Chronic constipation in the elderly: an unusual presentation of colonic dysmotility in an elderly patient.

Introduction. Chronic constipation is common in the elderly, and often no underlying pathology is found. Primary colonic dysmotility has been described in children but is rare in the elderly. Case report. We present an 82-year-old female with long standing constipation presenting acutely with large bowel obstruction. Laparotomy and Hartman's procedure was performed, and a grossly distended sigmoid colon was resected. Histology revealed a primary myopathic process. Conclusion. Primary colonic myopathy should be considered in elderly patients presenting with large bowel obstruction and a long preceding history of constipation, particularly when previous endoscopic examinations were normal.

Fetal haemopoiesis marking low-grade urinary bladder cancer.

BACKGROUND: The immunohistochemical features of fetal haemoglobin cells and their distribution patterns in solid tumours, such as colorectal cancer and blastomas, suggest that fetal haemopoiesis may take place in these tumour tissues. These locally highly concentrated fetal haemoglobin (HbF) cells may promote tumour growth by providing a more efficient oxygen supply. METHODS AND RESULTS: Biomarkers of HbF were checked in transitional cell carcinoma (TCC) of the urinary bladder, assessing this as a new parameter for disease management. Fetal haemoglobin was immunohistochemically examined in tumours from 60 patients with TCC of the bladder. Fetal haemoglobin erythrocytes and erythroblasts were mainly clonally distributed in proliferating blood vessels and not mixed with normal haemoglobin erythrocytes. The proportion of such HbF blood vessels could reach more than half of the total number of vessels. There were often many HbF erythroblasts distributed in one-cell or two-cell capillaries and present as 5-15% of cells in multi-cell vessels. This suggests a local proliferation of HbF-cell progenitors. Fetal haemoglobin cells were prominently marking lower grades of tumours, as 76% (n=21) of the patients with G1pTa were HbF+, whereas only 6.7% (n=30) of the patients with G3pT1-pT2a were HbF+. CONCLUSION: Our results suggest that HbF, besides being a potential new marker for early tumour detection, might be an essential factor of early tumour development, as in fetal life. Inhibiting HbF upregulation may provide a therapeutic target for the inhibition of tumour growth.

Voltage-gated potassium channel (K(v) 1) autoantibodies in patients with chagasic gut dysmotility and distribution of K(v) 1 channels in human enteric neuromusculature (autoantibodies in GI dysmotility).

BACKGROUND: Autoantibodies directed against specific neuronal antigens are found in a significant number of patients with gastrointestinal neuromuscular diseases (GINMDs) secondary to neoplasia. This study examined the presence of antineuronal antibodies in idiopathic GINMD and GINMD secondary to South American Trypanosomiasis. The GI distribution of voltage-gated potassium channels (VGKCs) was also investigated. METHODS: Seventy-three patients were included in the study with diagnoses of primary achalasia, enteric dysmotility, chronic intestinal pseudo-obstruction, esophageal or colonic dysmotility secondary to Chagas' disease. Sera were screened for specific antibodies to glutamic acid decarboxylase, voltage-gated calcium channels (VGCCs; P/Q subtype), nicotinic acetylcholine receptors (nAChRs; α3 subtype), and voltage-gated potassium channels (VGKCs, K(V) 1 subtype) using validated immunoprecipitation assays. The distribution of six VGKC subunits (K(V) 1.1-1.6), including those known to be antigenic targets of anti-VGKC antibodies was immunohistochemically investigated in all main human GI tract regions. KEY RESULTS: Three patients (14%) with chagasic GI dysmotility were found to have positive anti-VGKC antibody titers. No antibodies were detected in patients with idiopathic GINMD. The VGKCs were found in enteric neurons at every level of the gut in unique yet overlapping distributions. The VGKC expression in GI smooth muscle was found to be limited to the esophagus. CONCLUSIONS & INFERENCES: A small proportion of patients with GI dysfunction secondary to Chagas' disease have antibodies against VGKCs. The presence of these channels in the human enteric nervous system may have pathological relevance to the growing number of GINMDs with which anti-VGKC antibodies have been associated.

Lack of association of ACP1 gene with inflammatory bowel disease: a case-control study.

The red cell acid phosphatease (ACP1) gene, which encodes a low molecular weight phosphotyrosine phosphatase (LMW-PTP), has been suggested as a common genetic factor of autoimmunity. In the present study, we aimed to investigate the possible influence of ACP1 polymorphisms in the susceptibility of inflammatory bowel disease (IBD). A total of 1271 IBD Spanish patients [720 Crohn's disease (CD) and 551 ulcerative colitis (UC)] and 1877 healthy subjects were included. Four single-nucleotide polymorphisms (SNPs), rs10167992, rs11553742, rs7576247 and rs3828329, were genotyped using TaqMan SNP genotyping assays. Common ACP1 alleles (i.e. ACP1*A, ACP1*B and ACP1*C) were determined by two of these SNPs. After the analysis, no evidence of association of the ACP1 genetic variants was found with CD or UC. Therefore, our results suggest that the ACP1 gene may not play a relevant role in the development of IBD.

Quantitation of cellular components of the enteric nervous system in the normal human gastrointestinal tract--report on behalf of the Gastro 2009 International Working Group.

BACKGROUND: Patients with gastrointestinal neuromuscular diseases may undergo operative procedures that yield tissue appropriate to diagnosis of underlying neuromuscular pathology. Critical to accurate diagnosis is the determination of limits of normality based on the study of control human tissues. Although robust diagnostic criteria exist for many qualitative alterations in the neuromuscular apparatus, these do not include quantitative values due to lack of adequate control data. PURPOSE: The aim of this report was to summarize all relevant available published quantitative data for elements of the human enteric nervous system (neuronal cell bodies, glial cells, and nerve fibers) from the perspective of the practicing pathologist. Forty studies meeting inclusion criteria were systematically reviewed with data tabulated in detail and discussed in the context of methodological variations and limitations. The results reveal a lack of concordance between observations of different investigators resulting in data insufficient to produce robust normal ranges. This diversity highlights the need to standardize the way pathologists collect, process, and quantitate neuronal and glial elements in enteric neuropathologic samples, as suggested by recent international guidelines on gastrointestinal neuromuscular pathology.

Continuous hyperfractionated accelerated radiotherapy (CHART) and non-conventionally fractionated radiotherapy in the treatment of non-small cell lung cancer: a review and consideration of future directions.

There is a well-established role for radiation treatment in the management of non-small cell lung cancer. As a single modality, it is indicated as a radical treatment option for patients deemed unsuitable for chemotherapy with inoperable locoregional disease or who decline surgery. In this patient group, the evidence shows advantages for accelerated treatment regimes, e.g. continuous hyperfractionated accelerated radiotherapy (CHART). Research efforts should be directed towards dose escalation with the application of the new technologies available. The multi-modality approach of chemoradiotherapy is established in the radical treatment of non-small cell lung cancer in those who are inoperable, radically treatable and fit enough to receive chemotherapy. How best these two modalities are combined remains unclear, and the combination of CHART and other non-conventionally fractionated radiotherapy schedules with chemotherapy and targeted agents is another potentially productive research area.

Titrimetric immunohistochemical evaluation of DNA hypomethylation in uterine tumours.

BACKGROUND: Global DNA hypomethylation is a well established feature of many common cancers. AIMS: To establish a simple semi-quantitative, titrimetric immunohistochemical method in order to exploit this trait for prognostic purposes, in uterine cancers. METHODS: A monoclonal antibody against 5-methylcytidine was used for immunohistochemical staining of methylated DNA in tumour cells. The degree of methylated DNA in the tumour tissue was visually compared and matched to that of normal tissues stained by serial decreasing concentrations of antibody to 5-methylcytidine. RESULTS: Using this method a significant correlation was found between the histological stage and the reduction in DNA methylation in uterine adenocarcinoma (n = 39) and uterine squamous cell carcinoma (n = 23). CONCLUSIONS: A simple titrimetric immunohistochemical method has been developed for quantitative evaluation of ligands. This method should be further employed in follow-up studies, in order to establish the prognostic value of DNA hypomethylation in uterine cancer.

External radiation assessment in a wet phosphoric acid production plant.

The factories dedicated to the production of phosphoric acid by the so-called wet acid method are usually considered typical NORM industries, because the phosphate rock used as raw material usually contains high concentrations of (238)U-series radionuclides. The magnitude and behaviour of the radionuclides involved in the production process revealed the need to determine its dosimetric impact on workers. This work aims to partially compensate this lack of knowledge through the determination of external effective dose rates at different zones in the process at a typical plant located in the southwest of Spain. To this end, two dosimetric sampling campaigns have been carried out at this phosphoric acid production plant. The first sampling was carried out when phosphate rocks originating in Morocco were processed, and the second one when phosphate rock processed came from the Kola Peninsula (Russia Federation). This differentiation was necessary because the activity concentrations are almost one order of magnitude higher in Moroccan phosphate rock than in Kola phosphate rock. The results obtained have reflected external dose rate enhancements as high as 1.4microSvh(-1) (i.e., up to thirty times the external exposition due to radionuclides in unperturbed soils) at several points in the facility, particularly where the digested rock (pulp) is filtered. However, the most problematic points are characterised by a small occupation factor. That means that the increment in the annual effective external gamma dose received by the most-exposed worker is clearly below 1mSv (European Commission limit for the general population) under normal production. Nevertheless, special care in the design and schedule of cleaning and maintaining work in the areas with high doses should be taken in order to avoid any possibility of exceeding the previously mentioned general population limit. In addition, the results of the dosimetric campaign showed no clear correlation between (226,228)Ra activity concentrations in the material fluxing during the process (the most important radionuclides from the dosimetric point of view) and the external dose rates. Furthermore, any general dependence of the origin of the rock (i.e., on their radioactive contents) on the external effective dose rate measured has not been observed. These latter findings could be a consequence of three effects: (1) a variable radiation shielding at the different points along the process, (2) a changing geometry of irradiation (from a rock pile up to a thin-layered pulp passing through a solid mass inside pipes and deposits), and (3) the existence of a "memory effect", or background contamination in the installation equipment due to the presence of radionuclide-enriched scales and sludges in pipes and deposits.

Histopathology of trichinellosis in wild boar.

Histopathological study of Trichinella constitutes an important knowledge base to understand the pathogenesis of this disease. This study analyses cell response and macroscopic lesions in wild boar for the two species of Trichinella present in Spain: Trichinella spiralis and T. britovi. We carried out both trichinelloscopy and artificial digestion to calculate the parasitic load and relate this to the macroscopic lesions. The results obtained prove a lesser adaptation of T. britovi in wild boar. From a histological point of view, the organic region that was most affected was the skeletal muscle, where inflammatory infiltrates were observed around the larvae, and they were most abundant in calcified cysts.

Full-thickness biopsy findings in chronic intestinal pseudo-obstruction and enteric dysmotility.

BACKGROUND AND AIMS: Small bowel manometry is increasingly used in the clinical investigation of patients with symptoms of intestinal motor dysfunction. Enteric dysmotility (ED) has been suggested as a new diagnostic term for patients with abnormal intestinal motor activity but no radiological signs of chronic intestinal pseudo-obstruction (CIP). Histopathological features of adult patients with ED and CIP have been compared in a large case series to study differences and similarities between the two diagnostic groups. METHODS: Routine staining and an extensive panel of immunohistochemical stains on transversal and tangential cuts from full-thickness biopsies of the small bowel were used. RESULTS: 39 females and 11 males with CIP and 58 females and 7 males with ED were investigated. The underlying lesion was more often a visceral myopathy (22% vs 5%) or neuromyopathy (30% vs 12%) in patients with CIP than in those with ED, whereas the predominant lesion in ED was neuropathy with inflammation. CONCLUSION: CIP in adults is associated with very different underlying pathology, whereas ED is more homogeneously associated with neuropathy in the enteric nervous system. Neuropathy of enteric ganglia with inflammation seems to be the most common cause for measurable disturbances of intestinal motor function.

Safety and diagnostic yield of laparoscopically assisted full-thickness bowel biospy.

Advances in minimally invasive surgery have made laparoscopy and full-thickness bowel biopsy possible in the investigation of patients with suspected gastrointestinal neuromuscular disorders. The safety and diagnostic yield of this investigation have not been formally reported. A prospective study was undertaken of 124 patients with clinico-physiological diagnoses of chronic intestinal pseudo-obstruction, enteric dysmotility and severe irritable bowel syndrome undergoing LFTB in three European teaching centres with expertise in the management of gastrointestinal neuromuscular disorders. Perioperative data were collected including complications. Diagnostic yield was expressed as proportion with well-established specific neuromuscular abnormalities based on a protocol of routine and immunohistochemical techniques. The majority of patients underwent a laparoscopically assisted procedure with extracorporeal biopsy. Median operating time was 50 min, conversion rate 2% and length of stay 1 day. There was an 8% readmission rate for obstructive symptoms but minimal other morbidity and no mortality. Overall specific diagnostic yield was 81%, being high for jejunal biopsies (89%) but low for a small number of ileal and colonic biopsies. Laparoscopy and full-thickness biopsy of the bowel appears acceptable in terms of safety. It should be performed in a jejunal site to achieve a high diagnostic yield.

Dynein-dynactin complex subunits are differentially localized in brain and spinal cord, with selective involvement in pathological features of neurodegenerative disease.

AIMS: The dynein-dynactin complex, mostly recognized for axonal retrograde transport in neurones, has an ever growing list of essential subcellular functions. Here, the distribution of complex subunits in human central nervous system (CNS) has been assessed using immunohistochemistry in order to test the hypothesis that this may be altered in neurodegenerative disease. METHODS: Three dynactin and two dynein subunits were immunolocalized in the CNS of human post mortem sections from motor neurone disease, Alzheimer's disease and patients with no neurological disease. RESULTS: Unexpectedly, coordinated distribution of complex subunits was not evident, even in normal tissues. Complex subunits were differentially localized in brain and spinal cord, and localization of certain subunits, but not others, occurred in pathological structures of motor neurone and Alzheimer's diseases. CONCLUSIONS: These results suggest that dynein-dynactin complex subunits may have specific subcellular roles, and primary events that disturb the function of individual components may result in disequilibrium of subunit pools, with the possibility that availability for normal cytoplasmic functions becomes impaired, with consequent organelle and axonal transport misfunction.

Foetal haemoglobin-blood cells (F-cells) as a feature of embryonic tumours (blastomas).

Tumour markers are important in the diagnosis and monitoring of many tumours. This study tested the hypothesis that an oncofoetal protein, foetal haemoglobin (HbF) is a potential tumour marker in embryonic tumours, useful for management. An immunohistochemical investigation of HbF blood cell (Fc) distribution was carried out in tumours and in bone marrow samples from 83 children and 13 adults with various embryonic tumours (blastomas), and in bone marrow samples of 24 leukaemia patients. In the three, main blastoma types, nephroblastoma (Wilms' tumour), neuroblastoma and retinoblastoma, where all the patients, except two, were children, around 80% of the tumour samples had Fc within proliferating blood vessels and spaces between tumour cells. In parallel, clusters of Fc, mostly F-erythroblasts (Feb), were distributed in the bone marrow of some of those patients and in the bone marrow of 79% of the leukaemia patients. Foetal haemoglobin, as well as being a potential prognostic cancer marker, is a potential indicator of DNA hypomethylation implicated in the development of these tumours, as well as in others previously noted for the presence of HbF.

Development of fetal haemoglobin-blood cells (F cells) within colorectal tumour tissues.

AIM: To evaluate the sources of fetal haemoglobin (HbF) as an indicator in cancer. An immunohistochemical study was carried out on some of the most common kinds of cancer. All of these cancers had serologically high levels of HbF as evaluated previously. METHODS: Immunoaffinity-purified anti-HbF was immunohistochemically used to study F cell distribution in the following cancers: colorectal adenocarcinoma, urinary bladder transitional cell carcinoma, brain tumours, lung carcinoma, breast adenocarcinoma, leukaemia, Burkitt's lymphoma and endometrial carcinoma. RESULTS: In colorectal adenocarcinoma, HbF-containing red blood cells (FRBC) were present within thin-walled vessels or were disposed in dense clusters within the tumour. Some of these cells were nucleated or binucleated HbF-erythroblasts or HbF-normoblasts (FNBS). In two cases, high levels of mitoses within HbF-erythroblasts were observed. In half of the cases with transitional cell carcinoma of the urinary bladder, regional intratumoral blood vessels were found to contain 5-50% FRBC. In the other tumours examined, F cells were not observed. FRBCs, however, were occasionally observed in the regional lymph nodes of some of these cancers. CONCLUSIONS: The evaluation of HbF as a potential plasma marker is suggested by the high concentration of FRBCs in colorectal tumours. The apparent development of FRBCs in colorectal tumour tissues is an interesting observation, as these cells were previously thought to develop in medullary or lymphoid tissues. It is thus suggested that the colonic microenvironment may stimulate extramedullary fetal-type haematopoiesis.

Mutation of a UDP-glucose-4-epimerase alters nematode susceptibility and ethylene responses in Arabidopsis roots.

In Arabidopsis, mutation of RHD1, a UDP-glucose-4-epimerase, causes root-specific phenotypes, including hypersusceptibility to the cyst nematode Heterodera schachtii, increased root hair elongation, decreased root length, and root epidermal bulging. Previous experiments suggested that increased ethylene sensitivity or production mediated the rhd1-4 phenotypes. In the present study, double mutant analyses revealed that only rhd1-4 hypersusceptibility to H. schachtii and increased root hair elongation were dependent upon the ethylene signaling genes EIN2 and EIN3 but not upon ethylene signaling mediated by the auxin efflux carrier EIR1. In contrast, the rhd1-4 short root and root epidermal bulging phenotypes did not require EIN2, EIN3, or EIR1. A time-course analysis of RHD1 transcript levels in wild-type plants treated with the ethylene precursor 1-aminocyclopropane-1-carboxylic acid showed a root-specific downregulation of RHD1 expression by ethylene. This observation was corroborated by our finding of increased RHD1 transcript levels in roots of the ethylene-insensitive mutants etr1 and ein2. In addition to ethylene, auxin strongly influences H. schachtii susceptibility and root hair elongation. Therefore, we investigated the sensitivity of rhd1-4 roots to indole-3-acetic acid (IAA). Equivalent IAA concentrations caused a greater reduction in rhd1-4 root elongation compared with wild-type roots. Finally, H. schachtii parasitism was found to strongly downregulate RHD1 expression in the root 3 days after inoculation. We conclude that RHD1 is a likely target of root-specific negative regulation by ethylene and that loss of RHD1 function results in a heightened sensitivity of root tissues to both ethylene and auxin.

Blood cells with fetal haemoglobin (F-cells) detected by immunohistochemistry as indicators of solid tumours.

AIMS: Fetal hemoglobin (HbF) is an established serological indicator of cancer. However, its distribution in tumour tissues is rarely investigated. Therefore, HbF was studied immunohistologically in different cancers characterised by high blood HbF concentrations. METHODS: Anti-HbF was immunoaffinity purified and used to study HbF immunohistochemically in the following cancers: germ cell tumour (GCT), trophoblastic disease (TD), lymphoma, myelodysplastic syndrome (MDS), multiple myeloma (MM), and ovarian adenocarcinoma (OA). RESULTS: In GCT a distinction was made between tumours substantially without HbF positive red blood cells (F-RBC) and those with F-RBC. Those without F-RBC were non-metastatic mature teratomas and dermoid cysts. Those containing F-RBC were mainly embryonal carcinomas and metastatic teratomas. HbF positive myeloid cells (F-MLC), HbF positive normoblasts (F-NBS), and F-RBC were common in the bone marrow and in the lymphoid tissues of lymphoma, MDS, and MM. In TD, normal and nucleated F-RBC were seen in the trophoblastic villi in one case with incomplete molar pregnancy (ICM) but not in other cases of ICM and complete molar pregnancy. However, F-RBC and F-MLC were seen in the decidua of both types of TD. Generally, F-cells were observed either within blood vessels or concentrated in certain areas of the neoplastic tissue. CONCLUSIONS: HbF was evaluated as an inducible marker within different tumour tissue blood cells. The dual distribution of these cells-circulating in the blood or concentrated in areas of the neoplastic tissues-might reflect the two independent serological indicators of HbF: one in whole blood and the other in plasma of patients with cancer.

A role for autoantibodies in some cases of acquired non-paraneoplastic gut dysmotility.

BACKGROUND: Antibody-mediated autoimmunity underlies a diverse range of disorders, particularly in the nervous system where domains of ion channels and receptors are potential targets. The aetiology of many adult-onset conditions of severe gut dysmotility is not known. We looked for antibodies to neuronal antigens in patients with severe (slow-transit-type) constipation (STC). METHODS: Eleven sera from adult-onset STC patients and 18 from childhood onset cases were tested by routine immunoprecipitation assays for antibodies against neuronal antigens including voltage-gated potassium channels (VGKCs), calcium channels (VGCCs), both muscle and neuronal acetylcholine receptor and glutamic acid decarboxylase (GAD). Results were compared with positive and negative control populations. RESULTS: Two of the 11 sera from patients with adult-onset STC showed highly positive anti-VGKC antibodies. Both had onset of symptoms de novo in adulthood without evidence of autoimmune, neoplastic or neurological disease. One of these patients, and one other, had anti-GAD antibodies. None of the childhood-onset STC had evidence of anti-neuronal antibodies. CONCLUSIONS: Anti-neuronal antibodies are found in some patients with a condition of severe acquired gut dysmotility of previously unknown aetiology. Future studies may demonstrate an autoimmune role for such antibodies.

Behavioral treatment for smokers with a history of alcoholism: predictors of successful outcome.

This study examined baseline predictors associated with smoking abstinence among 205 smokers (113 men, 92 women) with a past history of alcoholism. Their mean age was 41.8 years, and 93% were Caucasian. Participants were randomly assigned to standard treatment (ST), behavioral counseling plus exercise (BEX), or behavioral counseling plus nicotine gum (BNIC). Factors multivariately associated with point-prevalence smoking abstinence at posttreatment (1 week after target quit date) were a longer duration of prior smoking abstinence and an interaction between treatment group and having an active 12-step sponsor. ST was more effective for those with an active sponsor, whereas both BEX and BNIC were more effective for those without an active sponsor. At 1-year follow-up, independent predictors of point-prevalence smoking abstinence were a lower Fagerström Tolerance Questionnaire score (K. O. Fagerström, 1978) and fewer years of smoking.