Inhibitory effects of apomorphine and pergolide on neurogenic vasoconstriction in the hindquarters of the rat

Summary The effects of locally administered apomorphine and pergolide were studied in the isolated autoperfused hindquarters of the rat, in an attempt to assess the possible role of presynaptic dopamine receptors at the level in the hypotensive effect of these dopamine agonists.Local infusion of apomorphine (1g·kg^–1·min^–1 for 5 min) or pergolide (1g·kg^–1·min^–1 for 5 min) [into the hindquarters] did not alter perfusion pressure per se, but reduced the pressor response to electrical stimulation of the lumbar sympathetic chains for the whole frequency range used during a cumulative frequency-response curve (0.25–16 Hz, 1 ms, supramaximal voltage). Apomorphine and pergolide reduced the pressor response elicited by 4 Hz electrical stimulation (applied until maximum response was reached) to 54.8±7.1% and 53.9±1.7% respectively, but they did not modify similar increases of perfusion pressure produced by locally administered noradrenaline.The inhibition by apomorphine and pergolide of the 4 Hz stimulation-evoked pressor response was completely antagonized by local administration of the dopamine antagonist haloperidol (1g·kg^–1), but was not influenced by the ₂-antagonist rauwolscine (100g·kg^–1). This dose of rauwolscine antagonized the inhibitory effect of the ₂-agonist UK-14,304, which was not influenced by haloperidol.Local administration of rauwolscine increased the pressor response to stimulation at 4 Hz by 37.4–46.2%. In contrast, local administration of haloperidol did not influence the 4 Hz stimulation-evoked pressor response.These results indicate that dopamine receptors are pressent on the sympathetic innervation of the vascular bed in the rat hindquarters but do not provide evidence for a physiological role of these receptors in modulating peripheral sympathetic neurotransmission. Stimulation of these receptors, leading to a decrease of noradrenaline release and thus of vasomotor tone, might—at least in part—explain the blood pressure lowering effects of intravenous apomorphine and pergolide in the rat.     

Two genes encoding steroid 21-hydroxylase are located near the genes encoding the fourth component of complement in man.

Two genes encoding steroid 21-hydroxylase [21-OHase; steroid 21-monooxygenase; steroid, hydrogen-donor: oxygen oxidoreductase (21-hydroxylating); EC 1.14.99.10], a cytochrome P-450 enzyme, have been located within the HLA major histocompatibility complex. Congenital adrenal hyperplasia due to 21-OHase deficiency is a common inherited disorder of cortisol biosynthesis which is in genetic linkage disequilibrium with certain extended HLA haplotypes. These haplotypes include characteristic serum complement allotypes. A series of cosmid clones was isolated from a human genomic library by using a probe encoding part of the fourth component of complement, C4. These clones also hybridized with a probe encoding most of human 21-OHase. Restriction mapping and hybridization analysis showed that there are two 21-OHase genes, each located near the 3' end of one of the two C4 genes. Hybridization with probes specific for the 5' and 3' ends of the 21-OHase gene showed that the 21-OHase and C4 genes all have the same orientation. The 21-OHase genes 3' to C4A and C4B carry T aq I fragments of 3.2 and 3.7 kilobases (kb), respectively. Both of these fragments are found in genomic DNA of most individuals. In DNA from an individual with the severe, "salt-wasting" form of 21-OHase deficiency who was homozygous for HLA-A3;Bw47;C4A*1;C4B*Q0(null); DR7, the 3.7-kb Taq I fragment is absent, whereas hormonally normal individuals homozygous for HLA-A1;B8;C4A*Q0;C4B*1;DR3 do not carry the 3.2-kb Taq I fragment. These data suggest that the 21-OHase "B" gene (3.7-kb Taq I fragment) is functional, but the 21-OHase "A" gene (3.2-kb Taq I fragment) is not.     

Therapy of primary breast cancer in the 21st century: A prediction

Biology

New treatment selection criteria will arise from molecular biology parameters of growth and treatment response, most probably coupled with the increasing use of initial chemotherapy and repeated minimally invasive surgery.

Prevention

Secondary and hopefully also primary prevention of breast cancer will become more and more successful in the era of molecular genetics, and such interventions will be more directed to individuals and groups at defined higher risk.

Surgery

Surgery will increasingly tend towards “minimally invasive surgery,” which favors not only cosmetics and quality of life, but also more appropriate imaging follow-up.

Chemotherapy

Primary (preoperative) chemo- and endocrine therapy will become the standard initial form of breast cancer treatment, with the intent of down-staging of the tumors to allow later breast-conserving procedures, but also to use the tumor as a biological response parameter and hopefully also for better clinical outcome.

Cost — Effectiveness

Economical parameters might become more and more decisive, as we will have to live with much more “evidence based medicine” and with much more restricted allocation of resources in the future. This might mean, that we will have to diligently develop more simple and cheaper, but not prognostically worse treatment strategies in years to come. More specifically: Do we still need all of the traditional steps in diagnosis and treatment of breast cancer in order to achieve the same results?

Gain of Life

Finally in all of this, we have to make clearcut assumptions, supported also by society and people involved: How do we value “gained years of life” in breast cancer adjuvant and prevention trials? This certainly is not predominantly a medical or economical, but rather an ethical, social and political problem, which has to be finally answered by our socio-cultural environment, and not by doctors alone.     

Metabolic differences between genetically lean and fat chickens are partly attributed to the alteration of insulin signaling in liver.

Insulin signaling [tyrosine phosphorylation of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), Src homology and collagen protein (Shc) and phosphatidyl inositol 3'-kinase activity (PI 3'-kinase)] was studied in the liver and thigh muscles of fat (FL) and lean (LL) chickens. These lines result from a divergent selection on abdominal fat pad size. The divergence is of metabolic origin. Extreme nutritional states were studied (fed, 48-h starved and 30-min refed). Such conditions significantly altered insulin signaling in chicken liver, but surprisingly not in the muscle (except the phosphorylation of Shc in the refed state). No major differences that could account for this divergence were found in muscle. Liver IR number and Shc protein did not differ between genotypes. Liver IRS-1 (protein and messenger) was lower in the fed state and higher in the starved state in FL compared to that in LL chickens. In the fed state, tyrosine phosphorylation of liver IR, IRS-1 and Shc action was higher in FL than in LL chickens that in the absence of insulin resistance rely on higher plasma insulin levels. In the starved state, phosphorylation of liver IR was lower, but the phosphorylation of IR and IRS-1 were higher in LL than in FL chickens, most likely in response to higher plasma glucose and insulin in the lean genotype. In the refed state, the phosphorylation of liver IR and IRS-1 did not differ between genotypes despite significantly lower plasma insulin in FL chickens. Finally, PI 3'-kinase was not affected by the genotype. A significant activation of early steps of insulin signaling in liver of fed FL chickens may at least partly account for their increased liver lipogenesis and ultimately their fattening.     

Stability of Natural Self-Reactive Antibody Repertoires During Aging

We have used a quantitative immunoblotting technique to analyze the repertoires of self-reactive antibodies in serum samples obtained from the same five healthy adults over a 25-year interval. The average age of the donors was 43 years at the time of the first serum sample and 69 years at the time of the second serum sample. The antibody repertoires of IgM and IgG were found to be strikingly similar among individuals in both early and late samples. Densitometric profiles of self-reactivity of serum IgM and of purified serum IgG remained unchanged over the 25-year interval. The total reactivity of serum IgG decreased significantly over the 25-year period. The observed stability of the natural self-reactive IgM and IgG antibody repertoires with aging supports the view that autoreactive B cells in the normal immune system are positively selected for reactivity with a limited set of immuno-dominant self-antigens throughout life.     

Regional brain activity during shape recognition impaired by a scopolamine challenge to encoding

In the present positron emission tomography (PET) study, we examine the effect of a scopolamine-induced challenge to encoding upon the pattern of regional cerebral blood flow during recognition of a list of abstract visual shapes 3 days after encoding of these shapes. This study was conducted to test hypotheses concerning the fusiform and thalamic contributions to object recognition arising from a previous imaging study of impaired recognition. In that study, we demonstrated that activity in the fusiform cortex and the thalamus during shape recognition was modulated by memory challenges. These memory challenges included, on one hand, impaired storage as a consequence of diazepam administration during encoding, and, on the other hand, impaired retrieval caused by a perceptual challenge. Activation in the fusiform cortex decreased during impaired recognition, irrespective of the type of challenge. In contrast, thalamic activation increased only when the recognition deficit resulted from impaired memory storage. Based on these results, we hypothesized that fusiform activation during recognition reflects the matching of an incoming stimulus with a stored one, whereas thalamic activation reflects retrieval attempts. These hypotheses would receive considerable support if scopolamine, which also impairs memory storage, induced similar modulations of fusiform and thalamic activation. In the present study, we observed that a scopolamine challenge to encoding does indeed modulate the activity in the very same regions that were previously modulated by a diazepam challenge. Hence, a similar memory deficit, although primarily effected through different neurochemical pathways, was paralleled by a similar modulation of activity in the same set of nodes in the shape recognition network. In the fusiform cortex, scopolamine decreased recognition-related activity, as did the sensory challenge of retrieval. Furthermore, covariate analysis demonstrated that the level of fusiform activity linearly correlates with behavioural performance. In the thalamus, activation increased following impaired encoding. This is in accordance with the idea that enhanced thalamic activity reflects increased effort expended in retrieval. In addition, in the intraparietal sulcus, differential activation also increased following impaired memory storage, possibly reflecting enhanced visuospatial attention in an effort to compensate for impaired performance.     

Reversible protein kinase C activation in PC12 cells: effect of NGF treatment

Although protein kinase C (PKC) is a key enzyme in the signal transduction process, there is little information on the mechanism leading to PKC activation in living cells. Using a new fluorescence imaging method, we studied this mechanism and correlated PKC conformational changes with intracellular Ca2+ concentration. PC12 cells were simultaneously loaded with Fura-2-AM and Fim-1, two fluorescent probes, which recognize Ca2+ and PKC, respectively. KCl and carbachol (an agonist to muscarinic receptors) applications induced dose-dependent increases of fluorescence for both probes. Both Ca2+ and PKC responses were observed within seconds following KCl or carbachol application, and were reversible upon stimulus withdrawal. PKC activation kinetics was slightly more rapid than the Ca2+ response after KCl application. After nerve growth factor (NGF) treatment of the cells, the amplitude of the KCl-induced PKC responses was larger indicating an increase in the activated PKC-pool in these cells. This difference between control and NGF-treated cells was not observed following carbachol application, suggesting the involvement of different PKC pools. While the Ca2+ response uniformly occurred in the cytosol, the PKC response displayed a patch pattern with higher intensities in the peripheral zone near the plasma membrane. This heterogeneous distribution of PKC activation sites was similar to the immunocytological localization of Ca2+-dependent and independent PKC isoforms, which suggested that at least several PKC isoforms interacted with intracellular elements. Upon repeated stimulation, the PKC response rapidly desensitized.     

Transfusion use in curatively operated patients with colorectal carcinomas. Swiss Study Group for Clinical Cancer Research

OBJECTIVE: Is there an improvement of the behaviour for restrective blood transfusions after the data in the literature and especially the preliminary data of the SAKK 40/81 study have been published? They have shown a worsening of the prognosis in patients with colorectal cancer after pre-/postoperative blood transfusions have been given. MATERIAL AND METHODS: Analysis of the retrospective transfusion data of the SAKK 40/81 study in comparison with the prospective transfusion data of the study SAKK 40/87. RESULTS: The analysis of the data showed that in the SAKK 40/81 study more patients received blood transfusions than in the SAKK 40/87 study (77% versus 49%). Especially there was a diminution from 90% in the SAKK 40/81 to 59% in the SAKK 40/87 study for the rectal cancer patients respectively from 70% to 44% in the colon cancer patients having received blood transfusions. The mean value of hemoglobin of the patients not having received transfusions has decreased from 11.2 (7.8-15) g/100 ml in the SAKK 40/81 to 10.6 (5.4-15) g/100 ml in the SAKK 40/87 study (p = 0.0001). CONCLUSION: The data of the two SAKK studies showed that in Switzerland the donation of blood transfusions in patients with colorectal cancer has continuously been handled more and more restrictive. An even more restrective use may be possible in future due to new operation techniques and the possibility of preoperative administration of erythropoetin to increase the hemoglobin level.