Bleeding jejunal varices and portal thrombosis in a splenectomized patient with hereditary spherocytosis

Bleeding from varices located in the small bowel is a very uncommon finding; nonetheless, such events accompany with a high mortality rate (1– 4). Moreover, early diagnosis of jejunal or ileal varices cannot usually be accomplished with standard diagnostic tools (ie, esophagogastroduodenoscopy, colonoscopy). Most reports in the literature relate to subjects with liver cirrhosis, often with hepatocarcinoma; in unusual anatomical situations, varices may develop beyond the ligament of Treitz in adjunct to the far more common location in the esophageal and gastric wall. Thrombosis of the portal vein is a common feature in such conditions. Portal thrombosis has also been described in association with overt or latent myeloproliferative diseases (5); its occurrence in nonneoplastic hematological conditions in subjects with normal liver function is quite uncommon. This report describes the observation of jejunal varices, with repeated episodes of “melena of unknown origin,” some of which quite severe, as their clinical presentation in a patient with portal thrombosis and with otherwise absolutely normal liver function, who had undergone splenectomy for hereditary spherocytosis in early adolescence

Age-associated alterations in cholesterol homeostasis: evidence from a cross-sectional study in a Northern Italy population.

BACKGROUND: The modifications of cholesterol metabolism associated with aging are ill-defined. The objective of this study was to define age-associated alterations of the different metabolic pathways controlling cholesterol homeostasis by analyzing circulating sterols. METHODS: We analyzed serum samples collected from 201 adult (75 male, 126 female) subjects within the epidemiological MICOL study (Multicentrica Italiana Colelitiasi). The age range was 38-79 years; 103 had evidence of gallstones. The concentrations of the different sterols, recognized as markers of the main pathways of cholesterol homeostasis, were analyzed by gas chromatography-mass spectrometry, including lathosterol (synthesis), campesterol and sitosterol (absorption), and 7α-hydroxy-4-cholesten-3-one (degradation to bile acids). RESULTS: A significant direct correlation was detected between age and cholesterol levels (r =0.34, P<0.01). The lathosterol/cholesterol ratio was lower in older age quartiles (P<0.05 by analysis of variance), with an inverse correlation between the lathosterol/cholesterol ratio and age (r=-0.32, P<0.01). Such correlation was particularly evident in females. The campesterol/cholesterol and sitosterol/cholesterol ratios were inversely correlated with aging in control, but not in gallstone patients. The levels of 7α-hydroxy-4-cholesten-3-one were not correlated with age. CONCLUSION: These data show a reduction of cholesterol synthesis with aging which is associated with increased circulating cholesterol levels. The finding might be related to a reduced metabolic need for cholesterol in advancing age, leading to a downregulation of the main mechanisms of cholesterol intake in the liver. A different age-related behavior was observed in gallstone-free versus gallstone patients regarding cholesterol absorption. The possible implications in terms of the pharmacological management of hypercholesterolemia in the elderly remain to be defined

Age-related changes in bile acid synthesis and hepatic nuclear receptor expression

BACKGROUND:Recent data highlighted the role of nuclear receptors in the transcriptional regulation of the limiting enzyme of bile acid synthesis, cholesterol 7alpha-hydroxylase, in cellular and animal models. This study was designed to analyze the effects of age on cholesterol 7alpha-hydroxylase and related nuclear receptor expression in human livers.DESIGN:Surgical liver biopsies were obtained in 23 patients requiring operation on the gastrointestinal tract. mRNA levels of cholesterol 7alpha-hydroxylase and related nuclear receptors and co-activators were assayed by quantitative real-time RT-PCR. Serum levels of 7alpha-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis, were assayed by gas-liquid chromatography:mass spectrometry.RESULTS:Ageing was inversely correlated with serum 7alpha-hydroxy-4-cholesten-3-one and with cholesterol 7alpha-hydroxylase mRNA levels (r = -0.44 and r = -0.45 on a semi-log scale, respectively, P < 0.05). Among different nuclear factors, cholesterol 7alpha-hydroxylase mRNA best correlated with hepatocyte nuclear factor-4 (r = 0.55 on a log scale, P < 0.05); hepatocyte nuclear factor-4 levels were also inversely correlated with age (r = -0.64 on a semi-log scale, P < 0.05). Age was inversely correlated with serum insulin-like growth factor-I levels, which were directly correlated with hepatocyte nuclear factor-4 and cholesterol 7alpha-hydroxylase expression. No suppressive effect of short heterodimer partner expression on cholesterol 7alpha-hydroxylase was observed.CONCLUSIONS:Ageing associates with reduced bile acid synthesis, possibly related to decreased hepatic expression of hepatocyte nuclear factor-4 and consequently of cholesterol 7alpha-hydroxylase. Age-related modifications of the growth hormone/insulin-like growth factor axis might play a role. These findings may help to elucidate the pathophysiology of age-related modifications of cholesterol metabolism

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease, is the leading monogenic cause of infant mortality. Homozygous loss of the gene survival of motor neuron 1 (SMN1) causes the selective degeneration of lower motor neurons and subsequent atrophy of proximal skeletal muscles. The SMN1 protein product, survival of motor neuron (SMN), is ubiquitously expressed and is a key factor in the assembly of the core splicing machinery. The molecular mechanisms by which disruption of the broad functions of SMN leads to neurodegeneration remain unclear. We used an antisense oligonucleotide (ASO)-based inducible mouse model of SMA to investigate the SMN-specific transcriptome changes associated with neurodegeneration. We found evidence of widespread intron retention, particularly of minor U12 introns, in the spinal cord of mice 30 d after SMA induction, which was then rescued by a therapeutic ASO. Intron retention was concomitant with a strong induction of the p53 pathway and DNA damage response, manifesting as gamma-H2A.X positivity in neurons of the spinal cord and brain. Widespread intron retention and markers of the DNA damage response were also observed with SMN depletion in human SH-SY5Y neuroblastoma cells and human induced pluripotent stem cell-derived motor neurons. We also found that retained introns, high in GC content, served as substrates for the formation of transcriptional R-loops. We propose that defects in intron removal in SMA promote DNA damage in part through the formation of RNA:DNA hybrid structures, leading to motor neuron death

Pharmacotherapy-Based Problems in the Management of Diabetes Mellitus: Needs Much More to be Done!

A total of 856 diabetic patients were evaluated for pharmacotherapy-based problems like for possible drug interactions, adverse drug reactions, and other mismatches, if any. Poor correlation between the advised insulin therapy and patients’ fasting blood glucose levels (12%, n=103) was observed. To most of the patients (41.66%, n= 357), insulin therapy was advised in combination with glucocorticoides, thiazides diuretics, and propranolol. Prescribing beta blocker (propranolol) with insulin is contraindicated. The higher incidence of diabetic foot patients was in the mean age of 57±3.4 years that was controlled with combination therapy of insulin and oral antidiabetics (63.0%, n=516). 11.1% of the treated patients could not take the prescribed therapy due to poor acceptance of insulin therapy due to its syringe needle prick. 41.66% risks of potential drug interactions, 7.93% adverse drug reactions, and 6.6% mismatches were recorded, as per the international approved algorithm, for managing a diabetes mellitus that reflects poor health care system. All these events necessitate for coordinating with other health professionals to make the therapy safer in the better interest of the patients. It is concluded that in practice prescribing pattern carries more risks for patients. It is imperative to improve the practice of pharmacotherapeutics rather than to practice in routine

Experience-Dependent Plasticity and Modulation of Growth Regulatory Molecules at Central Synapses

Structural remodeling or repair of neural circuits depends on the balance between intrinsic neuronal properties and regulatory cues present in the surrounding microenvironment. These processes are also influenced by experience, but it is still unclear how external stimuli modulate growth-regulatory mechanisms in the central nervous system. We asked whether environmental stimulation promotes neuronal plasticity by modifying the expression of growth-inhibitory molecules, specifically those of the extracellular matrix. We examined the effects of an enriched environment on neuritic remodeling and modulation of perineuronal nets in the deep cerebellar nuclei of adult mice. Perineuronal nets are meshworks of extracellular matrix that enwrap the neuronal perikaryon and restrict plasticity in the adult CNS. We found that exposure to an enriched environment induces significant morphological changes of Purkinje and precerebellar axon terminals in the cerebellar nuclei, accompanied by a conspicuous reduction of perineuronal nets. In the animals reared in an enriched environment, cerebellar nuclear neurons show decreased expression of mRNAs coding for key matrix components (as shown by real time PCR experiments), and enhanced activity of matrix degrading enzymes (matrix metalloproteinases 2 and 9), which was assessed by in situ zymography. Accordingly, we found that in mutant mice lacking a crucial perineuronal net component, cartilage link protein 1, perineuronal nets around cerebellar neurons are disrupted and plasticity of Purkinje cell terminal is enhanced. Moreover, all the effects of environmental stimulation are amplified if the afferent Purkinje axons are endowed with enhanced intrinsic growth capabilities, induced by overexpression of GAP-43. Our observations show that the maintenance and growth-inhibitory function of perineuronal nets are regulated by a dynamic interplay between pre- and postsynaptic neurons. External stimuli act on this interaction and shift the balance between synthesis and removal of matrix components in order to facilitate neuritic growth by locally dampening the activity of inhibitory cues

Co-prescription of medication for bipolar disorder and diabetes mellitus : a nationwide population based study with focus on gender differences

BackgroundStudies have shown a correlation between bipolar disorder and diabetes mellitus. It is unclear if this correlation is a part of common pathophysiological pathways, or if medication for bipolar disorder has negative effects on blood sugar regulation.MethodsThe Norwegian prescription database was analyzed. Prescriptions for lithium, lamotrigine, carbamazepine and valproate were used as proxies for bipolar disorder. Prescriptions for insulin and oral anti-diabetic agents were used as proxies for diabetes mellitus. We explored the association between medication for bipolar disorder and diabetes medication by logistic regressionResultsWe found a strong association between concomitant use of medication to treat diabetes mellitus and mood stabilizers for the treatment of bipolar disorder. Females had a 30% higher risk compared to men of being treated for both disorders. Persons using oral anti-diabetic agents had higher odds of receiving valproate than either lithium or lamotrigine. Use of insulin as monotherapy seemed to have lower odds than oral anti-diabetic agents of co-prescription of mood stabilizers, compared to the general population.ConclusionsThis study showed a strong association between the use of mood stabilizers and anti-diabetic agents. The association was stronger among women than men

Tyrosine kinase inhibitor therapy-induced changes in humoral immunity in patients with chronic myeloid leukemia

Purpose Tyrosine kinase inhibitors (TKIs) have well-characterized immunomodulatory effects on T and NK cells, but the effects on the humoral immunity are less well known. In this project, we studied TKI-induced changes in B cell-mediated immunity. Methods We collected peripheral blood (PB) and bone marrow (BM) samples from chronic myeloid leukemia (CML) patients before and during first-line imatinib (n = 20), dasatinib (n = 16), nilotinib (n = 8), and bosutinib (n = 12) treatment. Plasma immunoglobulin levels were measured, and different B cell populations in PB and BM were analyzed with flow cytometry. Results Imatinib treatment decreased plasma IgA and IgG levels, while dasatinib reduced IgM levels. At diagnosis, the proportion of patients with IgA, IgG, and IgM levels below the lower limit of normal (LLN) was 0, 11, and 6% of all CML patients, respectively, whereas at 12 months timepoint the proportions were 6% (p = 0.13), 31% (p = 0.042) and 28% (p = 0.0078). Lower initial Ig levels predisposed to the development of hypogammaglobulinemia during TKI therapy. Decreased Ig levels in imatinibtreated patients were associated with higher percentages of immature BM B cells. The patients, who had low Ig levels during the TKI therapy, had significantly more frequent minor infections during the follow-up compared with the patients with normal Ig values (33% vs. 3%, p = 0.0016). No severe infections were reported, except recurrent upper respiratory tract infections in one imatinib-treated patient, who developed severe hypogammaglobulinemia. Conclusions TKI treatment decreases plasma Ig levels, which should be measured in patients with recurrent infections.Peer reviewe

Imatinib Treatment Induces CD5+ B Lymphocytes and IgM Natural Antibodies with Anti-Leukemic Reactivity in Patients with Chronic Myelogenous Leukemia

Imatinib mesylate is a first line treatment of Chronic Myelogenous Leukemia and of a rare form of gastrointestinal stromal cancer, where the response to the drug is also linked to the immune system activation with production of antineoplastic cytokines. In this study, forty patients in the chronic phase of disease, treated with imatinib mesylate, were analyzed. Bone marrow aspirates were drawn at diagnosis, after 3, 6, 12, 18 months for haematological, cytofluorimetric, cytogenetic, biomolecular evaluation and cytokine measurement. Responder and non responder patients were defined according to the European LeukemiaNet recommendations. In responder patients (n = 32), the percentage of bone marrow CD20+CD5+sIgM+ lymphocytes, and the plasma levels of IgM, were significantly higher, at 3 months and up to 9 months, than in non responders. These IgM reacted with O-linked sugars expressed by leukemic cells and could induce tumor cell apoptosis. In responeìder patients the stromal-derived factor-1 and the B-lymphocyte-activating factor of the tumor necrosis factor family significantly raised in the bone marrow after imatinib administration, together with the bone morphogenetic proteins-2 and −7. All patients with high number of CD20+CD5+sIgM+ cells and high stromal-derived factor-1 and B lymphocyte activating factor levels, underwent complete cytogenetic and/or molecular remission by 12 months. We propose that CD20+CD5+sIgM+ lymphocytes producing anti-carbohydrate antibodies with anti-tumor activity, might contribute to the response to imatinib treatment. As in multivariate analysis bone marrow CD20+CD5+sIgM+ cells and stromal-derived factor-1 and B-lymphocyte-activating factor levels were significantly related to cytogenetical and molecular changes, they might contribute to the definition of the pharmacological response

Chondroitin sulfates and their binding molecules in the central nervous system

Chondroitin sulfate (CS) is the most abundant glycosaminoglycan (GAG) in the central nervous system (CNS) matrix. Its sulfation and epimerization patterns give rise to different forms of CS, which enables it to interact specifically and with a significant affinity with various signalling molecules in the matrix including growth factors, receptors and guidance molecules. These interactions control numerous biological and pathological processes, during development and in adulthood. In this review, we describe the specific interactions of different families of proteins involved in various physiological and cognitive mechanisms with CSs in CNS matrix. A better understanding of these interactions could promote a development of inhibitors to treat neurodegenerative diseases