Sign Tracking in an Enriched Environment: A Potential Ecologically Relevant Animal Model of Adaptive Behavior Change.

When an object conditioned stimulus (CS) is paired with a food unconditioned stimulus (US), anticipatory goal-directed action directed at the US location (goal tracking) is accompanied by behavior directed at the object CS (sign tracking). Sign-tracking behavior appears to be compulsive and habit-like and predicts increased vulnerability to the addictive potential of drugs in animal models. A large body of the literature also suggests that environmental enrichment protects against the development of addiction-prone phenotypes. Thus, we investigated whether compulsive-like sign tracking develops in environmentally enriched rats trained directly in their enriched home environment. We demonstrate that adolescent enriched-housed male Sprague-Dawley rats readily sign track a 5% ethanol bottle CS in their home environment and at a rate higher than adolescent standard-housed rats. We also show that enriched adolescent rats sign track less than enriched adult-trained rats and that acute isolation stress affects sign- and goal-tracking performance of adolescents and adults differently. Sign tracking increased more in the adult than the adolescent rats. Whereas the younger rats showed a decrease in goal tacking after the final stressor manipulation, the adults showed increased goal tracking. Our results are consistent with recent studies, which suggest that although sign tracking performance is compulsive-like, it is not as inflexible and habit-like as previously assumed. Testing in an enriched home environment with object CSs having greater affordance than "neutral" lever CSs may provide greater ecological relevance for investigating the development and expression of adaptive and compulsive-like behaviors in translational research.

The association between sarcopenia and functional outcomes among older patients with hip fracture undergoing in-hospital rehabilitation.

This study evaluates the prevalence of sarcopenia among older people admitted to a rehabilitation unit after hip fracture and the association between sarcopenia and functional outcomes. The results show that sarcopenia had a negative impact on functional recovery. The assessment of sarcopenia among older adults receiving rehabilitation programs is crucial. INTRODUCTION: Sarcopenia is a highly prevalent geriatric syndrome associated with adverse outcomes, including falls, disability, institutionalization, and mortality. Few studies assessed sarcopenia among older adults receiving rehabilitation programs. METHODS: Patients aged 70 years or more consecutively admitted to in-hospital rehabilitation programs that had suffered from hip fracture entered the study. Sarcopenia was defined according to the Foundation for National Institutes of Health (FNIH) criteria. Multivariable linear regression models were used to analyze the association between the sarcopenia and functional recovery. RESULTS: The recruited population was composed of 127 patients, with a mean age of 81.3 ± 4.8 years, predominantly females (64.6%). Using the criteria proposed by the FNIH, patients with a diagnosis of sarcopenia were 43 (33.9%). After adjustment for potential confounders, participants with sarcopenia had a significant increased risk of incomplete functional recovery compared with non-sarcopenic patients (OR 3.07, 95% CI 1.07-8.75). Compared with participants without sarcopenia, those with sarcopenia showed lower Barthel index scores at the time of discharge from the rehabilitation unit (69.2 versus 58.9, respectively; p < 0.001) and after 3 months of follow-up (90.9 versus 80.5, respectively; p = 0.02). CONCLUSIONS: These findings support the systematic assessment of sarcopenia among older adults receiving rehabilitation programs to assist in the development of personalized treatment plans aimed at improving functional outcomes.

Attributable mortality of carbapenem-resistant Klebsiella pneumoniae infections in a prospective matched cohort study in Italy, 2012-2013.

BACKGROUND: In Italy, infections with carbapenem-resistant Klebsiella pneumoniae (CRKP) have increased markedly since 2009, creating unprecedented problems in healthcare settings and limiting treatment options for infected patients. AIM: To assess the attributable mortality due to CRKP in ten Italian hospitals and to describe the clinical characteristics of patients with an invasive CRKP and carbapenem-susceptible K. pneumoniae (CSKP) infection. METHODS: We conducted a matched cohort study, and calculated crude and attributable mortality for CRKP. The attributable mortality was calculated by subtracting the crude mortality rate of the patients with CSKP from the crude mortality rate of the patients with CRKP. We also described the clinical characteristics of CRKP and CSKP patients and analysed the determinants of mortality by using conditional Poisson regression. FINDINGS: The study included 98 patients, 49 with CRKP and 49 with CSKP. CRKP patients had undergone more invasive procedures and also tended to have more serious conditions, measured by higher Simplified Acute Physiology Score II. The attributable mortality of CRKP at 30 days was 41%. CRKP patients were three times more likely to die within 30 days [matched incidence rate ratio (mIRR): 3.0; 95% confidence interval (CI): 1.5-6.1]. Adjusting for potential confounders, the risk remained the same (adjusted mIRR: 3.0; 95% CI: 1.3-7.1). CONCLUSION: CRKP infection had a marked effect on patient mortality, even after adjusting for other patient characteristics. To control the spread of CRKP we recommend prioritization of control measures in hospitals where CRKP is found.

[Family caregiver education: an Italian experience]. / L'educazione dei family caregiver: un'esperienza italiana.

The role of family caregivers is essential for optimal treatment of patients with chronic diseases since it ensures the compliance to treatment, continuity of care, emotional and social support. Despite the significant value of informal caregiving, the relatives report not to have the necessary knowledge and skills to provide ongoing support to the family member with chronic disease and, therefore, show the need to be educated in their role as caregivers. The reliance on family caregivers unprepared for the daily management of the illness patients may threaten the patients' quality of life and, moreover, contributes to increase the burden of care of the caregiver by exposing it to the risk of psychosocial distress. The Nursing Department of Campus Bio-Medico of Rome have addressed such a need promoting training courses on family caregivers since 2011 with the goal of supporting families in the acquisition of specific skills related to health care of patients with chronic conditions. The UCBM educational program has been developed in order to convey knowledge tools especially for: the role and challenges of the caregiver, the supply of health services to support patients and the family member. The UCBM educational program has been structured in lessons to analyze the deepening of chronic diseases related to different areas of medical interventions and in practical sessions guided by a nurse specialist in order to support the family in the acquisition of skills and competencies for the care management of patients at home. The positive feedback, received from users who have attended the two past editions of the UCBM educational program, demonstrates the importance of acquiring technical knowledge and practical tools that are essential to independently manage all aspects of patient care. It's important to notice, moreover, that learning these skills will support the family in the patient management, both in short and long term, and that is very relevant considering the temporal characteristics of the chronic disease.

Carbapenem non-susceptible Klebsiella pneumoniae from Micronet network hospitals, Italy, 2009 to 2012.

Carbapenem-resistant Klebsiella pneumoniae has recently been reported as a new, multidrug-resistant nosocomial pathogen in several hospitals from various Italian regions. Through Micronet, a new Italian sentinel laboratory-based surveillance network, we studied the trend of non-susceptibility of K. pneumoniae to selected carbapenems (imipenem and/or meropenem) in 14 of the 15 hospitals participating in the network. Analysis of data from 1 January 2009 to 30 April 2012 revealed a statistically significant increasing trend (p<0.01) in the proportion of carbapenem non-susceptible K. pneumoniae isolates from clinical specimens (from 2.2 % in 2009 to 19.4% in 2012). The increase in the proportion of non-susceptibility was very large for isolates from the respiratory tract (from 5.3% in 2009 to 38.5% in 2012) and blood (from 5.4% in 2009 to 29.2% in 2012). The results demonstrate the urgent need in Italy for infection control, guidelines, antibiotic stewardship programmes and utilisation of surveillance systems, such as Micronet, which are capable of receiving data from hospitals in real time for many pathogens and types of clinical specimens.

Diversity of spore-forming bacteria and identification of Bacillus amyloliquefaciens as a species frequently associated with the ropy spoilage of bread.

This study examines the diversity of spore-forming bacteria isolated from raw materials/bread using molecular methods along with a rapid and innovative technology, the FT-NIR spectroscopy. Microbiological analysis showed that 23% of semolina and 42% of other raw materials (including grain, brewer yeast, improvers) contained more than 100 spores/g and more than 50% of each kind of sample was contaminated at a level ranging from 1 to 100 spores/g. A high bacterial diversity characterized raw materials. In total 176 isolates were collected and characterized: 13 bacterial species belonging to Bacillus (10) and Paenibacillus (3) genera were identified by sequencing of 16S rRNA, gyrA or gyrB genes. The two closely related species Bacillus amyloliquefaciens (strain N45.1) and Bacillus subtilis (strain S63) were also analyzed by the spectroscopic technique FT-NIR. This analysis gave clear discrimination between the strains in the score plot obtained by the PCA and allowed to identify the spectral region 5600-4000 cm(-1) as the information-rich region for discrimination. B. amyloliquefaciens, possibly misidentified as B. subtilis in previous studies, was recognized as the most frequent species, found also in ropy bread. Moreover, the screening test for rope production indicated that mainly B. amyloliquefaciens, together with B. subtilis and Bacillus pumilus, could cause spoilage in bread, even if the last two species were represented by a low number of isolates. The Bacillus cereus group and Bacillus megaterium showed a lower percentage (30-70%) of isolates potentially able to cause the rope, but considering the high number of B. cereus group isolates detected in this study, this bacterial group should also be considered important in rope spoilage. In conclusion, results demonstrate that raw materials used to produce bread represent a rich source of spore-forming bacteria, therefore their microbiological quality should be monitored before use. Moreover, this study highlights for the first time the importance of the species B. amyloliquefaciens in rope spoilage and indicates that other species may also cause this alteration although strains of the same species may behave differently.

Distinct immunomodulatory properties of Lactobacillus paracasei strains.

AIMS: This study was performed to ascertain the immunomodulatory effect of Lactobacillus paracasei strains. These strains were also genetically characterized. METHODS AND RESULTS: The strains were genetically differentiated by using the fluorescent-amplified fragment length polymorphism technique, which led to the identification of several molecular markers unique to each strain. To determine the immunomodulatory properties, we evaluated the effect of strains on dendritic cell maturation, dextran uptake, ability to induce proliferation of allogenic T cells and cytokine secretion. The results indicated that all the strains stimulated phenotypic maturation of dendritic cells (DCs), but they acted differently on DCs in relation to the other tested properties; notably, a different effect on cytokine secretion was detected. CONCLUSIONS: The results of this study revealed different immunomodulatory properties of strains of the species Lact. paracasei. Strain IMPC 4.1 showed an interesting anti-inflammatory ability. Probiotic strains IMPC 2.1 and LMG P-17806 were characterized by a similar and intermediate ability to induce cytokine secretion in contrast to the very low ability of strain LMG 23554. SIGNIFICANCE AND IMPACT OF STUDY: Our results confirm that each single strain of a bacterial species appears to influence the immune system in a peculiar manner. The evaluation of the different types and/or levels of cytokines whose secretion is induced by each strain could be relevant to define its pro- or anti-inflammatory properties and its more appropriate clinical use.

Role of the probiotic strain Lactobacillus paracasei LMGP22043 carried by artichokes in influencing faecal bacteria and biochemical parameters in human subjects.

AIMS: To evaluate the positive influence of the probiotic strain Lactobacillus paracasei LMGP22043 carried by artichokes into the human gut with special reference to faecal bacterial balance, short-chain fatty acid concentrations and enzyme activities in a randomized, double-blind human trial in comparison with probiotic-free artichokes (control). METHODS: Twenty subjects were randomized into two groups, which consumed daily 180 g of the artichoke product (probiotic or control) during two 15-day study periods (periods 1 and 2) separated by a 15-day washout in a crossover manner. Faecal samples were subjected to microbiological and biochemical analyses, and a strain-specific PCR was performed to monitor the probiotic strain. RESULTS: The probiotic strain, transported by the vegetable matrix, transiently colonized the gut of 17/20 subjects (median 6·87 log CFU g⁻¹ faeces), antagonized Escherichia coli and Clostridium spp. and increased the genetic diversity of lactic population based on REP-PCR profiles, mainly after period 1. CONCLUSIONS: The probiotic L. paracasei LMGP22043 successfully colonized the human gut and positively influenced faecal bacteria and biochemical parameters. SIGNIFICANCE AND IMPACT OF THE STUDY: The association of the probiotic L. paracasei with a food carrier rich in fibre can represent a new strategy for favouring a daily supply of probiotics and attracting more consumers to vegetable food fortified with probiotic strains.

Knot Formation Caused by Pseudomonas syringae subsp. savastanoi on Olive Plants Is hrp-Dependent.

ABSTRACT The virulence of Pseudomonas syringae subsp. savastanoi, which causes hyperplastic symptoms (knots) on olive plants, is associated with secreted phytohormones. We identified a Tn5-induced mutant of P. syringae subsp. savastanoi that did not cause disease symptoms on olive plants although it was still able to produce phytohormones. In addition, the mutant failed to elicit a hypersensitive response in a nonhost plant. Molecular characterization of the mutant revealed that a single Tn5 insertion occurred within an open reading frame encoding a protein 92% identical to the HrcC protein of P. syringae pv. syringae. Moreover, sequence analysis revealed that the gene encoding the HrcC protein in P. syringae subsp. savastanoi was part of an operon that included five genes arranged as in other phytopathogenic bacteria. These results imply that hrp/hrc genes are functional in P. syringae subsp. savastanoi and that they play a key role in the pathogenicity of this plant pathogen.

Mass spectrometry and combinatorial chemistry: a short outline.

The rapid evolution of combinatorial chemistry in recent years has led to a dramatic improvement in synthetic capabilities. The goal is to accelerate the discovery of molecules showing affinity against a target, such as an enzyme or a receptor, through the simultaneous synthesis of a great number of structurally diverse compounds. This is done by generating combinatorial libraries containing as many as hundreds or thousands of compounds. The need to test all these compounds led to the development of high-throughput screening (HTS) techniques, and also high-throughput analytical techniques capable of assessing the occurrence, structure and purity of the products. In order to be applied effectively to the characterization of combinatorial libraries, an analytical technique must be adequately sensitive (to analyse samples which are typically produced in nanomole amounts or less), fast, affordable and easy to automate (to minimize analysis time and operator intervention). Although no method alone can meet all the analytical challenges underlying this task, the recent progress in mass spectrometric (MS) instrumentation renders this technique an essential tool for scientists working in this area. We describe here relevant aspects of the use of MS in combinatorial technologies, such as current methods of characterization, purification and screening of libraries. Some examples from our laboratory deal with the analysis of pooled oligomeric libraries containing n x 324(n = 1, 2) compounds, using both on-line high-performance liquid chromatography/MS with an ion trap mass spectrometer, and direct infusion into a triple quadrupole instrument. In the first approach, MS and product ion MS/MS with automatic selection of the precursor were performed in one run, allowing library confirmation and structural elucidation of unexpected by-products. The second approach used MS scans to characterize the entire library and also precursor ion and neutral loss scans to detect selectively components with given structural characteristics.

The effect of confinement on motivation to exercise in young dairy calves.

The objective of this research was to determine if confinement of 8-day-old calves for varying lengths of time is associated with an increase in motivation to perform locomotor behaviors. Holstein heifer and bull calves (N=48) were used in a factorial arrangement with two crossed factors. Factor A was housing with two levels (individual confinement versus group pens) and factor B was hours in confinement with four levels (6, 12, 24, and 48h). Individual confinement was in 1.06mx1.06m pens, while group pens had a 3.68mx6.09m outside run and a 3.68mx6.09m covered area that also contained a 3.68mx2.44m area bedded with wood shavings. The calves were placed on treatment when they were 8+/-2 days of age.At the end of the treatments, a blood sample was taken for plasma cortisol determination and lymphocyte counts and the calves were open-field tested for 5min.Walk, trot, distance traveled and behaviors performed while standing during the open-field test were higher in the calves kept in group pens (P=0.0003, 0.01, 0.04 and 0.04), but were not influenced by hours in treatment. Calves confined for 48h had greater incidences of kicking and falling (P=0.014 and 0.025). Lymphocyte count (P=0.029) was lower in the calves confined for 12h, but there was not a trend across hours in confinement that indicated a consistent effect. Housing or hours in treatment did not affect canter, buck, buck-kick, rear, stumble, vocalization and cortisol concentrations. The interaction between hours in treatment and housing was not significant for any of the variables tested.This study suggests that 2 days may not have been enough time for the effects of close confinement to influence motivation in young calves, or that calves averaging 8 days of age may be too young to display increased motivation for locomotor activity. Confinement of such young calves actually inhibits locomotor activity in open-field tests.

Pharmacology of MEN 11467: a potent new selective and orally- effective peptidomimetic tachykinin NK(1) receptor antagonist.

We have investigated the pharmacological properties of MEN 11467, a novel partially retro-inverse peptidomimetic antagonist of tachykinin NK(1) receptors. MEN 11467 potently inhibits the binding of [(3)H] substance P (SP) to tachykinin NK(1) receptors in the IM9 limphoblastoid cell line (pK(i) = 9.4 +/- 0.1). MEN 11467 is highly specific for the human tachykinin NK(1) receptors, since it has negligible effects (pK(i) <6) on the binding of specific ligands to tachykinin NK(2) or NK(3) receptors and to a panel of 30 receptors ion channels unrelated to tachykinin receptors. The antagonism exerted by MEN 11467 at tachykinin NK(1) receptors is insurmountable in saturation binding experiments, both K(D) and B(max) of SP were significantly reduced by MEN 11467 (0.3-10 nM). In the guinea-pig isolated ileum, MEN 11467 (0.03-1 nM) produced a nonparallel rightward shift of the concentration-response curve to SP methylester with a concomitant reduction of the Emax to the agonist (pK(B) = 10.7 +/- 0.1). Moreover the antagonist activity of MEN 11467 was hardly reversible despite prolonged washout. In vivo, MEN 11467 produced a long lasting (> 2-3h) dose-dependent antagonism of bronchoconstriction induced by the selective tachykinin NK(1) receptor agonist, [Sar(9), Met(O(2))(11)]SP in anaesthetized guinea-pigs (ID(50)s' = 29+/-5, 31+/-12 and 670+/-270 microg/kg, after intravenous, intranasal and intraduodenal administration, respectively), without affecting bronchoconstriction induced by methacholine. After oral administration MEN 11467 produced a dose-dependent inhibition of plasma protein extravasation induced in guinea-pig bronchi by [Sar(9), Met(O(2))(11)] (ID(50) = 6.7 +/- 2 mg/kg) or by antigen challenge in sensitized animals (ID(50) = 1.3 mg/kg). After i.v. administration MEN 11467 weakly inhibited the GR 73632-induced foot tapping behaviour in gerbil (ED(50) = 2.96 +/- 2 mg/kg), indicating a poor ability to block central tachykinin NK(1) receptors. These results demonstrate that MEN 11467 is a potent, highly selective and orally effective insurmountable pseudopeptide antagonist of peripheral tachykinin NK(1) receptors with a long duration of action.

[Clinical efficacy of intravesical BCG treatment for superficial bladder neoplasms with respect to the iduced immune response]. / Efficacia clinica del trattamento intravescicale con BCG per neoplasie vescicali superficiali in rapporto alla risposta immunitaria indotta.

We evaluated the immune response after BCG treatment in superficial bladder cancer analyzing the modifications induced on lymphocytic sub-populations. In 21 patients with superficial bladder cancer we performed TURB and after 12 days began the induction cycle of 6 weeks with Pasteur BCG (75 mg/50 micromilligrams), followed by one instillation monthly for one year. Before treatment every patients underwent Mantoux intradermoreaction, blood-count and determination of peripheral blood lymphocytic subpopulations. Blood-count and lymphocytic subpopulations were repeated after 1 week, after 6 weeks, after 3 months and after 1 year. During cystoscopy after 3 months every patients underwent vesical biopsy. CD4+ and CD8+ are mainly interested among lymphocytic subpopulations at the beginning: BCG decreased CD4+ value in the patients with complete response and then it increased CD4+ and reversed the ratio between CD4+ and CD8+ on vesical mucosa.

Lipopolysaccharides from three phytopathogenic pseudomonads.

Analysis of the polysaccharide and lipid moieties of the lipopolysaccharides (LPSs) of the phytopathogenic bacteria, Pseudomonas amygdali and P. syringae pv. ciccaronei has demonstrated that for both bacteria, the O-chain consists of a tetrasaccharide repeating unit of three alpha-L-Rhap and one terminal nonreducing alpha-D-Fucp3NAc. Two of the rhamnosyl residues are 3-linked, the third one 2,3-linked. This structure had been previously found for the O-chains of three phytopathogenic strains of P. syringae subsp. savastanoi, but this is the first report on its occurrence in P. amygdali and P. syringae pv. ciccaronei. The results of the LPS lipid residue analysis made it possible to make some chemotaxonomic considerations and therefore classify P. amygdali as a chemotype, which is different from that of the other two bacteria examined.

Absorption, emission, and chiroptical spectra of neurokinin 1 tachykinin receptor antagonists: the role of charge-transfer states on the biological activity.

A spectroscopic investigation, based on both electronic absorption and emission spectra as well as on chiroptical data, was performed on novel neurokinin 1 (NK1) tachykinin receptor antagonists, exhibiting interesting biological activity. These pseudopeptides have two fluorophores, i.e. indole (I) and naphthalene (N), and a central scaffold with different conformational mobility. Absorption spectra in methanol show the presence of a new band with respect to the sum spectrum of the isolated chromophores at around 285 nm, the intensity of which linearly increases as the bioactivity increases. This absorption disappears by using dioxane as solvent. It is ascribed to an intramolecular I-N charge-transfer (CT) complex that forms to different extent, depending on the flexibility of the scaffold. Under this condition, the molecules fold and apparently attain the correct conformation for competing substance P binding to the NK1 receptor, lending plausibility to the role of dipolar charged, spatially close aromatic moieties as topochemical elements in the mechanism of action of substance P antagonists. The excited-behavior parallels that in the ground state, as the quenching of the singlet state at 340 nm is found to be linearly dependent on the biological activity, too. Upon decreasing solvent polarity (methanol vs dioxane) the emissions of the dipolar state at around 370 nm disappears, while exciplex emission in the range of 400-500 nm occurs. This transition from charge-separated to exciplex-like states by lowering the dielectric constant of the medium very likely reflects a change in the structural features of the intramolecular I-N stacked complex, from a twisted or an asymmetrically overlapped conformation of the indolyl and naphthyl rings to a face-to-face geometry. Implications of the rigidity of the molecules, arising from the formation of the intramolecular CT complex, on the ellipticity are briefly discussed.

Synthesis and biological evaluation of novel NK-1 tachykinin receptor antagonists: the use of cycloalkyl amino acids as a template.

In the course of a program aimed at synthesizing novel, potent NK-1 tachykinin receptor antagonists, we developed upon a bioactive model by comparing the low energy structures of a series of peptide and nonpeptide Substance P antagonists. The comparison was based on the superimposition of the aromatic rings, assuming that the rest of the molecule behaves predominantly as a template to arrange the key aromatic groups in the right spatial position. A series of 2-aminocyclohexane carboxylic acid analogues were then selected as the best templates for reproducing the postulated bioactive structure, leading to several pseudo-peptides with interesting biological activity. According to the molecular modeling, these compounds exhibit a neat parallel facing of the indolyl and naphthyl groups at about 3 A distance. Ultraviolet absorption and steady state fluorescence measurements support this conclusion, showing a linear correlation between the spectral properties and the binding affinity of these analogues. Stacking of the indole ring with naphthalene gives rise to a complex characterized by a well-defined molar extinction coefficient. Consistently, steady state and lifetime fluorescence measurements suggest that the quenching process is ascribable to ground-state interactions between the chromophores. Implications of the pi stacking propensity of aromatic groups in the biological activity of the compounds examined are briefly discussed.

Comparison of tachykinin NK1 and NK2 receptors in the circular muscle of the guinea-pig ileum and proximal colon.

1. The aim of this study was the pharmacological characterization of tachykinin NK1 and NK2 receptors mediating contraction in the circular muscle of the guinea-pig ileum and proximal colon. The action of substance P (SP), neurokinin A (NKA) and of the synthetic agonists [Sar9]SP sulphone, [Glp6,Pro9]SP(6-11) (septide) and [beta Ala8]NKA(4-10) was investigated. The affinities of various peptide and nonpeptide antagonists for the NK1 and NK2 receptor was estimated by use of receptor selective agonists. 2. The natural agonists, SP and NKA, produced concentration-dependent contraction in both preparations. EC50 values were 100 pM and 5 nM for SP, 1.2 nM and 19 nM for NKA in the ileum and colon, respectively. The action of SP and NKA was not significantly modified by peptidase inhibitors (bestatin, captopril and thiorphan, 1 microM each). 3. Synthetic NK1 and NK2 receptor agonists produced concentration-dependent contraction of the circular muscle of the ileum and proximal colon. EC50 values were 83 pM, 36 pM and 10 nM in the ileum, 8 nM, 0.7 nM and 12 nM in the colon for [Sar9]SP sulphone, septide and [beta Ala8]NKA-(4-10), respectively. The pseudopeptide derivative of NKA(4-10), MDL 28,564 behaved as a full or near-to-full agonist in both preparations, its EC50s being 474 nM and 55 nM in the ileum and colon, respectively. 4. Nifedipine (1 microM) abolished the response to septide and [Sar9]SP sulphone in the ileum and produced a rightward shift and large depression of the response in the colon. The response to [beta Ala8]NKA(4-10) was abolished in the ileum and largely unaffected in the colon. 5. The NK1 receptor antagonists, (+/-)-CP 96,34, FK 888 and GR 82,334 competitively antagonized the response to septide and [Sar9]SP sulphone in both preparations without affecting that to [beta Ala8]NKA(4-10). In general, the NK1 receptor antagonists were significantly more potent toward septide than [Sar9]SP sulphone in both preparations. 6. The NK2 receptor antagonists, GR 94,800 and SR 48,968 selectively antagonized the response to [beta Ala8]NKA(4-10) without affecting that to [Sar9]SP sulphone or septide in the ileum and colon. SR 48,968 produced noncompetitive antagonism of the response to the NK2 receptor agonist in the ileum and competitive antagonism in the colon. 7. MEN 10,376 and the cyclic pseudopeptide MEN 10,573 antagonized in a competitive manner the response to [beta Ala8]NKA(4-10) in the ileum and colon. While MEN 10,573 was equipotent in both preparations, MEN 10,376 was significantly more potent in the colon than in the ileum. MEN 10,376was also effective against septide in both preparations, without affecting the response to [Sar9] SP sulphone. MEN 10,573 antagonized the response to [Sar9]SP sulphone and septide in both preparations,pKB values against septide being intermediate, and significantly different from, those measured against[Beta Ala 8]NKA(4-10) and [Sa9]lSP sulphone.8. These findings show that tachykinin NK1 and NK2 receptors mediate contraction of the circular muscle of the guinea-pig ileum and colon. In both preparations NK1 receptor antagonists display higher apparent affinity when tested against septide than [Sar9]SP sulphone. These findings are compatible with the proposed existence of NK1 receptor subtypes in guinea-pig, although alternative explanations (e.g.agonist binding to different epitopes of the same receptor protein) cannot be excluded at present.Furthermore, an intraspecies heterogeneity of the NK2 receptor in the circular muscle of the guinea-pig ileum and colon is suggested.

Decompensated cardiomyopathy mimicking hepatitis in a 13-year-old girl.

The name of a 13-year-old girl diagnosed as having idiopathic dilated cardiomyopathy was removed from the cardiac transplant list because a hepatitis-like picture developed that coincided with evidence of decompensation of her cardiac function. On admission, there was only modest evidence of cytolysis (ALT level, 115 U/L) and of cholestasis (bilirubin level, 3.0 mg/dl), but there was severe prolongation of her prothrombin time (28 s). This was followed by elevation of both her transaminases and bilirubin levels. A liver biopsy sample showed extensive necrosis involving both the central and midlobular zones, while periportal areas revealed dilated sinusoids and steatotic multinucleated hepatocytes. A brief improvement of both her liver and her heart was followed by rapid deterioration of the functions of both. Attention is drawn to the relationship between reduced cardiac output and hepatic dysfunction secondary to massive cytolysis.

Primary sclerosing cholangitis in children: study of five cases and review of the literature.

Primary sclerosing cholangitis in five children is described and 78 cases in the pediatric age group are reviewed. In 24% of the cases, primary sclerosing cholangitis is not associated with an underlying disease and may appear to be prolonged cholestasis of infancy. When an associated condition is present, chronic inflammatory bowel disease, in particular ulcerative colitis, is most common (47%). Histiocytosis X and a variety of immune disorders account for 15% and 10% of cases, respectively. Primary sclerosing cholangitis should be considered in the differential diagnosis of chronic liver disease in the pediatric age group, even in young infants. Results of this survey demonstrate that neither clinical features nor liver function tests are reliable diagnostic predictors, that histologic changes are often nonspecific, and that cholangiography is essential to establish the correct diagnosis.