Lower-than-standard dose peg-IFN alfa-2a for chronic hepatitis C caused by genotype 2 and 3 is sufficient when given in combination with weight-based ribavirin.

Mono-therapy with pegylated interferon (peg-IFN) has shown that a lower-than-standard dose yields the same sustained viral response (SVR) rates as standard doses for chronic hepatitis C virus (HCV) infection caused by genotypes 2 or 3. Our aim was to see if a fixed, lower-than-standard dose of peg-IFN alfa-2a (135 microg weekly) in combination with ribavirin 11 mg/kg daily for 24 weeks yields sufficient SVR rates for genotypes 2 or 3. Hundred consecutive patients with a mean age of 44 years (range 20-69 years), 59 with genotype 3 and 41 with genotype 2, were studied. Rapid viral response (RVR) with HCV-RNA <15 IU/mL at treatment week 4 and SVR were calculated. RVR was achieved by 28/40 (70%) patients with genotype 2 and 41/58 (71%) with genotype 3. Significantly more genotype 2 patients with RVR achieved SVR 27/28 (96%) than genotype 2 patients who failed to achieve RVR, 8/12 (66%), P = 0.009. The corresponding figures for genotype 3 patients were 39/41 (95%) vs 11/17 (65%), respectively, P = 0.002. In total, SVR was achieved by 35/41 (85%) patients with genotype 2 and 51/59 (86%) patients with genotype 3, respectively. We found that 135 microg peg-IFN alfa-2a weekly was sufficient for treatment of genotype 2 and 3 chronic hepatitis C when combined with RBV dosed daily according to body weight. This combination yielded high SVR rates (85-86%) and may be cost-saving.

Chronic fatigue syndrome differs from fibromyalgia. No evidence for elevated substance P levels in cerebrospinal fluid of patients with chronic fatigue syndrome.

Levels of substance P were determined in the cerebrospinal fluid (CSF) in 15 patients with chronic fatigue syndrome (CFS). All values were within normal range. This is in contrast to fibromyalgia (FM). The majority of patients with FM have increased substance P values in the CSF. The results support the notion that FM and CFS are different disorders in spite of overlapping symptomatology.

HBcAg induced T-cell independent anti-HBc production in chronic HBsAg carriers.

The capacity of the nucleocapsid protein of HBV to function as a T-cell independent antigen in man was studied. When T-cell depleted B-cell cultures were challenged with E coli-derived HBcAg, anti-HBc production was registered in culture supernatants from the majority of chronic HBsAg carriers in a quiescent stage of disease. In contrast, similarly prepared and stimulated cultures from donors with natural acquired immunity to hepatitis B or HB-susceptible controls were non-responsive. Addition of autologous T-cells effectively restored anti-HBc responsiveness in T-cell depleted B-cell cultures from HB-immune donors, demonstrating the T-cell dependency for anti-HBc induction in natural HBV-infection.

Low levels of serum acylcarnitine in chronic fatigue syndrome and chronic hepatitis type C, but not seen in other diseases.

Recently, we found a serum acylcarnitine (ACR) deficiency in Japanese patients with chronic fatigue syndrome (CFS). To clarify whether this ACR abnormality is a characteristic of CFS or not, we also studied the levels of serum carnitine in Swedish subjects. Both serum ACR and free carnitine (FCR) levels in normal healthy subjects were quite different between Japanese (n=131) and Swedish people (n=46) (p<0.001). However, it is confirmed that Swedish patients with CFS (n=57) also had serum ACR deficiency (p<0.001). When we studied the levels of serum ACR and FCR in Japanese patients with various kinds of diseases (CFS, hematological malignancies, chronic pancreatitis, hypertension, diabetes mellitus, chronic hepatitis type C, psychiatric diseases), a significant decrease in the levels of serum ACR was only found in patients with CFS and chronic hepatitis type C (p<0.001). Therefore, we concluded that ACR deficiency in serum might be a characteristic abnormality in only certain types of diseases.

Heterosexual contact as a major route for transmission of acute hepatitis B among adults.

Possible routes for transmission of acute hepatitis B were studied retrospectively in 78 consecutive adult patients seen at the Department of Infectious Diseases, Roslagstull Hospital in Stockholm. Sexual transmission was found to be a major route of transmission, being more common than intravenous drug abuse. A single possible route of transmission was found in 66/78 (84%) patients. Eleven of the 78 patients (14%) had two possible routes, sexual contact being one. Overall sexual contact possibly accounted for 53% of all cases of hepatitis B, homosexual contact being responsible for only 10%. Cases reported earlier as being of unknown origin or associated with a recent visit abroad or to be 'social contact cases' are probably most often due to heterosexual transmission. Seven patients (9%) were heterosexually infected by persons who had been recently receiving medical care for hepatitis B. Seven sexually transmitted cases of acute clinical hepatitis B secondary to the patients studied were seen also. These findings show that sexual transmission, mainly heterosexual, is a major route for transmission of hepatitis B in a western society. They also emphasise the importance of taking an adequate sexual history as a prerequisite for providing effective prophylaxis for sexual partners of patients with acute hepatitis B.

Smoking, plasma antioxidants and essential fatty acids before and after nutratherapy.

OBJECTIVE: To study the effect of smoking on plasma antioxidants with and without antioxidant vitamin nutratherapy. DESIGN: Chronic smokers (n = 10, 16 +/- 4 cigarettes a day) and nonsmokers (n = 17) of both sexes were recruited from patients with arthritis-like symptoms. After baseline studies of plasma antioxidant vitamins Q (ubiquinone) and E (alpha-tocopherol) and essential fatty acids (EFA, vitamin F), three months' nutratherapy with vitamins Q (90 mg) and E (350 mg) was administered and plasma reanalyzed. RESULTS: No sex differences were seen in smoking habits or plasma nutrients. Smokers had normal Q (0.71 +/- 0.07 mg/L) but depressed E (9.4 +/- 0.6 mg/L, P < 0.01). EFA were the same in both groups. Nutratherapy increased Q by about 90% in both groups and E by 47% in smokers and 101% in nonsmokers (P < 0.01). In nonsmokers, nutratherapy protected omega-3 fatty acids (vitamin F1)-plasma docosahexaenoic acid increased by 39%. The vitamin F index (omega-6:omega-3, ratio) remained unchanged in the smokers but decreased in the nonsmokers and became related to the individual plasma vitamin Q but not to vitamin E. CONCLUSIONS: There was no difference between smokers and nonsmokers before nutratherapy. Nonsmokers may have suffered from passive smoking. After nutratherapy the quantitatively most important antioxidant, ie, vitamin E, increased more in nonsmokers than in smokers. This resulted in less vitamin F1 peroxidation. Nutratherapy cannot overcome disadvantages associated with smoking. Nonsmokers might achieve an antioxidant protection with nutratherapy, which could mean a possible reduced risk of developing cardiovascular disease.

Hepatitis B seroprevalence in persons attending youth clinics in Stockholm, Sweden in 2008.

Sweden is a low endemicity country for hepatitis B virus (HBV). The previously reported prevalence of chronic HBV is <1% and of overall markers <5%. HBV is not included in the universal childhood vaccination programme. Instead, selected high-risk groups are targeted. Our aim was to examine the HBV seroprevalence in youth clinic clients in Stockholm and identify if this population might be a new target group for vaccination. In total, 515 clients aged 18-22 years were recruited. They completed a risk-assessment questionnaire and 464 (90%) had a serum specimen tested for HBV serology. Chronic HBV was found in 0.6% and 0.9% had previously been infected with HBV. A seroprevalence of 1.8% HBV markers was found among non-vaccinated persons. This is lower than reported from other countries and not different from the general population in Sweden. However, in persons originating from HBV endemic countries (n = 123), the prevalence was higher, 6.5%. Only 14% were vaccinated and the majority hence susceptible to HBV. The target groups are not reached by the present vaccination strategy. Youth clinics are ideal settings for catch-up vaccination.

Chronic hepatitis B. Impact of hepatitis D virus superinfection and the hepatitis B e-system on histological outcome, and correlation of the hepatitis B e-system to HBV-DNA in serum.

Chronic evolution after acute hepatitis B virus infection. During a 13 months period 1977-1978 a total of 129 cases of acute viral hepatitis type B occurred among patients who were admitted with hepatitis to Roslagstull, Hospital, Stockholm, Sweden. Less than 1% progressed to chronicity. Prevalence of Delta superinfection was studied among 60 patients with chronic hepatitis B. Nineteen (32%) were anti-delta positive. The majority of the positive patients were either non-European immigrants or addicts, both 9/19 (47%). Infections with the delta agent was found to have occurred in Stockholm already in the early 1970s. Rate of HBeAg clearance during chronic HBV was studied among 36 HBeAg positive patients. Seroconversion to anti-HBe was noted in 17 patients (47%), whereas HBeAg persisted in 19 during a mean follow-up period of 53 months. The spontaneous annual HBeAg seroconversion rate was 11%. HBeAg clearance occurred as frequently among homosexual men as among patients in other categories. However, 12/14 homosexual men were HBeAg positive after 2 years follow-up, compared with 1/13 drug addicts. Thus, homosexual men seemed to require a longer time for HBeAg seroconversion than i.v. drug addicts. HBV-DNA in serum, a strong indicator of viral particles and infectivity was analysed among patients with HBeAg seroconversion, initial HBeAg negativity and/or delta superinfection. HBV-DNA was found in 75-80% of our HBeAg positive patients. A correlation between chronic liver disease and presence of HBV-DNA in serum was also found. Thus, HBV DNA was found in 63% of patients with CAH or CAH/CI as compared with only 39% of patients with CPH. Delta infected patients had HBV-DNA more often than those without hepatitis D infection. Seven delta infected, anti-HBe positive, patients were still HBV-DNA positive five to eight years later. Therefore delta infected anti-HBe positive patients can be infectious for prolonged periods. Histological outcome. 63% (12/19) anti-delta positive patients were classified as CAH with or without cirrhosis as against 39% (16/41) of the anti-delta negative patients. Eleven of 15 homosexual men (73%) had histological findings classified as CAH or CAH/CI. None of them were superinfected with HDV. Thus homosexual men developed severe hepatic lesions without being delta infected. In contrast 78% (7/9) i.v. drug addicts with CAH were delta infected. A numerical scoring system was applied and compared with conventional morphological classification of liver histology to assess the histological outcome of 42 patients with repetitive liver biopsies.

Lyme borreliosis--an overdiagnosed disease?

Ninety-nine patients who were referred to a clinic for infectious diseases on suspicion of Lyme borreliosis and whose major symptoms were fatigue, headache, myalgia and arthralgia were studied retrospectively to find out if there was any difference in symptomatology between patients who were seropositive or seronegative to Borrelia burgdorferi. 64/82 (78%) patients remembered one or more tick bites during previous years and 32/74 (43%) patients had a history of erythema migrans. Fatigue, headache, myalgia and arthralgia occurred in 84%, 72%, 54%, and 63% of the patients, respectively. 62/99 (63%) patients had an elevated IgM and/or IgG antibody titer to B. burgdorferi. There was no difference in frequency of symptoms between seropositive and seronegative individuals. 48/99 (49%) patients were treated with antibiotics, mostly oral doxycycline. Only 50% were improved after treatment. On follow-up 2 to 4 years after the first visit, 40% of the patients had recovered completely, 31% were improved, 24% reported unaltered symptoms and four patients were impaired. There was no difference in symptoms on follow-up between seropositive or seronegative patients. It is concluded that there probably is an overdiagnosis of Lyme borreliosis and that better microbiological methods are needed to confirm active disease.

The application of a numerical scoring system for evaluating the histological outcome in patients with chronic hepatitis B followed in long-term.

A numerical scoring system was applied and compared with conventional histological classification to assess the histological outcome in 42 patients with chronic hepatitis B followed for 16 to 162 months (mean = 75 months). Four histological categories in the biopsies were assessed and scored: (i) piecemeal necrosis; (ii) lobular necrosis; (iii) portal inflammation, and (iv) fibrosis and cirrhosis. The sum of all four categories was defined as the "Histological Activity Index." Altogether, 102 liver specimens, including 2 to 4 repeats from each patient, were investigated. A good correlation was noted between a high value of the Histological Activity Index score and several liver histology as monitored by conventional terminology for chronic hepatitis. Among patients with HBeAg persistence, 8 of 14 (57%) deteriorated during follow-up as judged by an increase in the Histological Activity Index score compared to 3 of 13 (23%) of the patients with HBeAg seroconversion (0.5 less than p less than 0.1). Piecemeal necrosis has been postulated to be a predictive marker for the eventual development of cirrhosis. Here, we found that a low score for piecemeal necrosis in the initial liver biopsy was significantly less predictive of a high fibrosis score in the follow-up biopsy than was a high score for initial piecemeal necrosis (p less than 0.001). It is concluded that the scoring system used can be applied to monitor the histological long-term follow-up, especially when separated into its four constituent categories. It also offers a means of predicting a chronic hepatitis outcome.

Aseptic meningoencephalitis in adults: liberal or restrictive treatment?

39 adult patients suffering from aseptic meningoencephalitis were admitted to hospital during April-December 1976 and were divided into 2 groups, according to birth date. One group (n = 24) was treated with bed rest in the febrile stage and recommended to avoid for some weeks activities that promote headache. The other group (n = 15) was encouraged to resume daily life as soon as possible. No pertinent difference was found between the groups in admission. The patients were followed for 9 months by questionnaires and registration of sick leave. The average number of days away from work was 32 in the "restrictive" and 15 in the "liberal" group. No untoward effects were found from a shorter sick leave and a rapid resumption of normal physical activity.

Acute hepatitis B and hepatitis D co-infection in the Stockholm region in the 1970s and 1980s--a comparison.

The frequency and clinical features of acute hepatitis B virus (HBV) infection with and without a hepatitis D virus (HDV) co-infection was investigated retrospectively in the Stockholm region during two different time periods, September 1977-October 1978 and November 1984-October 1986. Totally, 31/229 (14%) patients with acute HBV infection had a HDV co-infection. No change in the frequency of co-infections, 12% and 15%, respectively, was observed between the 1970s and 1980s. Among the 31 HDV co-infected patients 74% were intravenous drug addicts. Totally 23/66 (35%) intravenous drug addicts with acute HBV infection had HDV co-infection. Clinically a biphasic rise of the serum levels of alanine aminotransferase and bilirubin was noted among 63% of the HDV co-infected patients but only among 8% of the solely HBV infected patients (p less than 0.001). A clinically more severe hepatitis was seen significantly more often among the HDV co-infected patients than among the solely HBV infected.

IgG subclasses in circulating immune complexes with hepatitis B e antigen in chronic hepatitis B.

IgG subclasses of antibodies to hepatitis B e antigen (anti-HBe) complexed to HBeAg were determined in 126 HBsAg-positive sera. In the assay HBeAg complexes were bound to microtitre plates by monoclonal anti-HBe and indicated by biotinylated monoclonals to each of the four human IgG subclasses. To evaluate the specificity of the complexed IgG, serum dilutions were also tested for HBeAg and for subclasses of anti-HBe IgG. Two groups of sera were investigated: (i) 64 sera from 64 HBsAg carriers; and (ii) 62 sera from 13 HBeAg-positive patients, of whom five seroconverted to anti-HBe. At least four sera were available from each of these patients. Complexed anti-HBe IgG was detected in 22 of 30 HBeAg-positive, and in three of HBeAg-negative carrier sera. There was no significant association between presence of complexed anti-HBe and levels of HBeAg in these sera. Complexes with multiple subclass composition were found in 13 of the 25 sera with complexed anti-HBe. The most common IgG subclasses found complexed to HBeAg were IgG1 (75%) and IgG4 (67%). A significant association (P less than 0.05) was found between the presence of free and complexed anti-HBe IgG1 in the carrier sera, indicating that the IgG1 antibodies, complexed to HBeAg, were specific for HBeAg. In the five patients who seroconverted to anti-HBe, anti-HBe IgG1 was detected in the HBeAg-positive phase before seroconversion. In the eight patients with persistent HBeAg antigenemia, free anti-HBe IgG1 was detected in only two sera from two different patients. In one patient, complexed anti-HBe IgG1/IgG4 was detected in all serum samples drawn during a period of 111 months. In conclusion, complexed anti-HBe might be detected several years before apparent seroconversion to anti-HBe in conventional anti-HBe assays. In contrast 'free' anti-HBe IgG1, when detected in HBeAg-positive sera with our anti-HBe subclass assay, seemed to signal ensuing apparent seroconversion to anti-HBe.

A 10-year follow-up study of tick-borne encephalitis in the Stockholm area and a review of the literature: need for a vaccination strategy.

143 people treated for tick-borne encephalitis (TBE) were included in a retrospective follow-up study. Sequelae and epidemiological characteristics in 114 individuals were analysed. The case fatality rate and the prevalence of residual paresis were low, 1.4 and 2.7%, respectively. However, 40 (35.7%) individuals were found to have a postencephalitic syndrome after a median follow-up time of 47 months, and a majority (77.5%) of these were classified as moderate to severe. Various mental disorders, balance and co-ordination disorders and headache were the most frequently reported symptoms. Increasing age was correlated to a longer duration of hospital stay, longer convalescence and increased risk of permanent sequelae. Results from a neuropsychiatric questionnaire showed marked differences between the subjects with sequelae compared to controls. 57% had noticed a tick bite before admission, and 48% were aware of at least one person in their environment who previously had contracted TBE. 79% were permanent residents or visited endemic areas often and regularly. In conclusion, we have found that TBE in the Stockholm area has a low case fatality rate, but gives rise to a considerable number of different neurological and mental sequelae, which justifies vaccination of a defined risk population in endemic areas.

Utility of an anonymous questionnaire for the identification of a primary transmission route and possible secondary transmission in adults with acute hepatitis B virus infection.

By letting adults with acute hepatitis B virus (HBV) infection answer an anonymous questionnaire covering risks associated with the acquisition and further transmission of HBV infection, we found that a likely relevant transmission route could be identified in most patients. Despite being informed of the diagnosis, 50% of the patients exposed others via sexual contact during their contagious period.

Delta infection among patients with chronic hepatitis B in the Stockholm region.

The prevalence, epidemiology and consequences of delta infection were analysed in 60 patients attending the Roslagstull Hospital for Infectious Diseases, Stockholm, Sweden, between 1972 and 1982. All of the patients had biopsy-documented chronic hepatitis B. Using radioimmunoassay techniques, sera from all patients were tested for antibodies to hepatitis A virus, for hepatitis B surface antigen and the corresponding antibody, for antibodies to hepatitis B core antigen, for hepatitis B e antigen and the corresponding antibody and for antibodies to delta antigen. All 60 patients underwent a liver biopsy which was repeated in 28 patients. 32% of the patients (19/60) were found to be anti-delta positive. The majority of the anti-delta positive patients were either immigrants from non-European countries or addicts (both 9/19 or 47%). Infections with delta agent were found to have already occurred in the Stockholm region in the early 1970s. During the study period, four of the patients developed clinical and laboratory signs of acute hepatitis in association with a delta infection. Among the anti-delta positive patients, 63% (12/19) were classified as having chronic active hepatitis, with or without cirrhosis, as against 39% (16/41) of the anti-delta negative patients. Histological progression to cirrhosis was observed in two of the four anti-delta positive patients with initial chronic active or chronic persistent hepatitis.

Alterations of transforming growth factor beta1 (TGF-beta1) and TGFbeta receptor expressions with progression in Dunning rat prostatic adenocarcinoma sublines.

Transforming growth factor-beta1 (TGF-beta1) inhibits epithelial cell proliferation in the normal prostate. Prostate tumours express high levels of TGF-beta1, and seem to acquire resistance to its anti-proliferative effects with tumour progression. In this study, TGFbeta variations with tumour progression were examined in the Dunning prostatic adenocarcinoma model. Expression of TGF-beta1 and TGFbeta receptor type I and type II (TGFbeta-RI and TGFbeta-RII) in rat dorsolateral prostate (DLP) and Dunning tumour sublines (PAP, AT-1, AT-2, AT-3 and MatLyLu) was examined in vitro and in vivo, using competitive reverse transcription-polymerase chain reaction (RT-PCR), Northern and Western blot, and immunohistochemistry. All tumours expressed elevated levels of TGF-beta1 and TGFbeta-RI mRNA, when compared with the DLP (P < or = 0.05). All tumours except MatLyLu also expressed elevated levels of TGFbeta-RII mRNA (P < or = 0.05). Interestingly, TGFbeta-RII protein levels were very low in the highly metastatic AT-3 and MatLyLu tumours in vivo, when compared with levels in the PAP, AT-1, and AT-2 tumours. This difference was not detected for the AT-1, AT-2, and AT-3 cells in vitro. Immunostaining of TGF-beta1, TGFbeta-RI, and TGFbeta-RII was localised principally in normal and tumour epithelial cells, and occasionally in smooth muscle cells. In conclusion, high expression of TGF-beta1 and TGFbeta-RI and low expression of TGFbeta-RII may contribute to tumour progression and metastasis in the Dunning prostatic adenocarcinoma model.

Critical life events, infections, and symptoms during the year preceding chronic fatigue syndrome (CFS): an examination of CFS patients and subjects with a nonspecific life crisis.

OBJECTIVE: The purpose of this study was to describe the sequence of psychosocial events and infections preceding the onset of chronic fatigue syndrome (CFS). This information was related to the temporal development of crucial symptoms in relation to the onset of, namely, fatigue, sadness, irritability, pain, and feeling of fever. METHODS: A personal interview was conducted in 46 patients (mean age, 39.5 years; SD, 9 years) who fulfilled international CFS criteria. These patients were matched with regard to age and gender to 46 carefully matched control subjects. Twenty-three percent of the study subjects were men, and 77% were women. The patient at first identified the month that coincided with the onset of CFS. Similarly, each control subject was asked to identify a "very difficult period" within approximately the same period as the patient with whom the control subject was matched. A list of 14 different life events was perused. Participants were asked to identify for each month whether each of the listed events had occurred. Furthermore, they were asked to rate the importance of the events they had experienced. In addition, for each of the cardinal symptoms (fatigue, sadness, irritability, pain, and feeling of fever) and for each month, the subjects were asked to rate, on a visual analogue scale, the symptom intensity. Also, the number of infections was noted. RESULTS: A statistically significant group difference in fatigue intensity existed during the period 4 to 10 months before the onset of CFS. During the 3 months preceding the diagnosis for the CFS patients or the peak of the crisis for the control group, there was a dramatic rise in fatigue in both groups. The CFS group reached a much higher fatigue level, which leveled off somewhat during the first year of follow-up but still remained very high in comparison with the control group, which reached precrisis levels 4 months after the peak. Similar patterns were observed for fever and pain. With regard to sadness and irritability, no group difference was observed during the period preceding the crisis. In the patient group, the level stayed high throughout the whole first year of follow-up, whereas a slow return started in the control group; precrisis levels were reached after 1 year in this group. The prevalence ratio (CFS patients/control subjects) for negative events was around 1.0 for the periods 4 to 12 months preceding CFS but 1.9 during the quarter year preceding the onset. For infections, the prevalence ratio increased successively during the four quarters preceding CFS (from 1.4 to 2.3). CONCLUSIONS: According to the retrospective self-reports, there were differences between the groups in fatigue, pain, and feeling of fever during the months preceding the crisis. With regard to depressive and irritable feelings, no preillness differences were reported between the groups. There was a reported excess prevalence of both infections and negative life events during the quarter year preceding the onset of CFS or crisis. Potential sources of error are discussed. These findings must be replicated in longitudinal studies.