary concern due to its broad-host-range distribution. This study investigated two potential in-vivo horizontal gene transfers (HGTs) of blaNDM between Enterobacterales and Pseudomonas aeruginosa, initially indicated by polymerase chain reaction. Whole-genome sequencing showed independent parallel acquisition of two different blaNDM variants (NDM-1 and NDM-5) in P. aeruginosa and Enterobacterales, respectively. The data show that short-read sequencing provides the necessary resolution to confirm or dispute HGT by the comparison of genetic elements surrounding the gene of interest, and thus provide a timely response to potential outbreaks.

Evaluation of translocator protein quantification as a tool for characterising macrophage burden in human carotid atherosclerosis.

Macrophage presence within atherosclerotic plaque is a feature of instability and a risk factor for plaque rupture and clinical events. Activated macrophages express high levels of the translocator protein/peripheral benzodiazepine receptor (TSPO/PBR). In this study, we investigated the potential for quantifying plaque inflammation by targeting this receptor. TSPO expression and distribution in the plaque were quantified using radioligand binding assays and autoradiography. We show that cultured human macrophages expressed 20 times more TSPO than cultured human vascular smooth muscle cells (VSMCs), the other abundant cell type in plaque. The TSPO ligands [3H](R)-1-(2-chlorophenyl)-N-methyl-(1-methylpropyl)-3-isoquinoline carboxamide ([3H](R)-PK11195) and [3H]N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide ([3H]-DAA1106) bound to the same sites in human carotid atherosclerotic plaques in vitro, and demonstrated significant correlation with macrophage-rich regions. In conclusion, our data indicate that radioisotope-labelled DAA1106 has the potential to quantify the macrophage content of atherosclerotic plaque.

Risk factors for cystoid macular oedema in patients with uveitis.

PURPOSE: To determine ophthalmologic and systemic factors associated with the presence of cystoid macular oedema (CMO) in patients with uveitis. METHODS: Retrospective cross-sectional study in which 97 consecutive patients with uveitis filled in an extensive questionnaire for the presence of cardiovascular diseases and its risk factors. An analysis of the ophthalmologic and questionnaire data was conducted. RESULTS: CMO was present in 44% (43/97) of patients. Its presence was strongly associated with increasing age (P=0.001) and age at onset of uveitis (P<0.001). For patients older than 50 years, the risk of having CMO was 3.8-fold (95% confidence intervals 1.6-9.0) larger than for younger patients. The most frequent anatomic location of uveitis associated with CMO was panuveitis (49%). Papillary leakage on fluorescein angiography was associated with CMO (P<0.001), independently of other risk factors. After adjustment for age, multivariate logistic regression showed no association between cardiovascular disease and its risk factors and the presence of CMO. CONCLUSIONS: Age, independent of duration of uveitis, was a major risk factor for the presence of CMO in uveitis. A positive correlation between CMO and papillary leakage on angiography was noted.

Solid-phase S-3CR generates N-substituted alpha-aminonitriles for the synthesis of alpha-phenyl-alpha-(1-piperazinyl) substituted amino acids.

Structurally diverse amino acids were prepared as versatile synthons for combinatorial chemistry. Using an optimized solid-phase synthesis by Strecker-three-component-reaction (S-3CR), two different polymer linker constructs carrying piperazine were investigated. (a) Acrylate derived base-labile linker yielded alpha-aminonitriles with N-alkylated piperazines via Hofmann elimination after quarternisation with an alkyl halide. The crude product purities were in the range of 54-87%. (b) A urethane type linker yielded alpha-aminonitriles with the free piperazine nitrogen when cleaved with acid and the product purities were 72-93%. The alpha-aminonitriles were easily converted to novel Nepsilon) - Fmoc-protected alpha-amino acids with alpha-(1-piperazinyl) and alpha-phenyl substituents.

Differential inflammatory involvement in retina and choroïd in birdshot chorioretinopathy.

BACKGROUND: Birdshot chorioretinopathy is characterised by dual unrelated inflammatory involvement of the retina and the choroid. Indocyanine green angiography made it possible to assess and follow choroidal disease with the same precision as retinal involvement was followed so far. The aim of this study was to analyse the severity, progression and response to therapy of both retinal involvement using fluorescein angiography and choroidal involvement using indocyanine green angiography. PATIENTS AND METHODS: Patients with birdshot retinochoroidopathy followed at La Source Eye Centre in Lausanne, Switzerland from January 1995 to December 2002 were subdivided into three subgroups according to the duration of evolution of the disease: untreated patients with no more than one year duration of the disease (group 1, n = 6); treated patients with disease duration of 1 - 7 years duration (group 2, n = 5) and patients with disease lasting for more than 7 years (group 3, n = 4). Fluorescein and indocyanine green angiographic signs (angiographic scores given by a masked observer) were analysed in the 3 groups and compared to the "cream-coloured" fundus lesions. RESULTS: Fifteen out of the 742 patients (2.0 %) seen at La Source Eye Centre during the time period considered presented BC and were included in the study. In the "early disease group" fluorescein and ICG angiography showed more severe choroidal than retinal involvement with respective scores of 3 +/- 0.79 (ICG) and 2 +/- 1.17 (FA) while there were few depigmented fundus lesions to be seen (score 1 +/- 0.27). The choroidal involvement responded well to systemic corticosteroids +/- immunosuppressive therapy (scores in groups 2 and 3 = 1.2 and 0.75), while retinal disease was stabilised at best (scores in groups 2 and 3 = 2.2. and 2.4) and depigmented fundus lesions increased (scores in groups 2 and 3 = 2.8 and 3). CONCLUSION: The evolution and response to therapy of retinal and choroidal disease in birdshot chorioretinopathy have a different course with choroidal disease responding well to therapy while retinal disease is more resistant, possibly explaining the slow deterioration of functional parameters despite therapy. The increase of "cream-coloured" fundus lesions despite good choroidal response to therapy could be explained by depigmentation left behind after resolution of choroidal stromal granulomas, a hypothesis recently confirmed by an autopsy case of birdshot chorioretinopathy.

Intraocular and plasma levels of cellular fibronectin in patients with uveitis and diabetes mellitus.

AIMS: To determine intraocular and plasma levels of cellular fibronectin (cFN) in patients with uveitis or diabetes mellitus (DM) and to assess the association with disease activity, macular oedema, and vascular leakage on fluorescein angiography. In addition, to examine whether cFN is locally produced in the eye. METHODS: Intraocular and plasma levels of cFN were determined by ELISA in 39 patients with uveitis (23 active, 16 non-active), in 11 patients with DM (eight with and three without diabetic retinopathy) and in 17 control patients. The influence of diabetic retinopathy, inflammatory activity, vascular leakage, and macular oedema (MO) on intraocular and plasma cFN levels was studied. Local production of cFN was determined by calculating absolute and relative intraocular to plasma ratios. Aqueous and vitreous levels of cFN were compared. RESULTS: No differences in plasma cFN levels were found between patients with uveitis, DM, or controls. Intraocular cFN levels were significantly raised in patients with uveitis and DM, specifically in those with active disease (active uveitis and active diabetic retinopathy versus controls: p = 0.001 and 0.002 respectively). Further, intraocular cFN levels were significantly elevated in patients with macular oedema or vascular leakage, irrespectively of whether associated with uveitis or DM (p = 0.001 and 0.002). Intraocular cFN levels were consistently higher in the vitreous than the aqueous. Intraocular production of cFN was documented by elevated absolute and relative intraocular to plasma ratios in nine out of 11 patients tested. CONCLUSIONS: Elevated intraocular cFN levels were found in uveitis and DM, especially in those with active processes, intraocular vascular damage, and MO. These results suggest that locally produced cFN levels reflect intraocular vascular damage.

Photoreceptor function in eyes with macular edema.

PURPOSE: The irreversible loss of visual acuity in macular edema is usually attributed to permanent loss of photoreceptor cells, although there is hardly any information on changes in photoreceptor function in macular edema. The purpose of this study was to assess photoreceptor function in various stages of macular edema and to relate the findings to visual acuity and angiographic changes. METHODS: Directional sensitivity (optical Stiles-Crawford effect) and visual pigment density of foveal cones was measured with a custom-built scanning laser ophthalmoscope (SLO) in 19 eyes of 19 patients. Twelve eyes exhibited macular edema: five of inflammatory origin, and seven of diabetic origin. Seven eyes with an intraocular inflammatory disease without clinical or angiographic evidence of edema were also included (four of which had previous macular edema and one of which had shown development of macular edema at the 1-year follow-up). Results of SLO measurements were related to findings using fluorescein angiography and Snellen visual acuity, both assessed at the time of SLO measurement and 6 months thereafter. RESULTS: Eyes with macular edema exhibited diminished directional sensitivity of photoreceptor cells in the fovea compared with eyes without (P = 0.02). Visual pigment density of eyes with macular edema was decreased and associated with both initial and follow-up visual function and with the angiographic macular edema grade at follow-up. Abnormal directional sensitivity and pigment density were already present in eyes with slight edematous changes and normal visual acuity. CONCLUSIONS: Eyes with inflammatory or diabetic macular edema showed decreased directional sensitivity and visual pigment density in the macular area. These findings may support a role for SLO measurements in detecting retinal damage due to macular edema.

Cortical local circuit axons do not mature after early deafferentation.

The processes underlying development, refinement, and retention of the intracortical connections critical for the function of the mammalian brain are unknown. Horseradish peroxidase-labeled fibers in mouse somatosensory barrel cortex, which is patterned like the whiskers on the contralateral face from which it receives inputs, were evaluated by automated image analysis. The sensory nerve to the whiskers was sectioned on postnatal day 7, after the whisker map is set. The deprived barrel cortices, examined in adults, showed drastically diminished intracortical projections relative to normal controls, although the map of the whiskers in the cortex was unchanged. This demonstrates anatomically that the normal pattern of intracortical connections, like the normal sensory map, is dependent upon the sensory periphery four synapses away.

Endocrine effects of a new histamine H2-receptor antagonist, nizatidine (LY139037), in the male rat.

A new orally active histamine H2-receptor antagonist, nizatidine (LY139037), was evaluated in male rats for effects on mechanisms regulating accessory sex organ growth and function. Cimetidine antagonized androgen binding to cytosolic receptors in vitro while nizatidine had no effect. Nizatidine and cimetidine were administered at the ED50, 5 X ED50, or 10 X ED50 doses for inhibition of gastric acid secretion previously determined using in vivo dog and rat models. The relative potencies of both agents to antagonize histamine H2-receptor-mediated gastric acid secretory responses have been confirmed in human clinical trials. Neither nizatidine nor cimetidine antagonized the in vivo uptake or nuclear translocation of radiolabeled androgen into the hypothalamic-preoptic-amygdala, pituitary, or ventral prostate. Nizatidine, given at doses equal to and 10 X the ED50 gastric acid secretion inhibitory values, and cimetidine (10 X ED50 value) had no effect on the response of male accessory sex organs to a submaximally stimulating dose of androgen in castrated rats. High doses of dietary nizatidine (greater than 500 mg/kg-day) administered for 6 months did not alter intact rat male accessory sex organ weights or circulating androgen levels relative to untreated controls. Acute administration of either nizatidine or cimetidine produced transient elevations in plasma prolactin (PRL) levels. Cimetidine was more potent and consistent than nizatidine in producing these increases in circulating PRL. The data described herein support the contention that unlike cimetidine, nizatidine is not a pharmacological antagonist of androgen action and has less of a stimulatory effect upon plasma prolactin. Taken together, these studies indicate that in the male rat, nizatidine exhibits a large therapeutic index between its gastric antisecretory activity and potential endocrinological effects.

Incidental carcinoma of the prostate: an improved modality for early detection.

In a prospective study 140 unselected patients with clinical evidence of benign adenoma of the prostate were resected via a transurethral approach. Pathohistological analysis was done according to selective criteria for tissue sampling. 16 incidental carcinomas (T0; 11.4%) were detected. In a retrospective analysis 244 patients were operated on by the same method compared with 326 patients with conventional transurethral resection. T0 tumors were found in 11.5 versus 5.2% of the patients. The increase in the incidence of T0 tumors was significant (p less than 0.004). We recommend this modality as a simple method to optimize early detection of T0 tumors in the transurethral resection specimens.

Preclinical toxicology studies with nizatidine, a new H2-receptor antagonist: acute, subchronic, and chronic toxicity evaluations.

Nizatidine (NIZ), a new antiulcer drug, was evaluated for toxicity in acute, subchronic, and chronic tests. Acute toxicity studies were conducted in rats, mice, dogs, and monkeys. Median lethal doses (MLD) in rodents were greater than 1600, 230, and 1000 mg/kg by oral (po), iv, and sc administration, respectively. No deaths occurred in dogs given single doses of 800 mg/kg (po), 75 mg/kg (iv), or 225 mg/kg (im) or in monkeys given 1200 mg/kg (po) or 200 mg/kg (iv). Rats survived up to 1.0% dietary NIZ (daily intake ranging from 24 to 800 mg/kg/day) for 1 year. Slight decreases in body weight gain and increases in liver and kidney weights occurred. Slight decreases in erythrocytic parameters at 3 months were not present at 6 or 12 months. Mice survived up to 1.5% dietary NIZ for 3 months and effects were limited to slight decreases in body weight gain and increases in relative liver weight. Dogs survived oral doses up to 800 mg/kg/day for 3 months but had numerous clinical signs of toxicity and body weight loss. All dogs given oral NIZ doses up to 400 mg/kg/day survived except for one high-dose dog that was killed in a moribund condition following convulsions in the 41st week of treatment. Effects in dogs included miosis, body weight loss, increased thrombocyte counts, and decreased hepatic microsomal enzyme activity and P450 content. The increase in thrombocyte counts was unaccompanied by changes in thrombocyte function and did not reoccur in a subsequent study. A decrease in plasma testosterone in two of three surviving male dogs given 400 mg/kg/day for 1 year was unaccompanied by effects on the size or morphology of testes or prostate. Peak plasma levels of NIZ in all species tested were in excess of human plasma levels after therapeutic doses. In conclusion, there was no evidence of significant toxicity in organs or tissues including those sites (gastric mucosa, male sex organs, and liver) that have been affected by some agents of this therapeutic class.

[Diagnosis for the localization of cemented intramedullar stem prostheses and ICLH-prostheses of the hip by means of stereo X-ray prints (author's transl)]. / Stereo-radiologische Lokalisationsdiagnostik von Schalen- und Totalendoprothesen des Hüftgelenkes.

It is known that the loosening of artificial hip joints leads to their shift relative to the carrying bone structure. For a quantitative radiological detection of even minimal dislocations fix-points both in the carrying bone structure as well as in the prostheses have to be defined. While for the stem prostheses and cups such points can be defined directly from their geometrical structure, they have to be generated artificially for the carrying bone structure by implanted metal pins, which can easily be detected in the X-ray print. Having defined in this way a complete and appropriate set of fix-points, the position of the prosthesis relative to the bone structure is uniquely defined by the distance vectors between the different fix-points. The main biometrical steps of such a concept as well as their computational formulation and realization are derived; the main advantages and the accuracy of the technique are elucidated and critically discussed.