Increased killer B cells in chronic HCV infection may lead to autoimmunity and increased viral load.

Regulatory B (Breg ) cells are characterized by various membrane markers and the secretion of different inhibitory cytokines. A new subset of Breg cells was identified as CD5hi Fas-ligand (FasL)hi . Their main reported role is to suppress anti-viral and anti-tumour immune responses, and, hence they have been dubbed 'killer' B cells. In this study, we aim to assess the role of these cells in chronic hepatitis C virus (HCV) infection, and determine if they contribute to the increased viral load and persistence of HCV and its related autoimmunity. (i) FasL expression on CD5hi B cells is increased significantly in HCV-infected patients compared to healthy individuals [28·06 ± 6·71 mean fluorescence intensity (MFI) ± standard error of the mean (s.e.m.), median = 27·9 versus 10·87 ± 3·97 MFI ± s.e.m., median = 10·3, respectively, P <  0·0001]. (ii) Killer B cells from HCV patients increased autologous CD4+ T cell apoptosis compared to the apoptosis in healthy individuals [39·17% ± 7·18% mean ± standard deviation (s.d.), median = 39·6 versus 25·92 ± 8·65%, mean ± s.d., median = 24·1%, P <  0·0001, respectively]. A similar increase was observed in CD8+ T cell apoptosis (54·67 ± 15·49% mean ± s.d., median = 57·3 versus 21·07% ± 7·4%, mean ± s.d., median = 20%, P = 0·0006, respectively). (iii) By neutralizing FasL with monoclonal anti-FasL antibodies, we have shown that the induction of apoptosis by killer B cells is FasL-dependent. (iv) Increased expression of FasL on CD5hi B cells is correlated positively with an increased viral load and the presence of anti-nuclear antibodies and rheumatoid factor in HCV. This is the first study in which killer B cells have been suggested to play a pathogenic role in HCV. They seem to be involved in HCV's ability to escape efficient immune responses.

Efficacy and safety of 12 weeks of elbasvir ± grazoprevir ± ribavirin in participants with hepatitis C virus genotype 2, 4, 5 or 6 infection: The C-SCAPE study.

People with hepatitis C virus (HCV) infection other than genotype 1 represent a heterogeneous group. The aim of the phase 2 C-SCAPE study was to evaluate elbasvir/grazoprevir (EBR/GZR), with or without ribavirin (RBV), in participants with HCV genotype 2, 4, 5 or 6 infection. This was a part randomised, open-label, parallel-group study (NCT01932762; PN047-03) of treatment-naive, noncirrhotic participants. Participants with HCV genotype 2 infection received GZR 100 mg + RBV ± EBR 50 mg for 12 weeks and those with genotype 4, 5 or 6 infection were randomized to receive EBR/GZR ± RBV for 12 weeks. The primary endpoint was sustained virological response 12 weeks after completion of treatment (SVR12; HCV RNA <25 IU/mL). Among participants with genotype 2 infection, SVR12 was achieved by 80% (24/30) of those receiving EBR/GZR + RBV and 73% (19/26) of those receiving GZR + RBV. SVR rates were high in participants with HCV genotype 4 infection receiving EBR/GZR with and without RBV (100% [10/10] and 90% [9/10]; respectively). In contrast, the addition of RBV to EBR/GZR appeared to increase SVR12 in participants with genotype 5 infection (EBR/GZR, 25%; EBR/GZR + RBV 100% [4/4]). In participants with genotype 6 infection, SVR12 was 75% (3/4) in both those receiving EBR/GZR and those receiving EBR/GZR + RBV. The safety profile was similar across treatment arms, with adverse events tending to occur more frequently among participants receiving RBV. In conclusion, these data support the inclusion of participants with genotype 4 or 6 infection in the EBR/GZR phase 3 studies. EBR/GZR ± RBV was unsatisfactory for participants with genotype 2 or 5 infection.

Real-world effectiveness of ombitasvir/paritaprevir/ritonavir±dasabuvir±ribavirin in patients with hepatitis C virus genotype 1 or 4 infection: A meta-analysis.

The direct-acting antiviral regimen of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r)±dasabuvir (DSV)±ribavirin (RBV) demonstrated high rates of sustained viral response at post-treatment week 12 (SVR12) in clinical trials for treatment of hepatitis C virus (HCV) genotypes (GT) 1 and 4. To confirm the effectiveness of this regimen in the real world, we conducted meta-analyses of published literature on 30 April 2016. Freeman-Tukey transformation determined the SVR rate within GTs 1a, 1b and 4, as well as specific SVR rates by cirrhosis or prior treatment experience status. Rates of virologic relapse, hepatic decompensation, drug discontinuation and serious adverse events were also analysed. In total, 20 cohorts across 12 countries were identified, totalling 5158 patients. The overall SVR12 rates were 96.8% (95% CI 95.8-97.7) for GT1 and 98.9% (95% CI 94.2-100) for GT4. For GT1a patients, the SVR rates were 94% and 97% for those with or without cirrhosis, and 94% overall. For GT1b patients, the SVR rates were 98% and 99% for those with or without cirrhosis, and 98% overall. The virologic relapse rate of GT1 patients was 1.3%, across 3524 patients in nine studies that reported this parameter. The rate of hepatic decompensation was less than 1% across five studies, including 3440 patients, 70% of which had cirrhosis. CONCLUSIONS: Real-world SVR12 rates for OBV/PTV/r±DSV±RBV were consistently high across HCV GT1 and four irrespective of cirrhosis status or prior HCV treatment experience, confirming effectiveness within a diverse patient population across multiple cohorts and countries.

Efficacy and safety of grazoprevir + ribavirin for 12 or 24 weeks in treatment-naïve patients with hepatitis C virus genotype 1 infection.

Grazoprevir (GZR) is a second-generation hepatitis C virus NS3/4A protease inhibitor. The aim of this study was to evaluate GZR plus ribavirin (RBV) in patients with HCV GT1 infection. Noncirrhotic, IL28B CC patients with HCV genotype 1 infection were randomized to GZR 100 mg once daily and RBV for 12 or 24 weeks. Patients in the 12-week arm with detectable HCV RNA at treatment week 4 (TW4) had treatment extended to 24 weeks (response-guided therapy, RGT). The primary endpoint was sustained virologic response (SVR12) at follow-up week 12 (HCV RNA <25 IU/mL) in the per-protocol (PP) population (excluding patients with important protocol deviations). Twenty-six patients were randomized and 22 were included in the PP population. SVR12 was 58.3% (7 of 12) and 90% (9 of 10) in the RGT and 24-week arms, respectively. Seven PP patients had virologic failure, including one patient in the 24-week arm who relapsed after follow-up week 12. All three breakthrough patients had wild-type (WT) virus at baseline and developed breakthrough at TW6 or TW12 with Y56H, A156T and D168A/N mutations. Of the five relapse patients, four had WT at baseline (at relapse three had WT and one had V55A and D168A), and one had S122A/T at baseline and S122T at relapse. There were no serious adverse events (AEs), discontinuations due to AEs or grade 3/4 elevations in total and/or direct bilirubin. Grazoprevir plus RBV was associated with a rapid and sustained suppression of HCV RNA. These results support further evaluation of grazoprevir-based regimens (NCT01716156; protocol P039).

Historical epidemiology of hepatitis C virus (HCV) in select countries - volume 2.

Chronic hepatitis C virus (HCV) infection is a leading cause of liver related morbidity and mortality. In many countries, there is a lack of comprehensive epidemiological data that are crucial in implementing disease control measures as new treatment options become available. Published literature, unpublished data and expert consensus were used to determine key parameters, including prevalence, viremia, genotype and the number of patients diagnosed and treated. In this study of 15 countries, viremic prevalence ranged from 0.13% in the Netherlands to 2.91% in Russia. The largest viremic populations were in India (8 666 000 cases) and Russia (4 162 000 cases). In most countries, males had a higher rate of infections, likely due to higher rates of injection drug use (IDU). Estimates characterizing the infected population are critical to focus screening and treatment efforts as new therapeutic options become available.

Peginterferon alfa-2b plus weight-based ribavirin for 24 weeks in patients with chronic hepatitis C virus genotype 1 with low viral load who achieve rapid viral response.

In chronic hepatitis C (CHC), treatment duration may be individualized according to time to first undetectable hepatitis C virus (HCV) RNA, with patients who attain undetectable HCV RNA early in treatment being candidates for shorter regimens. The aim of this study was to determine the relapse rate in patients with CHC genotype (G) 1 infection and low baseline viral load who achieved undetectable HCV RNA by week 4 [rapid virologic response (RVR)] when treated for 24 weeks. This was an open-label, multicentre, noninterventional study. Adult patients with G1 CHC infection and baseline viral load <600,000 IU/mL who attained RVR were treated with peginterferon alfa-2b (1.5 µg/kg/week) plus ribavirin (800-1200 mg/day) for 24 weeks, then followed for a further 24 weeks. The primary endpoint was relapse rate, defined as the proportion of patients with undetectable HCV RNA at treatment week 24 and detectable HCV RNA at week 24 follow-up. The secondary efficacy endpoint was sustained virologic response (SVR). Overall, 170 patients were included in the efficacy-evaluable population. The relapse rate was 9.7% (16/165, 95% confidence interval: 0.06-0.15), and SVR was attained by 149 of 170 patients (87.6%). Virologic outcomes were consistent regardless of age, gender, body weight and genotype. Seven patients reported treatment-emergent serious adverse events (AEs), and four patients discontinued treatment because of an AE. This study further demonstrates that peginterferon alfa-2b plus weight-based ribavirin for 24 weeks is an effective treatment strategy for treatment-naive patients with G1 CHC and low viral load who attain RVR.

Aortic involvement in rheumatic diseases.

OBJECTIVE: To review the prevalence, mechanisms, presentations and clinical significance of aortic involvement in rheumatic inflammatory diseases. METHODS: The medical literature, available through a PUBMED search was reviewed and the relevant information was summarized. In addition, selected articles related to aortic involvement in rheumatic diseases were included in this review. RESULTS: Rheumatic disorders may be categorized by their propensity to involve the aorta: conditions with a prevalence of 10% and more (Takayasu's arteritis, temporal arteritis, long-standing ankylosing spondylitis, Cogan's syndrome and relapsing polychondritis), disorders with uncommon but well documented aortic involvement and rheumatic conditions with rare case reports of such involvement. Clinical presentation of aortic disease is dependent on the part of aorta involved and may manifest by aortic pain and/or other symptoms caused by aortic dilatation, narrowing or aneurysm. The histopathology of inflammatory aortitis is characterized by lymphoplasmacytic infiltration with or without giant cells or granulomas. On the other hand, non-inflammatory aortic damage in rheumatic diseases may include Marfan-like cystic disintegration of the aortic media as well as accelerated atherosclerosis. Awareness of rheumatic conditions with a high potential for clinically significant aortic involvement may promote referral of such patients for aortic imaging and sometimes surgery before fatal complications intervene. CONCLUSION: Early diagnosis of aortic involvement can be advanced by informed consideration of such a complication in a rheumatic patient.

Biology of feline leukemia virus in the natural environment.

The feline leukemia virus (FeLV) was discovered in 1964 in a cluster of cats with lymphosarcoma. The observed clustering of cases of feline lymphosarcoma suggested that FeLV was an infectious agent for cats. The development of a simple immunofluorescent test for FeLV permitted a seroepidemiological study to be undertaken on the distribution of the virus in cats living in their natural environment. Over 2000 cats were tested, and the results showed conclusively that FeLV is an infectious agent for cats. This finding has now been independently confirmed using three different test procedures. After the infectious nature of FeLV was discovered, a simple FeLV test and removal program was devised to control the spread of the virus in the natural environment. The spread of FeLV was controlled in 45 households by removing the FeLV-infected cats, while in 25 households, where the infected cats were left in contact with the uninfected cats, 12% of the uninfected cats became infected. The ultimate control of FeLV awaits the development of an effective FeLV vaccine, which now seems feasible since we have already experimentally immunized some cats with attenuated FeLV. Although FeLV is infectious for cats there is no evidence that FeLV can infect humans.

Effect of megestrol acetate on quality of life in a dose-response trial in women with advanced breast cancer. The Cancer and Leukemia Group B.

PURPOSE: The impact of the side effects of megestrol acetate on the quality of life of noncachectic women with advanced breast cancer was studied in a dose-response clinical trial of the Cancer and Leukemia Group B (CALGB 8741). Side effects of appetite increase and weight gain at higher doses were predicted to have a negative effect on quality of life. PATIENTS AND METHODS: Stage IV breast cancer patients were randomized to receive either 160, 800, or 1,600 mg/d of megestrol acetate. Quality of life was assessed in 131 patients at trial entry and at 1 and 3 months while on treatment, by telephone interview, using the following measures: the Functional Living Index-Cancer (FLIC), Rand Functional Limitations Scale, Rand Mental Health Inventory (MHI), the Body Image Subscale, and linear analog scales of drug side effects. RESULTS: At 3 months, women treated with 160 mg/d reported less severe side effects (P < .0005), better physical functioning (FLS, P < .0005), less psychologic distress (MHI, P = .008), and an improvement in overall quality of life (FLIC, P = .003) from the time of study entry as compared with those treated with 1,600 mg/d. Patients who received the 800-mg/d dose fell between the low- and high-dose arms in reported intensity of drug side effects, but responded similarly to those in the 160-mg/d group in terms of physical functioning, psychologic distress, and overall quality of life. CONCLUSION: Unless additional follow-up data demonstrate a survival advantage at higher doses, the 160-mg/d dose is optimal, achieving maximal treatment effect with the fewest side effects and better quality of life.

Hepatitis C and B-cell lymphoma: the hemato-hepatologist linkage.

Hepatitis C virus (HCV)-lymphotropism may be responsible for the development of mixed cryoglobulinemia (MC) and other lymphoproliferative disorders associated with HCV infection. An association between HCV infection and B-cell lymphoma has been largely demonstrated in several geographical areas with prevalence ranging between 7.4 and 37%. However, the intimate pathogenetic mechanism involved in HCV-associated lymphomas remains considerably unknown. HCV may exerts its oncogenic potential via an indirect mechanism or utilizes other pathways directly. It is reasonable to assume that several different pathogenetic mechanisms operate in the wide spectrum of HCV-related lymphomas which includes the 'idiopathic', non-cryoglobulinemic, intermediate to high-grade lymphoma, and the more common indolent, low-grade lymphoma, preceded by long standing symptomatic MC type II. In most cases, HCV has no significant impact on response to chemotherapy or survival of lymphoma patients. Treatment with chemotherapy is relatively safe, and interruption of treatment regimens is usually not required. Whether to treat low-grade HCV-related lymphomas with anti-viral therapy is still debatable, but encouraging data emerge from recent studies.

Anticardiolipin antibodies and acute myocardial infarction in non-systemic lupus erythmatosus patients: a controlled prospective study.

PURPOSE: To examine the prevalence of anticardiolipin antibodies (ACLA) in relatively young patients with acute myocardial infarction (MI) and their role in subsequent coronary and thromboembolic events in the post-MI period. PATIENTS AND METHODS: In 124 relatively young survivors (aged 65 or younger) of acute MI, ACLA were measured in a controlled prospective study on admission and 3 months later. Myocardial reinfarction and thromboembolic events during a mean follow-up period of 19 +/- 3 months were diagnosed by standard tests. RESULTS: Seventeen (14%) of the 124 patients were ACLA positive (either IgM or IgG) upon admission compared with 2 out of 76 (3%) of the control group matched for age and coronary risk factors (P < 0.01). The levels of ACLA remained unchanged in all but 1 patient 3 months later. During the follow-up period the rate of thromboembolic events and myocardial reinfarction was significantly higher in the ACLA-positive patients as compared with the ACLA-negative group: 41% versus 4% (P < 0.0001) and 35% versus 10% (P < 0.05), respectively. Using logistic regression, high titer of ACLA was found to be the only independent risk factor for subsequent thromboembolic events or myocardial reinfarction after acute MI. CONCLUSIONS: High prevalence of ACLA was found in relatively young survivors of acute MI. The presence of ACLA is a marker for increased risk of subsequent myocardial reinfarction and thromboembolic events after acute MI.

Rheumatic syndromes: clues to occult neoplasia.

OBJECTIVES: Rheumatic disorders associated with cancer include a variety of conditions, most of which have no features distinguishing them from idiopathic rheumatic disorders. It is generally held that an extensive search for occult malignancy in most rheumatic syndromes is not recommended unless accompanied by specific findings suggestive of malignancy. The objective of this review are to identify rheumatic syndromes associated with cancer, to call attention to features that may suggest the presence of a hidden cancer, and to examine the role to additional clinical and laboratory data as clues to the possible neoplastic cause of those syndromes. METHODS: A MEDLINE search of the literature dealing with cancer-associated rheumatic syndromes was conducted. RESULTS: Review of the literature identified significant progress in this area. First, the association of malignancy with certain rheumatic syndromes was convincingly established, such as asymmetric polyarthritis presenting in the elderly with an explosive onset, rheumatoid arthritis with monoclonal gammopathy, Sjögren's syndrome with monoclonality, hypertrophic osteoarthropathy, dermatomyositis, polymyalgia rheumatica with atypical features, Lambert-Eaton myasthenic syndrome, palmar fasciitis and arthritis, eosinophilic fasciitis poorly responsive to corticosteroid therapy, erythema nodosum lasting more than 6 months, and onset of Raynaud's phenomenon or cutaneous leukocytoclastic vasculitis after age 50 years. Second, the list of cancer-associated rheumatic syndromes was extended by including additional entities such as benign edematous polysynovitis, sacroiliitis, adult-onset Still's disease, dermatomyositis sine myositis, systemic sclerosis, Sweet's syndrome, osteomalacia, skeletal hyperostosis, antiphospholipid syndrome, and essential mixed cryoglobulinemia. Third, evidence was provided substantiating that certain long-standing rheumatic syndromes, in particular rheumatoid arthritis, Felty's syndrome, Sjögren's syndrome, dermatomyositis, systemic sclerosis, systemic lupus erythematosus, and temporal arteritis behave like "premalignant conditions." Fourth, it was shown that the recognized tumor markers alpha-fetoprotein, prostate-specific antigen, CA-125, CA 19-9, and CA-3 have low sensitivity and specificity in screening for occult cancer in a population of rheumatic patients, whereas the presence of a monoclonal gammopathy in rheumatoid arthritis and the monoclonal antibody 17-109 in Sjögren's syndrome are reliable signs of malignant transformation. CONCLUSIONS: The presence of specific rheumatic syndromes and certain clinical and laboratory findings may justify a workup for hidden cancer. Studies of the epidemiology of the cancer-associated rheumatic syndromes and evaluation of the validity of aforementioned clues in prospective studies are goals for future investigations.

The fasciitis-panniculitis syndrome: clinical spectrum and response to cimetidine.

The term fasciitis-panniculitis syndrome (FPS) is proposed as a novel compilation encompassing several disorders, common to which is subcutaneous induration caused by cicatrizing fasciitis as well as septal and lobular panniculitis and perimysial fibrosis. Included herein are Shulman's eosinophilic fasciitis, morphea profunda, lupus profundus, venous lipodermatosclerosis, toxic oil syndrome, altered tryptophane-related eosinophilic myositis, graft-versus-host reaction, and fasciitis reactive to subjacent basal cell carcinoma. FPS should be differentiated from scleroderma, which primarily affects the dermal structures and in which arterioles are injured. In contrast, vasculopathy of the subcutaneous medium-sized veins accompanies the hypodermal lesions of FPS. The importance of recognizing and grouping these disorders lies in their different histopathology, characterization as reactive phenomena, enhanced responsiveness to treatment, and better prognosis than scleroderma. In view of the excellent prognosis of FPS, steroid treatment is not warranted. Long-term therapy with cimetidine appears to benefit the majority of patients.

The capnography head-up tilt test for evaluation of chronic fatigue syndrome.

OBJECTIVES: To compare the hemodynamic and ventilatory responses to autonomic challenge evoked by upright tilt table testing in patients with chronic fatigue syndrome (CFS) to healthy individuals. METHODS: Thirty-two consecutive patients with CFS and 32 healthy volunteers were evaluated with the aid of the recently introduced capnography head-up tilt test (CHUTT). The main outcome measures were values of blood pressure (BP), heart rate (HR), respiratory rate (RR), and end-tidal pressure of co2 (ETPco2) recorded during recumbence and tilt. In addition, the end points of vasodepressor and cardioinhibitory reactions, hyperventilation (defined by ETPco2 <25 mm Hg) and the postural tachycardia syndrome, were recorded. RESULTS: The BP, HR, RR, and ETPco2 recorded during recumbence were similar in both groups. During tilt, patients with CFS developed significantly lower systolic BP, diastolic BP, and ETPco2, and a significant rise in HR and RR (P<.01). In CFS patients, the postural tachycardia syndrome occurred in 44%, vasodepressor reaction in 41%, cardioinhibitory reaction in 13%, and hyperventilation in 31% of cases. One or more end points of the CHUTT were reached in 78% of patients with CFS but in none of the controls (P<.0001). CONCLUSIONS: In most patients with CFS, a spectrum of abnormal homeostatic reactions is diagnosed with the aid of the CHUTT. Data provided by the CHUTT may reinforce the clinical diagnosis by adding objective and unbiased criteria to the subjective assessment of CFS.

Preeclampsia and liver infarction in early pregnancy associated with the antiphospholipid syndrome.

BACKGROUND: Usually, preeclampsia is a disease of the second half of pregnancy (i.e., beyond 20 weeks' gestation). Early-onset preeclampsia has been reported in association with the antiphospholipid syndrome, however, the cases reported have been at 25-30 weeks' gestation. CASES: Three pregnant women presented with clinical and laboratory features of severe preeclampsia and the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP) before 20 weeks' gestation. On evaluation, they were found to have antiphospholipid antibodies (anticardiolipin and/or lupus anticoagulant). Two of the patients had abdominal computed tomography scans that showed a low-density area along the hepatic periphery, compatible with hepatic infarction. Spontaneous resolution of all clinical and laboratory manifestations of preeclampsia and HELLP syndrome was observed after fetal death and pregnancy termination. CONCLUSION: Preeclampsia and HELLP syndrome can present before 20 weeks' gestation in association with the antiphospholipid syndrome and may be associated with hepatic infarction.

The head-up tilt test with haemodynamic instability score in diagnosing chronic fatigue syndrome.

BACKGROUND: Studying patients with chronic fatigue syndrome (CFS), we have developed a method that uses a head-up tilt test (HUTT) to estimate BP and HR instability during tilt, expressed as a 'haemodynamic instability score' (HIS). AIM: To assess HIS sensitivity and specificity in the diagnosis of CFS. DESIGN: Prospective controlled study. METHODS: Patients with CFS (n=40), non-CFS chronic fatigue (n=73), fibromyalgia (n=41), neurally mediated syncope (n=58), generalized anxiety disorder (n=28), familial Mediterranean fever (n=50), arterial hypertension (n=28), and healthy subjects (n=59) were evaluated with a standardized head-up tilt test (HUTT). The HIS was calculated from blood pressure (BP) and heart rate (HR) changes during the HUTT. RESULTS: The tilt was prematurely terminated in 22% of CFS patients when postural symptoms occurred and the HIS could not be calculated. In the remainder, the median(IQR) HIS values were: CFS +2.14(4.67), non-CFS fatigue -3.98(5.35), fibromyalgia -2.81(2.62), syncope -3.7(4.36), generalized anxiety disorder -0.21(6.05), healthy controls -2.66(3.14), FMF -5.09(6.41), hypertensives -5.35(2.74) (p<0.0001 vs. CFS in all groups, except for anxiety disorder, p=NS). The sensitivity for CFS at HIS >-0.98 cut-off was 90.3% and the overall specificity was 84.5%. DISCUSSION: There is a particular dysautonomia in CFS that differs from dysautonomia in other disorders, characterized by HIS >-0.98. The HIS can reinforce the clinician's diagnosis by providing objective criteria for the assessment of CFS, which until now, could only be subjectively inferred.

Patterns of cardiovascular reactivity in disease diagnosis.

BACKGROUND: Aberrations of cardiovascular reactivity (CVR), an expression of autonomic function, occur in a number of clinical conditions, but lack specificity for a particular disorder. Recently, a CVR pattern particular to chronic fatigue syndrome was observed. AIM: To assess whether specific CVR patterns can be described for other clinical conditions. METHODS: Six groups of patients, matched for age and gender, were evaluated with a shortened head-up tilt test: patients with chronic fatigue syndrome (CFS) (n = 20), non-CFS fatigue (F) (n = 15), neurally-mediated syncope (SY) (n = 21), familial Mediterranean fever (FMF) (n = 17), psoriatic arthritis (PSOR) (n = 19) and healthy subjects (H) (n = 20). A 10-min supine phase was followed by recording 600 cardiac cycles on tilt (5-10 min). Beat-to-beat heart rate (HR) and pulse transit time (PTT) were measured. Results were analysed using conventional statistics, recurrence plot analysis and fractal analysis. RESULTS: Multivariate analysis evaluated independent predictors of the CVR in each patient group vs. all other groups. Based on these predictors, equations were determined for a linear discriminant score (DS) for each group. The best sensitivities and specificities of the DS, consistent with disease-related phenotypes of CVR, were noted in the following groups: CFS, 90.0% and 60%; SY, 93.3% and 62.5%; FMF, 90.1% and 75.4%, respectively. DISCUSSION: Pathological disturbances may alter cardiovascular reactivity. Our data support the existence of disease-related CVR phenotypes, with implications for pathogenesis and differential diagnosis.

Management of hepatitis C virus-related arthritis.

Hepatitis C virus (HCV) infection is often associated with extrahepatic manifestations among which arthropathy is common, affecting up to 20% of HCV-infected individuals. This arthropathy is to be distinguished from the more superficially prominent myalgias and fatigue. HCV-related arthritis is commonly presented as rheumatoid-like, symmetrical inflammatory polyarthritis involving mainly small joints, or, less commonly, as mono- or oligoarthritis, usually of the large joints. HCV arthritis usually runs a relatively benign course that, in contrast to 'true' rheumatoid arthritis (RA), is typically non-deforming and is not associated with articular bony erosions. In addition, unlike 'classic' RA, erythrocyte sedimentation rate is elevated only in about half of the patients and subcutaneous nodules are absent. In about two-thirds of the affected individuals morning stiffness may be severe, resolving after more than an hour. Several pathogenetic mechanisms may be involved: HCV arthritis may be part of the syndrome of mixed cryoglobulinaemia, or may be directly or indirectly mediated by HCV. Such possible, but yet not proven, mechanisms include direct invasion of synovial cells by the virus eliciting local inflammatory response, cytokine-induced disease or immune complex disease, particularly in genetically susceptible individuals. The diagnosis of HCV arthritis in patients with positive rheumatoid factor and chronic inflammatory polyarthritis may be difficult. Positive HCV antibody and HCV RNA, and the absence of bony erosions, subcutaneous nodules and antikeratin antibodies, may be useful in distinguishing between HCV-related arthritis and RA. The optimal treatment of HCV-related arthritis has not yet been established. Concerns may be raised regarding the use of immunosuppressive or potentially hepatotoxic drugs. However, it may be suggested that once the diagnosis of HCV-associated arthritis is made, combination antiviral treatment with interferon-alpha and ribavirin should be initiated as part of the therapeutic armamentarium. Low dose oral corticosteroids, nonsteroidal anti-inflammatory drugs, hydroxychloroquine or sulfasalazine in addition to the antiviral therapy can be used to control arthritis-related symptoms. Some patients may need long term anti-inflammatory treatment in various combinations, along with antiviral therapy. In patients with severe, disabling or life-threatening cryoglobulinaemia-related symptoms refractory to antiviral or anti-inflammatory treatment, high dose corticosteroids (including pulse therapy) and/or plasmapheresis may be needed.

Persistent symptoms among survivors of Hodgkin's disease: an explanatory model based on classical conditioning.

Persistent symptoms of nausea, distress, and vomiting triggered by reminders of cancer treatment were examined among 273 Hodgkin's disease survivors, 1 to 20 years posttreatment. Prevalence rates were high for distress and nausea but low for vomiting. Retrospective report of anticipatory symptoms during treatment was the strongest predictor of persistent symptoms, suggesting that treatment-induced symptoms are less likely to persist if conditioning does not occur initially. Time since treatment was also a significant predictor, with patients more recently treated more likely to experience persistent symptoms. Thus, an explanatory model based on classical conditioning theory successfully predicted presence of persistent symptoms. Symptoms also were associated with ongoing psychological distress, suggesting that quality of life is diminished among survivors with persistent symptoms. Recommendations for prevention and treatment of symptoms are discussed.

In-field validation of automatic blood pressure measuring devices.

The method for rapid evaluation of automatic blood pressure (BP) measurement devices (READ) is based on numerous BP measurements at rest and during a standardised postural challenge in a small number of subjects with a wide range of BPs. The present study proposes additional parameters of the READ for in-field validation of automatic BP measurement devices. BP measurements were done in supine position for 10 min followed by head-up tilt for 30 min and again supine for 10 min. BPs were determined simultaneously by automatic (AU) and mercury sphygmomanometric (MS) measurements on the same arm. The BP differences DeltaBP:AU-MS were calculated. Three units of the Colin BP-8800 and the Datex-Engstrom Cardiocaptrade mark II were evaluated. Based on DeltaBP(AU-MS), the grade of accuracy, aberration patterns and correlates of accuracy were assessed for each unit. Per unit, an average of 121 measurements were done, every BP category being met in >/=20 MS measurements. In general, the AU systolic BP values were higher than MS systolic BP values (mean systolic DeltaBP = 1.26 +/- 17.1 mm Hg) and AU diastolic BP values were lower than MS diastolic BP values (mean diastolic DeltaBP = -12.31 +/- 7.8 mm Hg). All units classified into category D of the British Hypertension Society grading system and exhibited inconsistent aberration patterns, making design of correction formulas impractical. Inaccuracy of the instruments was independent on mode of measurement, posture, magnitude of the BP and heart rate, early or late measurements from beginning of the head-up tilt test, and prolonged use of the unit. The READ permitted to identify rapidly the degree of accuracy of automatic BP measuring devices. Identification of the aberration pattern of an instrument could be the basis for calculating equations for correction of the measured BP. Further studies will show which parameters of the READ may expose specific defects of the instruments. Journal of Human Hypertension (2000) 14, 37-42.