Detection of significant liver fibrosis in Chinese psoriasis patients receiving methotrexate: a comparison between transient elastography and liver histology.

INTRODUCTION: Methotrexate (MTX) is effective for treating psoriasis and psoriatic arthritis, but its potential hepatoxicity remains a concern. Liver biopsy, the gold standard for detecting MTX-induced liver injury, is invasive and carries considerable risk. Transient elastography (TE) offers a non-invasive alternative for detecting advanced liver fibrosis. This study investigated the performance of TE in detecting MTX-induced liver fibrosis among Chinese psoriasis patients, compared with liver biopsy. METHODS: This study included adult patients with clinical psoriasis. Liver stiffness measurement using TE was performed in patients receiving MTX. Exclusion criteria were known liver cirrhosis, positive viral hepatitis carrier status, or conditions influencing TE performance. Liver biopsy was performed when liver stiffness was ≥7.1 kilopascals (kPa) or when the total cumulative dose (TCD) of MTX was ≥3.5 g. RESULTS: A total of 228 patients were screened; among 34 patients who met the inclusion criteria, nine (26.5%) had significant liver fibrosis (Roenigk grade ≥3a). The area under the receiver operating characteristic curve was 0.76 (95% confidence interval=0.59-0.93; P=0.021), indicating that TE had satisfactory performance in detecting liver fibrosis. A cut-off value of 7.1 kPa of liver stiffness yielded 100% sensitivity and 68% specificity. Liver fibrosis was not correlated with the TCD of MTX or the duration of MTX use; it was significantly correlated with obesity and diabetes status (body mass index ≥30 kg/m2, waist circumference ≥138 cm, and glycated haemoglobin level ≥7.8%). CONCLUSION: Transient elastography is reliable and superior to the TCD for detecting liver fibrosis in Chinese psoriasis patients receiving MTX. Liver biopsy should be reserved for high-risk patients or patients with liver stiffness ≥11.7 kPa on TE.

The course of symptoms of anxiety and depression from time of diagnosis up to 2 years follow-up in head and neck cancer patients treated with primary (chemo)radiation.

OBJECTIVES: To identify sociodemographic and clinical factors, health-related quality of life (HRQOL) and head and neck cancer (HNC) symptoms associated with the course of symptoms of anxiety and depression from pretreatment to 24-month follow-up among HNC patients after (chemo)radiation. MATERIALS AND METHODS: Patients (n = 345) completed questionnaires on anxiety and depression (HADS), HRQOL and symptoms (EORTC QLQ-C30/QLQ-H&N35) before treatment, and 6-weeks,3-,6-12-,18-, and 24-months after treatment. Mixed model analyses were used to investigate the course of anxiety and depression from pretreatment to 24-months in relation to factors assessed at baseline, and the course of anxiety and depression from 6- to 24-months, in relation to factors assessed at 6-months. RESULTS: Increased risk for anxiety (HADS-anxiety > 7) was 28.7% among patients before treatment, which declined to 10.0% at 24-months. Increased risk for depression (HADS-depression > 7) was 15.1% before treatment, 18.2% at 3-months, 7.2% at 12-months and 16.0% at 24-months. Factors assessed at baseline which were significantly associated with the course of anxiety were age, pain, problems with social contact, and feeling ill, whereas chemotherapy, worse emotional functioning, speech problems and weight loss were significantly associated with the course of depression. Regarding factors assessed at 6-months, chemotherapy, worse cognitive and social functioning, insomnia, swallowing problems and trouble with social eating were associated with the course of anxiety. Nausea/vomiting, dyspnea, coughing, and feeling ill were associated with the course of depression (p-values < 0.05). DISCUSSION: Factors associated with a worse course of anxiety and depression are younger age, treatment with chemotherapy, worse HRQOL and higher symptom burden.

Joint recommendations on management of anaemia in patients with gastrointestinal bleeding in Hong Kong.

The demand for blood products continues to grow in an unsustainable manner in Hong Kong. While anaemia associated with gastrointestinal bleeding (GIB) is the leading indication for transfusion, there is no local recommendation regarding best practices for transfusion. We aimed to provide evidence-based recommendations regarding management of anaemia in patients with acute and chronic GIB. We reviewed all original papers, meta-analyses, systematic reviews, or guidelines that were available in PubMed. For acute GIB, a restrictive transfusion strategy, targeting a haemoglobin threshold of 7 to 8 g/dL, should be adopted because overtransfusion is associated with significantly higher all-cause mortality and re-bleeding. A liberal transfusion strategy should only be considered in patients with co-existing symptomatic coronary artery disease, targeting a haemoglobin threshold of 9 to 10 g/dL. When acute GIB settles, patients should be prescribed iron supplements if iron deficiency is present. For chronic GIB, iron stores should be replenished aggressively via iron supplementation before consideration of blood transfusion, except in patients with symptoms of severe anaemia. Oral iron replacement is the preferred first-line therapy, while intravenous iron is indicated for patients with inflammatory bowel disease, poor response or poor tolerability to oral iron, and in whom a rapid correction of iron deficit is preferred. Intravenous iron is underutilised and the risk of anaphylactic reaction to current preparations is extremely low. These recommendations are provided to local clinicians to facilitate judicious and appropriate use of red cell products and iron replacement therapy in patients with GIB.

Inverse relationship between hepatic steatosis and hepatitis B viremia: Results of a large case-control study.

The potential interaction between chronic hepatitis B (CHB) and nonalcoholic fatty liver disease (NAFLD), two of the most prevalent liver diseases worldwide, has not been well defined. We performed liver stiffness (LS) and controlled attenuation parameter (CAP) measurements using transient elastography in 1202 CHB patients. Of these, 601 steatotic patients were matched with nonsteatotic controls in a 1:1 ratio by age, gender, nucleoside analogue treatment status, and treatment duration. Severe fibrosis was defined according to EASL-ALEH criteria, and steatosis was defined as CAP ≥222 dB m-1 . Anthropometric measurements and metabolic-related parameters were recorded. The mean age of the 1202 patients (51.4% male) was 51.8 years. 696 patients (57.9%) were on nucleoside analogues for a median duration of 76.2 months. Among treatment-naïve patients, median serum HBV DNA was lower in steatotic individuals than in controls (3.0 vs 3.4 log IU mL-1 , P < .05), with this inverse relationship remaining significant in multivariate analysis (odds ratio 0.859, 95% CI 0.743-0.994, P < .05). With increased steatosis severity, there was a stepwise decrease in median HBV DNA levels (3.1 and 2.6 log IU mL-1 in no steatosis and severe steatosis, respectively, P = .032). Steatosis was associated with a higher median LS (5.4 kPa vs 5.0 kPa, P < .001). Severe steatosis, when compared to mild/moderate steatosis, was associated with an increased percentage of severe fibrosis (23.2% and 12.6%, respectively, P = .005). We conclude that severe steatosis was associated with increased fibrosis in CHB patients. Increasing steatosis was independently associated with lower serum HBV DNA levels, suggesting its potential negative effects on viral replication.

Review article: hepatitis B core-related antigen (HBcrAg): an emerging marker for chronic hepatitis B virus infection.

BACKGROUND: Chronic hepatitis B (CHB) cannot be completely eradicated due to the presence of covalently closed circular DNA (cccDNA) in the nuclei of infected hepatocytes. While quantification of intrahepatic cccDNA requires liver biopsies, serological markers can be non-invasive alternatives to reflect intrahepatic viral replicative activity. Recently, hepatitis B core-related antigen (HBcrAg) has been advocated as a novel serum marker for disease monitoring and prognostication of CHB. AIM: To examine the virological aspect and clinical application of HBcrAg with respect to the natural history and treatment of CHB. METHODS: We reviewed all papers published in the PubMed journal list and abstracts from major international meetings that included the keyword "HBcrAg" or "hepatitis B core-related antigen" until March 2017. Selected studies were compared and summarised on the basis of existing theories, as well as the authors' experience. RESULTS: HBcrAg exhibited good correlation with intrahepatic (ih) cccDNA, ih total hepatitis B virus (HBV) DNA, serum HBV DNA and to a lesser extent HBV surface antigen (HBsAg). In situations where serum HBV DNA levels become undetectable or HBsAg loss is achieved, HBcrAg can still be detectable. This marker is helpful in differentiation of HBeAg-negative chronic hepatitis from HBeAg-negative chronic infection, predicting spontaneous or treatment-induced HBeAg seroconversion, sustained response to nucleos(t)ide analogue (NA), risk of HBV reactivation in occult HBV infection under immunosuppressive therapies, and risk of hepatocellular carcinoma (HCC) development as well as post-operative HCC recurrence. CONCLUSIONS: HBcrAg is a potential surrogate marker of cccDNA. It may soon become a useful marker for disease monitoring, predicting treatment response and disease outcome of chronic hepatitis B.

Body-mass index is associated with fibrosis regression during long-term nucleoside analogue therapy in chronic hepatitis B.

BACKGROUND: Factors influencing changes in liver stiffness measurements during long-term nucleoside analogue therapy for chronic hepatitis B (CHB) have not been thoroughly investigated. AIM: To identify determinants of on-treatment fibrosis regression in CHB. METHODS: We performed follow-up liver stiffness and controlled attenuation parameter measurements on nucleoside analogue-treated CHB patients with severe liver fibrosis, according to EASL-ALEH criteria, diagnosed by transient elastography in 2006-2008. Anthropometric measurements and different metabolic parameters were recorded. RESULTS: Among 257 patients with severe liver fibrosis by initial transient elastography, 123 (47.9%) were recruited for reassessment. Median treatment duration was 87.5 (interquartile range 75.3-102.2) months; 97.5% had undetectable HBV DNA. There was a significant reduction in median liver stiffness from 14.6 to 8.3 kPa (P < 0.001). A total of 29.3% had fibrosis regression, with lower rates of 17.9%, 14.9% and 11.5% noted in patients with body-mass index (BMI) ≥25 kg/m2 , metabolic syndrome and diabetes, respectively. Absence of BMI ≥25 kg/m2 , diabetes and metabolic syndrome, when compared with presence of any one of these three factors, was associated with increased fibrosis regression (43.1% vs. 16.9%, P = 0.001). Multivariate analysis found a lower BMI to be the only factor independently associated with fibrosis regression (P = 0.034, odds ratio 0.68, 95% CI 0.48-0.97). No association was noted between controlled attenuation parameter measurements and fibrosis regression (P > 0.05). CONCLUSION: An increased BMI hindered fibrosis regression in patients with chronic hepatitis B during nucleoside analogue treatment, suggesting that control of metabolic risk factors, in addition to virologic suppression via antiviral therapy, might be needed to halt the fibrogenic process in chronic hepatitis B.

Multinodular reticular schwannoma in the head and neck region: a potential diagnostic pitfall.

Reticular/microcystic schwannoma is a recently described morphologic variant of schwannoma that occurs predominantly in visceral organs, most commonly the gastrointestinal tract. This report describes a case occurring in the masticator space, accompanied by focal erosion of the orbital floor, clinically and radiologically worrisome for malignancy. The 26-year-old man presented with facial swelling for 3 month. The tumor shows a multinodular appearance, with dense lymphoplasmacytic infiltrates in the fibrous septa. The tumor nodules are composed of plump spindle cells disposed in a reticular pattern. The diagnosis is confirmed by strong positive staining for S100 protein. The differential diagnoses of reticular schwannoma in the soft tissues of head and neck region are different from those in the gastrointestinal tract.

Perceptions and attitudes of rehabilitation medicine physicians on complementary and alternative medicine in Australia.

BACKGROUND: The growing demand for complementary and alternative medicine (CAM) is undeniable. We report a first study about the attitudes and behaviour of Australian rehabilitation physicians to CAM. METHODS: A prospective cross-sectional survey was undertaken to document the prevalence of, knowledge about and referrals to CAM therapies and their perceived effectiveness, by a sample of Australian rehabilitation physicians. RESULTS: Thirty-six out of 94 actively practising rehabilitation physicians from the Australasian Faculty of Rehabilitation Medicine, the Royal Australasian College of Physicians, replied to the survey, a response rate of 38%, and 85% reported familiarity with CAM, the most familiar therapies being acupuncture (80%), yoga (74%) and Tai-Chi (72%). CAM referral was reported in 84%, 38% personally used CAM, 94% of patients enquired about CAM therapies, 32% of respondents routinely enquired about CAM use. Age, sex and year of Fellowship were not associated with familiarity, personal use or frequency of patient enquiry about CAM. Those who reported to be very familiar with CAM were more likely to routinely enquire about CAM use (P = 0.028) and be more confident in prescribing certain CAM therapies (P < 0.05). CONCLUSION: Australian rehabilitation physicians report similar CAM referral rates to Canadian physiatrists and Australian general practitioners. The most commonly prescribed therapies were acupuncture, yoga and Tai-Chi. Almost all patients use CAM therapies, but only a minority of rehabilitation physicians enquires about CAM use on a regular basis. The latter may avoid potentially harmful drug interactions, as well as improve the quality of the physician-patient relationship.

Electro-magnetic base technology for estremely sensitive immunosensors and DNA-chips.

We report on the development of an innovative electro-magnetic base technology for estremely sensitive sensors allowing the electrical detection of biological analytes like antigenes or DNA as well as a simple multiple detection of binding forces occurring at specific bonds between proteins. The technology is based on the strong impact of specifically captured magnetic microbeads on an electrical current generated in a fluid by a small sensor chip with an array of activated microelectrodes. The new technological principle with the on-chip detection of analytes will be suitable for large scale applications due to its mass production compatible technologies and allow an alternative way to monitor relevant substances without the consumption of critical additional solutions and reagents.

Primary histiocytic lymphoma of the central nervous system: a neoplasm frequently overshadowed by a prominent inflammatory component.

True histiocytic lymphoma, as defined by strict criteria, is a very rare neoplasm. We describe three cases occurring as primary tumors in the central nervous system. The patients, two females and one male, ranged in age from 11 to 69 years. The tumors involved the brain in two cases and spinal cord in one, with a size ranging from 7 to 17 mm. Two patients died at 4 months and 8 months, respectively, and one was alive with disease at 5 months. Pathologically, the tumors comprised groups and sheets of noncohesive large cells with pleomorphic vesicular nuclei, distinct nucleoli, and abundant eosinophilic cytoplasm. A dense inflammatory infiltrate consisting of neutrophils, lymphocytes, plasma cells, and histiocytes was present, with multiple foci of necrosis and abscess formation. All three cases demonstrated an identical immunophenotype: positive for CD68 and lysozyme; focally positive for S-100 protein, CD45RB, and CD4; and negative for CD3, CD20, CD21/CD35, CD1a, CD30, ALK1, myeloperoxidase, glial fibrillary acidic protein, and cytokeratin. The proliferative index ranged from 20% to 35%. Ultrastructural examination further confirmed the histiocytic nature of the tumor cells, characterized by irregularly folded or multisegmented nuclei and abundant cytoplasm containing lysosomes; Birbeck granules, interdigitating cell processes, and cell junctions were not found. Although the presence of abundant inflammatory cells could obscure the neoplastic histiocytes, making the distinction from inflammatory conditions difficult, awareness of this unusual histologic feature and the invariable finding of pleomorphic cells in some areas of the lesion permit the correct diagnosis to be made.

An hsr on chromosome 7 was shown to be an insertion of four copies of the 11q23 MLL gene region in an HIV-related lymphoma.

A 45-year-old male with AIDS presented with a cecal diffuse large B-cell lymphoma. Cytogenetic and flourescence in situ hybridization (FISH) studies revealed a complex karyotype with multiple aberrations that included a translocation, t(8;14) involving MYC on chromosome 14. This is specific to B-cell lymphomas. There were also frequently observed secondary changes such as chromosome 1 rearrangement leading to trisomy of 1q and loss of tp53 from the deleted chromosome 17. A unique secondary abnormality was an hsr on chromosome 7, which by FISH and SKY investigations was shown to originate from chromosome 11 involving 4 copies of the MLL gene region.

Segmental amplification of 11q23 region identified by fluorescence in situ hybridization in four patients with myeloid disorders: a review.

Four cases with a segmental amplification of 11q23 region were detected by FISH. The amplification was either contiguous amplification on chromosome 11, or multiple markers involving the 11q23 region. The markers were derivative chromosomes, or isochromosomes. Amplification of 11q23 region was associated with complex karyotypes at the time of diagnosis or following treatment in secondary leukemias. Three were AML cases belonging to either AML-M5a or AML-1 subtypes and one was a myeloproliferative disorder. These cases were resistant to treatment. Conventional cytogenetic analysis and fluorescence in situ hybridization (FISH) studies using MLL, 11 painting, or 11 centromere probes ascertained the segmental amplification. Since the patients did not respond to treatment the amplification of gene or genes that map to 11q23 may be responsible for the unfavorable prognosis. Hence, this type of amplifications could have clinical significance.

Mosaic unbalanced structural abnormalities confirmed using FISH on buccal mucosal cells.

Three rare mosaic unbalanced structural rearrangements found in routine peripheral blood analysis were confirmed in buccal mucosal cells using interphase FISH. Case 1 had a de novo mosaic triplication for 13q22q33 found in 22.5 % lymphocytes. D13S585 probe that maps to 13q32q33 confirmed the mosaicism in 41 % of buccal mucosal cells. Case 2 had additional material on a 3q derived from 14q31qter in 83 % of lymphocytes. The 14q-subtelomeric probe was used on buccal smear cells: 86 % had three signals and 14 % had two signals. Case 3 was a mosaic de novo add(5) in 32 % lymphocytes. The additional material was from 3p26pter. The 3p-subtelomere probe confirmed the mosaicism in 40 % buccal epithelial cells. This study shows the applicability of interphase FISH to confirm mosaic unbalanced rearrangements in a second tissue such as buccal mucosal cells.

A child with ALL and ETV6/AML1 fusion on a chromosome 12 due to an insertion of AML1 and loss of ETV6 from the homolog involved in a t(12;15)(p13;q15).

A 4-year-old boy was found to have acute lymphoblastic leukemia characterized by a t(12;15)(p13;q15). FISH investigation using a TEL(ETV6)/AML1 probe detected a fusion signal in 98% of the interphase cells. Sequential FISH on a G-banded slide showed a fusion signal on an apparently normal chromosome 12 and AML1 signals on chromosomes 21. The ETV6 was deleted from the chromosome 12 involved in the t(12;15). These results are best explained as an insertion of AML1 into TEL on one chromosome arm 12p and loss of ETV6 from the chromosome 12 involved in the t(12;15).

FISH analysis of an AML-M5a with segmental rearrangements involving 11q23-MLL region.

A 66-year-old man was diagnosed 10 years ago with thrombocytosis and treated with hydroxyurea. Recently, his condition deteriorated and he was found to have 68% blasts in the blood and AML-M5a. Conventional cytogenetic analysis and fluorescence in situ hybridization studies using 11-painting and MLL probes showed that chromosome 11 had duplications or triplications; the markers were also derived from the chromosome 11-MLL region. Therefore, we have demonstrated segmental rearrangement of chromosome 11 involving the MLL region resulting in multiple copies of the MLL gene.

Induction of keratinocyte IL-8 expression and secretion by IgG autoantibodies as a novel mechanism of epidermal neutrophil recruitment in a pemphigus variant.

A subset of pemphigus herpetiformis, a rare pemphigus variant, is characterized histopathologically by subcorneal acantholysis and neutrophilic infiltration. The mechanism of neutrophil infiltration is unknown, but chemokines such as IL-8 may play a role. We investigated the possible role of IL-8 in two such cases. Direct and indirect immunofluorescence studies demonstrated in vivo-bound and circulating IgG epithelial cell surface-binding autoantibodies, both predominated by IgG4 subclass. ELISA and immunoblotting studies revealed that the patients' IgG autoantibodies recognized recombinant desmoglein 1 but not desmoglein 3. Preadsorption of the patients' sera with recombinant desmoglein 1 completely removed the epidermal cell surface immunostaining. Significantly, immunohistochemistry demonstrated intense expression of IL-8, co-localized with in vivo-bound IgG, in the upper epidermis, where the acantholysis took place. Affinity-purified sera IgG from these two patients, a normal individual, and a pemphigus vulgaris patient containing desmoglein 1 autoantibodies, were incubated with normal human keratinocytes in vitro. Cells treated with these patients' IgG secreted a seven-to-nine-fold increase of IL-8 (30-37 pg/ml) compared with the controls (2-4 pg/ml) and expressed a higher intensity of cytoplasmic IL-8 staining. These data demonstrate a novel functional role for IL-8 in the pathogenesis of the neutrophil-dominant subset of pemphigus herpetiformis. The autoantibody-induced epidermal cell IL-8 expression may represent a novel mechanism of epidermal neutrophil recruitment.

Dual effect of spermine on mast cell secretion exhibits different calcium and temperature requirements.

Mast cells release many biologically active molecules upon stimulation by a variety of molecules such as immunoglobulin E (IgE) and specific antigen, anaphylatoxins, as well as a number of cationic compounds which include drugs, kinins and neuropeptides. The effect of the naturally occurring polyamine spermine was studied because, even though it is polycationic, it has been implicated in the modulation of secretory processes in a variety of cells. In particular, it was previously shown that oxidation products of spermine inhibit mast cell secretion. High concentrations of spermine (5 x 10(-3) M) added at 37 degrees C induced mast cell secretion that had similar characteristics with that triggered by compound 48/80 (48/80). However, spermine inhibited mast cell secretion in a dose-dependent manner as long as it was added at 4-10 degrees C for at least 10 min in the absence of Ca++ before warming the cells to 37 degrees C and triggering them with 48/80. These findings were true both for purified rat peritoneal mast cells and for rat skin mast cells in situ. Addition of calcium after the cells had been warmed to 37 degrees C could not reverse this inhibition. The inhibition seen when spermine was added at 4 degrees C was, however, overcome if phorbol myristate acetate (PMA) or NaF, which activate PKC and G proteins respectively, were added to mast cells at 37 degrees C together with Ca++. These results indicate that polyamines could be important modulators of the activation state of mast cells and might help further define the biochemical events involved in mast cell secretion.

Inhibition of mast cell secretion by oxidation products of natural polyamines.

Mast cells secrete many biologically active compounds upon stimulation by immunoglobulin E (IgE) and specific antigen (Ag), anaphylatoxins, as well as a number of cationic compounds which include drugs, kinins and neuropeptides. The effects of the two naturally occurring polyamines, spermine (SP) and spermidine (SPD), on mast cell secretion were studied because they have been implicated in the modulation of cellular processes, possibly through their cationic charge or the regulation of calcium ions. SP and SPD over the range of 10(-7) to 10(-4) M inhibited the release of 5-hydroxytryptamine (5-HT, serotonin) triggered by compound 48/80 (C48/80) in a time- and concentration-dependent manner, as long as at least 2% calf serum (CS) was present. SP also inhibited secretion of both histamine and serotonin stimulated immunologically by using IgE and anti-rat IgE. This inhibition was not accompanied by cytotoxicity. The major available polyamine metabolites tested, N1-acetyl spermine (N1-acSP) and N8-acetyl spermidine (N8-acSPD), also showed inhibition in the presence of CS, whereas putrescine, N8,N1-hexamethylene-bis-acetamide (HMBA) and benzylamine did not. Fetal bovine serum (FBS), as well as human and rat serum, which do not contain polyamine oxidase, did not result in any inhibition with the polyamines tested. Inhibitors of the polyamine oxidase blocked the polyamine effect, indicating that the inhibition of mast cell secretion must derive from aldehydes produced from these polyamines. Addition of the aldehyde inhibitor phenylhydrazine (phi-HDZ), simultaneously with, but not following the polyamines, blocked their inhibitory effect, further strengthening the involvement of aldehydes. These results indicate that naturally occurring polyamines may regulate mast cell secretion through metabolic products of polyamine oxidase, a similar enzyme of which is also present in human liver, placenta and pregnant serum.