Crohn's disease: small bowel motility impairment correlates with inflammatory-related markers C-reactive protein and calprotectin.

BACKGROUND: To evaluate the correlation between the levels of C-reactive protein (CRP), calprotectin, and small bowel motility in patients with Crohn's disease assessed with MRI. METHODS: This prospective institutional review board approved study included magnetic resonance imaging enterography (MRE) and analyses of inflammatory markers in blood (C-reactive protein) and feces (calprotectin). For cine MRE, a coronal 2D-T2w sequence was used on a 1.5 T MRI system. Small bowel motility was analyzed in 13 patients using dedicated magnetic resonance MR-motility assessment software (Motasso). Contraction frequency, amplitude, amplitude diameter ratio, and luminal diameter were determined as well as the blood levels of CRP (mg L(-1) ) and fecal levels of calprotectin (ug g(-1) ). Statistics were calculated using Pearson's correlation coefficient. KEY RESULTS: A significant inverse linear correlation was found between the contraction frequency and both the level of CRP (r = -0.701, P = 0.008) and calprotectin (r = -0.805, P = 0.001). Dilatation of small bowel diameter significantly correlated with calprotectin levels (r = 0.857, P =< 0.001) but not with CRP (r = 0.447, P = 0.126). The absolute amplitude of the contractions did not correlate neither with the level of CRP (r = -0.527, P = 0.064) nor with calprotectin (r = -0.612, P = 0.026). The ratio describing the contraction amplitude relatively to the individual luminal diameter significantly correlated with calprotectin (r = 0.736, P = 0.004) and with CRP (r = 0.577, P = 0.039). CONCLUSIONS & INFERENCES: Alterations of small bowel motility during CD flares significantly correlate with the level of calprotectin and CRP indicating that they represent inflammatory activity.

Lessons from a transplant patient with diarrhea, cryptosporidial infection, and possible mycophenolate mofetil-associated colitis.

Diarrhea in a transplant recipient may be caused by infection, metabolic problems, or adverse drug effects. The immunosuppressive drug most frequently associated with diarrhea in transplant recipients is mycophenolate mofetil (MMF). We present the case of a patient with 2 potential explanations for diarrhea lasting several weeks, which occurred years after liver transplantation. Whereas stool samples were positive for cryptosporidia, the histopathological findings were compatible with MMF colitis. However, diarrhea resolved after treatment of cryptosporidial infection, despite continued MMF medication. This case shows that histopathological findings of MMF colitis may be misleading and do not prove that diarrhea is drug induced.

The role of bile acid retention and a common polymorphism in the ABCB11 gene as host factors affecting antiviral treatment response in chronic hepatitis C.

The outcome of hepatitis C virus (HCV) infection and the likelihood of a sustained virological response (SVR) to antiviral therapy depends on both viral and host characteristics. In vitro studies demonstrated that bile acids (BA) interfere with antiviral interferon effects. We investigate the influence of plasma BA concentrations and an ABCB11 polymorphism associated with lower transporter expression on viral load and SVR. Four hundred and fifty-one Caucasian HCV-patients treated with PEG-interferon and ribavirin were included in the study. ABCB11 1331T>C was genotyped, and plasma BA levels were determined. The 1331C allele was slightly overrepresented in HCV-patients compared to controls. In HCV-patients, a significant difference between patients achieving SVR vs non-SVR was observed for HCV-2/3 (5 vs 9 µm; P=0.0001), while median BA levels in HCV-1 were marginally elevated. Normal BA levels <8 µm were significantly associated with SVR (58.3%vs 36.3%; OR 2.48; P=0.0001). This difference was significant for HCV-2/3 (90.7%vs 67.6%; P=0.002) but marginal in HCV-1 (38.7%vs 27.8%; P=0.058). SVR rates were equivalent between ABCB11 genotypes for HCV-1, but increased for HCV-2/3 (TT 100%vs CC 78%; OR 2.01; P=0.043). IL28B genotype had no influence on these associations. No correlation between BA levels and HCV RNA was detected for any HCV genotype. The higher allelic frequency of ABCB11 1331C in HCV-patients compared to controls may indirectly link increased BA to HCV chronicity. Our data support a role for BA as host factor affecting therapy response in HCV-2/3 patients, whereas a weaker association was found for HCV-1.

Pharmacokinetics of cefuroxime in traumatic wound secretion and antibacterial activity under vacuum therapy.

The objective of this study was to investigate the pharmacokinetics of cefuroxime in wound secretion and the antibacterial activity of the traumatic wound secretion in patients receiving cefuroxime and in those not receiving antibiotics. Included in the present controlled, prospective, non-randomized study were 12 patients with an open fracture who needed vacuum therapy (group A) and 12 patients with a closed fracture, who, due to soft tissue damage, also underwent treatment with vacuum therapy (group B). Wound secretion was obtained on the first, third and fifth postoperative days and exposed to the test bacteria, Staphylococcus aureus and Staphylococcus epidermidis. Patients in group A underwent systemic antibiotic treatment with cefuroxime administered intravenously at a dose of 1.5 g every 8 hours. Patients in group B did not receive antibiotics. Cefuroxime concentrations were determined using high-performance liquid chromatography (HPLC). Antibacterial activity was determined using the inhibition test. Maximum cefuroxime concentrations in wound secretion were measured at 4-5 hours following intravenous administration and, with a mean concentration of 10 mg/l, remained consistently above the minimum inhibitory concentration (MIC) for the test bacteria at all points during the measurement period. As expected, the antibacterial activity of the wound secretion in patients in group A (cefuroxime) was higher than that in group B (no antibiotics). In group A, antibacterial activity against S. aureus was 94.6% and 100% against S. epidermidis. In group B, antibacterial activity against S. aureus was 61% and 81% against S. epidermidis. Cefuroxime reaches the highest level in wound secretion after 4 hours. The high antibacterial activity of the wound secretion in traumatic closed fractures is elevated by cefuroxime. in addition, our findings show that vacuum therapy of wounds is suitable as a non-invasive method for studying the pharmacokinetics of antibiotics.

Sensitisation to Ambrosia in Switzerland: a public health threat on the wait.

BACKGROUND: Ambrosia artemisiifolia (short name = Ambrosia common ragweed) pollen is a potent allergen and has recently been found in Switzerland, spreading from the southwest of the country. The aim of this study is to describe Ambrosia sensitisation rates in the population-based SAPALDIA cohort (Swiss Study on Air Pollution And Lung Diseases In Adults) and to test whether an increase in these rates could be observed. METHODS: Among the 6345 participants from 8 areas who provided blood samples in 1991 and 2002, 5823 had valid results for specific IgE against common inhalant allergens tested with Phadiatop. In 2002 Ambrosia sensitisation was measured and positive tests were analysed for Artemisia vulgaris (mugwort). Blood samples taken in 1991 in Ticino and Geneva were also tested for Ambrosia. RESULTS: Sensitisation rate (Phadiatop) did not increase significantly between the two surveys and sensitisation was found in 30% of the participants. A proportion of 7.9% showed specific IgE to Ambrosia pollen. The sensitisation rate in Lugano and Geneva had not changed substantially since 1991. Among those sensitised to Ambrosia 82% also showed specific IgE against Artemisia, suggesting a high rate of cross-reactivity. Only 1.3% were sensitized to Ambrosia alone. The incidence of asthma or hay fever in participants with specific IgE to Ambrosia pollen was not higher than in the general study population. CONCLUSION: Currently Ambrosia pollen does not appear to be an important cause of inhalant allergies in Switzerland. Sensitisation rates are low and have not increased since 1991. Due to cross-reactivity Ambrosia sensitisation may be a consequence of primary sensitisation to Artemisia. Elimination of Ambrosia plants is nevertheless mandatory to avoid a future increase.

[Will broken glass bring luck?]. / Bringen Scherben Glück?

A 56 year old female patient presented to the emergency room because of a progressive, painful swelling of her thigh, clinically suspected to be a haematoma. Trauma was denied. Ultrasonography revealed a hyperechogenic structure, which appeared to be an intramuscular foreign body on computed tomography. Intraoperatively, a large piece of glass was found. Glass foreign bodies can be detected by x-rays with a high sensitivity. The threshold to order x-ray for the detection of glass foreign bodies should be low.

[Maxillary sinus infection with emphysema of the head as a "red herring" in steroid associated colon perforation]. / Kieferhöhleninfekt mit Kopfemphysem als "red herring" bei Steroid-assoziierter Kolonperforation.

Steroid therapy increases the risk of bowel perforation. Bowel perforation may occur at any time of steroid therapy, but the first weeks appear to hold the greatest potential for perforation. However, clinical findings after perforation may be misleading under steroids, and peritonitis may be absent. It is known that bowel perforation can lead to subcutaneous emphysema at various sites. Thus, in any patient with emphysema, bowel perforation must be included in the differential diagnosis, especially in patients receiving steroids. Missing knowledge of this entity may lead to marked delay between onset of initial signs and diagnosis, and hence worsen the survival rate. In this report we present a case of chronic steroid use, where asymptomatic sigma perforation led to a generalized emphysema, which was initially attributed to a maxillary sinus infection due to Aspergillus and anaerobic bacteria.

Absence of anti-hepatitis B surface antibody after vaccination does not necessarily mean absence of immune response.

A small number of subjects vaccinated against hepatitis B do not produce anti-hepatitis B surface (HBs) antibody levels detectable by commercial assays. Others lose detectable anti-HBs at some time after vaccination. The absence of clinical hepatitis despite potential exposure to hepatitis B virus (HBV) in both kinds of subjects suggests that they might be protected by low antibody levels. However, besides anti-HBs, T helper response and memory cells which may be induced by the vaccine are certainly also important for immunity against HBV. In the present study, samples from vaccinated subjects, found to be anti-HBs negative in an initial assay, subsequently showed positive results in, respectively, 25%, 36% and 38% of the cases, when a second, third and fourth assay was used. In addition, 360 samples from "nonresponders" and from vaccinees who had lost anti-HBs, the reactivity of which was under the enzyme-linked immunoassay-cut-off value were compared to that of nonvaccinated controls. The absorbances were found to be significantly higher in the nonresponders (0.038) and in the vaccinees having lost anti-HBs (0.041), than in the controls (0.025). Such findings contribute to explaining why so-called nonresponders as well as vaccinees who have lost anti-HBs nevertheless appear to be protected.

Presence of low levels of anti-HBs antibody in so-called 'anti-HBc alone' subjects.

BACKGROUND/AIMS: The 'anti-Hbc alone' pattern could sometimes be that of subjects who produced anti-HBs after recovery, but at a lower level than that detectable using commercial assays. This study aimed to test this hypothesis. METHODS: A total of 104 'anti-HBc alone' serum samples, i.e.positive for the anti-HBc antibody but not for HBsAg nor for anti-HBs antibody, were recruited when routine testing a broad population of employees, patients and pregnant women from a university hospital. A possible subliminal anti-HBs production, that would have escaped detection by commercial EIAs, was investigated by comparing the optical densities (ODs) obtained in vaccinees (commercial anti-HBs EIA) to those of a control group of 100 nonimmunised and nonvaccinated subjects. RESULTS: The median OD was significantly higher (p<0.0001) in the 'anti-HBc alone' subjects (OD=0.035) than in the controls (OD=0.023). Thirty-six percent of the 'anti-HBc alone' subjects had an anti-HBs OD higher than the median OD of the controls+2SD. 'Anti-HBc alone' subjects with anti-HBe antibody had higher anti-HBs ODs (0.041) than had those without anti-HBe (0.029). In 'anti-HBc alone' subjects, the anti-HBs ODs, although under the cut-off value of the EIA, were found to be higher than in the controls. CONCLUSION: Our results show low anti-HBs production in some of the subjects studied.

Comparison of the reactogenicity and immunogenicity of a two injection combined high-dose hepatitis A and hepatitis B vaccine to those of Twinrix.

Twinrix (SmithKline Beecham Biologicals) is a combined hepatitis A and B vaccine licensed with a three-dose schedule. A two-dose combined hepatitis A and B vaccine would facilitate immunisation programs. In this prospective study, 100 healthy adults, aged between 18 and 40, were enrolled. A first group of 50 was given a high-dose vaccine at month 0 and 6. A second group of 50 received Twinrix at month 0, 1 and 6. The reactogenicity was assessed after each vaccine dose. There were no severe local adverse events. Seven severe systemic reactions occurred, of which five were fatigue, one was headache and one consist in gastrointestinal symptoms. They all resolved during the 4-day follow-up period. One serious general adverse event was reported, but was clearly unrelated to the vaccine. Thus, both vaccines were well tolerated. The immunogenicity was evaluated by testing for anti-HBs and anti-HAV antibodies. Seroconversion rates and geometric mean titres (GMTs) were compared. At month 7, the anti-HAV GMTs were higher in the high-dose group than in the Twinrix group and, inversely, the anti-HBs GMTs were slightly higher in the Twinrix group than in the high-dose group. At month 7, all subjects in both groups were positive for anti-HAV. All subjects in the high-dose group and 97.6% subjects in the Twinrix group had seroconverted for anti-HBs. Therefore, it can be concluded that with two injections of the high-dose hepatitis A and B vaccine, 6 months apart, a similar immune response can be obtained as induced with three doses of Twinrix at months 0, 1 and 6.

Decrease in the prevalence of hepatitis B and a low prevalence of hepatitis C virus infections in the general population of the Seychelles.

A serological survey of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections was carried out on a random sex- and age-stratified sample of 1006 individuals aged 25-64 years in the Seychelles islands. Anti-HBc and anti-HCV antibodies were detected using commercially available enzyme-linked immunosorbent assays (ELISA), followed by a Western blot assay in the case of a positive result for anti-HCV. The age-adjusted seroprevalence of anti-HBc antibodies was 8.0% (95% CI: 6.5-9.9%) and the percentage prevalence among males/females increased from 7.0/3.1 to 19.1/13.4 in the age groups 25-34 to 55-64 years, respectively. Two men and three women were positive for anti-HCV antibodies, with an age-adjusted seroprevalence of 0.34% (95% CI: 0.1-0.8%). Two out of these five subjects who were positive for anti-HCV also had anti-HBc antibodies. The seroprevalence of anti-HBc was significantly higher in unskilled workers, persons with low education, and heavy drinkers. The age-specific seroprevalence of anti-HBc in this population-based survey, which was conducted in 1994, was approximately three times lower than in a previous patient-based survey carried out in 1979. Although there are methodological differences between the two surveys, it is likely that the substantial decrease in anti-HBc prevalence during the last 15 years may be due to significant socioeconomic development and the systematic screening of blood donors since 1981. Because hepatitis C virus infections are serious and the cost of treatment is high, the fact that the prevalence of anti-HCV antibodies is at present low should not be an argument for not screening blood donors for anti-HCV and eliminating those who are positive.

PIP: This study examined the prevalence of anti-hepatitis Bc virus (HBc) and anti-hepatitis C virus (HCV) antibodies in a random sex- and age-stratified sample of 1006 individuals aged 25-64 years in the Seychelles. The anti-HBc and anti-HCV antibodies were detected using an enzyme-linked immunosorbent assay, followed by a Western blot assay in the case of a positive result for anti-HCV antibodies. Findings revealed that the age-adjusted prevalence of anti-HBc antibodies was 10.4% and 5.8%, respectively, among men and women aged 25-63 years. The presence of anti-HBc antibodies was associated significantly with employment, educational level, and alcohol intake, marginally with economic status, and not at all with ethnic origin. 2 men and 3 women were positive for anti-HCV antibodies, with an age-adjusted seroprevalence of 0.34%. 2 out of these 5 subjects who were positive for anti-HCV antibodies were also positive for anti-HBc antibodies. The age-specific seroprevalence of anti-HBc antibodies in this population study conducted in 1994 was approximately 3 times lower than in a previous patient-based survey carried out in 1979. Although there were methodological differences between the two surveys, it is likely that the substantial decrease in the anti-HBc antibody prevalence during the last 15 years may be due to significant socioeconomic development and the systematic screening of blood donors since 1981.

Does hepatitis B virus (HBV) genotype influence the clinical outcome of HBV infection?

Between 5 and 10% of adults infected with the hepatitis B virus (HBV) develop a chronic infection lasting longer than 6 months, which may lead to advanced liver disease. HBV can be classified into six genotypic families: A, B, C, D, E and F, but only genotypes A and D are significantly represented in western Europe, where they account for some 90% of cases of infection with HBV. In the present study, we investigated a possible association between HBV genotype A or D and clinical outcome of the infection. We compared the prevalence of these genotypes in a group of patients with chronic active hepatitis to that of a group with acute resolving hepatitis. In patients with chronic active hepatitis, genotype A was found in 28 of 35 patients and genotype D in only four. The remaining three patients were infected with genotype non-A, non-D. In contrast, genotype D was found in 24 of 30 patients with acute hepatitis, whilst genotype A was found in only three patients of this group. Three were infected with genotype non-A, non-D. Our results show a clear association between genotype A and chronic outcome (Ficher's exact test: two-sided P-value, P < 0.0001). They suggest that HBV genotypes may play a role in the virus-host relationship. Possible mechanisms for such a role are discussed.

Multicenter evaluation study on a new HEp2 ANA screening enzyme immune assay.

The COBAS Core HEp2 ANA enzyme immune assay (EIA) was evaluated in a precision and a clinical sample study in comparison to indirect immunofluorescence assay (IFA) on HEp2-cells. In the precision study the COBAS Core EIA yielded intraassay coefficient variations (CVs) mostly below 9%, and interassay CVs between 4.7% and 10.4%. When comparing the COBAS Core EIA to IFA, the results corresponded well in healthy subjects, systemic lupus erythematosus, mixed connective tissue disease and rheumatoid arthritis. In the case of Sjögren's syndrome and scleroderma patients the COBAS Core EIA yielded a lower rate of positive results compared to IFA. This discrepancy may be explained by the lack of detection of autoantibodies to nuclear antigens that can be identified only by IFA due to their compartmentalization and higher localized antigen density in HEp2 cells. The discrepancies in the group of dermato/polymyositis patients are due to the fact that the EIA contains mainly nuclear antigens and was able to detect only antibodies against the cytoplasmic Jo1 antigen that was added to the HEp2 nuclear extract. Routine sera were also evaluated; good agreement was found in sera from patients attending tertiary reference centres for autoimmune diseases but a higher number of discrepancies was reported in sera from unselected populations.

The first combined vaccine against hepatitis A and B: an overview.

Hepatitis A and B infections are prevalent world-wide and are a significant cause of morbidity and mortality. A vaccine providing dual protection against hepatitis A and B is now available (Twinrix, SmithKline Beecham Biologicals). Six pivotal vaccine trials, involving 843 healthy adults, aged between 17 and 60 years and vaccinated following a 0, 1, 6 month schedule are discussed. At month 2 more than 99% of the vaccinees were seropositive for anti-HAV and 84% were protected against hepatitis B. The third dose induced a 12-fold increase in geometric mean titres (GMTs) to 5404 mIU/ml. One month after completion of the vaccination course nearly all vaccinees had protective titres against hepatitis B with a GMT of 4818 mIU/ml. Long term follow-up data until month 48 is available for two studies. At month 48 all 129 vaccinees sampled were still positive for anti-HAV antibodies and > 95% were still protected against hepatitis B. The combined hepatitis A and B vaccine Twinrix proves to be consistently safe, well tolerated and highly immunogenic and compares well with serological responses reached with monovalent vaccines. This combined hepatitis A and B vaccine offers more convenience, potentially better compliance and lower administration costs.

Mutations in the basal core promoter and precore/core gene of hepatitis B virus in patients with chronic active but not acute hepatitis B.

Around 5-10% of adults infected with hepatitis B virus (HBV) develop a chronic liver disease such as chronic active hepatitis (CAH), and it is unclear whether the clinical outcome depends solely on the immune response or whether viral factors also play a role. In this study, a search was therefore made for nucleotide mutations in the basic core promoter (BCP) and amino-acid substitutions in the precore/core region of HBV infecting patients with CAH or with acute hepatitis. The nucleotide sequences of the BCP and of the precore/core region were determined in virus from ten patients with CAH and ten with acute hepatitis. The precore/core sequences were also analysed in 14 additional patients (6 with CAH, 8 with acute hepatitis). In seven of the ten patients with CAH, five types of mutations were found in the BCP. Deletions in the precore/core region were observed in six patients. In all six patients where only the precore/core region was studied, amino-acid substitutions were present. In contrast, in the ten patients with acute hepatitis studied for BCP, a mutation was found in the BCP of one patient only. Of the 18 patients in whom the precore/core was studied, three had an amino-acid substitution in this region. The results show a clear link between CAH and both HBV BCP and precore/core region mutations, suggesting these mutations may play a role in the persistence of HBV infection.

[Hepatitis B virus and pathogenesis]. / Hepatitis-B-Virus und Pathogenese.

The hepatitis B virus belongs to the hepadna viruses family. Its genome consists of an incompletely double stranded DNA. The preS/S domain encodes proteins which make up the outer viral coat containing the HBs surface antigen (HBsAg). Other viral genes programme for structures inside the virus and for various regulatory enzymes. HBV mainly infects hepatocytes. The virus replicates in the cytoplasm and is primarily non-cytopathogenic. HBV can also integrate into the host cell. Various stable genotypes and subtypes are known, which have a characteristic geographic distribution. They all share a common HBsAg epitop, which has allowed the development of a vaccine which is efficient world-wide. The protective principle consists of inducing protective anti-HBs. The infected cell has to be destroyed to eliminate the virus. Cellular immune defence mechanisms are mainly relevant, the principle effectors being cytotoxic T lymphocytes, activated monocytes/macrophages and cytokines such as interferon-gamma. The natural course of infection is highly variable, comprising viral elimination with or without acute hepatitis and chronic infection which might lead to chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. This is due to the balance respectively to the inbalance between the viral replication capacity and the immune defence mechanisms.

[Serologic diagnosis and follow-up of hepatitis B]. / Serologische Diagnose und Verlaufsbeurteilung der Hepatitis B.

This paper is a short summary on the usefulness of two antigens (HBsAg and HBeAg), three antibodies (anti-HBc, anti-HBe and anti-HBs) and of HBV DNA, as markers for the diagnosis and the follow-up of hepatitis B. The significance of each of these markers at the various stages of disease history, a few patterns of co-existence of some of these markers and the occurrence of mutations in the core and pre-core regions of the genome are also described. The various indications for measuring HBV DNA, in addition to the classical serological markers, are also mentioned.