Biomedical subjects
Publications and source records attributed to A Carlin.
A highly unusual case of a pregnancy complicated by diffuse placental chorioangiomatosis that resulted in a live-birth and short-term fetal survival is reported. The potential for antenatal diagnosis and intrauterine treatment to optimise fetal outcome is discussed.
The natural antimicrobial peptides are ancient host defense effector molecules, present in organisms across the evolutionary spectrum. Several properties of alpha-melanocyte stimulating hormone (alpha-MSH) suggested that it could be a natural antimicrobial peptide. Alpha-MSH is a primordial peptide that appeared during the Paleozoic era, long before adaptive immunity developed and, like natural antimicrobial molecules, is produced by barrier epithelia, immunocytes, and within the central nervous system. alpha-MSH was discovered to have antimicrobial activity against two representative pathogens, Staphylococcus aureus and Candida albicans. The candidacidal influences of alpha-MSH appeared to be mediated by increases in cell cyclic adenosine monophosphate (cAMP). The cAMP-inducing capacity of alpha-MSH likely interferes with the yeast's own regulatory mechanisms of this essential signaling pathway. It is remarkable that this mechanism of action in yeast mimics the influences of alpha-MSH in mammalian cells in which the peptide binds to G-protein-linked melanocortin receptors, activates adenylyl cyclase, and increases cAMP. When considering that most of the natural antimicrobial peptides enhance the local inflammatory reaction, the anti-inflammatory and antipyretic effects of alpha-MSH confer unique properties to this molecule relative to other natural antimicrobial molecules. Synthetic derivatives, chemically stable and resistant to enzymatic degradation, could form the basis for novel therapies that combine anti-inflammatory and antimicrobial properties.
We have previously reported that the peptide a-melanocyte stimulating hormone (alpha-MSH) has antiproliferative effects in human malignant mesothelioma cells. To determine the molecular mechanisms underlying such effects, we investigated the changes in gene expression profile induced by the alpha-MSH analog [Nle4 -DPhe7 ]-alpha-MSH (NDP-alpha-MSH) in a human malignant mesothelioma cell line. The cDNA macroarray technique revealed changes in expression of genes involved in cell growth, adhesion, signal transduction, and transcription. In particular, NDP-alpha-MSH down-regulated expression of B-Myb and Myc, two oncogenes considered of paramount importance for cell proliferation and cancer. Further, NDP-alpha-MSH exerted a favorable transcriptional regulation of certain integrins and their signaling pathways. Finally, peptide treatment was associated with a prominent inhibition of IL-13, a cytokine with tumor-promoting effects. The data indicate that the influences of alpha-MSH extend beyond the established anti-inflammatory effects in normal cells to include cell cycle regulatory properties in malignant cells.
Explore the source record for details and available documents.
We have measured the growth of liquid Ar adsorbed on arrays of linear wedges structured in different ways. In the most regular patterns, a clear crossover from a planarlike to a geometry-dependent growth behavior is observed. This crossover is found to depend on the characteristic wedge size and its position, in the case of a regular pattern, agrees well with theoretical predictions. Near liquid-vapor bulk coexistence, the film mass is observed to diverge as a power law of the chemical potential difference from saturation with an exponent in very good agreement with the value of -2 expected for a linear wedge. This exponent is not affected by the opening angles of the wedges. The form of the next-to-leading order singular term in the asymptotic divergence of the mass has also been investigated. The experimentally determined value of the exponent is consistent with the expected theoretical result of -4/3.
We have measured the growth of liquid films of Ar adsorbed on well defined arrays of microscopic linear wedges sculpted on thin Si wafers and on a stainless steel disk. On these patterns, a clear cross-over from a planarlike to a geometry dependent growth behavior is observed. This crossover is found to depend on the characteristic wedge size. Near liquid-vapor bulk coexistence, the film mass is observed to diverge as a power law of the chemical potential difference from saturation with an exponent in very good agreement with the value of -2 expected for a linear wedge. This exponent is not affected by the opening angles of the wedges. All these findings are in accordance with a recent scaling theory.
We have employed the quartz-crystal microbalance technique to measure the sliding friction of krypton films physisorbed on gold. By slowly increasing the amplitude of the substrate oscillations, we have observed a sharp transition from a film locked to the substrate to a sliding one. This transition is characterized by hysteresis both in dissipation and inertial mass as the amplitude is decreased. Finally, the dependence of this transition on film coverage has been studied in some detail.
This study explored whether virtual reality (VR) exposure therapy was effective in the treatment of spider phobia. We compared a treatment condition vs. a waiting list condition in a between group design with 23 participants. Participants in the VR treatment group received an average of four one-hour exposure therapy sessions. VR exposure was effective in treating spider phobia compared to a control condition as measured with a Fear of Spiders questionnaire, a Behavioural Avoidance Test (BAT), and severity ratings made by the clinician and an independent assessor. Eighty-three percent of patients in the VR treatment group showed clinically significant improvement compared with 0% in the waiting list group, and no patients dropped out. This study shows that VR exposure can be effective in the treatment of phobias.
Nitrite concentrations in plasma were investigated in a population of migraine and cluster headache patients and a group of healthy non-headache controls. A hundred migraine patients and 69 cluster headache patients in the interictal period, and 112 controls, were studied. Significantly higher nitrite concentrations were found in migraine patients, with and without aura, and cluster headache patients, in remission and cluster phase, than in controls. These findings suggest that a basal dysfunction in the L-arginine-NO pathway may be involved in the peripheral mechanisms predisposing subjects with neurovascular headaches to individual attacks.
BACKGROUND: Oncologic resection techniques affect outcome for colon cancer and rectal cancer, but standardized guidelines have not been adopted. The National Cancer Institute sponsored a panel of experts to systematically review current literature and to draft guidelines that provide uniform definitions, principles, and practices. METHODS: Methods were similar to those described by the American Society of Clinical Oncology in developing practice guidelines. Experts representing oncology and surgery met to review current literature on oncologic resection techniques for level of evidence (I-V, where I is the best evidence and V is the least compelling) and grade of recommendation (A-D, where A is based on the best evidence and D is based on the weakest evidence). Initial guidelines were drafted, reviewed, and accepted by consensus. RESULTS: For the following seven factors, the level of evidence was II, III, or IV, and the findings were generally consistent (grade B): anatomic definition of colon versus rectum, tumor-node-metastasis staging, radial margins, adjuvant R0 stage, inadvertent rectal perforation, distal and proximal rectal margins, and en bloc resection of adherent tumors. For another seven factors, the level of evidence was II, III, or IV, but findings were inconsistent (grade C): laparoscopic colectomy; colon lymphadenectomy; level of proximal vessel ligation, mesorectal excision, and extended lateral pelvic lymph node dissection (all three for rectal cancer); no-touch technique; and bowel washout. For the other four factors, there was little or no systematic empirical evidence (grade D): abdominal exploration, oophorectomy, extent of colon resection, and total length of rectum resected. CONCLUSIONS: The panel reports surgical guidelines and definitions based on the best available evidence. The availability of more standardized information in the future should allow for more grade A recommendations.
Patients with pancreatic and/or duodenal trauma often have a high incidence of infectious complications. In this study we attempted to find the most important risk factors for these infections. A retrospective review of the records of 167 patients seen over 7 years (1989 through 1996) at an urban Level I trauma center for injury to the duodenum and/or pancreas was performed. Fifty-nine patients (35%) had isolated injury to the duodenum (13 blunt, 46 penetrating), 81 (49%) had isolated pancreatic trauma (18 blunt, 63 penetrating), and 27 (16%) had combined injuries (two blunt, 25 penetrating). The overall mortality rate was 21 per cent and the infectious morbidity rate was 40 per cent. The majority of patients had primary repair and/or drainage as treatment of their injuries. Patients with pancreatic injuries (alone or combined with a duodenal injury) had a much higher infection rate than duodenal injuries. The patients with duodenal injuries had significantly lower penetrating abdominal trauma indices, number of intra-abdominal organ injuries, and incidence of hypothermia. On multivariate analysis independent factors associated with infections included hypothermia and the presence of a pancreatic injury. Although injuries to the pancreas and duodenum often coexist it is the pancreatic injury that contributes most to the infectious morbidity.
BACKGROUND: Clinical and/or laboratory signs of systemic inflammation occur frequently in patients undergoing long-term haemodialysis. It is likely, therefore, that a compensatory release of endogenous anti-inflammatory molecules occurs to limit host reactions. The aim of the present research was to determine if the potent anti-inflammatory peptide alpha-melanocyte-stimulating hormone (alpha-MSH), a pro-opiomelanocortin derivative, is increased in plasma of haemodialysis patients. Because endotoxin and cytokines induce alpha-MSH in vivo and in vitro, we also measured plasma concentrations of endotoxin, interleukin-6 (IL-6), and tumour necrosis factor alpha (TNF-alpha), and the two circulating products of activated monocytes, nitric oxide (NO) and neopterin. METHODS: Thirty-five chronic haemodialysis patients, 20 patients with chronic renal failure not yet on dialysis, and 35 normal controls were included in the study. In the haemodialysis group, blood samples were obtained before and at the end of a dialysis session. Plasma alpha-MSH was measured using a double antibody radioimmunoassay, and IL-6, TNF-alpha, and neopterin using specific enzyme-linked immunosorbent assays. Plasma nitrites were determined by a colorimetric method, and endotoxin with the quantitative chromogenic LAL (limulus amoebocyte lysate) method. RESULTS: Mean plasma alpha-MSH was higher in haemodialysis patients than in control subjects, with the peptide concentrations being particularly elevated in dialysed patients with detectable endotoxin. High alpha-MSH concentrations were observed in the pre-dialysis samples, with no substantial change at the end of the dialysis session. Plasma concentrations of IL-6, TNF-alpha, neopterin, and NO were generally elevated in chronic haemodialysis patients and there was a negative correlation between circulating alpha-MSH and IL-6. In patients with renal failure not yet on dialysis, mean plasma alpha-MSH was similar to that of normal subjects. CONCLUSIONS: alpha-MSH is increased in the circulation of chronic haemodialysis patients and particularly so in case of detectable endotoxaemia. Reduction of renal clearance is unlikely to contribute to the observed rise of the peptide because alpha-MSH concentration is not increased in patients with chronic renal failure who are not yet on dialysis. It is likely that dialysis-associated endotoxaemia, directly and/or through cytokine release, enhances the production of the anti-inflammatory mediator alpha-MSH that limits host reactions.
BACKGROUND: Primary repair for penetrating colonic injury is an acceptable practice in uncomplicated injuries, but it is still viewed with trepidation in high risk patients. METHODS: The records of 350 patients evaluated at an urban Level I trauma center for penetrating colonic injuries over an 8-year period (1989-1997) were reviewed. These included 33 stab and 317 gunshot wounds. Thirty-nine patients died within 48 hours. Of the remaining 311 patients, 78 (25%) developed 152 infections. These infections were classified as traumatic or nosocomial in nature. Traumatic infections (46%) included abdominal abscesses or peritonitis (28), wound infections (30), missile tract infections (8), and fistulas (4), whereas nosocomial infections (54%) included pneumonia (25), bacteremia (25), urinary tract infections (17), miscellaneous (8), empyema (4), and sinusitis (3). Significance for analyses was set at p < 0.05. RESULTS: Univariate analysis was performed to identify risk factors for the development of infections. The five most significant risk factors, using all infections as an outcome, were as follows: penetrating abdominal trauma index (PATI) greater than 30, presence of an ostomy, multiple transfusions, Injury Severity Score (ISS) of 16 or greater, and Revised Trauma Score less than 7.8. All were highly significant (p < 0.0001). Multivariate analysis with all infections as an outcome revealed that four of the five risk factors had independent effects, with the following significance: PATI greater than 30, ISS of 16 or greater, ostomy, and multiple transfusions. Multivariate analysis for traumatic infections revealed only two of the above to be independent risk factors: presence of an ostomy (p = 0.004) and a PATI greater than 30 (p = 0.039), both of which can be considered local factors. Conversely, multivariate analysis of nosocomial infections revealed independent risk for the two other factors, both of which can be considered systemic factors: multiple transfusions (p = 0.011) and ISS of 16 or greater (p = 0.026). CONCLUSION: Although most of the above factors are beyond the control of the trauma surgeon, the creation of an ostomy is a clinical decision. The creation of an ostomy in high-risk patients does not protect them from septic complications and, indeed, may independently contribute to local abdominal infections.
The presence of the ancient peptide alpha-melanocyte-stimulating hormone (alpha-MSH) in barrier organs such as gut and skin suggests that this potent anti-inflammatory molecule may be a component of the innate host defense. In tests of antimicrobial activities, alpha-MSH and its fragment KPV showed inhibitory influences against the gram-positive bacterium Staphylococcus aureus and the yeast Candida albicans. Anti-tumor necrosis factor and antimicrobial effects of alpha-MSH suggest that the peptide might likewise reduce replication of human immunodeficiency virus (HIV). Treatment with alpha-MSH reduced HIV replication in chronically and acutely infected human monocytes. At the molecular level, alpha-MSH inhibited activation of the transcription factor NF-kappa B known to enhance HIV expression. alpha-MSH that combines antipyretic, anti-inflammatory, and antimicrobial effects could be useful in the treatment of disorders in which infection and inflammation coexist.
Until recently, inflammation was believed to arise from events taking place exclusively in the periphery. However, it is now clear that central neurogenic influences can either enhance or modulate peripheral inflammation. Therefore, it should be possible to improve treatment of inflammation by use of antiinflammatory agents that reduce peripheral host responses and inhibit proinflammatory signals in the central nervous system (CNS). One such strategy could be based on alpha-melanocyte stimulating hormone (alpha-MSH). Increases in circulating TNF-alpha and nitric oxide (NO), induced by intraperitoneal administration of endotoxin in mice, were modulated by central injection of a small concentration of alpha-MSH. Inducible nitric oxide synthase (iNOS) activity and iNOS mRNA in lungs and liver were likewise modulated by central alpha-MSH. Increase in lung myeloperoxidase (MPO) activity was significantly less in lungs of mice treated with central alpha-MSH. Proinflammatory agents induced by endotoxin were significantly greater after blockade of central alpha-MSH. The results suggest that antiinflammatory influences of neural origin that are triggered by alpha-MSH could be used to treat systemic inflammation. In addition to its central influences, alpha-MSH has inhibitory effects on peripheral host cells, in which it reduces release of proinflammatory mediators. alpha-MSH reduces chemotaxis of human neutrophils and production of TNF-alpha, neopterin, and NO by monocytes. In research on septic patients, alpha-MSH inhibited release of TNF-alpha, interleukin-1 beta (IL-1 beta), and interleukin-8 (IL-8) in whole blood samples in vitro. Combined central and peripheral influences can be beneficial in treatment of sepsis.
Explore the source record for details and available documents.
Inflammatory processes contribute to neurodegenerative disease, stroke, encephalitis, and other central nervous system (CNS) disorders. Activated microglia are a source of cytokines and other inflammatory agents within the CNS and it is therefore important to control glial function in order to preserve neural cells. Melanocortin peptides are pro-opiomelanocortin-derived amino acid sequences that include alpha-melanocyte-stimulating hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH). These peptides have potent and broad anti-inflammatory effects. We tested effects of alpha-MSH (1-13), alpha-MSH (11-13), and ACTH (1-24) on production of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and nitric oxide (NO) in a cultured murine microglial cell line (N9) stimulated with lipopolysaccharide (LPS) plus interferon gamma (IFN-gamma). Melanocortin peptides inhibited production of these cytokines and NO in a concentration-related fashion, probably by increasing intracellular cAMP. When stimulated with LPS + IFN-gamma, microglia increased release of alpha-MSH. Production of TNF-alpha, IL-6, and NO was greater in activated microglia after innmunoneutralization of endogenous alpha-MSH. The results suggest that alpha-MSH is an autocrine factor in microglia. Because melanocortin peptides inhibit production of pro-inflammatory mediators by activated microglia they might be useful in treatment of inflammatory/degenerative brain disorders.
Explore the source record for details and available documents.