Multidentate 2-pyridyl-phosphine ligands - towards ligand tuning and chirality.

In the current work a range of multidentate pyridyl-phosphine ligands are synthesised with tuneable electronic and steric character, through the incorporation of a variety of alcohols into (amino)pyridyl-phosphine frameworks. The stoichiometric reactions of compounds of the type (R2N)xP(2-py)3-x (2-py = 2-pyridyl) with alkyl as well as aryl alcohols result in the formation of (alkoxy)pyridyl-phosphines (RO)xP(2-py)3-x (R = Me, 2-Bu, Ph). This synthetic procedure also allows the introduction of enantiomerically pure alcohols, like (R)-(-)-2-BuOH and (S)-(+)-2-BuOH, and as such provides a very convenient two-step route to chiral multidentate pyridyl-phosphine ligand sets. Using the bis-amino-phosphine (Et2N)2P(2-py), the stepwise introduction of alcohols enables the synthesis of racemic alkoxy-amino-phosphines (R2N)(RO)P(2-py), as well as alkoxy-phosphines (RO)2P(2-py) and therefore offers easy access to a library of different pyridyl-phosphine ligands. Coordination studies of the (amino)pyridyl-phosphines and (alkoxy)pyridyl-phosphines with copper(i) reveal that ligands with two N donor atoms form dimeric arrangements, while (PhO)2P(2-py), in-corporating only one N donor atom, shows completely different coordination behaviour.

Comparison of a new metamizole formulation and carprofen for extended post-operative analgesia in dogs undergoing ovariohysterectomy.

A newly developed slow-release tablet formulation of metamizole was compared with carprofen for post-operative analgesia in dogs undergoing ovariohysterectomy. Twenty-three dogs were randomly assigned to one of two groups, and administered 50 mg/kg metamizole PO (Group M) or 4 mg/kg carprofen PO (Group C) 1 h before anaesthetic induction and 24 and 48 h later. Anaesthesia was induced with propofol and maintained with isoflurane and fentanyl, after premedication with 0.005 mg/kg medetomidine and 0.3 mg/kg methadone IM. A blinded observer assessed post-operative sedation, and analgesia using a visual analogue scale, a dynamic interactive visual analogue scale, the Glasgow composite pain scale (GCPS), and a mechanical nociceptive threshold device (T = 0.5, 1, 2, 4, 8, 12, 18, 21, 24, 36, 45, 60 and 70 h after surgery). Rescue methadone was administered if the GCPS was >6/24 in ambulatory dogs, or >5/20 in non-ambulatory dogs. Plasma concentrations of test drugs were quantified. The dose range for metamizole was 39-56 mg/kg. At T = 0.5 h sedation scores were significantly higher in Group C and GCPS scores were significantly higher in Group M. Three dogs required rescue methadone (Group M, n = 1; Group C, n = 2). Vomiting occurred post-operatively in 45% of dogs in Group M. Carprofen and metamizole were both well absorbed; peak concentrations occurred within 4-24 h, and 4-16 h for carprofen and metamizole, respectively. Both drugs provided adequate analgesia of similar duration. No side effects were observed with carprofen while vomiting was frequent following administration of metamizole.

Prolactin--to be reconsidered in canine mammary tumourigenesis?

Mammary tumours represent the most common neoplastic disease of the female dog, and the incidence in female dogs is much higher than in women. Whereas the influence of sexual steroids on breast cancer (BC) development in dogs has been studied, very little is known about the role of prolactin (PRL). New studies show that until recently, the importance of PRL in human BC development and progression has been highly underestimated. PRL plays a role in promoting benign as well as malignant neoplastic cell growth in BC in vitro and in vivo. Sporadic publications proposed a tumour promotor role in the dog. The goal of this review is to summarize our knowledge about PRL and human BC as well as canine mammary tumourigenesis, and propose future research in this area.

Comparative analysis of proliferative potential and clonogenicity of MACS-immunomagnetic isolated CD34+ and CD133+ blood stem cells derived from a single donor.

A novel stem cell marker prominin-1 (CD133) has been shown to be expressed on a subpopulation of CD34(+) haematopoietic stem and progenitor cells. The aim of this study was to compare in parallel commercially available CD34(+) and CD133(+) isolation methods based on paramagnetic bead-coupled antibodies using clinical-grade samples of mobilized peripheral blood from 10 individual healthy donors under identical conditions. The CD133 negative fraction from the first selection was used for CD34(+) enrichment to obtain an additional CD34(+)/CD133(-) population. Although no significant difference in total cell expansion between cells isolated from the three procedures was observed in a 7-day cytokine-driven suspension culture, the long-term culture-initiating cell assay demonstrated that cells derived by CD34(+) isolation contain less primitive progenitors than those isolated based on CD133(+) selection. Interestingly, CD34(+)-enriched progenitors, especially the CD34(+)/CD133(-) fraction, contained a significantly higher proportion of erythroid colony-forming cells, whereas the highest content of myeloid colony-forming cells was concentrated in the CD133(+) selected cells. These subtle differences between CD34(+) and CD133(+) immunomagnetic selection will have to be explored for their potential clinical relevance.

Sonographic quantification of the type IV reaction after intradermal application of recall antigens.

20-MHz B-scan high-resolution sonography permits non-invasive, two-dimensional visualisation of micromorphological structures in vivo, and allows precise measurement of the depth and extent of inflammatory skin lesions. In 50 patients, the reactions following intradermal application of 8 recall antigens to the volar forearm were evaluated clinically and sonographically at various times (0, 24, 48, 72 h). In 30 patients, one of the inflammatory papules was excised after 48 h for complete histological work-up (serial sections) and subsequent comparison with the sonographic image. Infiltrates were characterised in the ultrasound scans by the almost regular occurrence of convexity of the skin surface, by a loosened structure (loss of echogenicity) of the corium and by protrusion of the corium into the subcutaneous fatty tissue. It was also possible to follow the dynamics of the type IV reaction with the measurement of echogenicity (densitometry). High-frequency ultrasound is an objective, exact and very sensitive tool for the measurement of type IV reactions after intradermal application of recall antigens and therefore superior to clinical evaluation. The B-scan was superior to the A-scan. However, for routine evaluation of tuberculin-like reactions, sonography is too time-consuming. Our results suggest that densitometry provides no additional or necessary information compared to sonometry.

Elicitation and habituation of the electrodermal orienting response in a short interstimulus interval paradigm.

The present experiment was carried out to investigate elicitation and habituation of the electrodermal Orienting Response with stimulus trains utilising a short interstimulus interval (ISI) of 1.1 s. We sought evidence for within-train response decrement to repeated stimulus presentation, response recovery to a change stimulus and dishabituation following the change stimulus--the three properties necessary to unequivocally identify a decremental process as habituation. No autonomic study could be found using such a short ISI. Autonomic studies on this time scale are necessary if these measures are to be integrated with central event-related potential (ERP) measures of electrical brain function. Overcoming this paradigm gap required the development of novel measurement procedures to estimate the small electrodermal responses obtained, usually occurring on the recovery slope of the response to the previous stimulus in the train. With our novel measurement procedures, evidence was found indicating that electrodermal activity in such a paradigm exhibited the three classic criteria of habituation.

Cloning and expression of the genes for xylose isomerase and xylulokinase from Klebsiella pneumoniae 1033 in Escherichia coli K12.

The genes xylA and xylB were cloned together with their promoter region from the chromosome of Klebsiella pneumoniae var. aerogenes 1033 and the DNA sequence (3225 bp) was determined. The gene xylA encodes the enzyme xylose isomerase (XI or XylA) consisting of 440 amino acids (calculated M(r) of 49,793). The gene xylB encodes the enzyme xylulokinase (XK or XylB) with a calculated M(r) of 51,783 (483 amino acids). The two genes successfully complemented xyl mutants of Escherichia coli K12, but no gene dosage effect was detected. E. coli wild-type cells which harbored plasmids with the intact xylAKp 5' upstream region in high copy number (but lacking an active xylB gene on the plasmids) were phenotypically xylose-negative and xylose isomerase and xylulokinase activities were drastically diminished. Deletion of 5' upstream regions of xylA on these plasmids and their substitution by a lac promoter resulted in a xylose-positive phenotype. This also resulted in overproduction of plasmid-encoded xylose isomerase and xylulokinase activities in recombinant E. coli cells.

Antiestrogen and antiandrogen administration reduce bone mass in the rat.

In mature female and male rats sex hormone deficiency was produced by surgical castration and by antiestrogen or antiandrogen administration. For the latter purpose we used the nonsteroidal antiestrogens tamoxifen, keoxifene (LY156758) and tetramethylhexestrol, and the steroidal antiandrogen cyproterone acetate. Dosages of 0.4 mg tamoxifen/rat/day and isomolar dosages of keoxifene and tetramethylhexestrol led to a bone mass reduction which was comparable to ovariectomized rats. Cyproterone acetate showed, at 10 mg/rat/day, a similar decrease in bone mass like orchidectomy. The often discussed intrinsic estrogen activity of the antiestrogens was present only in the highest dosage tested of tamoxifen. Keoxifene and tetramethylhexestrol showed no estrogenic effects, but this may be a dosage problem. Cyproterone acetate revealed no androgenic side-effects. These results indicate that antigonadal hormone drugs reduce bone mass to a varying extent.

[The unrecognized myocardial infarct in the aged--contribution to prognosis]. / Der unbekannte Herzinfarkt im Alter--Beitrag zur Prognose.

The poor prognosis of myocardial infarction in old people is based almost completely upon clinical observations. But in the case of patients of advancing years it seems likely that the percentage of undiagnosed infarctions-whether due to atypical symptoms or to the fact that the patient is not admitted to hospital-is considerable. To estimate the level of this percentage a clinical-autoptical analysis of 124 decreased with transmural myocardial scars was carried out (mean age of death: 80 years). This reveals that 80% of all myocardials scars had not hitherto been diagnosed. Only 35% of the electrocardiograms showed definite scars, mostly in the case of patients with known myocardial infarction. 22% of deceased had complained about angina pectoris, again mostly patients with known myocardial infarction. In comparison with other studies of people in the same age group, the results are not surprising. This is only explained in part by old people's poor powers of recollection and their limited ability to communicate. These results indicate that the over all prognosis of acute myocardial infarction in old people, which often does not occur in hospital without being diagnosed should be viewed in a more favourable light than clinical results would suggest.

[Survived brain infarction in old age - clinical and morphological findings. II. Risk factors (author's transl)]. / Der überlebte Hirninfarkt im Alter - Klinische und morphologische Befunde - II. Teil: Risikofaktoren.

208 hospitalized patients, nearly 80 years old, were investigated because of risk factors and complicating diseases. Hypertension (58.2%), typical myocardial infarctions (37.2%) and diabetes (45.2%) were twice often as in our comparable cases without stroke. Corresponding we found signs of left ventricular hypertrophy in more than 50% post mortem. The dimensions of heart failure by hypertension are visible in ECG indicating LVH with many dysrhythmias. Early mortality (40%) as survival time are dependent on the size of the stroke. Cardiovascular causes of death were found mainly. The differences to younger patients with brain infarction seem to be only of gradually nature and especially to refer to the more intensive damaged heart.

[Survived brain infarction in old age - clinical and morphological findings. part I: extracranial stenoses of carotis arteries (author's transl)]. / Der überlebte Hirninfarkt im hohen Alter - Klinische und morphologische Befunde 1. Teil: Extrakranielle Karotisstenosen.

By clinical and post mortem findings we searched for the risk factors, important for brain infarctions in people of nearly 80 years. We were especially interested in the conditions of the extracranial vessels such as the carotid arteries and the murmurs at this point. The number of arterial stenoses in this region, ascertained in younger people is similar in old age. Besides of others factors, caused by old age, the many cases of multiple extracranial stenoses are probably responsible for the overproportional big brain infarctions in this series. In nearly 50% of all stenoses we heard vascular murmurs, mostly in both of the carotid arteries. Despite of some uncertainly of the clinical importance - just in old age many cardiac murmurs of the ejection type with tendency to transmission have been heard - they should give rise to investigate carefully the region of the neck in symptomatic patients.