Haem iron versus ferrous iron salts to treat iron deficiency anaemia in Gambian children: protocol for randomised controlled trial {1}.

BACKGROUND: The World Health Organization recommends universal iron supplementation for children aged 6-23 months in countries where anaemia is seen in over 40% of the population. Conventional ferrous salts have low efficacy due to low oral absorption in children with inflammation. Haem iron is more bioavailable, and its absorption may not be decreased by inflammation. This study aims to compare daily supplementation with haem iron versus ferrous sulphate on haemoglobin concentration and serum ferritin concentration after 12 weeks of supplementation. METHODS: This will be a two-arm, randomised controlled trial. Gambian children aged 6-12 months with anaemia will be recruited within a predefined geographical area and recruited by trained field workers. Eligible participants will be individually randomised using a 1:1 ratio within permuted blocks to daily supplementation for 12 weeks with either 10.0 mg of elemental iron as haem or ferrous sulphate. Safety outcomes such as diarrhoea and infection-related adverse events will be assessed daily by the clinical team (see Bah et al. Additional file 4_Adverse event eCRF). Linear regression will be used to analyse continuous outcomes, with log transformation to normalise residuals as needed. Binary outcomes will be analysed by binomial regression or logistic regression, Primary analysis will be by modified intention-to-treat (i.e., those randomised and who ingested at least one supplement dose of iron), with multiple imputations to replace missing data. Effect estimates will be adjusted for baseline covariates (C-reactive protein, alpha-1-acid glycoprotein, haemoglobin, ferritin, soluble transferrin receptor). DISCUSSION: This study will determine if therapeutic supplementation with haem iron is more efficacious than with conventional ferrous sulphate in enhancing haemoglobin and ferritin concentrations in anaemic children aged 6-12 months. TRIAL REGISTRATION: Pan African Clinical Trial Registry PACTR202210523178727.

Biologically synthesized black ginger-selenium nanoparticle induces apoptosis and autophagy of AGS gastric cancer cells by suppressing the PI3K/Akt/mTOR signaling pathway.

BACKGROUND: Despite being a promising strategy, current chemotherapy for gastric cancer (GC) is limited due to adverse side effects and poor survival rates. Therefore, new drug-delivery platforms with good biocompatibility are needed. Recent studies have shown that nanoparticle-based drug delivery can be safe, eco-friendly, and nontoxic making them attractive candidates. Here, we develop a novel selenium-nanoparticle based drug-delivery agent for cancer treatment from plant extracts and selenium salts. RESULTS: Selenium cations were reduced to selenium nanoparticles using Kaempferia parviflora (black ginger) root extract and named KP-SeNP. Transmission electron microscopy, selected area electron diffraction, X-ray diffraction, energy dispersive X-ray, dynamic light scattering, and Fourier-transform infrared spectrum were utilized to confirm the physicochemical features of the nanoparticles. The KP-SeNPs showed significant cytotoxicity in human gastric adenocarcinoma cell (AGS cells) but not in normal cells. We determined that the intracellular signaling pathway mechanisms associated with the anticancer effects of KP-SeNPs involve the upregulation of intrinsic apoptotic signaling markers, such as B-cell lymphoma 2, Bcl-associated X protein, and caspase 3 in AGS cells. KP-SeNPs also caused autophagy of AGS by increasing the autophagic flux-marker protein, LC3B-II, whilst inhibiting autophagic cargo protein, p62. Additionally, phosphorylation of PI3K/Akt/mTOR pathway markers and downstream targets was decreased in KP-SeNP-treated AGS cells. AGS-cell xenograft model results further validated our in vitro findings, showing that KP-SeNPs are biologically safe and exert anticancer effects via autophagy and apoptosis. CONCLUSIONS: These results show that KP-SeNPs treatment of AGS cells induces apoptosis and autophagic cell death through the PI3K/Akt/mTOR pathway, suppressing GC progression. Thus, our research strongly suggests that KP-SeNPs could act as a novel potential therapeutic agent for GC.

Comparative Study between Acacia Nilotica versus Povidone Iodine in Topical Treatment of Omphalocele Major.

Well established and common practice in conservative management of omphalocele major is escharotics therapy with different topical agents. Among them mercurochrome, alcohol, silver salts, povidone iodine, acacia nilotca paste are commonly used. It is a comparative study between application of acacia nilotica paste and povidone iodine solution as a primary non surgical treatment of omphalocele major regarding efficacy and safety of these two topical agents. A double blind randomized controlled study was conducted at the department of Paediatric Surgery, Mymensingh Medical College Hospital, Mymensingh, Bangladesh from July 2016 to June 2019. In this study 20 cases of omphalocele major and randomly divided into two equal groups. Group A and Group B treated with acacia nilotica paste and povidone iodine solution respectively. Gastroschisis, ruptured-omphalocele major or omphalocele minor excluded in this study. The size of the fascial defect in cm, time required for full oral feeding tolerance and duration of hospital stay were evaluating parameters. Patients with Group A tolerated full oral feeding earlier, shorter total hospital stay duration and low mortality rate than those from Group B. Application of acacia nilotica is a safe and effective treatment of omphalocele major regarding rapid full oral feeding tolerance, shorter hospital stay and low mortality rate.

Regression of calcinosis cutis after inkless tattoo in a patient with dermatomyositis: therapeutic potential of microneedling.

Calcinosis cutis is defined as abnormal deposition of calcium salts in the skin and subcutaneous tissues. Dystrophic calcification, the most common form of calcinosis cutis, is associated with autoimmune connective tissue diseases. This condition is associated with severe pain and can affect the patient's quality of life and lead to long-term disability. Treatment is often challenging, and there is a very limited evidence base for potential treatments of calcinosis cutis associated with systemic sclerosis and dermatomyositis. Inkless tattoo is very similar to microneedling, a minimally invasive procedure stimulating the wound-healing cascade contributing to elastin and collagen formation as well as neovascularization. This technique has not been reported as a potential therapeutic option for calcinosis cutis. Here, we present a patient with calcinosis cutis in the setting of dermatomyositis that responded dramatically to inkless tattoo application. Our results support the need for future studies of microneedling in patients with this disorder.

Supplementation with Sucrosomial® iron leads to favourable changes in the intestinal microbiome when compared to ferrous sulfate in mice.

Iron deficiency is one of the most common nutritional deficiencies worldwide and is often treated with oral iron supplements. However, commonly used supplements, including those based on ferrous iron salts, are associated with gastrointestinal side effects and unfavorable changes in the intestinal microbiome. Sucrosomial® iron is a novel iron formulation that is effective at treating iron deficiency, and with fewer gastrointestinal side effects, yet its effect on the gut microbiome has not been examined previously. Thus, we treated mice for two weeks with diets containing either Sucrosomial® iron or ferrous sulfate as the sole iron source and examined bacterial communities in the intestine using 16S Microbial Profiling of DNA extracted from feces collected both prior to and following dietary treatment. Mice treated with Sucrosomial® iron showed an increase in Shannon diversity over the course of the study. This was associated with a decrease in the abundance of the phylum Proteobacteria, which contains many pathogenic species, and an increase in short chain fatty acid producing bacteria such as Lachnospiraceae, Oscillibacter and Faecalibaculum. None of these changes were observed in mice treated with ferrous sulfate. These results suggest that Sucrosomial® iron may have a beneficial effect on the intestinal microbiome when compared to ferrous sulfate and that this form of iron is a promising alternative to ferrous iron salts for the treatment of iron deficiency.

Influence of Medications Containing Acid Salts on Serum Bicarbonate in CKD.

Background: Many medications are formulated with acid salts. Their effect on acid-base balance in CKD is unclear. Methods: We calculated the acid load (meq/d) from medications prescribed to 74 United States veterans with diabetes and CKD to identify agents with high potential acid load. We also determined cross-sectional associations between the acid load from medications and acid-base parameters after adjusting for demographics, eGFR, protein intake, and other confounders. Results: Of the 125 medications prescribed, 31 (25%) contained an acid salt. Metformin hydrochloride (15.4 meq/d at 2550 mg/d) and gabapentin hydrochloride (13.0 meq/d at 2700 mg/d) were identified as agents with a high potential acid load. Mean daily acid load from medications was 6.6 meq/d in the overall cohort, 14.2 meq/d in the high medication acid load group (≥7.7 meq/d, n=29), and 1.6 meq/d in the low medication acid load group (<7.7 meq/d, n=45). After adjusting for potential confounders, those in the high acid load group had 1.7 meq/L lower total carbon dioxide (CO2) and 2.2 meq/L higher anion gap than those in the low acid load group. Use of gabapentin alone was not associated with differences in total CO2 or anion gap. Use of metformin alone was associated with 0.7 meq/L lower total CO2 and 1.0 meq/L higher anion gap. Use of metformin with gabapentin was associated with 1.8 meq/L lower total CO2 and 2.4 meq/L higher anion gap. The higher anion gap was not explained by higher serum lactate levels. The acid load from medications was not associated with differences in urinary ammonium, titratable acid, or pH. Conclusions: Medications containing acid salts, particularly metformin hydrochloride and gabapentin hydrochloride, are sources of an exogenous acid load. These agents may influence serum total CO2 levels and serum anion gap in individuals with CKD. Clinical Trial registry name and registration number: Investigations of the Optimum Serum Bicarbonate Level in Renal Disease, NCT01574157.

The Possibilities of Using Chromium Salts as an Agent Supporting Treatment of Polycystic Ovary Syndrome.

The polycystic ovary syndrome (PCOS) is the most frequent endocrinopathy in women in reproductive age with the so far undetermined causes of development. In the etiopathogenesis of PCOS, the role of insulin resistance is emphasised, which was an indication for the attempts at using chromium III salts (Cr) in augmenting pharmacotherapy applied in patients. The analysis of the usefulness and efficacy of this approach was the direct goal of this thesis. Animal tests confirmed the efficacy of chromium in maintaining the appropriate level of glycaemia and insulinaemia, normalisation of plasma concentrations of microelements and also a correlation between the Cr level, insulin and dehydroepiandrosterone (DHEA) was found. A decrease in the expression of 3ß-hydroxysteroid dehydrogenase and 17ß-hydroxysteroid dehydrogenase was identified in adipose tissue. Clinical studies, although sparse, show that the supplementation with chromium can improve BMI and the parameters evaluating the control of glycaemia and increase the chances for ovulation and regular menstruation. However, the small number and a variability in study protocols makes comparing them very difficult. A completely new subject that has not been yet studied is the possibility of using chromium in levelling mood disorders in patients with PCOS. Currently, there are still no sufficient proofs for introducing chromium as a standard in treating and preventing insulin resistance in patients with PCOS. However, this direction remains open, and treating insulin resistance is an important challenge in clinical practice.

Disentangling the effects of a multiple behaviour change intervention for diarrhoea control in Zambia: a theory-based process evaluation.

BACKGROUND: Diarrhoea is a leading cause of child death in Zambia. As elsewhere, the disease burden could be greatly reduced through caregiver uptake of existing prevention and treatment strategies. We recently reported the results of the Komboni Housewives intervention which tested a novel strategy employing motives including affiliation and disgust to improve caregiver practice of four diarrhoea control behaviours: exclusive breastfeeding; handwashing with soap; and correct preparation and use of oral rehydration salts (ORS) and zinc. The intervention was delivered via community events (women's forums and road shows), at health clinics (group session) and via radio. A cluster randomised trial revealed that the intervention resulted in a small improvement in exclusive breastfeeding practices, but was only associated with small changes in the other behaviours in areas with greater intervention exposure. This paper reports the findings of the process evaluation that was conducted alongside the trial to investigate how factors associated with intervention delivery and receipt influenced caregiver uptake of the target behaviours. METHODS: Process data were collected from the eight peri-urban and rural intervention areas throughout the six-month implementation period and in all 16 clusters 4-6 weeks afterwards. Intervention implementation (fidelity, reach, dose delivered and recruitment strategies) and receipt (participant engagement and responses, and mediators) were explored through review of intervention activity logs, unannounced observation of intervention events, semi-structured interviews, focus groups with implementers and intervention recipients, and household surveys. Evaluation methods and analyses were guided by the intervention's theory of change and the evaluation framework of Linnan and Steckler. RESULTS: Intervention reach was lower than intended: 39% of the surveyed population reported attending one or more face-to-face intervention event, of whom only 11% attended two or more intervention events. The intervention was not equally feasible to deliver in all settings: fewer events took place in remote rural areas, and the intervention did not adequately penetrate communities in several peri-urban sites where the population density was high, the population was slightly higher socio-economic status, recruitment was challenging, and numerous alternative sources of entertainment existed. Adaptations made by the implementers affected the fidelity of implementation of messages for all target behaviours. Incorrect messages were consequently recalled by intervention recipients. Participants were most receptive to the novel disgust and skills-based interactive demonstrations targeting exclusive breastfeeding and ORS preparation respectively. However, initial disgust elicitation was not followed by a change in associated psychological mediators, and social norms were not measurably changed. CONCLUSIONS: The lack of measured behaviour change was likely due to issues with both the intervention's content and its delivery. Achieving high reach and intensity in community interventions delivered in diverse settings is challenging. Achieving high fidelity is also challenging when multiple behaviours are targeted for change. Further work using improved tools is needed to explore the use of subconscious motives in behaviour change interventions. To better uncover how and why interventions achieve their measured effects, process evaluations of complex interventions should develop and employ frameworks for investigation and interpretation that are structured around the intervention's theory of change and the local context. TRIAL REGISTRATION: The study was registered as part of the larger trial on 5 March 2014 with ClinicalTrials.gov: NCT02081521 .

Saline irrigations following sinus surgery - a controlled, single blinded, randomized trial.

BACKGROUND: Chronic rhinosinusitis (CRS) is a common health problem. If medical treatment fails, endonasal sinus surgery is a valuable treatment option. A thorough postsurgical treatment is needed including, among others, nasal saline irrigations (NSI). In this prospective, controlled, single blinded, randomized trial, we aimed to evaluate efficacy of nasal saline irrigations following endonasal sinus surgery in CRS-patients with nasal polyps. METHODOLOGY: We examined patient's nasal symptoms, general quality of life and postoperative condition of the mucosa. We also investigated whether or not NSI reduced the number of missed workdays after surgery (MWD). Patients were randomized into an irrigation and non-irrigation arm. RESULTS: Following treatment, mean nasal sum-score in the irrigation arm was 4.4 and in the non-irrigation arm it was 6.3. Accordingly, mean general sum-score in the irrigation arm was 2.5 and in the non-irrigation arm 4.8. Thus, nasal irrigation led to a more pronounced improvement of nasal and general symptoms than in the non-irrigation arm. No differences were observed in postoperative condition of mucosa or number of MWD. CONCLUSIONS: Nasal irrigation improves symptoms score after ESS in patients with CRSwNP.

[The multifunctional therapy of various forms of irritable bowel syndrome]. / Mnogofunktsional'naya terapiya pri razlichnykh formakh sindroma razdrazhennogo kishechnika.

Irritable bowel syndrome (IBS) is a pathological condition characterized by heterogeneous etiology, pathogenesis, and clinical symptoms. These characteristics dictate the necessity of prescribing multiple medications for the treatment of IBS. Such compulsory polypharmacy inadvertently enhances the risk of adverse reactions to the treatment, increases its cost, and impairs compliance on the part of the patients. The objective of the present study was to evaluate the effectiveness of the administration of the clorine-bromine brine with the use of sinusoidal modulated current electrophoresis (SMC-phoresis) for the treatment of different forms of IBS. THE PATIENTS AND METHODS: We examined and treated 80 patients with different forms of IBS. The patients were divided into two equal groups comprised of 40 patients each. The patients of the study group were treated with the use of SMС-phoresis of the bromine-chlorine brine based at the «Varzi-yatchi¼ spa and health resort (the Udmurt Republic) making use of the sparing or stimulating techniques depending on the type of IBS. Each therapeutic course consisted of 10-12 sessions. The patients in the group of comparison received the standard pharmaceutical treatment for IBS (myotropic anti-spasmodics and lactulose). The emphasis was laid on the evaluation of dynamics of the intestinal motor function in different variants of IBS with the use of the EGS-4M apparatus based on the GSRS questionnaire (Gastrointestinal Symptom Rating Scale). Special attention was given to the interpretation of the main gastrointestinal syndromes and the evaluation of the quality of life of the patients in the course of the treatment and after its completion. RESULTS: Тhe main symptoms of IBS after a course of SMC-phoresis with the natural brine were significantly less pronounced compared to those in the patients managed by means of standard pharmacotherapy. Positive dynamics in the clinical picture of the disease had beneficial influence on the quality of life of the patients which approached that of the healthy subjects in the group of comparison. The results of colonography suggested the presence of various types of disturbances of motor function of the intestines. SMC-phoresis of the natural chlorine-bromine brine had a positive influence on dyskinesia associated with diarrhea and constipation associated with IBS, while the effect of the standard pharmaceutical treatment was unidirectional and significantly inferior to it in terms of efficiency. CONCLUSION: The use of complementary therapy can provide a better clinical outcome of IBS and to a greater extent improve the quality of life of the patients presenting with various forms of this pathology.

Therapeutic application of hydrogen sulfide donors: the potential and challenges.

Hydrogen sulfide (H2S), a colorless gas smelling of rotten egg, has long been considered a toxic gas and environment hazard. However, evidences show that H2S plays a great role in many physiological and pathological activities, and it exhibits different effects when applied at various doses. In this review, we summarize the chemistry and biomedical applications of H2S-releasing compounds, including inorganic salts, phosphorodithioate derivatives, derivatives of Allium sativum extracts, derivatives of thioaminoacids, and derivatives of antiinflammatory drugs.

Effect of salt supplementation on the rate of inadequate sweat collection for infants less than 3 months of age referred for the sweat test.

BACKGROUND: Sweat testing in young infants (≤ 3 months) with a positive newborn screen for Cystic Fibrosis (CF) can yield higher rates of inadequate sweat collection. The role of salt supplements in improving sweat collection has not been studied before. METHODS: All young infants referred to our CF center for sweat testing were randomized to either receive salt supplements {1/8th teaspoon salt (750 mg)} mixed in formula feeds 1 day prior to sweat testing (study group) or no salt supplement (controls). RESULTS: Of the 151 young infants that underwent sweat testing over 18 months, 75 received salt supplements, while 76 did not. A total of 9 (11.8%) infants in the salt supplement group had inadequate sweat collection, as compared to 4 (5.2%) infants in the control group (p = 0.16, Fisher's Exact Test). CONCLUSIONS: Oral salt supplementation for young infants prior to sweat testing does not help to reduce the rates of inadequate sweat collection.

Oral rehydration salts: an effective choice for the treatment of children with vasovagal syncope.

To explore whether oral rehydration salts (ORS) is effective in the treatment of children with vasovagal syncope (VVS). One hundred and sixty-six consecutive patients with recurrent syncope and positive head-up tilt testing (HUTT) were recruited, randomly divided to conventional therapy (health education and tilt training) plus ORS (with 500 ml of water) group (Group I, 87 patients) and conventional therapy group (Group II, 79 patients). Therapeutic effect was evaluated by changes of syncopal episode and reperformed HUTT response. At the end of 6-month follow-up, syncopal episode did not reoccur in 49 (56.3 %) patients, decreased in 34 (39.1 %) patients, and had no obvious change or increased in four (4.6 %) patients in Group I, and the results were 31 (39.2 %), 37 (46.8 %), and 11 (14 %) in Group II, respectively. The difference was significant (χ (2) = 7.074, P < 0.05). When HUTT was reperformed, 57 (65.5 %) and 28 (35.4 %) patients had negative response and 30 (34.5 %) and 51 (64.6 %) patients had positive response, respectively, in Group I and Group II. The difference was also significant (χ (2) = 13.808, P < 0.01). In Group I, the two aspects had no difference between vasodepressor type and mixed type; however, syncopal episode had a significant difference between children aged ≤12 and >12 years (χ (2) = 6.371, P < 0.05); there was no difference in reperformed HUTT response. ORS with 500 ml of water is an effective therapy for VVS. It can be recommended as one of non- pharmacological treatment measures in children with VVS.

A practical and successful desensitization protocol for immediate hypersensitivity reactions to iron salts.

Orally administered iron salts (OAS) are widely used in the management of iron deficiency anemia and hypersensitivity reactions to OAS are not common. If an offending drug is the sole option or is significantly more effective than its alternatives, it can be readministered by desensitization. The oral desensitization protocols for iron published so far concern either desensitization that was completed only over a long period or did not attain the recommended therapeutic dose. We aimed to develop a more effective protocol. We report here on 2 patients who experienced hypersensitivity reactions to OAS. After confirming the diagnosis, both patients were desensitized to oral ferrous (II) glycine sulfate complex according to a 2-day desensitization protocol. A commercial suspension of oral ferrous glycine sulfate, which contains 4 mg of elemental iron in 1 ml, was preferred. We started with a dose as low as 0.1 ml from a 1/100 dilution (0.004 mg elemental iron) of the original suspension and reached the maximum effective dose in 2 days. Both patients were successfully desensitized and they went on to complete the 6-month iron treatment without any adverse effects. Although hypersensitvity reactions to iron are not common, there is no alternative for iron administration. Therefore, desensitization has to be the choice. This easy desensitization protocol seems to be a promising option.

Antimutagenic activity and in vitro anticancer effects of bamboo salt on HepG2 human hepatoma cells.

Bamboo salt is a traditional Korean baked solar salt processed by packing the solar salt in bamboo joint cases and heating it several times to high temperatures. The antimutagenic activity and in vitro anticancer effects of bamboo salt on HepG2 human hepatoma cells were investigated and compared to those of other salt samples. Although solar salt and purified salt exhibited comutagenicity with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in the Salmonella typhimurium TA100 strain, bamboo salt was associated with a lower degree of comutagenicity or antimutagenic activity. Bamboo salt baked nine times (9×) showed a greater increase in antimutagenic activity than salts baked once (1×) or three times (3×). At a concentration of 1%, the growth rate of HepG2 cells treated with 9× bamboo salt determined by a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MIT) assay was reduced by 65%; this rate of inhibition was higher than that achieved with 1× baked bamboo salt (40%). Purified and solar salts had relatively lower inhibitory effects on growth rate (25% and 29%, respectively). Compared to the other salt samples, 9× bamboo salt significantly (p<0.05) induced apoptosis as determined by 4,6-diamidino-2-phenylindole (DAPI) staining and flow cytometry analysis. It also upregulated the expression of Bax, caspase-9 and caspase-3; and downregulated Bcl-2 expression. The bamboo salts, especially 9× bamboo salt, also significantly (p<0.05) downregulated the expression of inflammation-related NF-κB, iNOS, and COX-2, and upregulated the gene expression of IκB-α compared to the other salt sample.

Assessment of the efficacy of a new formulation for plantar wart mummification: new experimental design and human papillomavirus identification.

Cutaneous warts are caused by infection of the epidermis with human papillomavirus (HPV). Cryotherapy using liquid nitrogen is one of the most common local treatments. In this study, we used a novel ex vivo approach to compare the efficacy of a new product with conventional liquid-nitrogen cryotherapy by studying epidermal histology and assessing the presence of HPV types 1 and 2 DNA in plantar warts. The studied formulation, which acts by tissues mummification, is a combination of nitric acid, organic acids and metallic salts. We found that, similar to liquid nitrogen, the studied product induced alterations in the wart structure. In addition, unlike liquid nitrogen, this product also reduced the amount of HPV DNA. The results suggest that there is a poor correlation between the histological response and the antiviral efficacy of standard wart treatment.

A randomized clinical trial in psoriasis: synchronous balneophototherapy with bathing in Dead Sea salt solution plus narrowband UVB vs. narrowband UVB alone (TOMESA-study group).

BACKGROUND: Synchronous balneophototherapy (sBPT) simulates treatment conditions at the Dead Sea for outpatient use. In the past, sBPT proved to be an effective treatment for psoriasis. However, there is a lack of sufficiently large randomized controlled clinical trials evaluating the additional benefit of sBPT compared with ultraviolet B (UVB) monotherapy. OBJECTIVES: The purpose of this study was to compare the effectiveness and safety of sBPT with UVB phototherapy (PT) alone in a randomized controlled effectiveness study. METHODS: In this phase III, multicentre effectiveness study, 367 patients with moderate to severe psoriasis were randomly allocated in a 1 : 1 ratio to receive either sBPT consisting of narrowband UVB PT with 311 nm and synchronous bathing in 10% Dead Sea salt solution or PT with 311 nm alone. Primary endpoint, analysed on an intention-to-treat basis (n = 356), was the relative improvement of the Psoriasis Area and Severity Index (PASI) from baseline to end of treatment (35 sessions or clearance). Sample size calculation aimed at the detection of superiority of at least 10%. RESULTS: Median PASI values were comparable at baseline (sBPT: 15.1, interquartile range: 10.9-24.3; PT: 15.3, interquartile range: 10.0-23.7). A clinically relevant and statistically significant difference of 49.5% between sBPT and PT could be proven at the end of the therapy phase (P < 0.001; Wilcoxon-Mann-Whitney test). Exploratory testing showed a statistically significant superiority of sBPT after 6 months. CONCLUSIONS: In routine clinical practice, sBPT is superior to PT alone after 35 treatment sessions and a follow-up of 6 months. Both treatments demonstrated to be safe.

Modulation of extracellular matrix by nutritional hepatotrophic factors in thioacetamide-induced liver cirrhosis in the rat

Nutritional substances associated to some hormones enhance liver regeneration when injected intraperitoneally, being denominated hepatotrophic factors (HF). Here we verified if a solution of HF (glucose, vitamins, salts, amino acids, glucagon, insulin, and triiodothyronine) can revert liver cirrhosis and how some extracellular matrices are affected. Cirrhosis was induced for 14 weeks in 45 female Wistar rats (200 mg) by intraperitoneal injections of thioacetamide (200 mg/kg). Twenty-five rats received intraperitoneal HF twice a day for 10 days (40 mL·kg-1·day-1) and 20 rats received physiological saline. Fifteen rats were used as control. The HF applied to cirrhotic rats significantly: a) reduced the relative mRNA expression of the genes: Col-α1 (-53 percent), TIMP-1 (-31.7 percent), TGF-β1 (-57.7 percent), and MMP-2 (-41.6 percent), whereas Plau mRNA remained unchanged; b) reduced GGT (-43.1 percent), ALT (-17.6 percent), and AST (-12.2 percent) serum levels; c) increased liver weight (11.3 percent), and reduced liver collagen (-37.1 percent), regenerative nodules size (-22.1 percent), and fibrous septum thickness. Progranulin protein (immunohistochemistry) and mRNA (in situ hybridization) were found in fibrous septa and areas of bile duct proliferation in cirrhotic livers. Concluding, HF improved the histology and serum biochemistry of liver cirrhosis, with an important reduction of interstitial collagen and increased extracelullar matrix degradation by reducing profibrotic gene expression.

Amphiphilic pyridinium salts block TNF alpha/NF kappa B signaling and constitutive hypersecretion of interleukin-8 (IL-8) from cystic fibrosis lung epithelial cells.

Cystic fibrosis (CF) is a common, lethal genetic disease, which is due to mutations in the CFTR gene. The CF lung expresses a profoundly proinflammatory phenotype, due to constitutive hypersecretion of IL-8 from epithelial cells lining the airways. In a systematic search for candidate drugs that might be used therapeutically to suppress IL-8 secretion from these cells, we have identified a potent and efficacious series of amphiphilic pyridinium salts. The most potent of these salts is MRS2481, an (R)-1-phenylpropionic acid ester, with an IC50 of ca. 1microM. We have synthesized 21 analogues of MRS2481, which have proven sufficient to develop a preliminary structure-activity relationship (SAR). For optimal activity, we have found that the ester must be connected to the pyridinium derivative by an eight-carbon chain. An optical isomer of the lead compound, containing an (S)-1-phenylpropionic acid ester, has been found to be a much less active. The mechanism of action of MRS2481 appears to involve inhibition of signaling of the NF(kappa)B and AP-1 transcription factors to the IL-8 promoter. MRS2481 is a potent inhibitor of TNFalpha-induced phosphorylation and proteosomal destruction of I(kappa)B(alpha). Inasmuch as I(kappa)B(alpha) is the principal inhibitor of the NF(kappa)B signaling pathway, preservation of intact I(kappa)B(alpha) would serve to keep the IL-8 promoter silent. We also find that MRS2481 blocks TNF(alpha)-activated phosphorylation of JNK, the c-JUN kinase. The IL-8 promoter is also activated by an AP-1 site, which requires a phospho-c-JUN/c-FOS dimer for activity. We therefore interpret these data to suggest that the mechanism of MRS2481 action is to inhibit both NF(kappa)B and AP-1 signaling on the IL-8 promoter. Given the medicinally promising properties of water-solubility, potency in the low muM concentration range, and high efficacy, we anticipate that MRS2481, or a further optimized derivative, may find an important place in the armamentarium of pharmaceutical strategies yet to be arrayed against the inflammatory phenotype of the CF lung.