Only subsequently did the in vitro (laboratory-based) heating exp

Only subsequently did the in vitro (laboratory-based) heating experiments suggest that heat-treated products might reduce (if not eliminate) the risk for transmitting HIV, but no actual clinical (in vivo) data existed on the efficacy of heat-treated factor in reducing HIV infection. Normally, clinical PD0332991 efficacy, determined by prospective clinical trials, would be required before licensing. However, a significant and growing portion of the haemophilia population was being infected in 1984 and the haemophilia community was desperate for any possible preventive measure.

Most readily accepted the use of heat-treated concentrates based only on the in vitro data with evaluation of the level of viral safety by subsequent surveillance [1]. Although DHF established surveillance mechanisms to identify possible HIV seroconversions in patients taking heat-treated clotting factors, several problems made the task difficult. Logistically, the surveillance was voluntary and passive, rendering it less sensitive. Second, the majority of infected haemophilia patients were still unidentified, either by clinical symptoms or testing. These patients had to be distinguished from persons seroconverting from the new heat-treated products. Patients

often used more than one brand of clotting factor concentrate; when these persons were included, identifying an unsafe product depended Trametinib clinical trial on statistical analysis of a number of suspected seroconversions. Finally, although most patients in the United States were using heat-treated clotting factors in early 1985, some physicians

and organizations still objected to its use. Unfortunately, this resistance caused delay in utilizing the new products in some countries. Large, expensive inventories of non-heat-treated clotting factors still existed in manufacturers’, distributors’, hospitals’ and clinics’ storage. Although in retrospect, these should have immediately been destroyed, the FDA did not order a formal recall of non-heat-treated products, but allowed manufacturers to ‘phase in’ distribution of the heat-treated factors; therefore non-heat-treated products continued to be available in many countries for another year [6]. Reportedly, Dolutegravir in vitro this policy was justified by the lack of clinical effectiveness data for heat-treated products and concern in the haemophilia community that the withdrawal of untreated clotting factor would create shortages. For example, following MASAC’s recommendation, the Canadian Bureau of Biologics, in November 1984, issued directives to the Canadian Red Cross and manufacturers to switch to heat-treated products ‘as soon as possible’ [7]. However, the sole Canadian manufacturer of clotting factor, Connaught Laboratories, did not have the equipment or technology to produce heat-treated products [7].

In addition, immunohistochemistry for alpha smooth muscle actin (

In addition, immunohistochemistry for alpha smooth muscle actin (α-SMA) in liver sections of TAA-treated rats, compared to nontreated control rats, showed increasing numbers of α-SMA-positive cells in intralobular septa in areas of fibrosis, indicating activation of hepatic stellate cells. To determine the Birinapant purchase expression levels of genes relevant

to advanced fibrosis/cirrhosis, we performed RT-PCR analysis in liver tissues 3 months after TAA administration compared to age-matched nontreated liver (Fig. 2A,B). We observed elevated expression of α-SMA, platelet-derived growth factor receptor β (PDGFRβ), desmin, neural cell adhesion molecule (N-CAM), and vimentin messenger RNA (mRNA) (Fig. 2A). In addition, after induction of advanced fibrosis/cirrhosis, procollagen α2(I) (Col1α2), matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP1), TIMP2 were up-regulated, and glial fibrillary acidic protein (GFAP) was down-regulated (Fig. 2A). The expression profiles of these genes clearly reflect activation of stellate cells and ongoing fibrogenesis. Furthermore, biochemical analysis

of the relative HYP content in nontreated versus TAA-treated liver (n = 6/6 rats) increased from 0.23 ± 0.02 to 1.38 ± 0.18 mg HYP/g liver, indicating advanced fibrosis/cirrhosis at 3 months after TAA administration. selleck We observed increased expression of AFP, Dlk-1, CD133, Sox-9, FoxJ1, and nestin mRNAs (Fig. 2A), indicating increased numbers of progenitor cells[14, 16, 25-28] after induction of advanced fibrosis/cirrhosis. Compared to normal hepatic tissue, liver samples with advanced fibrosis also showed down-regulation of Mirabegron glucose-6-phosphatase (G6Pase), asialoglycoprotein receptor (ASGPR), and cytochrome 3A1 (CYP3A1) mRNAs (all of which are related to hepatocyte-specific cell functions), indicating hepatocellular damage or loss. In contrast, biliary epithelial cell-specific genes (cytokeratin-19 [CK-19], connexin43, EpCAM) were up-regulated in strongly

fibrotic liver (Fig. 2A). These data were confirmed and fold changes quantified by qRT-PCR analysis for selected genes (Fig. 2B). In a pilot experiment, we tested whether fetal liver cells are capable of repopulating the fibrotic liver. To induce moderate hepatic fibrosis, 200 mg/kg TAA was injected into DPPIV− F344 rats twice weekly for 6 weeks, followed by a maintenance dose of 100 mg/kg TAA after cell transplantation. Since repopulation of the normal liver by FLSPCs occurs only after two-thirds PH,[13, 19] PH was performed just prior to cell infusion (∼1.5 × 107 ED14 unfractionated fetal liver cells, of which ∼2.5% are AFP+/CK-19+ bipotential stem/progenitor cells[17, 22]). At both 1 and 2 months after cell transplantation, we observed extensive liver repopulation with more than 50% tissue replacement in many areas of TAA-treated recipient liver (n = 3 rats) (Fig. 3A, upper left and middle panel).

35 These results

35 These results BMS-777607 research buy were supported by a study36 that showed low total magnesium in erythrocytes and low ionized magnesium in lymphocytes in migraine patients, both of which increased significantly after a 2-week trial of drinking mineral water containing 110 mg/L magnesium. Given its commercial availability, the RBC magnesium assay may therefore

be a good way of assessing for deficiency. Future trials should focus on patients with deficiencies in ionized or RBC magnesium, as improvements in clinical symptoms correlating with corrected levels would clearly demonstrate the benefits of magnesium supplementation. Treatment With Oral Magnesium Several randomized controlled trials (RCTs) DAPT price have shown that Mg2+ supplementation is effective in migraine treatment. In the first, 24 women with menstrual migraine31 received either 360 mg of magnesium pyrrolidone carboxylic acid or placebo in 3 divided doses. Women received 2 cycles of study medication, taken daily from ovulation to the

first day of flow. Magnesium treatment resulted in a significant reduction of the number of days with headache (P < .1), total pain index (P > .03), as well as an improvement of the Menstrual Distress Questionnaire score in the treatment group compared to placebo. A larger study comprising 81 migraineurs also showed a significant improvement in patients who received magnesium.37 Attack frequency was reduced by 41.6% in the magnesium group and by 15.8% in the placebo group. The active

treatment group received 600 mg of trimagnesium dicitrate in a water-soluble granular powder taken every morning. More recently, Aldehyde dehydrogenase Koseoglu et al38 studied the prophylactic effects of 600 mg/day of oral magnesium citrate supplementation in patients with migraine without aura and found that active treatment resulted in a significant decrease in migraine attack frequency and severity. A 4th RCT showed no effect of oral magnesium on migraine.39 This negative result was likely because of the use of a poorly absorbed magnesium salt, as diarrhea occurred in almost half of patients in the treatment group. The most common adverse effect associated with oral magnesium supplementation is diarrhea. While diarrhea itself usually prevents the development of magnesium-related toxicity, patients should be cautioned about this side effect. Magnesium toxicity is marked by the loss of deep tendon reflexes followed by muscle weakness. Severe toxicity can lead to cardiac muscle weakness, respiratory paralysis, and death. Patients with kidney disease are at higher risk of developing toxicity as magnesium is excreted through the kidneys.40 Treatment With Intravenous Magnesium Several studies have evaluated the use of intravenous magnesium in acute migraine treatment, with conflicting results.

Improved thinking is also needed in specifying the end points of

Improved thinking is also needed in specifying the end points of such studies. For example, we have mentioned the focus on longer acting products, but can a longer half-life be viewed as an automatic benefit? The actual clinical need is for the prolongation of the time during which the patients are at higher trough levels and, as Collins has shown [15], longer acting products can also result in the prolongation of suboptimal trough level periods. It should be noted that similar effects in prolonging optimal trough levels can be obtained by increasing the dosage of current established

products. Such considerations should be factored into studies for novel molecules, keeping in

mind that adverse effects, such as the possibility of inhibitors, are unlikely to be detected in the preapproval phase of assessment, Maraviroc in vivo irrespective of the design. After a drug has completed all the phases required for licensure, there is still much to learn about the real impact of the drug on the overall health of the target population for which it has been approved. Several factors come into play when routine use starts, among which the most relevant are the willingness of doctors to prescribe and of patients to be compliant to the prescribed regimen. Indeed, the effectiveness of a drug is the balance of the expected benefits, usually lower if the patient is not compliant, and the unwanted side buy CHIR-99021 effects, very often erratically related to exposure, so that the most likely consequence of non-adherence is a reduction in the net clinical Forskolin concentration benefit [26]. Furthermore, the role of anticipated

and unanticipated drug interactions, and of variability in efficacy with concomitant comorbidities such as renal impairment or in specific populations like children or the elderly, is usually unknown at the time of initial approval. In most cases, new drugs are found to be beneficial in these populations, and long-term assessment of their use generates important knowledge. Finally, side effects uncommon enough to escape the detection power of registration trials may be recognized only when large populations are exposed for a sufficient length of time. This has sometimes led to drug withdrawals, as happened with thalidomide in the 1950s or rosiglitazone in 2011; or the issuing of drug warnings even for commonly prescribed drugs, as was the case for beta-agonists in children [27] or for certain opiates [28, 29]. Factor concentrates are no exception to the need for long-term assessment of efficacy and safety, and especially so as we consider new therapeutics with enhanced characteristics, which no longer fit into the category of simple replacement therapy.

Interestingly, a similar regulation was detected in primary murin

Interestingly, a similar regulation was detected in primary murine hepatocytes (Supporting Fig.

S3C). Next we tested learn more whether miR-29 members are able to modulate the expression of extracellular matrix genes during hepatic fibrogenesis. Possible miR-29 target genes were identified by three different miRNA target prediction algorithms (see Materials and Methods). We identified a high number of fibrosis-related mRNAs, including collagens, integrins, and metallopeptidases as possible targets for the miR-29 family (Supporting Table S3B). Expression of exemplary insilico identified targets was analyzed in liver samples from CCl4-treated and oil-treated Balb/c mice (Fig. 4A), which confirmed up-regulation of the potential target genes Col1a1, Col1a2, Col4a5, and Col5a3 on CCl4 treatment. We next transfected miR-29b at different concentrations into immortalized murine HSC. As shown in Fig. 4B and Fig. 4C, overexpression of miR-29b resulted in a dose-dependent and significant decrease in expression of Col1a1, Col4a5, and Col5a3, whereas down-regulation of Col1a2 failed statistical significance. Transfected scrambled miRNA had no effect on the expression of the respective genes (Fig. 4B, C, and Supporting Fig. S4). Moreover, expression of other fibrosis-related genes (Ctgf, Timp-1, and αSma) was not affected by transfection

of miR-29 (Fig. 4D and Supporting Fig. SB203580 nmr S4). Collectively, these experiments suggest a direct link between the Carbohydrate TGF-β–dependent miR-29 down-regulation and collagen up-regulation in HSC during liver fibrosis. Micro RNAs normally do not act in linear signaling cascades but are able to integrate signals from distinct upstream signaling pathways,10 suggesting that regulation of miR-29 during liver fibrosis is not only regulated by TGF-β. Recently, it was shown that miR-29 can be regulated by the transcription factor NF-κB during myogenic cancer via recruitment of histone deacetylase 1 to the miR-29 promoter region.11 We therefore examined a possible role of this pathway in the regulation of miR-29 in HSCs. Indeed, intraperitoneal injection of LPS into mice resulted in significant down-regulation

of all miR-29 members in whole liver RNA extracts (Fig. 5A). Moreover, stimulation of primary HSC as well as primary hepatocytes with LPS resulted in down-regulation of miR-29a/b/c (Fig. 5B,C). However, LPS stimulation did not significantly enhance collagen expression in these cells (Fig. 5B). Stimulation with tumor necrosis factor (TNF) but not interleukin-1 led to a strong decrease in miR-29b expression (Fig. 5D). Finally, we treated GRX-HSCs and primary HSCs with a chemical inhibitor of NF-κB activation, pyrrolidine dithiocarbamate.12 Although this treatment resulted in early cytotoxicity in primary HSCs (data not shown), GRX-HSCs—which were probably more resistant to NF-κB inhibition—showed a significantly higher expression of miR-29 compared with untreated cells (Fig. 5E).

305 Routine monitoring of conventional liver tests and blood coun

305 Routine monitoring of conventional liver tests and blood counts and amylase are performed at 4 to 6 week intervals. The decision to terminate therapy in children is based on laboratory evidence of prolonged

inactivity, and it is a consideration in only 20%-30% of patients.361 After 2-3 years of treatment, drug withdrawal is considered in children if liver function tests and IgG are repeatedly normal, and autoantibodies negative Napabucasin price or ≤ 1:20, for at least 1 year on low-dose corticosteroids. At that time, a liver biopsy examination should be performed and therapy withdrawn only if there is no histological evidence of inflammation. Relapse after drug withdrawal occurs in 60%-80% of children, and parents and patients must be informed that the probability of retreatment is high.35,36,279-281,283,305,358-361 Recommendations: 25. Improvements in the serum AST or ALT level, total bilirubin concentration, and γ-globulin or IgG level should

be monitored at 3-6 month intervals click here during treatment. (Class IIa, Level C) 26. Treatment should be continued until normal serum AST or ALT level, total bilirubin concentration, γ-globulin or IgG level, and normal liver histology not exhibiting inflammatory activity is achieved. (Table9). (Class IIa, Level C) 27. Patients should experience a minimum duration of biochemical remission before immunosuppression is terminated after at least 24 months of therapy. (Class II a, Level C) 28. Worsening symptoms, laboratory tests or histological features during conventional therapy (treatment failure) compel the institution of high dose prednisone alone (60 mg daily) or prednisone (30 mg daily) in combination with azathioprine (150 mg daily) (Table9). (Class IIa, Level C) 29. Clinical, laboratory and histological improvement which is insufficient to satisfy criteria for a treatment endpoint after continuous therapy for at least 36 months (incomplete response) should be treated with long-term prednisone Tideglusib therapy or azathioprine

maintenance in doses adjusted to ensure absence of symptoms and stable laboratory abnormalities (Table9). (Class IIa, Level C) 30. Intolerance to the medication (drug toxicity) should be managed by reducing the dose of the offending agent or discontinuing its use (Table9). (Class IIa, Level C) Relapse connotes recrudescence of disease activity after induction of remission and termination of therapy.345,347,348,362 It is characterized by an increase in the serum AST level to more than three-fold the ULN and/or increase in the serum γ-globulin level to more than 2 g/dL.349 Laboratory changes of this degree are invariably associated with the re-appearance of interface hepatitis in the liver tissue, and they preclude the need for a liver biopsy examination to document relapse.349 Progression to cirrhosis (38% versus 4%, P = 0.004) and death from liver failure or requirement for liver transplantation (20% versus 0%, P = 0.

The variables

analyzed as possible risk factors included

The variables

analyzed as possible risk factors included demographic and living characteristics, socioeconomic status, potential mode of transmission, and clinical indications of H. pylori infection. A total of 303 children were included in the study. The overall prevalence of H. pylori infection was 49.8%. Among the studied variables, the following were positively associated with the presence of H. pylori in multivariable analyses: age above 10 years(OR = 11.84, 95% CI = 3.90–35.94, p < .0001), an income of <5000 SR (OR = 2.06, 95% CI = 1.07–3.95), more than eight persons in the household (OR = 3.46, selleckchem 95% CI = 1.67–7.20), bed sharing (OR = 2.26, 95% CI = 1.32–3.86), and two affected parents (OR = 11.19, 95% CI = 1.29–97.27). Abdominal pain and anorexia were significant predictors of H. pylori infection (p = .005 and .009, respectively). Helicobacter pylori infection had a high prevalence among Saudi children in the cities of Jeddah and Riyadh. It was a relatively common cause of abdominal pain and anorexia. In this cohort of children, H. pylori infection was associated with variables indicative of a crowded environment and poor living conditions, further supporting the conclusion that improving socioeconomic conditions and designing a preventive health strategy in Saudi Arabia

will likely protect children against this infection. “
“In the previous year, some extragastric diseases, possibly linked to Helicobacter pylori infection, have been largely investigated. There are, in fact, several studies concerning cardiovascular diseases, lung diseases, hematologic www.selleckchem.com/products/SB-203580.html diseases, eye and skin diseases, hepatobiliary diseases, diabetes mellitus, and neurological disorders. Among them, the relationship between bacterial CagA positivity and coronary heart disease is reportedly emphasized. Concerning

normal tension glaucoma, new interesting data are playing in favor of the association with H. pylori infection. For other diseases, there are many interesting results, although more studies are needed to clarify the reality of the proposed association. The topic of the extragastric manifestations of Helicobacter pylori infection continues to capture the attention of many researchers all over the world, as demonstrated by the number Carbohydrate of studies published. Here, we review the results of the studies published last year. Several studies have been published in the last year on the possible role of H. pylori infection in cardiovascular diseases. Jafarzadeh et al. [1] focused on the prevalence of CagA-positive strains in patients with acute myocardial infarction (MI), unstable angina (UA), and healthy controls. They clearly showed that the seroprevalence of CagA-positive strains was significantly higher in patients with acute MI and UA than controls (86.7, 91.7, and 58.3%, respectively).

Recent work has identified the NALP3 inflammasome as a critical p

Recent work has identified the NALP3 inflammasome as a critical pathway in the generation of proinflammatory signals during liver injury. Moreover, IL-1 generated through this pathway exerts profibrogenic activities through the modulation of TIMP-1 and MMP9. Aim of this study was to evaluate the role of CCR5

in mediating inflammasome activation in response to gp120, in cells involved in liver tissue repair, including HSC. Myofibroblastic human HSCs were isolated from normal human liver tissue and cultured on plastic until fully activated. PBMC were separated from human whole blood. Gene expression was measured by qPCR. Protein IL-1 β protein levels were assayed by ELISA. HSCs or PBMC were exposed to 500 ng/ml recombinant M-tropic gp120 PD98059 concentration (CN54) for 2, 8 and 24 hours showed a time-dependent, significant up-regulation of pycard and NALP3, critical proteins for the assembly

of NALP3-dependent inflammasome, and of cas-pase-1 and IL-1 β. gp120 efficiently induced secretion of mature IL-1β, as shown by ELISA tests performed on the supernatants of both cell types. Notably, pre-incubation of HSCs with TAK779, a CCR5 receptor antagonist or with neutralizing α-CCR5 antibody reverted gp120-mediated IL-1 β production, indicating a primary role for this receptor in the activation of inflammasome Natural Product Library complex. Interestingly, when HSC were stimulated with CCL5 (RANTES), a natural agonist of CCR5, we also found a significant up-regulation of IL-1 b, confirming that CCR5 may mediate activation of this inflammatory complex in HSC. In conclusion, HIV-gp1 20 significantly increases the expression of components of the NALP3 Carbachol inflammasome pathway in human HSC and PBMC, through activation of CCR5. These data identify a novel mechanism by which HIV-gp1 20 may directly influence hepatic

necroinflammation and fibrosis during HCV/HIV coinfection, i.e. through increased production of IL-1 β. Moreover, these data establish for the first time a direct link between the inflammasome complex, HIV proteins and CCR5. We thank aid-sreagent.org for the kind gift of gp120. Disclosures: Fabio Marra – Advisory Committees or Review Panels: Abbott; Consulting: Bayer Healthcare, Gilead; Grant/Research Support: ViiV The following people have nothing to disclose: Andrea Cappon, Raffaele Bruno, Sandra Gessani, Andrea Masotti Matrix metalloproteinases (MMPs) are involved in various processes such as modulation of inflammation, tissue remodeling and collagen turnover. MMP-8 plays a yet ill-defined role in liver fibrogenesis and fibrolysis. Thus, we investigated the role of MMP-8 in toxin-induced liver fibrosis and spontaneous fibrosis regression using MMP-8 knock-out mice. Six week old female MMP-8 KO mice (n=10/group,C57/BL6 background) were treated according to an optimized CCl4 and TAA fibrosis-induction protocol for 4 and 8 weeks. For fibrosis regression, mice were harvested 5 days, 2 weeks, and 4 weeks after discontinuation of toxin treatment.

The appearance of the bands representing cleaved caspase-3 was pr

The appearance of the bands representing cleaved caspase-3 was prominent in cytoplasmic liver samples 120 minutes after TNFα/D-galN treatment in WT mice but only after 480 minutes in NS3/4A-Tg mice

to a much lower degree (Fig. 2A). This could be confirmed in liver sections from LPS/D-galN–treated mice using immunohistochemistry. Whereas a significant staining for cleaved caspase-3 was visible in WT mice 6 hours after application of LPS/D-galN, only a weak staining for cleaved caspase-3 was evident in NS3/4A-Tg mice (Fig. 2B). Furthermore, we analyzed the degree of apoptosis and necrosis in murine liver samples taken at different time points after LPS/D-galN administration through TUNEL staining. Again, liver sections from WT mice taken 6 hours after LPS/D-galN injection

had a significantly (P < 0,0001) higher PD0332991 research buy number of TUNEL-positive cells per 10 mm2 of liver compared with NS3/4A-Tg mice (Fig. 3A, upper right). Additionally, WT mice showed extensive and severe changes in the liver parenchyma with a high infiltration of inflammatory cells 6 hours after LPS/D-galN application (Fig. 3A, lower right). Thus, NS3/4A-Tg mice are less sensitive to TNFα-induced apoptosis compared with WT mice. These antiapoptotic effects might be exerted by the NS3/4A-related increase in NFκB activation. Activated NFκB is known both to protect hepatocytes from apoptosis and to PF-562271 purchase promote liver regeneration.13 We therefore determined the total number of hepatocyte nuclei and the number of dividing hepatocyte nuclei per 10 mm2 of liver in hematoxylin-eosin–stained liver sections from WT and NS3/4A-Tg mice left untreated or treated with LPS/D-galN. The total number of hepatocyte nuclei decreased during LPS/D-galN treatment in both WT and NS3/4A-Tg mice, with a more pronounced reduction in WT mice, compared with NS3/4A-Tg mice illustrating LPS/D-galN–mediated liver injury (Fig. 3B, left). In order to investigate liver regeneration, the amount of actively dividing hepatocyte nuclei was determined. Interestingly, this showed that, whereas the number of dividing hepatocyte

Orotic acid nuclei decreased in WT mice, NS3/4A-Tg mice revealed an increase in the number of dividing hepatocyte nuclei during LPS/D-galN treatment (Fig. 3B, right). Furthermore, after staining for the proliferation marker Ki67, liver sections from NS3/4A-Tg mice treated with LPS/D-galN had a significantly higher number of Ki67-positive nuclei compared with WT mice treated the same way (19.20 ± 2.49 versus 5.60 ± 1.65 positive nuclei per 10 mm2 of liver; P < 0.0001 [Mann-Whitney]) (Fig. 3C). Thus, NS3/4A not only exerts antiapoptotic effects but also promotes hepatocyte regeneration, most likely by increasing NFκB activation. NFκB regulates the transcription of an exceptionally large number of genes, many of which participate in immune and inflammatory responses, including TNFα, IL-1α, and IL-6.

Link -

Employment: Gilead Sciences; Patent Held/Filed: Gi

Link -

Employment: Gilead Sciences; Patent Held/Filed: Gilead Sciences; Stock Shareholder: Gilead Sciences, Pfizer Hongmei Mo – Employment: Gilead Science Inc The following people have nothing to disclose: Viktoria Gontcharova Background: A recently discovered novel surface receptor involved in EX 527 HCV entry, the Niemann-Pick C1-like 1 cholesterol (NPC1L1), is an HCV entry factor amendable to therapeutic intervention. Previously, DNA sequencing studies revealed that nonsynonymous variants in NPC1L1 are collectively common in general population. The aim of the present study was to elucidate whether genetic variants of the NPC1L1 are linked to the antiviral response in a group of patients with Pexidartinib cell line chronic hepatitis C (CHC). Methods: We included 38 patients with CHC genotype 1 treated with pegylated interferon alpha2 and ribavirin (20 patients with SVR and 18 null responders). The whole coding sequence of NPC1L1 gene was amplified by 30 different

PCR reactions. PCR products were barcoded and sequenced in a Junior-454 deep-sequencing platform (Roche). The resulting reads were aligned against the human genome (GRCh37) using BLAT algorithm and the variants were identified using GATK Unified genotyper. The functional consequence of the

sequence variants were determined using SNPEff algorithm and association studies with patient phenotypes were performed using Plink suite. Results: 24 different sequence variants in NPC1L1 gene were identified in total in the 38 patients sequenced. 15 were small insertions and deletions (indels), whereas 9 of them constitute single nucleotide variants (SNV), from which 6 had been already Uroporphyrinogen III synthase reported in dbSNP database. According to a negative selection of deleterious sequence variants in the normal population, most of the identified variants were predicted to play synonymous or regulatory roles in the gene. Nevertheless, even with this limited sample size, association studies shown significative association between two of the sequence variants (a single nucleotide substitution and a single base deletion) with therapy response (rs186726309 and a novel SNV, Chr7: 44575955Del(G)). Additionally, a new SNV has been found which is not present in dbSNP database (Crh7: 44561370) and is present in a low frequency in our cohort; and produces a significant aminoacid change (S919C) in the coding region of the gene. Conclusions.