Chemical mapping of the colorectal cancer microenvironment via MALDI imaging mass spectrometry (MALDI-MSI) reveals novel cancer-associated field effects.

Matrix-assisted laser desorption ionisation imaging mass spectrometry (MALDI-MSI) is a rapidly advancing technique for intact tissue analysis that allows simultaneous localisation and quantification of biomolecules in different histological regions of interest. This approach can potentially offer novel insights into tumour microenvironmental (TME) biochemistry. In this study we employed MALDI-MSI to evaluate fresh frozen sections of colorectal cancer (CRC) tissue and adjacent healthy mucosa obtained from 12 consenting patients undergoing surgery for confirmed CRC. Specifically, we sought to address three objectives: (1) To identify biochemical differences between different morphological regions within the CRC TME; (2) To characterise the biochemical differences between cancerous and healthy colorectal tissue using MALDI-MSI; (3) To determine whether MALDI-MSI profiling of tumour-adjacent tissue can identify novel metabolic 'field effects' associated with cancer. Our results demonstrate that CRC tissue harbours characteristic phospholipid signatures compared with healthy tissue and additionally, different tissue regions within the CRC TME reveal distinct biochemical profiles. Furthermore we observed biochemical differences between tumour-adjacent and tumour-remote healthy mucosa. We have referred to this 'field effect', exhibited by the tumour locale, as cancer-adjacent metaboplasia (CAM) and this finding builds on the established concept of field cancerisation.

A comparison of 31P magnetic resonance spectroscopy and microbubble-enhanced ultrasound for characterizing hepatitis c-related liver disease.

We compared in vivo hepatic (31) P magnetic resonance spectroscopy ((31) P MRS) and hepatic vein transit times (HVTT) using contrast-enhanced ultrasound with a microbubble agent to assess the severity of hepatitis C virus (HCV)-related liver disease. Forty-six patients with biopsy-proven HCV-related liver disease and nine healthy volunteers had (31) P MRS and HVTT performed on the same day. (31) P MR spectra were obtained at 1.5 T. Peak areas were calculated for metabolites, including phosphomonoesters (PME) and phosphodiesters (PDE). Patients also had the microbubble ultrasound contrast agent, Levovist (2 g), injected into an antecubital vein, and time-intensity Doppler ultrasound signals of the right and middle hepatic veins were measured. The HVTT was calculated as the time from injection to a sustained rise in Doppler signal 10% greater than baseline. The shortest times were used for analysis. Based on Ishak histological scoring, there were 15 patients with mild hepatitis, 20 with moderate/severe hepatitis and 11 with cirrhosis. With increasing severity of disease, the PME/PDE ratio was steadily elevated, while the HVTT showed a monotonic decrease. Both imaging modalities could separate patients with cirrhosis from the mild and moderate/severe hepatitis groups. No statistical difference was observed in the accuracy of each test to denote mild, moderate/severe hepatitis and cirrhosis (Fisher's exact test P =1.00). (31) P MRS and HVTT show much promise as noninvasive imaging tests for assessing the severity of chronic liver disease. Both are equally effective and highly sensitive in detecting cirrhosis.

Hepatic vein transit times of a microbubble agent in assessing response to antiviral treatment in patients with chronic hepatitis C.

Microbubble measurement of hepatic vein transit times (HVTT) may have the potential to assess severity of hepatitis C virus (HCV)-related liver disease, where there is a shorter HVTT with more severe disease. We investigated the utility of this test as a marker of response to antiviral treatment. Thirty-seven patients with biopsy-proven HCV-related disease undergoing antiviral treatment were studied. All had baseline scans and then repeat scans 6 months after the end of treatment. HVTT using Levovist were obtained from the right and middle hepatic veins, and the shorter time was used for analysis. The aspartate aminotransferase to platelet ratio index (APRI) scores were calculated retrospectively. There were seven patients with mild hepatitis, 23 with moderate/severe hepatitis and seven with cirrhosis. The mean baseline HVTT in responders ± SE increased from 27.3 ± 2.29 s to 33.5 ± 2.8 s posttreatment (P = 0.01). In the 10 nonresponders, the HVTT remained the same; 43.3 ± 9 s baseline compared to 44 ± 7.8 s posttreatment (P = 0.84). This trend was also seen with the APRI score where in responders, the mean score decreased from 1.1 ± 0.2 to 0.74 ± 1 (P = 0.03) and in nonresponders, the score remained unchanged; 0.88 ± 0.2 compared to 0.84 ± 0.2 (P = 0.31). HVTT measurement lengthened, while APRI scores decreased in patients who responded to antiviral treatment while both remained the same, shortened (HVTT) or increased (APRI), respectively, in patients who were nonresponders. These results are encouraging and indicate that these tests could be potentially used as markers of response to treatment and could obviate the need for serial biopsies in antiviral future treatment studies.

Optimal combinations of ultrasound-based and serum markers of disease severity in patients with chronic hepatitis C.

Combinations of noninvasive markers may improve discrimination of chronic liver disease severity. The aims of this study were to compare four validated serum and ultrasound-based markers of hepatic disease severity head-to-head with liver biopsy and to assess optimal combinations with consideration of cost. A total of 67 patients with biopsy-proven chronic hepatitis C underwent all four techniques on the same visit [aspartate aminotransferase (AST) to platelet ratio index (APRI); Enhanced Liver Fibrosis (ELF) panel; transient elastography (TE) and ultrasound microbubble hepatic transit times (HTT)]. Markers were combined according to increasing financial cost and ordinal regression used to determine contributions. APRI, ELF, TE and HTT predicted cirrhosis with diagnostic accuracy of 86%, 91%, 90% and 83% respectively. ELF and TE were the most reliable tests with an intra-class correlation of 0.94 each. Either ELF or TE significantly enhanced the prediction of fibrosis stage when combined with APRI, but when combined together, did not improve the model further. Addition of third or fourth markers did not significantly improve prediction of fibrosis. Combination of APRI with either ELF or TE effectively predicts fibrosis stage, but combinations of three or more tests lead to redundancy of information and increased cost.

A missense mutation in the non-neural G-protein alpha-subunit isoforms modulates susceptibility to obesity.

OBJECTIVE: The Gnas transcription unit located within an imprinting region encodes several proteins, including the G-protein alpha-subunit, Gsalpha, its isoform XLalphas and their variant truncated neural forms GsalphaN1 and XLN1. Gsalpha and GsalphaN1 are expressed predominantly from the maternally derived allele in some tissues, whereas XLalphas and XLN1 are expressed exclusively from the paternally derived allele. The relative contribution of full-length Gsalpha and XLalphas, and truncated forms GsalphaN1 and XLN1 to phenotype is unknown. The edematous-small point mutation (Oed-Sml) in exon 6 of Gnas lies downstream of GsalphaN1 and XLN1, but affects full-length Gsalpha and XLalphas, allowing us to address the role of full-length Gsalpha and XLalphas. The aim of this study was therefore to determine the metabolic phenotypes of Oed and Sml mice, and to correlate phenotypes with affected transcripts. METHODS: Mice were fed standard or high-fat diets and weighed regularly. Fat mass was determined by DEXA analysis. Indirect calorimetry was used to measure metabolic rate. Glucose was measured in tolerance tests and biochemical parameters in fasted plasma samples. Histological analysis of fat and liver was carried out post mortem. RESULTS: Oed mice are obese on either diet and have a reduced metabolic rate. Sml mice are lean and are resistant to a high-fat diet and have an increased metabolic rate. CONCLUSION: Adult Oed and Sml mice have opposite metabolic phenotypes. On maternal inheritance, the obese Oed phenotype can be attributed to non-functional full-length Gsalpha. In contrast, on paternal inheritance, Sml mice were small and resistant to the development of obesity on a high-fat diet, effects that can be attributed to mutant XLalphas. Thus, the neural isoforms, GsalphaN1 and XLN1, do not appear to play a role in these metabolic phenotypes.

Characterization of materials eliciting foreign body reaction in stapled human gastrointestinal anastomoses.

BACKGROUND: Staples are made of titanium, which elicits minimal tissue reaction. The authors have encountered foreign body reaction associated with stapled human gastrointestinal anastomoses, although the literature has no reports of this. The aim of this study was to identify the refractile foreign materials causing this reaction. METHODS: Histological sections were taken from 14 gastrointestinal specimens from patients with a history of a stapled anastomosis within the specimen excised. These were reviewed by light and polarization microscopy. Scanning electron microscopy and energy dispersive X-ray analysis were carried out on these sections, staples and stapler cartridges used for gastrointestinal surgery. RESULTS: Foreign bodies rich in fluorine were found in three patients, and those rich in carbon in 12. Other elements identified included oxygen, calcium, sodium, potassium, magnesium, aluminium and silicon. One specimen was found to contain titanium with no surrounding foreign body reaction. Stapler cartridges contained carbon, oxygen, fluorine, calcium, sodium, potassium, magnesium, aluminium, silicon and traces of titanium. Staples were composed of pure titanium with some fibrous material on the surface containing elements found in stapler cartridges. CONCLUSION: The presence of foreign body reaction was confirmed in stapled human gastrointestinal anastomoses. The source of refractile materials eliciting this reaction was the stapler cartridges.

Coagulation status modulates murine hepatic fibrogenesis: implications for the development of novel therapies.

BACKGROUND: There is strong evidence demonstrating that coagulation system activation contributes to wound healing and promotes organ fibrosis. Several epidemiological studies have now shown that prothrombotic status, including carriage of the factor (F)V Leiden mutation, is associated with rapid progression of hepatic fibrosis. OBJECTIVES: To assess the effect of a procoagulant state on progression of hepatic fibrosis in a controlled environment and to test whether anticoagulation could attenuate fibrogenesis. METHODS: We investigated the effects of coagulation status on liver fibrosis development in a mouse model of chronic toxic liver injury. Prothrombotic FV Leiden mutant mice, C57BL/6 control animals and anticoagulated mice were studied after chronic exposure to carbon tetrachloride. RESULTS: Carriage of the FV Leiden mutation caused a significant increase in hepatic fibrosis. Anticoagulation with warfarin significantly reduced fibrosis progression in wild-type mice but was less effective against the profibrotic FV Leiden mutation. Changes in the fibrosis scores were mirrored by changes in liver hydroxyproline content and hepatic stellate cell activation detected by alpha-smooth muscle actin expression. CONCLUSIONS: These results demonstrate that coagulation status has a strong influence on hepatic fibrogenesis. It is likely that thrombin signaling through the proteinase-activated receptor 1 (PAR(1)) receptor expressed on hepatic stellate cells is responsible for this relationship. These results represent the first reported use of anticoagulation to slow hepatic fibrogenesis and suggest a potential novel anti-fibrotic therapeutic approach for the future.

Placental pathology of recurrent spontaneous abortion: the role of histopathological examination of products of conception in routine clinical practice: a mini review.

BACKGROUND: Histopathological examination of products of conception from miscarriages is part of routine clinical practice. The extent of additional clinically relevant information provided by this investigation in the setting of recurrent spontaneous abortion remains uncertain. METHODS: Review of the literature was performed to identify studies reporting on findings of histological examination of routinely obtained products of conception in the setting of recurrent spontaneous abortion. The initial search identified 312 potential references, but 300 were excluded on further examination due to lack of data on specific histopathological findings in routine products of conception specimens from patients with recurrent spontaneous abortion. The 12 included studies indicated that such examination may identify hydatidiform moles, villous dysmorphic features suggesting fetal aneuploidy, chronic histiocytic intervillositis (CHI) and massive perivillous fibrin deposition and impaired trophoblast invasion. However, in most cases, morphological assessment cannot reliably determine the cause of the miscarriage or distinguish recurrent from sporadic miscarriage. Studies reporting on the use of additional immunohistochemical methods do not currently provide additional clinically useful diagnostic or prognostic information. CONCLUSION: Routine histological examination of products of conception in the setting of recurrent spontaneous abortion can provide important clinical information in a minority of cases.

Case 31: Eosinophilia and pruritus.

A 39-year-old man presented with a pruritic rash, abdominal pain, weight loss and eosinophilia. A subsequent emergency laparotomy disclosed the nature of his underlying illness and the cause of the eosinophilia.

Term preeclampsia is associated with minimal histopathological placental features regardless of clinical severity.

Preeclampsia (PET) is a serious complication of pregnancy, which is associated with uteroplacental disease and reduced uteroplacental perfusion. One of the histological features in placentas from pregnancies complicated by PET is infarction, representing focal severe uteroplacental ischaemia. This study examines the relationship between gestation at induced delivery and the prevalence of placental infarction using a placental pathology database to identify induced or operative deliveries on the basis of severe PET. The clinical and pathological findings were reviewed. Thirty-seven cases were identified, (4.9% of all placentas submitted). In 16 (43%), non-peripheral significant infarcts were identified histologically, including 13/20 (65%) requiring delivery before 34 weeks' compared to 3/17 (17%) requiring delivery > or = 34 weeks (z=2.9, P<0.01). Histological infarction is common in placentas from pregnancies complicated by severe PET but the prevalence is significantly greater in cases requiring delivery at earlier gestations, even when similar clinical indications for delivery are applied.

Hepatic triglyceride content and its relation to body adiposity: a magnetic resonance imaging and proton magnetic resonance spectroscopy study.

BACKGROUND: Hepatic steatosis is associated with obesity and type II diabetes. Proton magnetic resonance spectroscopy (1H MRS) is a non-invasive method for measurement of tissue fat content, including intrahepatocellular lipids (IHCL) and intramyocellular lipids (IMCL). PATIENTS AND METHODS: We used 1H MRS and whole body magnetic resonance imaging (MRI) to assess the relationship between IHCL accumulation, total body adipose tissue (AT) content/distribution, and IMCL content in 11 subjects with biopsy proven hepatic steatosis and 23 normal volunteers. RESULTS: IHCL signals were detectable in all subjects but were significantly greater in hepatic steatosis (geometric mean (GM) 11.5 (interquartile range (IQR) 7.0-39.0)) than in normal volunteers (GM 2.7 (IQR 0.7-9.3); p=0.02). In the study group as a whole, IHCL levels were significantly greater in overweight compared with lean subjects (body mass index (BMI) >25 kg/m2 (n=23): GM 7.7 (IQR 4.0-28.6) v BMI <25 kg/m2 (n=11): GM 1.3 (IQR 0.3-3.6; p=0.004)). There was a significant association between IHCL content and indices of overall obesity (expressed as a percentage of body weight) for total body fat (p=0.001), total subcutaneous AT (p=0.007), and central obesity (subcutaneous abdominal AT (p=0.001) and intra-abdominal AT (p=0.001)), after allowing for sex and age. No correlation between IHCL content and IMCL was observed. A significant correlation was observed between serum alanine aminotransferase and liver fat content (r=0.57, p=0.006). CONCLUSIONS: Our results suggest that hepatic steatosis appears to be closely related to body adiposity, especially central obesity. MRS may be a useful method for monitoring IHCL in future interventional studies.

Hepatic vein transit times using a microbubble agent can predict disease severity non-invasively in patients with hepatitis C.

BACKGROUND AND AIMS: A reliable non-invasive assessment of the severity of diffuse liver disease is much needed. We investigated the utility of hepatic vein transit times (HVTT) for grading and staging diffuse liver disease in a cohort of patients with hepatitis C virus (HCV) infection using an ultrasound microbubble contrast agent as a tracer. MATERIALS AND METHODS: Eighty five untreated patients with biopsy proven HCV induced liver disease were studied prospectively. All were HCV RNA positive on polymerase chain reaction testing. Based on their histological fibrosis (F) and necroinflammatory (NI) scores, untreated patients were divided into mild hepatitis (F < or =2/6, NI < or =3/18), moderate/severe hepatitis (3 < or =F <6 or NI > or =4), and cirrhosis (F=6/6) groups. In addition, 20 age matched healthy volunteers were studied. After an overnight fast, a bolus of contrast agent (Levovist) was injected into an antecubital vein and spectral Doppler signals were recorded from both the right and middle hepatic veins for analysis. HVTTs were calculated as the time from injection to a sustained rise in Doppler signal >10% above baseline. The Doppler signals from the carotid artery were also measured in 60 patients and carotid delay times (CDT) calculated as the difference between carotid and hepatic vein arrival times. The earliest HVTT in each patient was used for analysis. RESULTS: Mean (SEM) HVTT for the control, mild hepatitis, moderate/severe hepatitis, and cirrhosis groups showed a monotonic decrease of 38.1 (2.8), 38.8 (2.4), 26.0 (2.4), and 15.8 (0.8) seconds, respectively. Mean (SEM) CDT for the control, mild hepatitis, moderate/severe hepatitis, and cirrhosis patients again showed progressive shortening of 30.3 (2.6), 25.9 (2.6), 14.8 (2.1), and 5.6 (1.2) seconds, respectively. There were significant differences between the groups for HVTT (ANOVA, p<0.001) and CDT (ANOVA, p<0.001). There was 100% sensitivity and 80% specificity for diagnosing cirrhosis and 95% sensitivity and 86% specificity for differentiating mild hepatitis from more severe liver disease. CONCLUSION: We have shown, for the first time, that HVTT using an ultrasound microbubble contrast agent can assess HCV related liver disease with clear differentiation between mild hepatitis and cirrhosis. There were significant differences between these two groups and the moderate/severe hepatitis group. CDT offers no additional benefit or greater differentiation than HVTT and can be omitted, thus simplifying this technique. HVTT may complement liver biopsy and may also be a useful alternative for assessment of liver disease in patients who have contraindications to biopsy.

Negative correlation between intrahepatic expression of hepatitis C antigens and apoptosis despite high-level expression of Fas and HLA antigens.

The role of virus-related apoptosis in hepatic injury in chronic HCV is unclear. It is unknown whether HCV induces apoptosis directly or whether cellular injury is immunologically mediated. We studied the relationship between infected hepatocytes, apoptosis and necroinflammation. We established a Fluorescence Activated Cell Sorter (FACS) based intracellular staining technique for the HCV NS3 protein and examined intrahepatic viraemia, disease activity and apoptosis. We also stained infected cells for expression of human leucocyte antigen (HLA) class I and Fas antigens. We examined 34 liver biopsies (24 from patients with HCV) and found marked variation in the proportion of infected cells (2.5-42%). The number of infected cells correlated with serum viraemia but not histology. The number of infected cells was inversely related to the number of apoptotic cells (P < 0.001); infected cells expressed both HLA class I (14 cases) and Fas antigens (12 cases). The number of hepatocytes infected with hepatitis C is variable and does not influence histological activity. In infected patients, the majority of HCV-positive hepatocytes express target molecules for activated lymphocytes (Fas and HLA class I antigens) but they do not undergo apoptosis, suggesting that hepatitis C may inhibit apoptosis by modulating intracellular pro-apoptotic signals.

Antinuclear antibodies (ANA) in chronic hepatitis C virus infection: correlates of positivity and clinical relevance.

We examined correlates of antinuclear antibody (ANA) positivity (ANA+) in individuals with chronic hepatitis C virus (HCV) infection and the effect of positivity on clinical outcome of HCV. Pretreatment sera from 645 patients from three centres in Sweden (n = 225), the UK (n = 207) and Italy (n = 213) were evaluated by indirect immunofluorescence on Hep-2 cells for ANA pattern and titre by a single laboratory. Liver biopsies were all scored by one pathologist. A total of 258 patients were subsequently treated with interferon monotherapy. There was a significant difference in the prevalence of ANA (1:40) by geographic location: Lund 4.4%, London 8.7%, Padova 10.3% [odds ratio (OR) = 0.66; 95% CI: 0.46-0.94; P = 0.023]. Duration of HCV infection, age at infection, current age, route of infection, viral genotype, alcohol consumption, fibrosis stage and inflammatory score were not correlated with ANA+ or ANA pattern. Female gender was correlated with ANA+ and this association persisted in multivariable analyses (OR = 3.0; P = 0.002). Increased plasma cells were observed in the liver biopsies of ANA-positive individuals compared with ANA-negative individuals, while a trend towards decreased lymphoid aggregates was observed [hazard ratio (HR) = 9.0, P = 0.037; HR = 0.291, P = 0.118, respectively]. No correlations were observed between ANA positivity and nonresponse to therapy (OR = 1.4; P = 0.513), although ANA+ was correlated with faster rates of liver fibrosis, this was not statistically significant (OR = 1.8; P = 0.1452). Low titre ANA+ should not be a contraindication for interferon treatment. Our observation of increased plasma cells in ANA+ biopsies might suggest B-cell polyclonal activity with a secondary clinical manifestation of increased serum immunoglobulins.

Placental pathology, antiphospholipid antibodies, and pregnancy outcome in recurrent miscarriage patients.

OBJECTIVE: To examine whether there are characteristic histological features in placentas from ongoing pregnancies of patients with a history of recurrent miscarriage, with and without primary antiphospholipid antibody syndrome, in relation to clinical pregnancy outcome. METHODS: Patients attending a recurrent miscarriage clinic were investigated and treated according to an established protocol. One hundred twenty-one consecutive patients achieving a potentially viable pregnancy (at least 24 completed weeks' gestation), including 60 primary antiphospholipid antibody syndrome-positive cases and 61 primary antiphospholipid antibody syndrome-negative cases were included. After delivery, placental pathologic examination was carried out by a pathologist unaware of the clinical details. Histological sections were examined by two pathologists independently. Pregnancy outcome and placental findings were reviewed in relation to the maternal antiphospholipid antibody status. RESULTS: Pregnancy outcome was similar in primary antiphospholipid antibody syndrome-positive and primary antiphospholipid antibody syndrome-negative groups regarding gestation at delivery and antepartum obstetric complications. Several histological placental abnormalities were identified in both groups, but most pregnancies were clinically uncomplicated, with no significant placental abnormalities. In cases with pregnancy complications, the placental pathology was primarily that of uteroplacental vasculopathy, such as placental infarction and preeclampsia, but there were no specific placental lesions or patterns of abnormalities characteristic of primary antiphospholipid antibody syndrome-positive patients. A small subgroup of primary antiphospholipid antibody syndrome-positive patients may be at increased risk of development of maternal floor infarction or massive perivillus fibrin deposition. CONCLUSION: There are no specific histopathologic placental abnormalities characteristic of treated patients with antiphospholipid antibody syndrome and poor reproductive history, but complications of uteroplacental disease are more common.

A sebaceous cyst with a difference: Dermatobia hominis.

Dermatobia hominis causes furuncular myiasis and is endemic to South America. This report describes a case in a young woman who had recently visited Belize, highlighting the importance of clinical history (including travel history) and close liaison between pathologist and surgeon.

Increase in alcohol related deaths: is hepatitis C a factor?

AIM: To evaluate recent trends in alcohol related deaths in the UK and to consider possible causative factors. DESIGN: Observational retrospective study of the database of the Office for National Statistics, alcohol consumption data reported by the General Household Survey, and other published data. SETTING: England, 1993-9. RESULTS: Deaths for each million of the population from alcohol related illness increased by 59% in men and 40% in women over the years 1993 to 1999. One subgroup of alcohol related deaths, ICD 571.3 (alcoholic liver damage unspecified), showed a 243% increase in men aged 40 to 49 years over the same period. Figures for younger men, and women in all age groups, showed less pronounced increases. There has been no associated rise in alcohol intake. There has been an increase in the incidence of hepatitis C virus (HCV) infection in recent years, and alcohol consumption in HCV positive individuals accelerates the progression to cirrhosis. Circumstantial evidence links the rise in HCV infection to the use of illicit drugs in the 1970s and 1980s, among those currently aged 40 to 59 years. CONCLUSIONS: The recent increase in alcohol related deaths cannot be solely explained by a change in drinking habits. It is suggested that this probably results from the rapid progression of alcoholic cirrhosis in people who have acquired HCV infection through intravenous drug use. Alcohol consumption in HCV positive individuals is firmly linked with a poor outcome.

Analysis of pathogen-host cell interactions in purpura fulminans: expression of capsule, type IV pili, and PorA by Neisseria meningitidis in vivo.

The pattern of meningococcal surface structure expression in different microenvironments following bloodstream invasion in vivo is not known. We used immunohistochemistry to determine the expression of capsule, type IV pili, and PorA by meningococci residing in the skin lesions of children with purpura fulminans. All the skin biopsy samples showed evidence of thrombosis and, frequently, a perivascular inflammatory cell infiltrate consisting of neutrophils (elastase positive) and monocytes/macrophages (CD68 positive). Modified Gram staining revealed 20 to over 100 gram-negative diplococci in each 4-microm-thick section, usually grouped into microcolonies. Immunoperoxidase staining demonstrated that the invading meningococci expressed PorA, capsule, and type IV pilin. Expression of these antigens was not restricted to any particular environment and was found in association with meningococci located in leukocytes, small blood vessels, and the dermal interstitium. Confocal laser scanning microscopy demonstrated coexpression of pilin and capsule by numerous microcolonies. However, there was some discordance in capsule and pilin expression within the microcolonies, suggesting phase variation. The strategy employed in this study will be helpful in investigating invasive bacterial diseases where antigenic and phase variation has a significant impact on virulence and on vaccine design.

Placental massive perivillous fibrin deposition associated with antiphospholipid antibody syndrome.

We present three pregnancies in which massive perivillous fibrous deposition (MPVFD) and maternal floor infarction (MFI) occurred in patients with primary antiphospholipid antibody syndrome (PAPS) attending a recurrent miscarriage clinic, and who were treated with low dose aspirin and heparin. We hypothesise that PAPS may be a predisposing factor to the development of this condition. The increased prevalence of late pregnancy complications in PAPS patients with a history of early miscarriage suggests that aspirin and heparin therapy does not eradicate the underlying pathological process but merely reduces the severity. Therefore, untreated early pregnancy losses may be converted into treated pregnancies with late antenatal complications. Some patients with PAPS may therefore be prone to suffer either the previously reported complications of the uteroplacental vasculature, such as pre-eclampsia, and/or specific complications related to the environment of the intervillus space, such as MPVFD/MFI.