Pneumonia: are we putting the CURB score into practice?
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Anti-Bacterial Agents↗
Biomedical subjects
D Owen
Publications and source records attributed to D Owen.
Central regulation of the hypothalamic-pituitary-adrenal axis during fetal development in the Guinea-pig.
We have previously shown that the foetal guinea-pig hypothalamic-pituitary-adrenal (HPA) axis is activated near the time of parturition and that this is associated with changes in limbic glucocorticoid receptors (GR) and mineralocorticoid receptors. In the present study, we hypothesized that the foetal hypothalamic paraventricular nucleus (PVN) and pituitary contribute significantly to foetal HPA drive but that these areas remain sensitive to negative feedback by circulating glucocorticoids in late gestation. However, we observed decreased corticotrophin-releasing hormone mRNA expression in the PVN and decreased pro-opiomelanocortin (POMC) mRNA levels in the anterior pituitary with advanced gestational age. The reduction in POMC mRNA expression was likely the result of negative feedback via circulating glucocorticoids because GR mRNA was unchanged during development in the foetal pituitary. Furthermore, we found that maternally administered glucocorticoids significantly decreased foetal pituitary POMC mRNA expression in a dose-dependent manner at gestational day (gd) 62 with male foetuses being more sensitive to these effects. These findings show that the foetal HPA axis remains highly sensitive to glucocorticoid feedback even as plasma adrenocorticotropic hormone and cortisol levels are elevated at the end of gestation.
Animals↗
Gastric ciliated metaplasia. A study of 3406 gastrectomy specimens from dwellers of the Atlantic and the Pacific basins.
BACKGROUND: Ciliated cells in gastrectomies from patients dwelling in the Pacific and Atlantic basins have been reported previously. AIM: To compare all the results in an attempt to explain the findings. METHODS: Sections from 3406 gastrectomies were reviewed: 1966 and 1440 from the Atlantic and Pacific basins, respectively. Ciliated cells and intestinal metaplasia (IM) were recorded; IM was classified into focal or extensive IM. The total number of sections/gastrectomy was noted. RESULTS: In the Atlantic basin, 5% of specimens had ciliated metaplasia (CM); it was more frequent in intestinal carcinoma (IC; 9%) than diffuse carcinoma (DC; 3%) or miscellaneous gastric diseases (MGD; 3%). In the Pacific basin, the frequency of specimens with CM was 29%: it was more frequent in IC (43%) than in DC (16%) or MGD (10%). The difference between the frequency of CM in specimens with IC or with DC/MGD in the Atlantic and the Pacific basins was significant (p < or = 0.05). The presence of CM was influenced by age and the extent of IM in both basins, but not by sex or the number of sections investigated. CONCLUSIONS: CM-apparently an independent microscopic marker-was significantly higher in the Pacific than in the Atlantic basin. Environmental carcinogens involved in the evolution of IM and IC seem to be implicated in gastric ciliogenesis. Carcinogens that differ in nature and/or in strength in both basins might activate the latent natural genes encoding ciliated processes in gastric cells in patients subsequently developing gastric carcinoma, more notably of intestinal type.
Adult↗
Extensive intestinal metaplasia in gastric carcinoma and in other lesions requiring surgery: a study of 3,421 gastrectomy specimens from dwellers of the Atlantic and Pacific basins.
BACKGROUND: Extensive intestinal metaplasia (EIM) has been reported in gastrectomies from patients dwelling in the Pacific and Atlantic basins. AIMS: To compare all the results in an attempt to explain the findings. METHOD: All sections from 3,421 gastrectomies were reviewed at various hospitals: 1946 in the Atlantic and 1475 in the Pacific basin. Sections with EIM showed IM encompassing one or more entire low power field (>or=5 mm in length/section) in one or more section. RESULTS: In the Atlantic basin, EIM was present in 18.8% (153 of 814) of specimens with intestinal carcinoma (IC) and in 10.3% (65 of 630) of those with diffuse carcinoma (DC). In the Pacific basin, EIM was found in 62.9% (412 of 655) of gastrectomies with IC and in 33.3% (160 of 481) of those with DC. The numbers of specimens with EIM were significantly higher in the Pacific than in the Atlantic basin for both carcinoma phenotypes, particularly among elderly patients (>or=60 years). CONCLUSIONS: The proportion of gastrectomies with EIM was higher among populations at a higher gastric cancer risk than in those with a lower cancer risk. EIM was mostly associated with IC rather than DC or with miscellaneous gastric diseases (841 control gastrectomies) in both basins. The proportion of gastrectomies with EIM was significantly higher in Vancouver than in New York and in Santiago de Chile than in Buenos Aires, even though these populations reside at approximately the same geographical latitude, but in different basins. Environmental factors seem to accelerate the evolution of EIM.
Age Factors↗
Gastric glassy cells: a study of 3202 gastrectomy specimens from dwellers of the Atlantic and Pacific basins.
Fifteen years ago we detected gastric cells with glassy cytoplasm (GCs) in the human pyloric antrum. The frequency of these cells was subsequently investigated in sections from gastrectomies carried on in populations dwelling on the rim of the Atlantic and Pacific basins. In this work we compared the results obtained in these disparate geographic regions. We reviewed sections from 3203 gastrectomies (1942 in the Atlantic basin and 1261 in the Pacific basin). In the Atlantic basin 12/1942 (0.6%) of the gastrectomies had GCs, whereas in the Pacific basin 26/1261 (2.1%) of the gastrectomies had GCs. The difference was significant (p<0.05). The proportion of gastrectomies with GCs was higher in patients in Vancouver, Canada, than in New York, and higher in Santiago de Chile than in Buenos Aires, despite the fact that these populations reside at approximately the same geographic latitude. Previous studies with the same material indicated that both the extension of intestinal metaplasia and the frequency of ciliated metaplasia were significantly higher in the Pacific than in the Atlantic basin. Hence, the difference in the frequencies of GCs appears to be a new indication that dissimilar environmental exposures in the two basins might have influenced the histological make-up of the gastric mucosa.
Aged↗
How do homeopaths make decisions? An exploratory study of inter-rater reliability and intuition in the decision making process.
The validity of clinical decision making in homeopathy is largely unexplored and little is understood about the process or its reliability. This exploratory study investigated, in the context of a questionnaire based re-proving of Belladonna 30c, the extent to which decisions are based on clinical facts or intuition and how reliable decisions are. Three experienced, independent homeopathic clinicians/proving researchers rated the symptom diaries of the 206 subjects taking part. They reported their proving decision (ie positive proving response, no proving response or undecided) based on the total symptom profiles and rated (on a scale of 0-10) their use of clinical facts or intuition. Keynote symptoms and overall confidence scores were also reported. The level of agreement between raters was generally poor (weighted kappa 0.349-0.064). All raters used both facts and intuition. The rater's reliance on the facts was significantly associated with classifying those subjects who had no proving response [rater 1, P<0.001; rater 2, P<0.001]. Raters used significantly higher intuition scores when classifying a prover [rater 2, P= 0.001; rater 3, P= 0.012]. Issues regarding the education and practice of homeopathy are discussed.
Adult↗
Identification and characterisation of SB-366791, a potent and selective vanilloid receptor (VR1/TRPV1) antagonist.
Vanilloid receptor-1 (TRPV1) is a non-selective cation channel, predominantly expressed by peripheral sensory neurones, which is known to play a key role in the detection of noxious painful stimuli, such as capsaicin, acid and heat. To date, a number of antagonists have been used to study the physiological role of TRPV1; however, antagonists such as capsazepine are somewhat compromised by non-selective actions at other receptors and apparent modality-specific properties. SB-366791 is a novel, potent, and selective, cinnamide TRPV1 antagonist isolated via high-throughput screening of a large chemical library. In a FLIPR-based Ca(2+)-assay, SB-366791 produced a concentration-dependent inhibition of the response to capsaicin with an apparent pK(b) of 7.74 +/- 0.08. Schild analysis indicated a competitive mechanism of action with a pA2 of 7.71. In electrophysiological experiments, SB-366791 was demonstrated to be an effective antagonist of hTRPV1 when activated by different modalities, such as capsaicin, acid or noxious heat (50 degrees C). Unlike capsazepine, SB-366791 was also an effective antagonist vs. the acid-mediated activation of rTRPV1. With the aim of defining a useful tool compound, we also profiled SB-366791 in a wide range of selectivity assays. SB-366791 had a good selectivity profile exhibiting little or no effect in a panel of 47 binding assays (containing a wide range of G-protein-coupled receptors and ion channels) and a number of electrophysiological assays including hippocampal synaptic transmission and action potential firing of locus coeruleus or dorsal raphe neurones. Furthermore, unlike capsazepine, SB-366791 had no effect on either the hyperpolarisation-activated current (I(h)) or Voltage-gated Ca(2+)-channels (VGCC) in cultured rodent sensory neurones. In summary, SB-366791 is a new TRPV1 antagonist with high potency and an improved selectivity profile with respect to other commonly used TRPV1 antagonists. SB-366791 may therefore prove to be a useful tool to further study the biology of TRPV1.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Stress-induced alternative splicing of acetylcholinesterase results in enhanced fear memory and long-term potentiation.
Stress insults intensify fear memory; however, the mechanism(s) facilitating this physiological response is still unclear. Here, we report the molecular, neurophysiological and behavioral findings attributing much of this effect to alternative splicing of the acetylcholinesterase (AChE) gene in hippocampal neurons. As a case study, we explored immobilization-stressed mice with intensified fear memory and enhanced long-term potentiation (LTP), in which alternative splicing was found to induce overproduction of neuronal 'readthrough' AChE-R (AChE-R). Selective downregulation of AChE-R mRNA and protein by antisense oligonucleotides abolished the stress-associated increase in AChE-R, the elevation of contextual fear and LTP in the hippocampal CA1 region. Reciprocally, we intrahippocampally injected a synthetic peptide representing the C-terminal sequence unique to AChE-R. The injected peptide, which has been earlier found to exhibit no enzymatic activity, was incorporated into cortical, hippocampal and basal nuclei neurons by endocytosis and retrograde transport and enhanced contextual fear. Compatible with this hypothesis, inherited AChE-R overexpression in transgenic mice resulted in perikaryal clusters enriched with PKCbetaII, accompanied by PKC-augmented LTP enhancement. Our findings demonstrate a primary role for stress-induced alternative splicing of the AChE gene to elevated contextual fear and synaptic plasticity, and attribute to the AChE-R splice variant a major role in this process.
Acetylcholinesterase↗
Fetal glucocorticoid exposure and hypothalamo-pituitary-adrenal (HPA) function after birth.
The fetus may be exposed to increased endogenous glucocorticoid or synthetic glucocorticoid in late gestation. Indeed, 7-10% of pregnant women in Europe and North America are treated with synthetic glucocorticoid to promote lung maturation in fetuses at risk of preterm delivery. Such therapy is effective in reducing respiratory complications. However, very little is known about the mechanisms by which synthetic glucocorticoid or prenatal stress influence neurodevelopment in the human, or whether specific time windows of increased sensitivity exist. Glucocorticoids are essential for many aspects of normal brain development. However, there is growing evidence that exposure of the fetal brain to excess glucocorticoid can have lifelong effects on neuroendocrine function and behavior. We have shown that both endogenous glucocorticoid and synthetic glucocorticoid exposure has a number of rapid effects in the fetal brain in late gestation, including modification of neurotransmitter systems and transcriptional machinery. Such fetal exposure permanently alters hypothalamo-pituitary-adrenal (HPA) function in prepubertal, postpubertal, and aging offspring, in a sex-dependent manner. These effects are linked to changes in central glucocorticoid feedback machinery after birth. Prenatal glucocorticoid manipulation also leads to modification of HPA-associated behaviors, brain and organ morphology, as well as altered regulation of other endocrine systems. Permanent changes in endocrine function will have a long-term impact on health, since elevated cumulative exposure to endogenous glucocorticoid is linked to the premature onset of pathologies associated with aging.
Animals↗
Characterisation of integrin-linked kinase signalling in sporadic human colon cancer.
The putative oncogene, integrin-linked kinase (ILK) is a protein serine/threonine kinase that has been reported to regulate a number of biological properties including anchorage-independent cell cycle progression, tumour cell invasion and apoptosis. Overexpression of ILK has been documented in a wide variety of human malignancies including Ewing's sarcoma (ES), primitive neural ectodermal tumours (PNETs) and prostate tumours (PT). We recently reported that ILK signalling was also dysregulated in patients with the genetic condition familial adenomatous polyposis (FAP), a precursor to colon cancer. In this study, we extended our previous work by investigating the ILK-signalling pathway in sporadic human colon cancer and representative lymph node metastases. The data indicate that the ILK protein is significantly hyperexpressed in malignant acini in relation to normal crypts. Moreover, overexpression of ILK not only coincided with increased MBP phosphotransferase activity but as well with effects on downstream targets like GSK3beta. Based upon the presented data, we propose that ILK signalling is dysregulated early during the development of human colon cancer, and that selective inhibition of this molecule alone or in combination with the standard therapeutic modality might be a more effective means of treating colon cancer.
Colon↗
Curcumin attenuates DNB-induced murine colitis.
Numerous therapies used for inflammatory bowel disease (IBD) target the transcription factor NF-kappaB, which is involved in the production of cytokines and chemokines integral for inflammation. Here we show that curcumin, a component of the spice turmeric, is able to attenuate colitis in the dinitrobenzene sulfonic acid (DNB)-induced murine model of colitis. When given before the induction of colitis it reduced macroscopic damage scores and NF-kappaB activation. This was accompanied by a reduction in myeloperoxidase activity, and using semiquantitative RT-PCR, an attenuation of the DNB-induced message for IL-1beta was detected. Western blotting analysis revealed that there was a reproducible DNB-induced activation of p38 MAPK detected in intestinal lysates by using a phosphospecific antibody. This signal was significantly attenuated by curcumin. Furthermore, we show that the immunohistochemical signal is dramatically attenuated at the level of the mucosa by curcumin. We conclude that the widely used food additive curcumin is able to attenuate experimental colitis through a mechanism correlated with the inhibition of the activation of NF-kappaB and effects a reduction in the activity of p38 MAPK. We propose that this agent may have therapeutic implications for human IBD.
Animals↗
Differential inactivation of Na,K-ATPase by erythrosin isothiocyanate.
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Affinity Labels↗
Aggregation of proteins with expanded glutamine and alanine repeats of the glutamine-rich and asparagine-rich domains of Sup35 and of the amyloid beta-peptide of amyloid plaques.
The exon-1 peptide of huntingtin has 51 Gln repeats and produces the symptoms of Huntington's disease in transgenic mice. Aggregation of the yeast Sup35 protein into prions has been attributed to its glutamine-rich and asparagine-rich domain. Here, we show that poly-L-asparagine forms polar zippers similar to those of poly-L-glutamine. In solution at acid pH, the glutamine-rich and asparagine-rich 18-residue Sup35 peptide, rendered soluble by the addition of two aspartates at the amino end and two lysines at the carboxyl end, gives a beta-sheet CD spectrum; it aggregates at neutral pH. A poly-alanine peptide D(2)A(10)K(2) gives an alpha-helical CD spectrum at all pHs and does not aggregate; a peptide with the sequence of the C-terminal helix of the alpha-chain of human hemoglobin, preceded by two aspartates and followed by two lysines, exhibits a random coil spectrum and does not aggregate either. Alignment of several beta-strands with the sequence of the 42-residue Alzheimer's amyloid beta-peptide shows that they can be linked together by a network of salt bridges. We also asked why single amino acid replacements can so destabilize the native structures of proteins that they unfold and form amyloids. The difference in free energy of a protein molecule between its native, fully ordered structure and an amorphous mixture of randomly coiled chains is only of the order of 10 kcal/mol. Theory shows that destabilization of the native structure by no more than 2 kcal/mol can increase the probability of nucleation of disordered aggregates from which amyloids could grow 130,000-fold.
Alanine↗
Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1.
The vanilloid receptor-1 (VR1) is a heat-gated ion channel that is responsible for the burning sensation elicited by capsaicin. A similar sensation is reported by patients with esophagitis when they consume alcoholic beverages or are administered alcohol by injection as a medical treatment. We report here that ethanol activates primary sensory neurons, resulting in neuropeptide release or plasma extravasation in the esophagus, spinal cord or skin. Sensory neurons from trigeminal or dorsal root ganglia as well as VR1-expressing HEK293 cells responded to ethanol in a concentration-dependent and capsazepine-sensitive fashion. Ethanol potentiated the response of VR1 to capsaicin, protons and heat and lowered the threshold for heat activation of VR1 from approximately 42 degrees C to approximately 34 degrees C. This provides a likely mechanistic explanation for the ethanol-induced sensory responses that occur at body temperature and for the sensitivity of inflamed tissues to ethanol, such as might be found in esophagitis, neuralgia or wounds.
Animals↗
Learning experiences--what works for postgraduates.
Supervision and postgraduate education for health professionals studying homeopathy was investigated using feedback and comparative questioning of participants who have taken part in group supervision. Objectives set by supervisors, influenced by previous feedback, are scored and ranked. The key areas of postgraduate learning of homeopathy and how well the supervision model met these are analysed and discussed. Learning experiences are ranked in order of preference. Aspects of case presentation are compared for interest and relevance.
Attitude of Health Personnel↗
Glucocorticoids, hypothalamo-pituitary-adrenal (HPA) development, and life after birth.
Approximately 10% of women in North America are treated with synthetic glucocorticoid (sGC) between 24 and 32 weeks of pregnancy (term approximately 40 weeks), to promote lung maturation in fetuses at risk of preterm delivery. Such therapy is highly effective in reducing the frequency of respiratory complications, and as a result, repeated course treatment has become widespread. Nothing is known about the impact of repeated sGC treatment on neuroendocrine development in the human, or if specific time windows of increased sensitivity exist. Glucocorticoids are essential for many aspects of normal brain development. However, there is growing evidence from a number of species, that exposure of the fetal brain to excess glucocorticoid can have life-long effects on behaviour and neuroendocrine function. We have shown that exposure of fetuses to sGC in late gestation permanently alters HPA function in pre-pubertal, post-pubertal, and aging offspring, in a sex-dependent manner. These effects are linked to changes in central glucocorticoid feedback. Prenatal glucocorticoid exposure also leads to modification of HPA-associated behaviours and organ morphology, as well as altered regulation of other neuroendocrine systems. Permanent changes in HPA function will have a long-term impact on health, since elevated cumulative exposure to endogenous glucocorticoid has been linked to the premature onset of pathologies associated with aging.
Animals↗
Comparison of effects of anandamide at recombinant and endogenous rat vanilloid receptors.
BACKGROUND: Anandamide, an endogenous lipid, activates both cannabinoid (CB(1)) and vanilloid (VR1) receptors, both of which are co-expressed in rat dorsal root ganglion (DRG) cells. Activation of either receptor results in analgesia but the relative contribution of CB(1) and VR1 in anandamide-induced analgesia remains controversial. Here we compare the in vitro pharmacology of recombinant and endogenous VR1 receptors using calcium imaging, in clonal and DRG cells, respectively. We also consider the contribution of CB(1) and VR1 receptors to anandamide-induced analgesia. METHODS: Using a Flurometric Imaging Plate Reader (FLIPR), calcium imaging has been used to study the effects of several vanilloid and cannabinoid ligands in rat VR1-transfected HEK293 (rVR1-HEK) cells and in DRG cells. The effect of pre-exposure of several vanilloid and cannabinoids has also been compared in DRG cells. RESULTS: The VR1 agonists capsaicin, olvanil, (N-(4-hydroxyphenyl-arachinoylamide) (AM404) and anandamide caused a concentration-dependent increase in intracellular calcium concentration ([Ca(2+)](i)), with similar temporal profiles in both rVR1-HEK and DRG cells, and potency (pEC(50)) values of 8.25 (SEM 0.11), 8.37 (0.04), 6.96 (0.06), 5.85 (0.01) and 7.45 (0.10), 7.55 (0.07), 6.10 (0.13), approximately 5.5, respectively. These responses were inhibited by the VR1 antagonist capsazepine (1 micro M). In contrast, application of synthetic cannabinoid antagonists failed to inhibit the anandamide-induced increase in [Ca(2+)](i). Reapplication of VR1 agonists significantly inhibited a subsequent challenge to either capsaicin or anandamide in either cell type, whilst pre-exposure to cannabinoid agonists were without effect. CONCLUSION: Here we provide evidence that the pharmacology of recombinant rVR1 receptors is similar to those endogenously expressed in DRG cells. Moreover, we have shown that VR1, but not CB(1), receptors are involved in anandamide-induced responses in dorsal root primary neurones in vitro. Therefore, the analgesic properties of anandamide are likely to be mediated, at least in part, by VR1 activation in DRG cells in vivo.
Animals↗
Anal gland carcinoma.
BACKGROUND: Anal gland carcinoma is a rare entity. The authors conducted a joint study of cases coded as definite or possible anal gland carcinoma from the archives of the Armed Forces Institute of Pathology and the Canadian Reference Center for Cancer Pathology. METHODS: Seven cases of potential anal gland carcinoma were identified from the Canadian files and 12 from the Armed Forces Institute of Pathology archives. Of these 19 cases, 14 had adequate material to allow clinical, histologic, and immunohistochemical analysis. RESULTS: Seven of these 14 cases met a modified World Health Organization (WHO) definition of anal gland carcinoma. The mean age of these patients was 66 years (range, 60-72 years), with a male-to-female ratio of 6:1. The tumors were composed of haphazardly dispersed, small glands with scant mucin production that invaded the wall of the anorectal area with no obvious intraluminal component observed clinically or microscopically. Immunohistochemical studies were performed on all seven of these cases, revealing cytokeratin (CK) 7+/CK 20- expression in six cases, and CK 7+/CK 20+ expression in one case. The remaining seven cases showed no intraluminal component but did not meet a modified WHO definition of anal gland carcinoma. This group included three mucinous adenocarcinomas (two clinically arising in anal fistulas), all of which were CK 7+/CK 20+, and a rectal-type adenocarcinoma that was CK 7-/CK 20+. There was also a tumor interpreted as probable rectal-type adenocarcinoma that was CK 7+/CK 20+, and a tumor interpreted as probable squamous cell carcinoma that was CK 7-/CK 20-. The seventh tumor in this group, which could not be classified, was CK 7+/CK 20-. CONCLUSIONS: A useful and discriminating definition of anal gland carcinoma is an anal canal tumor composed of haphazardly dispersed, small glands with scant mucin production invading the wall of the anorectal area without an intraluminal component. The glands are positive for CK 7.
Aged↗