Investigation of acute lower gastrointestinal bleeding with 16‐ and 64‐slice multidetector CT†

We evaluated the usefulness of 16‐ and 64‐slice multidetector CT (MDCT) in the detection of a bleeding site in acute lower gastrointestinal tract (GIT) haemorrhage by conducting a retrospective study of cases of presumed acute lower GIT haemorrhage imaged with CT in two teaching hospitals in an 11‐month period. The patients underwent contrast enhanced CT using either a 16 or 64 MDCT. No oral contrast was used. One hundred milliliters of non‐ionic intravenous contrast agent was injected at 4.5 mL/s, followed by a 60 mL saline flush at 4 mL/s through a dual head injector. Images were acquired in arterial phase with or without non‐contrast and portal phase imaging with 16 × 1.5 mm or 64 × 0.625 mm collimation. Active bleeding was diagnosed by the presence of iodinated contrast extravasation into the bowel lumen on arterial phase images with attenuation greater than and distinct from the normal mucosal enhancement or focal pooling of increased attenuation contrast material within a bowel segment on portal‐venous images. Further management and final diagnosis was recorded. Fourteen patients and 15 studies were reviewed. CT detected and localized a presumed bleeding site or potential causative pathology in 12 (80%) of the patients. Seven of these were supported by other investigations or surgery, while five were not demonstrated by other modalities. Eight patients had mesenteric angiography, of which only four corroborated the site of bleeding. CT did not detect the bleeding site in three patients, of which two required further investigation and definitive treatment. We propose that MDCT serves a useful role as the initial rapid investigation to triage patients presenting with lower GIT bleeding for further investigation and management.     

The relationship between the hemorrhagic and antithrombotic properties of low molecular weight heparin in rabbits

We have compared the hemorrhagic and antithrombotic effects of a low molecular weight (LMW) heparin fraction and standard heparin in rabbits. Similar LMW heparin fractions have antithrombotic effects when tested in animals, but their hemorrhagic effects relative to standard heparin have not been established. Standard porcine mucosal heparin (mol wt 15,000 daltons) was depolymerized by nitrous acid to a low molecular weight fraction (mol wt 4600 daltons). Using equal USP units, the standard and Dep LMW heparin were compared in vitro, ex vivo, and in vivo. In vitro, when diluted in rabbit plasma, the Dep LMW heparin at equivalent anti-Xa activity showed less prolongation of thrombin clotting times or activated partial thromboplastin times. Ex vivo, platelets from rabbits treated with the Dep LMW heparin showed less inhibition of collagen-induced aggregation. The relative hemorrhagic properties of the two heparins were compared in vivo in rabbits using a sensitive blood loss assay, and the antithrombotic properties were compared in a thrombin-induced venous stasis model. By using an optimal threshold heparin dose in each test system, it was possible to demonstrate that equal USP units of Dep LMW heparin caused less blood loss but showed greater antithrombotic activity than standard heparin.     

Schwangerschaft und maternales Immunsystem

Pregnancy is a successful natural model of immune tolerance. The fetus is not only passively tolerated by the maternal immune system – it is actively supported in its development (immunotrophism), which is in apparent conflict with the primary mechanism of transplantation immunology (recognition of foreign bodies). Its ‘invasive’ growth is made possible by an immunologic situation whose characteristics are being more and more understood. However, disbalance in this fine network can lead to disturbances in implantation and placentation and result in intrauterine growth retardation or spontaneous miscarriage. Understanding immunologic communication at the trophoblastic level can improve understanding of other invasive processes, for example those of malignant degeneration, and open new therapeutic possibilities. We describe three main functions of the immune system that apply in the fetomaternal interphase: (1) trophoblast immune function and the cytokine network, (2) uterine natural killer cells, and (3) the function of the immunosuppressive glycoprotein glycodelin. Current recommendations for immunotherapy in case of recurrent miscarriage are discussed.     

Fibrillin‐1 staining anomalies are associated with increased staining for TGF‐β and elastic fibre degradation; new clues to the pathogenesis of emphysema

We recently demonstrated aberrant staining of fibrillin‐1 in lung tissue specimens with emphysematous lesions. In this study, we have extended this observation by an elaborate analysis of the elastic fibre. Using domain‐specific antibodies to fibrillin‐1, and to other elastin fibre‐associated molecules, lung tissue derived from patients without obvious clinical emphysema, but harbouring various degrees of microscopical emphysematous lesions, was analysed. In addition, the fibrillin‐regulated growth factor TGF‐β was studied. Electron microscopy and biochemical analysis of desmosine (a marker for elastin) were also performed. Results were compared with lung tissue derived from patients with clinical emphysema. Domain‐specific antibodies recognizing the C‐terminal, N‐terminal, and middle part of fibrillin‐1 showed aberrant staining patterns associated with increasing degrees of microscopical emphysema. Staining for elastin, emilin‐1, and fibulin‐2 was, however, not aberrant. TGF‐β staining was markedly increased. On the electron microscopic, but not light microscopical, level, initial elastic fibre degradation was noticed in specimens with microscopical emphysema. Lung specimens from patients with clinical emphysema also displayed fragmented fibrillin‐1 staining and, in addition, displayed extensive degradation of the elastic fibre. The results suggest that fibrillin‐1 anomalies and TGF‐β overexpression are associated with initial events occurring during the emphysematous process. Based on these and other data, a mechanism for emphysematogenesis is proposed. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Analysis of VH genes used by neoplastic B cells in endemic Burkitt's lymphoma shows somatic hypermutation and intraclonal heterogeneity

Tumor cell lines from six typical cases of endemic Epstein-Barr virus (EBV) genome-positive Burkitt's lymphoma (BL) have been investigated for usage and mutational pattern of Ig VH genes. The neoplastic cells all had a t(8;14) (q24;q32) translocation involving the c-myc protooncogene. The VH genes were derived from VH1, VH3 and VH4, and both the IgM-positive (four cases) and IgG-positive (two cases) were extensively mutated from germline sequence. In two cases, early and late passage tumor cells were available, and the VH nucleotide sequences were identical, indicating that mutations had not accumulated in vitro. In a further case, there was evidence of sequence heterogeneity, which appeared to have been generated in vivo, indicating that the tumor cell VH gene was able to undergo posttranslocation somatic hypermutation. Analysis of the relatively nonpolymorphic VH4 genes for the pattern of replacement or silent mutations did not show a role for antigen selection in the expressed sequences.     

Headache syndromes after acoustic neuroma surgery and their implications for quality of life

The patients of this prospective study were analysed for headache as a sequela of surgery for acoustic neuroma (AN). Thirty-two per cent (30/95) of patients complained about a persisting headache syndrome with a severity of at least 6/10 on the nominal analogue scale 6 months after surgery. The occurrence of headache was significantly correlated with the prospectively evaluated parameters preoperative headache and the number of perioperative complications. Postoperative failure to return to the preoperative level of activity was also associated with the occurrence of headache, but also with the risk of retirement after successful surgery of the AN. Headache is therefore, like postoperative ataxia, dysgeusia and probably facial paresis, an important factor for the overall outcome of patients after AN surgery. Hypacusis is not as important. The symptoms and course of each individual patient were analysed. The attempt to categorize the headaches according to the second edition of the International Classification of Headache Disorders revealed five headache syndromes, the most prevalent being tension-type-like headache (46.7%), followed by neuralgia of the occipital nerve (16.6%), trigeminal neuropathy (16.6%), neuropathy of the intermedian nerve (10.0%) and cervicogenic headache (10.0%). The respective pathophysiological mechanisms are discussed and treatment options based on the clinical picture are presented.     

Molecular basis of the brindled mouse mutant (Mo(br)): a murine model of Menkes disease

The brindled mouse mutant (Mo(br)) is the closest animal model of the human genetic copper deficiency, Menkes disease, which is presumed to be due to a mutation at the X-linked mottled locus (Mo). The mutant mice are hypopigmented and die at around 15 days after birth, but can be saved by treatment with copper before the 10th postnatal day. Menkes disease has been shown to be due to mutations of the gene ATP7A which encodes P-type ATPase (referred to here as MNK). MNK is likely to function in copper efflux from cells, but the full range of its biological activity is not fully understood. The nature of the mutation in the brindled mouse is of importance in our understanding of the role of MNK and for devising treatment strategies for Menkes disease. Here we show that the brindled mouse has a deletion of two amino acids in a highly conserved, but functionally uncharacterized, region of Mnk. Comparison with the Ca ATPases suggests this region may be involved in conformational changes associated with the E1/E2 transition fundamental to the action of P-type ATPases. We also describe the first Western blot data for Mnk in tissues, and these show normal levels of Mnk in mutant and brindled kidneys but none in liver. In the kidney, immunohistochemistry demonstrated Mnk in the proximal and distal tubules, the distribution is identical in mutant and normal. This distribution is consistent with Mnk being involved in copper resorption from the urine.      

Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects

It is now well recognized that periconceptional folic acid or folic acid containing multivitamin supplementation reduces the risk of neural tube defects (NTDs). Recently we were able to show that homozygosity for a thermolabile variant of the enzyme methylenetetrahydrofolate reductase is associated with an increased risk for spina bifida in patients recruited from the Dutch population. However, this genetic risk factor could not account for all folic acid preventable NTDs. In an attempt to identify additional folate related enzymes that contribute to NTD etiology we now studied the methylenetetrahydrofolate dehydrogenase gene on chromosome 14q24 which encodes a single protein with three catalytic properties important in the folate metabolism. The cDNA sequence of 38 familial and 79 sporadic patients was screened for the presence of mutations by single strand conformation polymorphism (SSCP) analysis followed by sequencing. Two amino acid substitutions were identified. The first one (R293H) was detected in a patient with familial spina bifida and not in 300 control individuals. The mutation was inherited from the unaffected maternal grandmother and was also present in two younger brothers of the index patient, one of them displaying spina bifida occulta and the other being unaffected. The second change turned out to be an amino acid polymorphism (R653Q) that was present in both patients and controls with similar frequencies. Our results so far provide no evidence for a major role of the methylenetetrahydrofolate-dehydrogenase (MTHFD) gene in NTD etiology. However, the identification of a mutation in one family suggests that this gene can act as a risk factor for human NTD.