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Synthesis and SAR of highly potent dual 5-HT1A and 5-HT1B antagonists as potential antidepressant drugs.

Novel 5-HT(1) autoreceptor ligands based on the N-4-aryl-piperazinyl-N'-ethyl-5,6,7,8-tetrahydropyrido[4', 3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one core are described. Aiming at antidepressants with a novel mode of action our objective was to identify potent antagonists showing balanced affinities and high selectivity for the 5-HT(1A) and 5-HT(1B) receptors. Strategies for the development of dual 5-HT(1A) and 5-HT(1B) antagonists based on 1 and 2 as leads and the corresponding results are discussed. Isoquinoline analogue 33 displayed high affinity and an antagonistic mode of action for the 5-HT(1A) and the 5-HT(1B) receptors and was characterized further with respect to selectivity, electrically stimulated [(3)H]5-HT release and in vivo efficacy.

Antidepressive Agents↗

Psychosis: a costly by-product of social brain evolution in Homo sapiens.

The plethora of varied and often conflictual research evidence on the functional psychoses calls for a unifying explanatory framework. An evolutionary framework is appropriate in view of the paradoxical epidemiology of the disorders. Evolutionary models that rely on balanced polymorphism or group selection models are not supported by the evidence. Rather, a hypothesis is presented arguing that the spectrum of psychoses should be regarded as a costly by-product of social brain evolution in Homo sapiens. Under social selective pressures, hominid ancestors evolved a sophisticated neural network supporting social cognition and adaptive interpersonal behaviour--this is termed the 'social brain'. The functional psychoses (and schizophrenia in particular) are characterised by functional and structural deficits in these fronto-temporal and fronto-parietal circuits; hence the epithet 'social brain disorders' is fitting. I argue that accumulating evidence for an evolved social brain calls for a new philosophy of mind; a philosophy focussed on the social and interpersonal nature of human experience and derived from the philosophies of Fromm, Heidegger and Merleau-Ponty. Such a paradigm shift would aid modern neuroscience in finally abandoning Cartesian dualism and would guide psychiatry towards an integrated and 'socio-neurologically' embedded understanding of mental disorders.

Biological Evolution↗

Living & learning with allergy: a European perception study on respiratory allergic disorders.

BACKGROUND: Knowledge of allergy patients' perception of own disease is inadequate, and understanding of the impact of local environment, including family and health-care system, on patients' management of disease is insufficient. We examined the potential of telephone-based survey techniques for establishing this knowledge in 10 European countries. METHODS: A two-phased questionnaire developed by use of focus groups in seven countries was translated into 10 languages. To ensure that the true values of the populations were restored in randomly selected populations, 75,343 telephone numbers selected for screening represented balanced national distributions of households. RESULTS: Eight thousand two hundred and sixty-eight respiratory allergy sufferers were identified by the telephone screening process. 85.4% accepted to participate in the survey and 89.6% completed both phases comprising 34 questions and rating of 49 statements. Data for each country were weighted in terms of age, sex and the recorded allergy prevalence within age intervals. CONCLUSIONS: The telephone survey technique allowed for establishment of random representative samples, and application of mathematical weighting procedures assured that the true national values were restored in the data set. As all interviews were performed in a standardised manner we conclude that the telephone-based survey methodology enables national representative data set to be established and compared.

Adaptation, Psychological↗

Opiate modulation of dynorphin conversion in primary cultures of rat cerebral cortex.

Rat brain cortical cells in primary culture were used to investigate long-term effects of opiates on endopeptidases acting on dynorphin peptides. Enzyme activity in the soluble fraction of the cells converted dynorphin B to Leu-enkephalin-Arg6 and to a lesser extent to Leu-enkephalin. Five day treatment with 10 microM morphine increased the conversion to Leu-enkephalin-Arg6 by 370%. This effect was prevented by the presence of naloxone in the culture medium. The opiate-inducible activity was directed to the Arg-Arg bond in dynorphins with preference for dynorphin B > alpha-neoendorphin > > dynorphin A. The Km for the generation of Leu-enkephalin-Arg6 from dynorphin B was 40 microM. Enzyme activity was inhibited by dynorphin fragments, in the following order of potency: dynorphin A(1-13) > A(2-13) > A(1-17) > A(2-17) and by SH-reagents, suggesting the presence of a cysteine-protease. The opiate-stimulated dynorphin-converting enzyme (DCE)-activity affects the balance between dynorphin peptides (selective for kappa-opioid receptors) and enkephalin peptides (selective for delta-opioid receptors). Since both types of opioid peptides can influence the development of opiate tolerance, the change in the extent of this transformation may be functionally important.

Animals↗

Accurate confidence intervals for binomial proportion and Poisson rate estimation.

Estimates of proportion and rate-based performance measures may involve discrete distributions, small sample sizes, and extreme outcomes. Common methods for uncertainty characterization have limited accuracy in these circumstances. Accurate confidence interval estimators for proportions, rates, and their differences are described and MATLAB programs are made available. The resulting confidence intervals are validated and compared to common methods. The programs search for confidence intervals using an integration of the Bayesian posterior with diffuse priors to measure the confidence level. The confidence interval estimators can find one or two-sided intervals. For two-sided intervals, either minimal-length, balanced-tail probabilities, or balanced-width can be selected.

Binomial Distribution↗

Creatinine biosensors: principles and designs.

Creatinine biosensors, based on both potentiometric and amperometric devices, have been created. However, there are significant problems still to be addressed, including the balance between sensitivity and selectivity, interference rejection and sensor stability. In addition, many devices still rely on a dual-sensor approach for creatine and creatinine subtractive measurements. However, creatinine biosensors appear close to attaining the performance goals necessary for their widespread application. This article looks at the operating principle and design of both potentiometric and amperometric creatinine biosensors, and shows how the design of these devices affects their performance.

Aminohydrolases↗

[Impact of antibiotic prophylaxis on microbial ecology].

This review of the literature analysed the impact of prophylactic antibiotics on patients, nurses, the ecosystem of the wards, the hospital and the general environment. After prophylactic antibiotics a qualitative and quantitative modification of the cutaneous and digestive flora of the patient can occur, as well as modification of susceptibility to antibiotics. Several factors may modulate their action on the bacterial flora: the breadth of the spectrum, the administered dose, the duration of treatment, the form of development of resistance and the type of antibiotics. Numerous studies have demonstrated the role of the nursing staff as a reservoir of multi-resistant micro-organisms. Staff of intensive care units is apparently the most affected. Prophylactic antibiotics can also induce changes in the quantitative and qualitative features both in the ward and hospital flora. An increase in the bacterial resistance to antibiotics in the general environment can occur; a long duration of oral prophylactic antibiotic administration is undoubtedly associated with this phenomenon. Thus, the benefit associated with prophylactic antibiotic in the prevention of postoperative infections, unquestionable in some indications, must be balanced with the possible selection of resistant micro-organisms and their consequences on the environment.

Anti-Bacterial Agents↗

Bridged bicyclic vasopressin receptor antagonists with V(2)-selective or dual V(1a)/V(2) activity.

The synthesis and biological testing of a novel series of nonpeptide vasopressin receptor antagonists, containing a bridged bicyclic nucleus, are reported. Variation of substituents (R(1)-R(3)) in general formula 3, and the configuration of the stereocenter, resulted in potent V(2)-selective (e.g., 5) and balanced dual V(1a)/V(2) (e.g., 10) compounds. Data from receptor binding, cell-based functional, and in vivo assays are presented [corrected]

Animals↗

Questioning the assumptions in the debate on assisted reproduction: comment on the House of Commons report Human Reproductive Technologies and the Law.

The House of Commons Science and Technology Committee has issued a series of non-dogmatic recommendations. Also regarding elective sex selection, it has adopted a controversial position. Sex selection should be allowed for family balancing. However, the acceptability of preimplantation genetic diagnosis as a method for selecting the embryos can be questioned on the basis of social harm. In countries with a shortage of medical personnel and a limited health care budget, elective procedures are a loss to society. This loss should be compensated by imposing a 'social compensation tax' for every application of elective sexing.

Advisory Committees↗

Fluctuating asymmetry: a biological monitor of environmental and genomic stress.

Increased fluctuating asymmetry (FA) of morphological traits occurs under environmental and genomic stress. Such conditions will therefore lead to a reduction in developmental homeostasis. Based upon temperature extreme experiments, relatively severe stress is needed to increase FA under field conditions. Increasing asymmetry tends, therefore, to occur in stressed marginal habitats. Genetic perturbations implying genomic stress include certain specific genes, directional selection, inbreeding, and chromosome balance alterations. It is for these reasons that transgenic organisms may show increased FA. As there is evidence that the effects of genomic and environmental stress are cumulative, organisms in a state of genomic stress may provide sensitive biological monitors of environmental stress.

Animals↗

Cortical substrates for exploratory decisions in humans.

Decision making in an uncertain environment poses a conflict between the opposing demands of gathering and exploiting information. In a classic illustration of this 'exploration-exploitation' dilemma, a gambler choosing between multiple slot machines balances the desire to select what seems, on the basis of accumulated experience, the richest option, against the desire to choose a less familiar option that might turn out more advantageous (and thereby provide information for improving future decisions). Far from representing idle curiosity, such exploration is often critical for organisms to discover how best to harvest resources such as food and water. In appetitive choice, substantial experimental evidence, underpinned by computational reinforcement learning (RL) theory, indicates that a dopaminergic, striatal and medial prefrontal network mediates learning to exploit. In contrast, although exploration has been well studied from both theoretical and ethological perspectives, its neural substrates are much less clear. Here we show, in a gambling task, that human subjects' choices can be characterized by a computationally well-regarded strategy for addressing the explore/exploit dilemma. Furthermore, using this characterization to classify decisions as exploratory or exploitative, we employ functional magnetic resonance imaging to show that the frontopolar cortex and intraparietal sulcus are preferentially active during exploratory decisions. In contrast, regions of striatum and ventromedial prefrontal cortex exhibit activity characteristic of an involvement in value-based exploitative decision making. The results suggest a model of action selection under uncertainty that involves switching between exploratory and exploitative behavioural modes, and provide a computationally precise characterization of the contribution of key decision-related brain systems to each of these functions.

Choice Behavior↗

Long-term outcome of urinary function after extended lymphadenectomy in patients with distal rectal cancer.

AIMS: Extended lymphadenectomy for rectal cancer has been superseded by autonomic nerve-sparing surgery, but it still has historical significance. It is useful to document the long-term outcome of urinary function in cases who had resection of the inferior hypogastric nerve plexus (pelvic nerve plexus). METHODS: The long-term urinary function following extended lymphadenectomy was studied retrospectively through the medical records of 83 patients who had been followed-up for more than 5 years after surgery. RESULTS: Forty-four per cent of the male patients and 17% of the female patients had to perform clean intermittent self-catheterization (CIC) for more than 1 year; these rates were almost the same at 3 years after the procedure. Urinary incontinence was reported in 34% of the male patients and 45% of the female patients. Complicated cystitis (eight patients), complicated pyelonephritis (two patients), bladder stones (five patients) that required surgical treatment, and chronic renal failure (two patients) were considered as adverse outcomes of extended surgery. In particular, one case needed to undergo urinary diversion. CONCLUSIONS: A surprisingly large proportion of patients suffered various urinary tract problems due to extended lymphadenectomy. The findings demonstrate the importance of selection of well-balanced operations that can encompass both radicality and quality of life. The extent of resection should be decided by the extent of the cancer and routine excision of the inferior hypogastric nerve plexus should not be performed.

Adult↗

Synthesis of the butanamide derivative S 19812, a new dual inhibitor of cyclooxygenase and lipoxygenase pathways.

The general synthetic pathway and the interactions with arachidonic acid metabolism of the new compound S 19812 (N-hydroxy-N-methyl 4-(2,3-bis-(4-methoxyphenyl)-thiophen-5-yl)butanamide, CAS 181308-68-9) were investigated. S 19812 was selected for its well balanced dual inhibition of cyclooxygenase and 5-lipoxygenase pathways in vitro in rat polymorphonuclear neutrophils (PMNs) (IC50 PGE2: 0.10 mumol/l, LTB4: 0.07 mumol/l) and ex vivo in mice blood (ED50 PGE2: 13.1 mg/kg, LTB4: 20.8 mg/kg). These properties make this drug a promising therapeutic agent for pain and inflammation associated with osteoarthritis.

Amides↗

[Lymphadenectomy in gastric carcinoma?].

Lymphadenectomy in gastric carcinoma is still discussed. Based on non-randomised and randomised studies D2-lymphadenectomy is indicated only in R0-resections. D2-lymph-node dissection requires great experience with this technique as well as for the management of possible postoperative complications. Survival advantages can be expected in patients with a limited nodal involvement, a favorable lymph node ratio between resected and involved nodes and in stage II disease. Therefore, survival improvement can be expected in 15-20 % of all R0-resections. Despite these limited prognostic advantages D2-lymphadenectomy should be performed in all R0-procedures since only the pathologic data of the resected specimen supply reliable prognostic parameter. If in the future sentinel lymphadenectomy allows selection criteria for a balanced indication for D2-lymphadenectomy in gastric carcinoma, needs to be awaited.

Gastrectomy↗

A new gastrocamera technique using infrared color film.

An attempt at infrared photography of the human gastric mucosa was made using the Olympus fiberoptic gastrocamera type S2 (GTF-S2) and Kodak Ektachrome Infrared Film (IE Film) (4). By critical selection of the illumination balance with No. 12 and doubled CC50C-2 of Kodak Wratten Filters (3), vessel patterns of the mucosa and deeper layers were photographed in orange and dark blue respectively; these patterns were invisible to the naked eye and were also not recorded by an ordinary gastrocamera.

Color↗

Molecular genetic basis of allelic polymorphism in malate dehydrogenase (mdh) in natural populations of Escherichia coli and Salmonella enterica.

Nucleotide sequences of the mdh gene encoding the metabolic enzyme malate dehydrogenase (MDH) were determined for 44 strains representing the major lineages of Escherichia coli and the eight subspecies of Salmonella enterica. Sequence diversity was four times greater in S. enterica than in E. coli, and in both species the rate of amino acid substitution was lower in the NAD(+)-binding domain than in the catalytic domain. Divergence of the mdh genes of the two species apparently has not involved excess nonsynonymous substitutions resulting from the fixation of adaptive amino acid mutations. Allozyme analysis detected 57% of the distinctive amino acid sequences. Statistical tests of the distribution of polymorphic synonymous nucleotide sites identified four possible intragenic recombination events, one involving a single allele of E. coli and three involving alleles of the three subspecies of S. enterica. But recombination at mdh has not occurred with sufficient frequency to obscure the phylogenetic relationships among strains indicated by multilocus enzyme electrophoresis, total DNA hybridization, and sequence analysis of the gapA and putP genes. These findings provide further evidence that the effective (realized) rates of horizontal transfer and recombination for metabolic enzyme and other housekeeping genes are generally low in these species, in contrast to those for loci encoding or mediating the structure of cell-surface and other macromolecules for which recombinants may be subject to strong balancing, directional, or diversifying selection.

Adaptation, Physiological↗

Treatment of neuromuscular and musculoskeletal problems in cerebral palsy.

Cerebral palsy typically involves a variety of neuromuscular and musculoskeletal problems. These problems include spasticity, dystonia, contractures, abnormal bone growth, poor balance, and loss of selective motor control. These problems can interfere with function and treating them can improve function. The treatments include physical and occupational therapy, bracing, oral medications, neurolytic blocks, neurosurgical procedures, orthopaedic surgery and others. Using a multidisciplinary treatment team with a good understanding of cerebral palsy, the best treatment options can be determined and functional outcomes maximized.

Cerebral Palsy↗

A preliminary analysis of the balance between Th1 and Th2 cells after CD34+ cell-selected autologous PBSC transplantation.

BACKGROUND: CD34+ cell-selected autologous PBSC transplantation (CD34+ APBSCT) is a procedure used for the treatment of patients with malignant disease that is intended to eliminate residual tumor cells from autologous grafts. However, frequent infectious complications after CD34+ APBSCT can occur. A delay of recovery of the absolute number of CD4+ T cells after transplantation was reported to be one disadvantageous factor. As data on T-cell function after CD34+ APBSCT are scanty, we analyzed changes in T-helper cell 1 (Th1) and T-helper cell 2 (Th2) after CD34+ APBSCT to evaluate immune reconstitution. METHODS: Twelve patients underwent APBSCT (CD34+APBSCT group, n=4, and unselected APBSCT, n=8). Peripheral blood (PB) samples were obtained at 2, 4, 8, 12 and 16 weeks after the transplantation. The dynamics of the Th1 and Th2 were analyzed at a single-cell level, using flow cytometry. RESULTS: In the CD34+ APBSCT group, not only the absolute count of CD4+ T cells but also the proportion of Th1 cells in CD4+ T cells and the ratio of Th1 to Th2 after transplantation were significantly decreased at 2 and 4 weeks after transplantation compared with findings in the unselected APBSCT group. DISCUSSION: We suggest that higher rates of infectious complications after CD34+ APBSCT may be due to the inability of residual T cells from the CD34+ cell selection to generate mature T cells that function adequately against infection. Although further study would be required, our preliminary data provide some information on the immune reconstitution after CD34+ APBSCT and differentiation of T lymphocytes into Th1 and Th2 in vivo.

Adult↗