Alkaline phosphatase (alp) levels in multiple myeloma and solid cancers with bone lesions: Is there any difference?

INTRODUCTION: Bone involvement in Multiple Myeloma results from increased osteoclast formation and activity that occurs in proximity to myeloma cells. The role of Alkaline Phosphatse (ALP) in this process and the diagnostic significance of plasma levels in patients with MM are unclear. AIM: To compare plasma ALP levels in patients with MM and solid cancers and metastatic lesions to the bone. RESULTS: In this observational retrospective study we enrolled 901 patients were enrolled: 440 patients (49%) with Multiple Myeloma, 461 (51%) with solid cancers. All 901 patients had bone lesions. Among patients with Multiple Myeloma, ALP values were mainly in the range of normality than those observed in patients with solid cancers and bone lesions. This difference is independent of stage, number and type of bone lesions. CONCLUSION: This study suggests that plasma ALP has a different clinical significance in MM than in other neoplasms and could be used as a discriminating marker in presence of bone lesions. In particular, lower or normal values, should suggest further investigations such as urinary and serum electrophoresis, associated with bone marrow aspirate in case of the presence of a monoclonal component, in order to confirm or exclude a MM diagnosis.

Trinigyrus spp. (Monogenea: Dactylogyridae) from Brazilian catfishes: new species, molecular data and new morphological contributions to the genus.

This study describes two new species, Trinigyrus anthus n. sp. and Trinigyrus carvalhoi n. sp., from gills of Hypostomus spp. from the Upper Paraná River basin, Brazil. Trinigyrus peregrinus is redescribed based on examination of its holotype, paratypes and new material of specimens parasitizing Pterygoplichthys ambrosettii, also from the Upper Paraná River basin, Brazil. New morphological features were included in the diagnosis of the genus, such as the presence of a sclerotized border on the anchor base, and a weakly sclerotized fringe on the base of the male copulatory organ (MCO). Trinigyrus anthus n. sp. differs from other congeners by the shape of the MCO, presenting an enlarged base with sclerotized fringes resembling flower petals. Trinigyrus carvalhoi n. sp. and T. peregrinus are similar but can be differentiated from each other mainly by the sclerotization of the vagina (absent in the new species), and the morphology of the MCO (C-shaped versus one counterclockwise circle, respectively). For the first time, gene sequences of Trinigyrus spp. from Brazil were obtained (partial ribosomal 28S and mitochondrial cytochrome c oxidase I (mtCOI)). The genetic divergences among the new species and T. peregrinus varied from 2 to 3% (6‒18 pb) based on sequences of 28S ribosomal DNA (rDNA), and 6-7% (83‒92 pb) using mtCOI. Phylogenetic analyses based on partial 28S rDNA revealed that Trinigyrus, Heteropriapulus and Unilatus formed a monophyletic and well-supported clade of monogeneans from Neotropical freshwater loricariids, suggesting a closer relationship among these dactylogyrids and their hosts.

Gain of 20q11.21 in Human Pluripotent Stem Cells Impairs TGF-ß-Dependent Neuroectodermal Commitment.

Gain of 20q11.21 is one of the most common recurrent genomic aberrations in human pluripotent stem cells. Although it is known that overexpression of the antiapoptotic gene Bcl-xL confers a survival advantage to the abnormal cells, their differentiation capacity has not been fully investigated. RNA sequencing of mutant and control hESC lines, and a line transgenically overexpressing Bcl-xL, shows that overexpression of Bcl-xL is sufficient to cause most transcriptional changes induced by the gain of 20q11.21. Moreover, the differentially expressed genes in mutant and Bcl-xL overexpressing lines are enriched for genes involved in TGF-ß- and SMAD-mediated signaling, and neuron differentiation. Finally, we show that this altered signaling has a dramatic negative effect on neuroectodermal differentiation, while the cells maintain their ability to differentiate to mesendoderm derivatives. These findings stress the importance of thorough genetic testing of the lines before their use in research or the clinic.

Morphology and molecular characterization of Demidospermus spirophallus n. sp., D. prolixus n. sp. (Monogenea: Dactylogyridae) and a redescription of D. anus in siluriform catfish from Brazil.

The present study describes Demidospermus spirophallus n. sp. and Demidospermus prolixus n. sp. (Monogenea, Dactylogyridae) from the siluriform catfish Loricaria prolixa Isbrücker & Nijssen, 1978 (Siluriformes, Loricariidae) from the state of São Paulo, Brazil, supported by morphological and molecular data. In addition, notes on the circumscription of the genus with a redescription of Demisdospermus anus are presented. Demidospermus spirophallus n. sp. differed from other congeners mainly because of the morphology of the male copulatory organ (MCO), which exhibited 2½ counterclockwise rings, a tubular accessory piece with one bifurcated end and a weakly sclerotized vagina with sinistral opening. Demidospermus prolixus n. sp. presents a counterclockwise-coiled MCO with 1½ rings, an ovate base, a non-articulated groove-like accessory piece serving as an MCO guide, two different hook shapes, inconspicuous tegumental annulations, a non-sclerotized vagina with sinistral opening and the absence of eyes or accessory eyespots. The present study provides, for the first time, molecular characterization data using the partial ribosomal gene (28S) of two new species of Demidospermus from Brazil (D. spirophallus n. sp. and D. prolixus n. sp.), and Demidospermus anus from Loricariichthys platymetopon Isbrücker & Nijssen, 1979 collected in the Upper Paraná River floodplain, Brazil. Additionally, a revision of the species composition of this genus and others that occur in catfish is proposed to elucidate problems with their circumscription. The Brazilian species of Demidospermus clustered together as sister taxa among Neotropical dactylogyrids from siluriforms. The morphological characterization of D. spirophallus n. sp. and D. prolixus n. sp., and the molecular data of the three species in the present study will extend knowledge about this monogenean genus from the Neotropical region, and provide new information for future phylogeny studies.

Uric acid and bone mineral density in postmenopausal osteoporotic women: the link lies within the fat.

The association between serum uric acid (SUA) levels and bone mineral density (BMD) is controversial. Fat accumulation is linked to SUA and BMD, thus possibly explaining the mixed results. We found that adiposity drives part of the association between SUA and BMD in women with postmenopausal osteoporosis. INTRODUCTION: Both positive and negative associations between SUA and BMD have been reported. SUA levels and BMD increase with higher body weight and other indices of adiposity; hence, the association between SUA and BMD might be a consequence of the confounding effect of adiposity. We investigated in this cross-sectional study whether the association between SUA and BMD is independent of measures of fat accumulation and other potential confounders. METHODS: SUA levels, femur BMD, markers of bone metabolism, body mass index (BMI), fat mass (FM), waist circumference (WC), and abdominal visceral fat area were measured in 180 treatment-naive postmenopausal osteoporotic women (mean age 66.3 ± 8.5 years, age range 48-81 years). RESULTS: Women with higher SUA levels (third tertile) had significantly higher femur BMD and lower cross-linked C-terminal telopeptide of type I collagen (CTX) and bone alkaline phosphatase (bALP) levels. SUA levels were positively associated with all indices of adiposity. In multivariable analysis with femur BMD as dependent variable, the association between logarithmic (LG)-transformed SUA levels and BMD (beta = 0.42, p < 0.001) was lessened progressively by the different indices of adiposity, like LG-BMI (beta = 0.22, p = 0.007), LG-WC (beta = 0.21, p = 0.01), LG-FM (beta = 0.18, p = 0.01), and LG-abdominal visceral fat area (beta = 0.12, p = 0.05). The association between SUA levels and markers of bone metabolism was dependent on the effect of confounders. CONCLUSION: In postmenopausal osteoporotic women, the strong univariable association between SUA levels and femur BMD is partly explained by the confounding effect of indices of adiposity.

The influence of cage farming on infection of the corvine fish Plagioscion squamosissimus (Perciformes: Sciaenidae) with metacercariae of Austrodiplostomum compactum (Digenea: Diplostomidae) from the Chavantes reservoir, São Paulo State, Brazil.

The development of cage fish farms has been associated with an increase in parasitic diseases. Organic matter resulting from feed waste and faeces attracts animals such as birds and invertebrates that can act as hosts for parasites. The aim of this study was to evaluate the influence of cage farming on Austrodiplostomum compactum metacercariae infections of Plagioscion squamosissimus collected close to a cage farm in the Chavantes reservoir (Paranapanema River). Thirty-seven fish were collected in an area close to cages (CF), and 28 in an area not influenced by cages (CT). All specimens were weighed, measured and the eyes removed for morphological analyses of metacercariae. The prevalence, mean intensity of infection, mean abundance and condition factor were calculated. The prevalence (CF = 86.4%, CT = 57.1%), mean infection intensity (CF = 20.31 ± 1.13, CT = 4.29 ± 7.14) and mean abundance (CF = 17.70 ± 6.27, CT = 2.35 ± 0.77) were higher in the CF (P< 0.05) group. There were no significant correlations (P> 0.05) between the mean abundance and standard length or the total weight and condition factor in either group (P> 0.05). Fish farms may interfere with the life cycle of A. compactum, leading to more infections with P. squamosissimus. This could be due to an increase in the number of host animals that are attracted by the availability of food resources derived from fish farms.

The helminth community of Geophagus proximus (Perciformes: Cichlidae) from a tributary of the Paraná River, Ilha Solteira Reservoir, São Paulo State, Brazil.

This study aimed to evaluate the helminth parasites of Geophagus proximus from the São José dos Dourados River, a tributary of Paraná River, Ilha Solteira Reservoir, São Paulo State, Brazil. From May 2006 to May 2007, 116 G. proximus specimens were examined and seven different taxa of helminth were collected and identified: proteocephalidean plerocercoids (Cestoda); metacercariae of Austrodiplostomum compactum, Clinostomum heluans and Clinostomum sp. (Trematoda); and Raphidascaris (Sprentascaris) hypostomi, and larvae of Raphidascaris sp. and Contracaecum sp. (Nematoda). All parasites presented the typical aggregated pattern of distribution, as well as the presence of a high number of larval stages, an absence of influence of the host sex and seasonality upon community parameters, as well as a correlation between species richness and host body weight. Moreover, with the exception of A. compactum metacercariae, all helminths found in this study are reported for the first time in G. proximus.

Large-scale survey of naturally occurring HBV polymerase mutations associated with anti-HBV drug resistance in untreated patients with chronic hepatitis B.

Drug resistance is a major limitation for the long-term efficacy of antiviral therapy with nucleos(t)ide analogues (NAs) in chronic hepatitis B (CHB). Antiviral resistance mutations may pre-exist in the overall viral population of untreated patients. We aimed to assess the prevalence of such hepatitis B virus (HBV) variants in a large cohort of NAs-naïve patients with CHB and to explore possible association with viral and host variables. Serum samples from 286 NAs-naïve consecutive patients with CHB were tested for serum HBV-DNA, and 255 of them having HBV-DNA > 1000 IU/mL were further analysed for drug resistance mutations by INNO-LiPA HBV DRv2/v3. NAs-naïve patients analysed were mainly men (73%), Caucasians (85%), hepatitis B e Antigen (HBeAg) negative (79%) and genotype D (69%), with a mean age of 43.2 ± 13.4 years. HBV mutations associated with antiviral drug resistance were detected in 13 (5%) patients: three patients infected with HBV genotype C had the rtM204V + rtL180M mutations associated with lamivudine (LMV) resistance. Four patients had the rtI233V mutation that may reduce sensitivity to adefovir, and three patients had the rtM250L/V mutation typical of entecavir resistance. LMV compensatory mutations rtL80V and rtV173L were seen in two and one patients, respectively. No relationship was seen between presence of resistant or compensatory mutations and HBV-DNA levels, HBeAg/anti-HBe status or previous IFN therapy. These results confirm that HBV mutations, which confer resistance against currently available anti-HBV NAs, may already exist in patients who have never received the drug.

Relationship between major adverse cardiac events and angiographic findings in dialysis patients.

BACKGROUND: In dialysis patients, coronary angiography (CA) predicts major adverse coronary events (MACE) better than non-invasive tests. The aim of this study was to investigate in such patients the relationship between coronary atherosclerotic damage shown by angiography and MACE, during an average follow-up period of more than 5 years. PATIENTS AND METHODS: Coronary angiography was performed in 63 dialysis patients (mean age 56 ± 12 years, 49 men); 37 subjects awaiting kidney transplantation had no history of cardiac disease, whereas the remaining 26 patients had clinical evidence of coronary artery disease (CAD). During a follow-up period of 62 ± 20 months (range 12-109), all the MACE were recorded. Statistical analysis was carried out by dividing the patients into two groups, those who had MACE (MACE group) and those who were free of cardiac events (FCE group). Severe CAD on CA was defined as luminal stenosis ≥ 75% in at least one vessel. Logistic regression analysis and Cox regression analysis were carried out in order to evaluate which variable was associated with MACE. RESULTS: At the end of follow-up, 17 subjects had MACE and severe CAD was shown in the epicardial arteries of 31 patients (49%). Compared to the FCE group, the MACE group had older age (65 ± 10 vs 53 ± 11 years, P = 0.002), lower diastolic blood pressure (79 ± 7 vs 85 ± 7 mmHg, P = 0.0037), higher prevalence of CAD (82 vs 30%, P = 0.0002) and cerebrovascular disease (41 vs 15%, P = 0.0278). Coronary artery damage was higher in the MACE group than in the FCE group. Logistic and Cox regression analyses showed that age was the only variable independently associated with MACE (OR 1.109 95% CI 1.022-1.204, P = 0.0133, hazard ratio 1.066 95% CI 1.010-1.125, P = 0.02, respectively). After removal of age from the model, MACE were independently associated with haemodynamic stenosis of coronary arteries (OR 7.429 95% CI 1.829-30.173, P = 0.005, hazard ratio 5.992 95% CI 1.655-21.698, P = 0.006, respectively). Event-free survival was much better in the 37 renal transplant candidates with no history of CAD than in the 26 patients who had clinical evidence of CAD. CONCLUSIONS: This observational study confirms that in dialysis patients coronary atherosclerotic damage shown by angiography is strongly related to MACE and that age and severe CAD are major risk factors for MACE.

Hyperinsulinaemia reduces the 24-h virological response to PEG-interferon therapy in patients with chronic hepatitis C and insulin resistance.

Insulin resistance (IR) reduces response to pegylated-interferon (PEG-IFN)/ribavirin in chronic hepatitis C (CHC), but the mechanisms are still undefined. We examined the relationship between baseline insulin levels, the main component affecting homeostasis model of assessment - insulin resistance (HOMA-IR) for assessment of IR in non-diabetic patients, and the 'acute' virological response to PEG-IFN measured 24 h after the first injection and taken as correlate of intracellular interferon signalling. In 62 patients treated with PEG-IFN/Ribavirin, serum insulin and HOMA-IR were assessed at baseline, while hepatitis C virus (HCV)-RNA was measured at baseline and 24 h, 1, 2, 4 and 12 weeks after treatment initiation. Sustained virological response was examined 24 weeks after therapy discontinuation. Mean baseline insulin was 11.52 +/- 8.51 U/L and mean HOMA-IR was 2.65 +/- 2.01 both being significantly higher with advanced liver fibrosis. Hepatitis C virus-RNA decay observed 24 h after the first injection of PEG-IFN was significantly lower (0.7 +/- 0.8 log) in patients with HOMA > or =3 compared with those with HOMA <3 (1.7 +/- 0.8, P = 0.001). A highly significant (r = -0.42) inverse correlation was observed between baseline insulin levels and the 24-h HCV-RNA decay. The difference in early viral kinetics between patients with HOMA > or =3 or <3 resulted in a significant difference in the percentage of patients achieving rapid (week 4) and sustained virological response. Multivariate analysis, inclusive of patient age, HCV genotype and fibrosis stage, identified baseline insulin levels as the main independent variable affecting the 24-h response to PEG-IFN. Hyperinsulinaemia reduces the cellular response to Pegylated-interferon in CHC with IR. Strategies to reduce insulin levels before initiation of treatment should be pursued to improve efficacy of anti-viral treatment.

The relationship between carotid and coronary atherosclerotic damage in dialysis patients.

BACKGROUND: Data relating carotid ultrasound (CU) to atherosclerotic damage evaluated by coronary angiography in hemodialysis patients are scarce. METHODS: We carried out a cross-sectional study in 33 uremic subjects (age 55 +/- 12 years, 22 male, 7 diabetic), who have been on dialysis for 41 +/- 48 months (range 2-192). Twenty-two underwent a coronary angiography in order to complete clinical evaluation for inclusion on the kidney transplantation waiting list, and 11 because of coronary artery disease (CAD); Gensini's score was calculated. Intima-media thickness (IMT) and presence of plaques were related to the degree of coronary stenosis and to cardiovascular risk factors. Patients were divided into two groups depending on mean IMT (group 1 IM 0.9 mm, n=15). RESULTS: Group 2 was older (60 +/- 8 vs 50 +/- 12 year, p=0.01), had higher frequency of CAD (53 vs 16%, p=0.02) and had higher prevalence of coronary artery stenosis >or= 75% in the right (60 vs 22%, p=0.02), left anterior descending (46 vs 16%, p=0.06) and left circumflex coronary arteriers (60 vs 11%, p=0.05) than group 1. IMT was not related to the degree of CAD evaluated by Gensini's score. IMT sensibility and specificity in detecting the presence of hemodynamically significant coronary stenosis were 64% and 68%, respectively. Coronary narrowing was correlated with the degree of stenosis of common, internal and external carotid arteries (Spearman's rank correlation coefficient). During two years of follow-up, six major cardiac events were recorded and they were related to Gensini's score. CONCLUSIONS: In uremic patients, ultrasonographic evaluation of carotid arteries is a simple, noninvasive examination that could be a helpful tool in detecting coronary atherosclerotic damage, but IMT does not appear to add more information regarding risk stratification of CAD.

Infantile encephalomyopathy and nephropathy with CoQ10 deficiency: a CoQ10-responsive condition.

Coenzyme Q10 (CoQ10) deficiency has been associated with various clinical phenotypes, including an infantile multisystem disorder. The authors report a 33-month-old boy who presented with corticosteroid-resistant nephrotic syndrome in whom progressive encephalomyopathy later developed. CoQ10 was decreased both in muscle and in fibroblasts. Oral CoQ10 improved the neurologic picture but not the renal dysfunction.

Amino-terminal propeptide of type III procollagen is associated with restrictive mitral filling pattern in patients with dilated cardiomyopathy: a possible link between diastolic dysfunction and prognosis.

OBJECTIVE: To analyse the relation between restrictive mitral pattern, amino-terminal propeptide of type III procollagen (PIIINP), and prognosis in patients with dilated cardiomyopathy. DESIGN: Prospective cohort study of 106 patients with dilated cardiomyopathy. SETTING: Tertiary care centre. MAIN OUTCOME MEASURES: PIIINP concentration, echocardiographic variables, oxygen consumption, hospitalisation for heart failure, and cardiac mortality were evaluated in patients grouped by the presence of non-restrictive (group 1), reversible (group 2), and irreversible restrictive mitral pattern (group 3). RESULTS: Groups differed regarding left ventricular ejection fraction (group 1, mean (SD) 36 (6)%, group 2, 29 (8)%, group 3, 25 (6)%; p = 0.0001), left atrial ejection fraction (group 1, 0.47 (0.1)%, group 2, 0.43 (0.2)%, group 3, 0.26 (0.1)%; p < 0.0001), and PIIINP (p = 0.001). Multivariate analysis showed that PIIINP was related to mitral pattern (odds ratio 0.8, 95% confidence interval 0.23 to 1.4, p = 0.006) independently of left atrial and ventricular ejection fractions. After 21 months, survival was 88% and 34% (p = 0.0001) in patients with non-restrictive and irreversible restrictive mitral patterns, respectively. CONCLUSION: In patients with dilated cardiomyopathy, restrictive mitral pattern is associated with higher PIIINP and worse prognosis.

Failure of aldosterone suppression despite angiotensin-converting enzyme (ACE) inhibitor administration in chronic heart failure is associated with ACE DD genotype.

OBJECTIVES: The objective of this study was to assess whether the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism influences the adequacy of the neurohormonal response to ACE inhibitors in patients with chronic heart failure (CHF). BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathophysiology of CHF, and aldosterone levels closely relate to outcome in patients with CHF. Angiotensin-converting enzyme inhibitors suppress the RAAS, but a significant proportion of patients exhibit elevated serum levels of aldosterone despite long-term administration of apparently adequate doses of these agents. METHODS: We prospectively studied 132 patients with CHF (ejection fraction <45%) receiving long-term therapy with ACE inhibitors for over six months. Patients taking aldosterone antagonists were excluded from the study. "Aldosterone escape" was defined as being present when plasma aldosterone levels were above the normal range in our laboratory (>42 nmol/L). Patients were then divided into two subgroups according to the presence (group 1) or absence (group 2) of aldosterone escape. Genotype analysis for the ACE I/D polymorphism was performed by polymerase chain reaction. RESULTS: The prevalence of aldosterone escape in our patients was 10% (13/132). The two groups of patients did not differ regarding the dose of ACE inhibitor, diuretics and their renal function. There was a statistically significant different distribution of genotypes between the two groups, with a higher proportion of DD genotype in group 1 compared with group 2 (62% vs. 24%, p = 0.005). CONCLUSIONS: Patients with CHF with aldosterone escape have a higher prevalence of DD genotype compared with patients with aldosterone within the normal limits. Angiotensin-converting enzyme gene polymorphism contributes to the modulation and adequacy of the neurohormonal response to long-term ACE-inhibitor administration in CHF.

Skeletal muscle mass independently predicts peak oxygen consumption and ventilatory response during exercise in noncachectic patients with chronic heart failure.

OBJECTIVES: We sought to assess whether skeletal muscle mass might be a predictor of peak oxygen consumption (Vo2) and relation of the ventilation to carbon dioxide production (VE/VCo2) slope in patients with chronic heart failure (CHF) independent of clinical conditions, neurohormonal activation and resting hemodynamics. BACKGROUND: A variety of abnormalities characterize skeletal muscle and contribute to exercise intolerance in patients with CHF. Skeletal muscle mass is a determinant of peak Vo2 both in healthy patients and in patients with CHF, but there are no reports on the independent predictive value of this parameter, which can be measured with great accuracy by whole-body dual energy X-ray absorptiometry (DEXA). The influence of skeletal muscle mass on VE/VCo2 slope is not known either. METHODS: We prospectively evaluated 120 consecutive noncachectic patients with CHF. Every patient underwent a cardiopulmonary exercise test, an echo-Doppler examination and an evaluation of neurohormonal activation and body composition as assessed by DEXA. RESULTS: At the univariate analysis, New York Heart Association (NYHA) class (p < 0.0001), age (p < 0.0001), male gender (p < 0.0001) and plasma renin (p < 0.0001) significantly related with peak Vo2. There was a significant correlation between lean mass and absolute peak Vo2 (r = 0.70, p < 0.0001) and VE/VCo2 slope (r = -0.27; p < 0.01). At the multivariate analysis, lean mass predicted peak Vo2 and VE/VCo2 slope independently of NYHA functional class, age, gender, neurohormonal activation and resting hemodynamics. CONCLUSIONS: Skeletal muscle mass is an independent predictor of peak Vo2 and VE/VCo2 slope in stable noncachectic patients with CHF. Future studies will determine whether an increase in skeletal muscle mass in the individual patient might result in an improvement in parameters of exercise capacity.

A 15-year follow-up of a boy with pyridoxine (vitamin B6)-dependent seizures with autism, breath holding, and severe mental retardation.

Pyridoxine (vitamin B6) (2q31) dependency is a rare autosomal-recessive disorder that causes a severe seizure disorder of prenatal or neonatal onset. The abnormality appears to inhibit the binding of vitamin B6 to the enzyme glutamic acid decarboxylase-1, which is needed for the biosynthesis of gamma-aminobutyric acid (GABA). Most patients with pyridoxine-dependent seizures require lifelong treatment with pyridoxine. The full range of associated symptomatology is unknown since fewer than 100 cases have been reported. A majority of cases are mentally retarded. We report a 15-year-old boy with pyridoxine-dependent seizures, nonpyridoxine-dependent seizures, severe mental retardation, autistic disorder, aerophagia, breath holding, and self-injury. This complex outcome should alert clinicians to the wide range of neuropsychiatric outcomes associated with this disorder.