R0 Liver Resections for Primary Malignant Liver Tumors in the Noncirrhotic Liver: A Diagnosis-Related Analysis

Background Primary liver cancer constitutes an increasingly malignancy in the Western world and one of the leading causes of cancer-related deaths worldwide. The purpose of this study was to evaluate and compare long-term outcomes after R0 resections in noncirrhotic livers for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Methods Between April 1998 and May 2006 a total of 102 patients with either ICC (n = 41, group 1) or HCC (n = 61, group 2) in the absence of cirrhosis underwent curative liver resection in our department. Demographic characteristics, operative details, perioperative complications, pathologic findings, tumor recurrence and survival were analyzed. Results Gender (P = 0.007), extent of liver resection (P = 0.036), additional surgical procedures (P < 0.001) and operative morbidity (P = 0.018) differed among the two groups. Following resection, after a median follow-up of 28 months, the calculated 5-year survival was 44% and 40% for ICC and HCC, respectively (P = 0.38). The corresponding recurrence-free survival was 25% for both ICC and HCC (P = 0.66). UICC stage was found to predict overall and recurrence-free survival in both types of tumors. Multifocality in the case of ICC, and tumor differentiation and vascular invasion in the case of HCC, were predictive factors for overall and recurrence-free survival, respectively. In multivariable analyses, vascular invasion for HCC was predictive for overall and recurrence-free survival, whereas in the case of ICC significant differences were detected in the recurrence analysis for multifocality and UICC stage. Conclusions R0 resections for both ICC and HCC result to similar long-term outcomes, which are characterized by good overall and acceptable recurrence-free survival rates.     

Periodic Therapeutic Plasma Exchange in Patients With Moderate to Severe Chronic Myasthenia Gravis Non‐Responsive to Immunosuppressive Agents: An Eight Year Follow‐Up

Few patients with moderate or severe myasthenia gravis (MG) do not respond to immunosuppressive treatment. We present our experience with periodic therapeutic plasma exchange (TPE), in 11 patients with MG resistant to intravenous immunoglobulin (IVIg) therapy, who had frequent relapses even whilst on high doses of immunosuppressive drugs, over a period of 8 years. All patients underwent TPE until control of their symptoms was achieved, and afterwards TPE sessions were continued periodically in an attempt to achieve remission of the disease, without immunosuppressant therapy. Two of the patients were progressively weaned off immunosuppressive agents, as well as TPE, and they are now symptom free. The other nine patients are still under a periodic TPE regime. Seven of them were weaned off all medications and required an average of 3.7 TPE sessions per year during the last 5 years. In the other two patients, those with the most severe form of the disease, the immunosuppressant dosage has been decreased and a TPE session every 2–3 weeks is required in order to control their symptoms. Through all these years TPE has been well tolerated and only minor side‐effects were observed in two patients. Finally, during this 8 year follow‐up period, nine of the patients treated with periodic TPE have been in good control of their symptoms over the last 5 years, and the other two patients live a normal life without any treatment in the last 3 years. Our results suggest that periodic TPE is safe and effective in the control of symptoms in patients with moderate to severe MG who do not respond to immunosuppressive therapies.     

Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-kappaB ligand concentrations and normalises indices of bone remodelling in patients with relapsed multiple myeloma

The effect of bortezomib on bone remodelling was evaluated in 34 relapsed myeloma patients. At baseline, patients had increased serum concentrations of dickkopf-1 (DKK-1), soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), sRANKL/osteoprotegerin ratio, C-telopeptide of type-I collagen (CTX) and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b); bone-alkaline phosphatase and osteocalcin were reduced. Serum DKK-1 correlated with CTX and severe bone disease. Bortezomib administration significantly reduced serum DKK-1, sRANKL, CTX, and TRACP-5b after four cycles, and dramatically increased bone-alkaline phosphatase and osteocalcin, irrespective of treatment response. This is the first study showing that bortezomib reduces DKK-1 and RANKL serum levels, leading to the normalisation of bone remodelling in relapsed myeloma.     

Short-term effect of orlistat on dietary glycotoxins in healthy women and women with polycystic ovary syndrome

Exogenous advanced glycation endproducts (AGEs, known atherogenic molecules) abundant in everyday precooked, rich in fat, overheated meals can possibly contribute to the increased risk for diabetes and cardiovascular disease in women with polycystic ovary syndrome (PCOS). The aim of the present study was to investigate the effect of a lipase inhibitor on absorbed food glycotoxins in healthy women and those with PCOS. A 2-day protocol was followed. In the first day, a meal rich in AGE was provided, which on the second day was followed by two 120-mg capsules of lipase inhibitor, orlistat. Serum AGE levels were evaluated at baseline (0 hours), and at 3 and 5 hours postmeal during the study. Thirty-six women were studied, 15 controls (mean age, 28.80 +/- 5.47 years; body mass index, 25.85 +/- 6.73 kg/m(2)) and 21 with PCOS (mean age, 25.29 +/- 5.06 years; body mass index, 30.40 +/- 7.51 kg/m(2)) (University Hospital, Athens, Greece, institutional practice). Serum AGE levels, on day 1, were significantly increased both in the control group and in the PCOS group as compared with basal values (control group, 14.1%; PCOS group, 6.0%; P < .001). The corresponding rise was significantly lower on day 2 when the same meal was combined with orlistat (control group, 4.1%; PCOS group, 2.0%; P < .01). A limitation of the study is that it is a nonplacebo, nonrandomized therapeutic trial where each subject is considered as its own control. In conclusion, this study demonstrated the beneficial effect of orlistat on the absorption of food glycotoxins.     

Alterations of leptin during IFN-alpha therapy in patients with chronic viral hepatitis

BACKGROUND/AIMS: Leptin has a particular profibrogenic role in the liver. We investigated whether IFN-alpha influences leptin production in patients with chronic hepatitis B (CHB) and C (CHC). Leptin was determined in serial samples from 63 CHB and 42 CHC IFN-alpha treated patients. Furthermore, we evaluated whether leptin alterations were associated with patients' characteristics. METHODS: Sera were investigated at serial time-points using an enzyme-linked-immunosorbent-assay. Controls consisted of 36 patients with autoimmune liver diseases and 44 healthy patients. RESULTS: Leptin levels before IFN-alpha administration were higher in CHB and CHC compared to healthy (P<0.004) and diseased controls (P=0.0001). In CHB patients, we observed a significant reduction of leptin during IFN-alpha treatment and lasting for up to 6 months after the end of treatment, followed by an increase reaching pretreatment levels at 1.5 years after stopping therapy. The pattern of leptin alterations was similar in CHC patients where leptin's decrease was more pronounced at 6 months after the end of treatment. Biochemical or virological response to treatment was not associated with leptin reduction in both groups. CONCLUSIONS: This study provides information on leptin kinetics during IFN-alpha treatment and follow-up in CHB and CHC patients and suggests IFN-alpha as a potential inhibitor of leptin production.     

Non-resident fathers' relationships with their secondary school age children: determinants and children's mental health outcomes

Data from 520 British secondary school age children were used to explore determinants of and mental health outcomes (measured with the Strengths and Difficulties Questionnaire) from their non-resident fathers' relationships (child-reported father's involvement and frequency of contact) with them. Frequency of contact was negatively related to time elapsed since parents separated, and was higher if fathers were single than partnered. Compared to White, non-White adolescents reported lower frequency of father's contact but not lower father's involvement. Father's involvement was related positively to mother's involvement and negatively to interparental conflict. As a whole, non-resident father's involvement and frequency of contact did not improve the regression models predicting children's total difficulties or pro-social behaviour. Even after controlling for other factors non-resident father's involvement did not predict child's difficulties or pro-social behaviour, although frequency of contact was negatively associated with child's emotional symptoms. Neither child's ethnicity or gender nor mother's partner status moderated the link between child's mental health outcomes and non-resident father's involvement or frequency of contact.     

Comparing accommodative function between the dominant and non-dominant eye

Background

To compare the accommodative amplitude (AA), facility (AF), and lag between dominant and non-dominant eyes.

Methods

Seventy students [mean (SD) age: 21.2 (1.7) years, range 18–25] from Zahedan University of Medical Sciences were selected. Retinoscopy and subjective refraction was used to determine the refractive error. The hole-in-the card method was used to determine eye dominance. The accommodative amplitude (AA) was measured in the dominant and non-dominant eye using the push-up method, and accommodative facility (AF) using ±2.00 dioptre flipper lenses at 40 cm. Accommodative lag was determined using monocular estimate method (MEM) retinoscopy at 40 cm.

Results

The right eye was dominant in 53 subjects (75.7 %). There was no significant difference in refractive error (sphere, cylinder, and spherical equivalent) between dominant and non-dominant eyes. The mean (SD) for the AA, AF, and lag in dominant eyes was 12.48 (2.56) dioptres, 12.45 (4.83) cycles per minute, and 0.80 (0.27) dioptres respectively. The mean (SD) for the AA, AF, and lag in non-dominant eyes was 12.16 (2.37) dioptres, 12.20 (4.88) cycles per minute, and 0.83 (0.28) dioptres respectively. The mean (SD) difference in AA, AF, and lag between dominant and non dominant eyes was 0.32 (0.75) dioptres (P?=?0.001), 0.25 (1.05) cycles per minute (P?=?0.04), and ?0.02 (0.11) dioptres (P?=?0.10) respectively. The AA and AF was statistically better (P?<?0.05) in the dominant eye group than in the non-dominant eye group. These data provided little evidence of any difference in the accommodative lag between dominant and non-dominant eyes (P?>?0.05).

Conclusion

The right eye was dominant in 76 % of subjects. Superior AA and AF was found in the dominant eye as determined by hole-in-the card method in young healthy adults, although these differences are perhaps not of clinical significance (<0.50 dioptres and <2 cycles per minute).     

IgA Anti-b2GPI Antibodies in Patients with Autoimmune Liver Diseases

INTRODUCTION: Recently, we reported a high prevalence of immunoglobulin G and/or immunoglobulin M anticardiolipin antibodies (aCL) in patients with autoimmune liver diseases, namely, autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC), which were independent of the respective isotypes of antibodies against beta2-glycoprotein I (anti-b2GPI). Immunoglobulin A (IgA) aCL and IgA anti-b2GPI are the least studied of the three specific isotypes either in antiphospholipid syndrome (APS) or in other conditions. METHODS: Therefore, we investigated the prevalence and clinical significance of IgA anti-b2GPI and IgA aCL by enzyme-linked immunosorbent assays in another set of Caucasian patients with autoimmune liver diseases (59 AIH, 96 PBC, and 37 PSC). The disease controls group consisted of 50 hepatitis C virus (HCV) patients, 50 hepatitis B virus (HBV), 30 alcoholic liver disease (ALD), 30 non-alcoholic steatohepatitis (NASH), and 110 healthy controls. RESULTS AND DISCUSSION: IgA anti-b2GPI prevalence was higher in AIH (50.8%) compared to PBC (p = 0.005), PSC (p = 0.008), NASH (p = 0.004), ALD (p = 0.01), and HCV (p = 0.002). The titers were also significantly higher in AIH compared to any other group of the study. IgA aCL prevalence was higher in AIH (33.9%) compared to PBC (p = 0.005), PSC (p = 0.014), NASH (p = 0.001), ALD (p = 0.004), and HCV (p < 0.001). IgA anti-b2GPI or IgA aCL were not associated with APS features in patients with liver autoimmunity. Of note, IgA anti-b2GPI and IgA aCL were associated with clinical and biochemical markers of disease severity in AIH and PBC. We demonstrated a high prevalence and high titers of IgA anti-b2GPI in patients with AIH compared to any other liver disease of the study. CONCLUSION: IgA anti-b2GPI and IgA aCL were associated with the severity and biochemical activity of AIH and PBC, but long-term prospective studies are needed to address whether this new finding is of clinical importance in AIH and PBC patients.     

MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans

An interesting variant of familial glucocorticoid deficiency (FGD), an autosomal recessive form of adrenal failure, exists in a genetically isolated Irish population. In addition to hypocortisolemia, affected children show signs of growth failure, increased chromosomal breakage, and NK cell deficiency. Targeted exome sequencing in 8 patients identified a variant (c.71-1insG) in minichromosome maintenance-deficient 4 (MCM4) that was predicted to result in a severely truncated protein (p.Pro24ArgfsX4). Western blotting of patient samples revealed that the major 96-kDa isoform present in unaffected human controls was absent, while the presence of the minor 85-kDa isoform was preserved. Interestingly, histological studies with Mcm4-depleted mice showed grossly abnormal adrenal morphology that was characterized by non-steroidogenic GATA4- and Gli1-positive cells within the steroidogenic cortex, which reduced the number of steroidogenic cells in the zona fasciculata of the adrenal cortex. Since MCM4 is one part of a MCM2-7 complex recently confirmed as the replicative helicase essential for normal DNA replication and genome stability in all eukaryotes, it is possible that our patients may have an increased risk of neoplastic change. In summary, we have identified what we believe to be the first human mutation in MCM4 and have shown that it is associated with adrenal insufficiency, short stature, and NK cell deficiency.     

Twin studies in autoimmune disease: genetics, gender and environment

Twin studies are powerful tools to discriminate whether a complex disease is due to genetic or environmental factors. High concordance rates among monozygotic (MZ) twins support genetic factors being predominantly involved, whilst low rates are suggestive of environmental factors. Twin studies have often been utilised in the study of systemic and organ specific autoimmune diseases. As an example, type I diabetes mellitus has been investigated to establish that that disease is largely affected by genetic factors, compared to rheumatoid arthritis or scleroderma, which have a weaker genetic association. However, large twin studies are scarce or virtually non-existent in other autoimmune diseases which have been limited to few sets of twins and individual case reports. In addition to the study of the genetic and environmental contributions to disease, it is likely that twin studies will also provide data in regards to the clinical course of disease, as well as risk for development in related individuals. More importantly, genome-wide association studies have thus far reported genomic variants that only account for a minority of autoimmunity cases, and cannot explain disease discordance in MZ twins. Future research is therefore encouraged not only in the analysis of twins with autoimmune disease, but also in regards to epigenetic factors or rare variants that may be discovered with next-generation sequencing. This review will examine the literature surrounding twin studies in autoimmune disease including discussions of genetics and gender.