Hyperhomocysteinemia and the MTHFR C677T polymorphism promote steatosis and fibrosis in chronic hepatitis C patients

The factors and mechanisms implicated in the development of hepatitis C virus (HCV)-related steatosis are unknown. Hyperhomocysteinemia causes steatosis, and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism induces hyperhomocysteinemia. We investigated the role of these factors in the development of HCV-related steatosis and in the progression of chronic hepatitis C (CHC). One hundred sixteen CHC patients were evaluated for HAI, fibrosis and steatosis grades, body mass index, HCV genotypes, HCV RNA levels, homocysteinemia, and the MTHFR C677T polymorphism. Hyperhomocysteinemia was associated with the TT genotype of MTHFR (r = 0.367; P = .001). Median values of homocysteine in the CC, CT, and TT genotypes of the MTHFR gene were 9.3, 12.2, and 18.6 micromol/L, respectively (P = .006). Steatosis correlated with the MTHFR polymorphism, homocysteinemia, HAI and fibrosis. Steatosis above 20% was significantly associated with fibrosis. Prevalence and high grade (>20%) of steatosis were 41% and 11% in CC, 61% and 49% in CT, and 79% and 64% in TT, respectively (P = .01). Relative risk of developing high levels of steatosis was 20 times higher for TT genotypes than CC genotypes. According to multivariate analysis, steatosis was independently associated with hyperhomocysteinemia (OR = 7.1), HAI (OR = 3.8), liver fibrosis (OR = 4.0), and HCV genotype 3 (OR = 4.6). On univariate analysis, fibrosis was associated with age, steatosis, MTHFR, homocysteinemia and HAI; however, on multivariate analysis, liver fibrosis was independently associated with age (P = .03), HAI (P = .0001), and steatosis (P = .007). In conclusion, a genetic background such as the MTHFR C677T polymorphism responsible for hyperhomocysteinemia plays a role in the development of higher degree of steatosis, which in turn accelerates the progression of liver fibrosis in CHC.     

Potent relaxant effect of a Celastrus paniculatus extract in the rat and human ileum

Ethnopharmacological importance

Celastrus paniculatus Willd. (Celastraceae) is an Ayurvedic remedy used for the treatment of a number of diseases, including bowel spasms.

Aim of the study

To investigate the mode of the relaxing action of a methanolic extract prepared from the seeds of Celastrus paniculatus (CPE, 0.0001–10 μg/mL) in the rat ileum and to try to confirm on human tissues the intestinal pharmacological activity of the extract.

Materials and methods

The relaxant effect of CPE was studied in vitro by evaluating its effect on the spontaneous contractions of the isolated ileum.

Results

CPE exerted a tetrodotoxin- and ω-conotoxin-resistant inhibitory effect on rat ileum motility (IC₅₀: 0.24 ± 0.02 μg/mL; E_max: 99.0 ± 0.60%). The inhibitory effect was reduced by nifedipine but not by cyclopiazonic acid. Experiments with specific antagonists enabled us to exclude the involvement of the main endogenous spasmogenic (i.e. acetylcholine and tachykinins) and relaxing (noradrenaline, nitric oxide, ATP) compounds. CPE also relaxed the isolated human ileum (IC₅₀: 0.26 ± 0.02 μg/mL; E_max: 99.1 ± 0.46%).

Conclusion

It is concluded that (i) CPE exerted a powerful myogenic and L-type Ca²⁺-dependent relaxing effect in the isolated rat ileum and that (ii) the human ileum is sensitive to the inhibitory effect of CPE. If confirmed in vivo, our data could explain the traditional use of this herb in the treatment of intestinal spasms.     

Vitamin D Deficiency in Women with Breast Cancer: A Correlation with Osteoporosis? A Machine Learning Approach with Multiple Factor Analysis

Breast cancer (BC) is the most frequent malignant tumor in women in Europe and North America, and the use of aromatase inhibitors (AIs) is recommended in women affected by estrogen receptor-positive BCs. AIs, by inhibiting the enzyme that converts androgens into estrogen, cause a decrement in bone mineral density (BMD), with a consequent increased risk of fragility fractures. This study aimed to evaluate the role of vitamin D3 deficiency in women with breast cancer and its correlation with osteoporosis and BMD modifications. This observational cross-sectional study collected the following data regarding bone health: osteoporosis and osteopenia diagnosis, lumbar spine (LS) and femoral neck bone mineral density (BMD), serum levels of 25-hydroxyvitamin D3 (25(OH)D3), calcium and parathyroid hormone. The study included 54 women with BC, mean age 67.3 ± 8.16 years. Given a significantly low correlation with the LS BMD value (r² = 0.30, p = 0.025), we assessed the role of vitamin D3 via multiple factor analysis and found that BMD and vitamin D3 contributed to the arrangement of clusters, reported as vectors, providing similar trajectories of influence to the construction of the machine learning model. Thus, in a cohort of women with BC undergoing Ais, we identified a very low prevalence (5.6%) of patients with adequate bone health and a normal vitamin D3 status. According to our cluster model, we may conclude that the assessment and management of bone health and vitamin D3 status are crucial in BC survivors.     

Inhibition of macrophage phagocytic activity by SV-IV, a major protein secreted from the rat seminal vesicle epithelium

The protein SV-IV, one of the major secretory proteins produced by the rat seminal vesicle epithelium, has been found to possess a marked ability to inhibit in vitro the phagocytic properties of activated peritoneal rat macrophages, by a mechanism that apparently involves phagocytes and target cells. Although SV-IV is a substrate for transglutaminase (TGase), an enzyme secreted by activated macrophages, TGase does not seem to play any significant role either in the binding of the protein to the cells participating in the phagocytic process or in the inhibition of macrophage phagocytosis by SV-IV. The significance of the findings in relation to the reproductive process and their possible clinical implications are discussed.     

Pica: a clinical case and therapeutic problems

Pica is a psychotic disorder characterized by compulsive ingestion of nonfood substances; the primary treatment is the prevention with antipsychotic therapy. When the patient ingests foreign body, endoscopical removal is recommended. Surgical treatment is necessary when an acute abdomen is present, with intestinal occlusion and/or bowel perforation. The Authors report a peculiar case of pica, and analyse the problems of organization and assistance, besides surgical approach, also on the base of international literature.     

Technical standardization of laparoscopic splenectomy: experience with 105 cases

Background: Some reports have suggested that laparoscopic splenectomy (LS) can be successfully performed in adults. However, several aspects of this procedure remain as yet undefined; therefore, several attempts have been made to modify the standard technique to try to optimize the procedure. Herein we analyze our experience with 105 laparoscopic splenectomies. Methods: From 1993 to 2000, 105 patients underwent LS at our hospital. Twelve of these patients also underwent a concomitant cholecystectomy. There were 66 women and 39 men whose ages ranged between 4 and 78 years (median, 27.7). All patients underwent an elective laparoscopic splenectomy. Seventy five patients had thrombocytopenia (ITP), 14 had hereditary spherocytosis, eight were affected by b-thalassemia, two had splenic cysts, two had lymphoma, (two had myeloid chronic leukemia, one patient presented with a splenic abscess and one had incurred an iatrogenic spleen lesion during adrenalectomy. The first patients in this series were positioned in dorsal decubitus; however, as the team's experience increased, the right lateral decubitus became the position of choice because it provides better exposure of the splenic hilum. This procedure requires the use of only four trocars. Results: Mean operating time was 95 min (range, 35–320). Hospital stay ranged from 2 to 21 days (median, 4.5). There was only one conversion to open surgery. One patient died in the postoperative period due to the evolution of a preexisting malignant disease. We recorded nine complications—four subphrenic abscesses, two cases of pleuritis, two episodes of postoperative bleeding, and one intestinal infarction 16 days after surgery. Only two patients needed redo surgery. Conclusions: We believe that the laparoscopic approach is a valid alternative to open splenectomy, but mastery of some of the technical details of this procedure could greatly help avoid its complications. On the basis of our experience, it seems that the lateral approach should be considered the position of choice because it provides exposure and easier dissection of the splenic hilar structures. We also found that a 30° scope and an ultrasonic dissector allowed for perfect vision and optimal hemostasis during the procedure. At the end of procedure, the spleen should be fragmented and then extracted using an extraction bag.     

Episodic pain in patients with advanced cancer

Episodic pain is a common problem for patients with advanced cancer and is often difficult to manage successfully. In this article, the daily variations in cancer-related episodic pain in a patient with metastatic lung cancer are described. The definition, etiology, prevalence, and pharmacological management of episodic pain are also reviewed     

Design and development of 2,3-benzodiazepine (CFM) noncompetitive AMPA receptor antagonists

2,3-Benzodiazepines represent a class of heterocyclic compounds that interact with AMPA-type glutamate receptors in a noncompetitive manner. These compounds have attracted great interest for their pharmacological effects against acute and chronic neurodegenerative diseases, such as ischemia and epilepsy. We synthesized a large number of 2,3-benzodiazepine derivatives, which showed anticonvulsant properties in different seizure models and a noncompetitive blockade of AMPA receptor. This article will briefly mention our work in this field and the main SAR considerations.     

Novel potent AMPA/kainate receptor antagonists: synthesis and anticonvulsant activity of a series of 2-[(4-alkylsemicarbazono)-(4-amino-phenyl)methyl]-4,5-methylenedioxyphenylacetic acid alkyl esters

In this paper we describe the synthesis of a series of novel 2-[(4-alkylsemicarbazono)-(4-aminophenyl)-methyl]-4,5-methylenedioxyphenylacetic acid alkyl esters (10-19) carrying an alkylsemicarbazono moiety at a benzylic site. The influence of this group on the biological activity was evaluated by testing the corresponding derivatives 20-22 in which the 4-alkylsemicarbazono moiety was removed (compound 20) or its alkylureido portion shifted at position 1 (compounds 21-22). Furthermore, the involvement of the 4-aminobenzyl moiety in the anticonvulsant activity was evaluated by testing derivative 23. The anticonvulsant activity of all compounds was assayed against audiogenic seizures induced in DBA/2 mice. Within this series of derivatives, 2-[(4-aminophenyl)-(4-methylsemicarbazono)-methyl]-4,5-methylenedioxyphenylacetic acid methyl ester (10) proved to be the most active compound. It displayed a potency 5-fold higher than that shown by 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (1, GYKI 52466), a well-known noncompetitive 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptor antagonist. Compound 10 was also effective in suppressing seizures induced in Swiss mice by maximal electroshock (MES) or pentylenetetrazole (PTZ). Furthermore, it antagonized in vivo seizures induced by icv administration of AMPA or kainate (KA). Using the patch-clamp technique in primary cultures of granule neurons we tested compounds 10 and 21 for their ability to modulate currents evoked by KA and 2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propionic acid (ATPA). These two derivatives reduced KA and ATPA currents to a larger extent than that shown by reference compound 1. Compounds 10 and 21 were also able to reduce neuronal cell death induced by the application of KA (100 microM).