Updates and new medical treatments for vitiligo (Review).

Vitiligo is a multifactorial disease characterized by the loss of skin pigment, which results in achromic macules and patches. There are currently several medical treatments available, which aim to arrest progression and induce skin repigmentation. These treatments alone or combined have exhibited varying degrees of pigmentation, and the majority are safe and effective. All therapies for vitiligo are limited, and no known treatment can consistently produce repigmentation in all patients. Individualized treatment is appropriate according to the location, clinical presentation and the presence of disease activity. The present review summarizes the medical treatments available for vitiligo: Systemic and topic pharmacological therapies, physical and depigmentation treatments. Several treatments are still underway and have not yet been approved. However, due to the promising preliminary results, these are also mentioned in the present review.

Novel immunological and genetic factors associated with vitiligo: A review.

Vitiligo is a skin disorder characterized by depigmentation of the skin due to a lack of melanin. This condition affects men and woman of all ages and its incidence is not restricted by ethnicity or region. Vitiligo is a multifactorial disease, in which melanocytes, which serve important functions in skin pigmentation and immune processes, are impaired. There is sufficient evidence that immunological and genetic factors are primarily responsible for the destruction and dysfunction of melanocytes. Therefore, genetic DNA sequence variants that participate in skin homeostasis, pigmentation and immune response regulation, as well as altered expression patterns, may contribute to the risk of developing vitiligo. The current review presented an overview of the mechanism of pigmentation and of currently known factors involved in depigmentation, as well as the classification, epidemiology, associated comorbidities, risk factors, immunopathogenesis and several genetic and molecular changes associated with vitiligo.

Anti­inflammatory and anti­catabolic effect of non­animal stabilized hyaluronic acid and mesenchymal stem cell­conditioned medium in an osteoarthritis coculture model.

Previous clinical studies have reported the clinical effectiveness of non­animal stabilized hyaluronic acid (NASHA) and adipose­derived mesenchymal stromal/stem cells (MSC) in the treatment of knee osteoarthritis (OA). Unlike MSC secreted mediators, in vitro anti­inflammatory effects of NASHA have not been evaluated. We aimed to evaluate and compare the anti­inflammatory effect of NASHA and MSC conditioned medium (stem cell­conditioned medium; SC­CM), in an explant­based coculture model of OA. Cartilage and synovial membrane from seven patients undergoing total knee arthroplasty were used to create a coculture system. Recombinant IL­1ß was added to the cocultures to induce inflammation. Four experimental groups were generated: i) Basal; ii) IL­1ß; iii) NASHA (NASHA + IL­1ß); and iv) SC­CM (SC­CM + IL­1ß). Glycosaminoglycans (GAG) released in the culture medium and of nitric oxide (NO) production were quantified. Gene expression in cartilage and synovium of IL­1ß, matrix metallopeptidase 13 (MMP13), ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS5) and tissue inhibitor of metalloproteinases 1 (TIMP1) was measured by reverse transcription­quantitative PCR. Media GAG concentration was decreased in cocultures with NASHA and SC­CM (48 h, P<0.05; 72 h, P<0.01) compared with IL­1ß. Production of NO was significantly lower only in SC­CM after 72 h (P<0.01). In cartilage, SC­CM inhibited the expression of IL­1ß, MMP13 and ADAMTS5, while NASHA had this effect only in MMP13 and ADAMTS5. In synovium, SC­CM decreased the expression level of MMP13 and ADAMTS5, while NASHA only decreased ADAMTS5 expression. Both NASHA and SC­CM increased TIMP1 expression in cartilage and synovium. Treatments with NASHA and SC­CM were shown to be a therapeutic option that may help counteract the catabolism produced by the inflammatory state in knee OA. The anti­inflammatory mediators produced by MSC promote a lower expression of inflammatory targets in our study model.

Schwann Cell Precursor Transplant in a Rat Spinal Cord Injury Model.

BACKGROUND: Differentiation of mesenchymal stem cells into Schwann cell precursors could reverse established lesions and sequelae of medullary transection. OBJECTIVE: The objective of this study was to study the clinical response of mesenchymal stem cell transplantation with Schwann precursor cell transplantation in a rat spinal cord injury model, using motor function and histopathologic studies. MATERIALS AND METHODS: A total of 28 Sprague-Dawley rats were randomly divided among four groups (n = 7 in each): sham group, control group, mesenchymal stem cell transplant group, and Schwann cell precursor transplant group. The surgical procedure was a laminectomy with transection of the spinal cord at the T11 level in the transplant groups and the injury control group. After 1 week, the transplant groups received stem cells directly in the injury site. Hind limb motor function was assessed using the locomotive scale of Basso, Beattie, and Bresnahan. 1 month after transplantation, all specimens were sacrificed to make a histopathologic description of sections taken from the site of injury and where stem cells were transplanted. Mean scores of mobility were compared using analysis of variance (ANOVA) of one factor with 95% reliability between groups and ANOVA of repetitive measures to evaluate evolution in the same group. RESULTS: We observed that the control group had statistically greater mobility than the other groups (p < 0.0001) and that the group with spinal injury without treatment had the lowest mean mobility. The mobility score values from the Schwann cell precursor group were statistically higher than the group treated with mesenchymal stem cells (p < 0.0001). CONCLUSION: Schwann precursor cells had a greater effect on locomotive function than mesenchymal stem cells.

A New Gene Expression Signature for Triple Negative Breast Cancer Using Frozen Fresh Tissue before Neoadjuvant Chemotherapy.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer tumors. Comparisons between TNBC and non-triple negative breast cancer (nTNBC) may help to differentiate key components involved in TNBC neoplasms. The purpose of the study was to analyze the expression profile of TNBC versus nTNBC tumors in a homogeneous population from northeastern Mexico. A prospective study of 50 patients was conducted (25 TNBC and 25 nTNBC). Clinic parameters were equally distributed for TNBC and nTNBC: age at diagnosis (51 vs 47 years, p=0.1), glucose levels (107 mg/dl vs 104 mg/dl, p=0.64), and body mass index (28 vs 29, p=0.14), respectively. Core biopsies were collected for histopathological diagnosis and gene expression analyses. Total RNA was isolated and expression profiling was performed. 40 genes showed differential expression pattern in TNBC tumors. Among these, 9 over-expressed genes (PRKX/PRKY, UGT8, HMGA1, LPIN1, HAPLN3, and ANKRD11), and one under-expressed (ANX9) gene are involved in general metabolism. Based on this biochemical peculiarity, and the over-expression of BCL11A and FOXC1 (involved in tumor growth and metastasis, respectively) we validated by qPCR the expression profile of 7 genes out of the signature. In this report, a new gene signature for TNBC is proposed. To our knowledge, this is the first TNBC signature which describes genes involved in general metabolism. The findings may be pertinent for Mexican patients and require to be evaluated in further ethnic groups and populations.

Leukocyte-poor platelet-rich plasma is more effective than the conventional therapy with acetaminophen for the treatment of early knee osteoarthritis.

INTRODUCTION: Knee osteoarthritis (OA) is a degenerative and progressive articular cartilage disease. Infiltration of autologous platelet-rich plasma (PRP) has been proposed as a therapeutic alternative due to the content of biologically active cytokines in PRP. We aimed to compare the clinical response of acetaminophen and intra-articular leukocyte-poor PRP (LP-PRP) in early knee OA. MATERIALS AND METHODS: A total of 65 patients with clinically and radiographically documented knee OA (grade 1-2) were analyzed. Patients were randomized into two groups: 32 were treated with acetaminophen (500 mg/8 h) over 6 weeks, and 33 received three intra-articular injections of autologous LP-PRP (once every 2 weeks). All patients were evaluated by the Visual Analogue Scale (VAS), the Western Ontario and McMaster Universities (WOMAC) score, and the SF-12 health survey at baseline and 6, 12, and 24 weeks of follow-up. All LP-PRP preparations were analyzed for the platelet, leukocyte, IL-1ra, and TGF-ß concentrations. RESULTS: The decrease in the VAS pain level in the LP-PRP group was greater than that in the acetaminophen group (p < 0.05). Patients treated with LP-PRP showed a sustained improvement in knee function at week 24 (p < 0.01). The SF-12 results only indicated an improvement in quality-of-life in the LP-PRP group at 6, 12, and 24 weeks of follow-up (p < 0.01). Both IL-1ra and TGF-ß were detected in the LP-PRP samples (313.8 ± 231.6 and 21,183.8 ± 8556.3 pg/mL, respectively). CONCLUSIONS: Treatment with LP-PRP injections resulted in a significantly better clinical outcome than did treatment with acetaminophen, with sustained lower EVA and WOMAC scores and improvement in quality-of-life (higher SF-12 score). Therapy with LP-PRP may positively modify the inflammatory joint environment by counteracting IL-1ß action.

Circulating microRNA expression profile in B-cell acute lymphoblastic leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is a highly diverse disease characterized by cytogenetic and molecular abnormalities, including altered microRNA (miRNA) expression signatures. AIM: We perform and validate a plasma miRNA expression profiling to identify potential miRNA involved in leukemogenesis METHODS: MiRNA expression profiling assay was realized in 39 B-ALL and 7 normal control plasma samples using TaqMan Low Density Array (TLDA) plates on Applied Biosystems 7900 HT Fast Real-Time PCR System. MiRNA validation was done for six miRNA differentially expressed by quantitative real-time PCR. RESULTS: Seventy-seven circulating miRNA differentially expressed: hsa-miR-511, -222, and -34a were overexpressed, whereas hsa-miR-199a-3p, -223, -221, and -26a were underexpressed (p values < 0.005 for both sets). According to operating characteristic curve analysis, hsa-miR-511 was the most valuable biomarker for distinguishing B-ALL from normal controls, with an area under curve value of 1 and 100% for sensitivity, and specificity respectively. CONCLUSIONS: Measuring circulating levels of specific miRNA implicated in regulation of cell differentiation and/or cell proliferation such as hsa-miRNA-511, offers high sensitivity and specificity in B-ALL detection and may be potentially useful for detection of disease progression, as indicator of therapeutic response, and in the assessment of biological and/or therapeutic targets for patients with B-ALL.

Saturated lipids decrease mitofusin 2 leading to endoplasmic reticulum stress activation and insulin resistance in hypothalamic cells.

Endoplasmic reticulum (ER) and mitochondria dysfunction contribute to insulin resistance generation during obesity and diabetes. ER and mitochondria interact through Mitofusin 2 (MTF2), which anchors in the outer mitochondrial and ER membranes regulating energy metabolism. Ablation of MTF2 leads to ER stress activation and insulin resistance. Here we determine whether lipotoxic insult induced by saturated lipids decreases MTF2 expression leading to ER stress response in hypothalamus and its effects on insulin sensitivity using in vitro and in vivo models. We found that lipotoxic stimulation induced by palmitic acid, but not the monounsaturated palmitoleic acid, decreases MTF2 protein levels in hypothalamic mHypoA-CLU192 cells. Also, palmitic acid incubation activates ER stress response evidenced by increase in the protein levels of GRP78/BIP marker at later stage than MTF2 downregulation. Additionally, we found that MTF2 alterations induced by palmitic, but not palmitoleic, stimulation exacerbate insulin resistance in hypothalamic cells. Insulin resistance induced by palmitic acid is prevented by pre-incubation of the anti-inflammatory and the ER stress release reagents, sodium salicylate and 4 phenylbutirate, respectively. Finally, we demonstrated that lipotoxic insult induced by high fat feeding to mice decreases MTF2 proteins levels in arcuate nucleus of hypothalamus. Our data indicate that saturated lipids modulate MTF2 expression in hypothalamus coordinating the ER stress response and the susceptibility to insulin resistance.

[Platelet-rich plasma in knee osteoarthritis treatment]. / El plasma rico en plaquetas en osteoartrosis de rodilla: una alternativa de tratamiento. Artículo de revisión.

The biological changes that commonly cause degenerative articular cartilage injuries in the knee are primarily associated to misalignment of the joint and metabolic changes related to age, as occurs in osteoarthritis. Furthermore, the capacity for cartilage self-regeneration is quite limited due to the lack of vascularity of the tissue. To date there is no ideal treatment capable to stimulate cartilage regeneration; thus there is a need to seek alternative therapies for the treatment of such conditions. The number of publications demonstrating the therapeutic and regenerative benefits of using platelet-rich plasma as a treatment for knee osteoarthritis has been increasing in recent years. In spite of encouraging results, there are still only a few randomised control studies with strong clinical evidence, lacking clarity on points such as the optimum formulation or the mechanism of action of platelet-rich plasma. Up to this point and based on the results of clinical studies, not all patients can benefit from this therapy. It is important to consider aspects such as the age and grade of cartilage degeneration. The aim of the present paper is to review the recent scientific literature on the treatment of knee osteoarthritis with platelet-rich plasma, and the biological bases of this therapy, as well as presenting the current opinion on this subject.

Correlations between major risk factors and closely related Mycobacterium tuberculosis isolates grouped by three current genotyping procedures: a population-based study in northeast Mexico.

The characteristics of tuberculosis (TB) patients related to a chain of recent TB transmissions were investigated. Mycobacterium tuberculosis (MTB) isolates (120) were genotyped using the restriction fragment length polymorphism-IS6110 (R), spacer oligotyping (S) and mycobacterial interspersed repetitive units-variable number of tandem repeats (M) methods. The MTB isolates were clustered and the clusters were grouped according to the similarities of their genotypes. Spearman's rank correlation coefficients between the groups of MTB isolates with similar genotypes and those patient characteristics indicating a risk for a pulmonary TB (PTB) chain transmission were ana- lysed. The isolates showing similar genotypes were distributed as follows: SMR (5%), SM (12.5%), SR (1.67%), MR (0%), S (46.67%), M (5%) and R (0%). The remaining 35 cases were orphans. SMR exhibited a significant correlation (p < 0.05) with visits to clinics, municipalities and comorbidities (primarily diabetes mellitus). S correlated with drug consumption and M with comorbidities. SMR is needed to identify a social network in metropolitan areas for PTB transmission and S and M are able to detect risk factors as secondary components of a transmission chain of TB.

Correlations between major risk factors and closely related Mycobacterium tuberculosis isolates grouped by three current enotyping procedures: a population-based study in northeast Mexico

The characteristics of tuberculosis (TB) patients related to a chain of recent TB transmissions were investigated. Mycobacterium tuberculosis (MTB) isolates (120) were genotyped using the restriction fragment length polymorphism-IS6110 (R), spacer oligotyping (S) and mycobacterial interspersed repetitive units-variable number of tandem repeats (M) methods. The MTB isolates were clustered and the clusters were grouped according to the similarities of their genotypes. Spearman’s rank correlation coefficients between the groups of MTB isolates with similar genotypes and those patient characteristics indicating a risk for a pulmonary TB (PTB) chain transmission were ana- lysed. The isolates showing similar genotypes were distributed as follows: SMR (5%), SM (12.5%), SR (1.67%), MR (0%), S (46.67%), M (5%) and R (0%). The remaining 35 cases were orphans. SMR exhibited a significant correlation (p < 0.05) with visits to clinics, municipalities and comorbidities (primarily diabetes mellitus). S correlated with drug consumption and M with comorbidities. SMR is needed to identify a social network in metropolitan areas for PTB transmission and S and M are able to detect risk factors as secondary components of a transmission chain of TB.

Low-income status is an important risk factor in North East Mexican patients with cystic fibrosis.

BACKGROUND. Factors such as environment, income status, as well as access to proper healthcare influence the survival and quality of life of people affected by chronic diseases including cystic fibrosis (CF). Survival factors in Mexican patients with CF have not been reported before, even when it has been estimated that this disease could not be negligible in the Mexican population. OBJECTIVE. To compare the influence of the mutant allele ΔF508 and environmental factors on the survival of Mexican CF patients. MATERIAL AND METHODS. We collected epidemiological data of 40 patients molecularly tested between 1987 and 2008 in the Clínica de Fibrosis Quística from the Hospital Universitario of the Universidad Autónoma de Nuevo León in Northeastern México. Kaplan-Meier plots and survival statistics were estimated and compared. RESULTS. Survival analysis revealed statistical significance for low-income status (p = 3.13 x 10-6), cor pulmonale (p = 0.00169), severe pulmonary disease (p = 0.00136), and BMI ≤15 kg/m2 (p = 0.00678). Statistical significance was not observed for the predominant allele ΔF508 considering two (p = 0.992), one (p = 0.503) or no (p = 0.403) mutant allele. CONCLUSIONS. Low income status was the most detrimental factor; followed by cor pulmonale, severe pulmonary disease and BMI ≤ 15 kg/m2 for the survival in North East Mexican patients with CF. Carrying the ΔF508 allele did not influence survival.

A population-based study of first and second-line drug-resistant tuberculosis in a high-burden area of the Mexico/United States border.

The resistance of 139 Mycobacterium tuberculosis (MTB) isolates from the city of Monterrey, Northeast Mexico, to first and second-line anti-TB drugs was analysed. A total of 73 isolates were susceptible and 66 were resistant to anti-TB drugs. Monoresistance to streptomycin, isoniazid (INH) and ethambutol was observed in 29 cases. Resistance to INH was found in 52 cases and in 29 cases INH resistance was combined with resistance to two or three drugs. A total of 24 isolates were multidrug-resistant (MDR) resistant to at least INH and rifampicin and 11 MDR cases were resistant to five drugs. The proportion of MDR-TB among new TB cases in our target population was 0.72% (1/139 cases). The proportion of MDR-TB among previously treated cases was 25.18% (35/139 cases). The 13 polyresistant and 24 MDR isolates were assayed against the following seven second-line drugs: amikacin (AMK), kanamycin (KAN), capreomycin (CAP), clofazimine (CLF), ethionamide (ETH), ofloxacin (OFL) and cycloserine (CLS). Resistance to CLF, OFL or CLS was not observed. Resistance was detected to ETH (10.80%) and to AMK (2.70%), KAN (2.70%) and CAP (2.70%). One isolate of MDR with primary resistance was also resistant to three second-line drugs. Monterrey has a high prevalence of MDR-TB among previously treated cases and extensively drug-resistant-MTB strains may soon appear.

A population-based study of first and second-line drug-resistant tuberculosis in a high-burden area of the Mexico/United States border

The resistance of 139 Mycobacterium tuberculosis (MTB) isolates from the city of Monterrey, Northeast Mexico, to first and second-line anti-TB drugs was analysed. A total of 73 isolates were susceptible and 66 were resistant to anti-TB drugs. Monoresistance to streptomycin, isoniazid (INH) and ethambutol was observed in 29 cases. Resistance to INH was found in 52 cases and in 29 cases INH resistance was combined with resistance to two or three drugs. A total of 24 isolates were multidrug-resistant (MDR) resistant to at least INH and rifampicin and 11 MDR cases were resistant to five drugs. The proportion of MDR-TB among new TB cases in our target population was 0.72% (1/139 cases). The proportion of MDR-TB among previously treated cases was 25.18% (35/139 cases). The 13 polyresistant and 24 MDR isolates were assayed against the following seven second-line drugs: amikacin (AMK), kanamycin (KAN), capreomycin (CAP), clofazimine (CLF), ethionamide (ETH), ofloxacin (OFL) and cycloserine (CLS). Resistance to CLF, OFL or CLS was not observed. Resistance was detected to ETH (10.80%) and to AMK (2.70%), KAN (2.70%) and CAP (2.70%). One isolate of MDR with primary resistance was also resistant to three second-line drugs. Monterrey has a high prevalence of MDR-TB among previously treated cases and extensively drug-resistant-MTB strains may soon appear.

Flourensia cernua: Hexane Extracts a Very Active Mycobactericidal Fraction from an Inactive Leaf Decoction against Pansensitive and Panresistant Mycobacterium tuberculosis.

The efficacy of decoction in extracting mycobactericidal compounds from Flourensia cernua (Hojasé) leaves and fractionation with solvents having ascending polarity was compared with that of (i) ethanol extraction by still maceration, extraction with a Soxhlet device, shake-assisted maceration, or ultrasound-assisted maceration, followed by fractionation with n-hexane, ethyl acetate, and n-butanol; (ii) sequential extraction with n-hexane, ethyl acetate, and n-butanol, by still maceration, using a Soxhlet device, shake-assisted maceration, or ultrasound-assisted maceration. The in vitro mycobactericidal activity of each preparation was measured against drug-sensitive (SMtb) and drug-resistant (RMtb) Mycobacterium tuberculosis strains. The results of which were expressed as absolute mycobactericidal activity (AMA). These data were normalized to the ΣAMA of the decoction fraction set. Although decoction was inactive, the anti-RMtb normalized ΣAMA (NAMA) of its fractions was comparable with the anti-RMtb NAMA of the still maceration extracts and significantly higher than the anti-SMtb and anti-RMtb NAMAs of every other ethanol extract and serial extract and fraction. Hexane extracted, from decoction, material having 55.17% and 92.62% of antituberculosis activity against SMtb and RMtb, respectively. Although the mycobactericidal activity of decoction is undetectable; its efficacy in extracting F. cernua active metabolites against M. tuberculosis is substantially greater than almost all pharmacognostic methods.

Frequency of S and Z alleles for alpha-1-antitrypsin and tumor necrosis factor alpha -308 promoter polymorphism in northeastern Mexico.

Diseases characterized by airway inflammation, excessive secretion, and obstruction affect a substantial proportion of the population. Studies for understanding the mechanisms underlying these processes are focused on the initiation and maintenance of inflammation. Polymorphisms on DNA sequence of response mediators such as alpha-1-antitrypsin (AAT) and tumor necrosis factor (TNF) alpha have the capacity to influence presentation of diseases, affecting protein amount and/or functionality, and can be analyzed as disease modulators. The purpose of this study was to analyze AAT S and Z alleles and -308G/A TNF-alpha polymorphism on the northeast Mexico mestizo population to compare the influence of these genes in several diseases. DNA samples from 103 volunteers (healthy group) were tested for modifier gene variants by polymerase chain reaction-RFLP as follows: AAT gene for S and Z alleles and TNF-alpha promoter -308G/A (TNF1/TNF2) alleles. Allele frequency for S and TNF2 alleles were 1.5 and 2.4%, respectively, whereas the Z allele was not detected. This study shows low frequencies of the AAT S and TNF2 alleles, and the Z allele was not found. Correlation studies in the future will allow to determine if these alleles have some influence in the clinical presentation of diverse diseases in this group of people.

Experimental models for hepatitis C virus (HCV): new opportunities for combating hepatitis C.

Infection with hepatitis C virus (HCV) is a global public health issue. More than 200 million people in the world are infected with HCV. Hepatitis C is considered one of the main causes of chronic hepatitis, cirrhosis, hepatocellular carcinoma and liver transplantation. The identification of the viral genome quickly allowed delineation of genomic organization, and the structure and biochemical characterization of the proteins of HCV. However, it has been difficult to study its life cycle, as well as the development of antiviral agents due to the lack of a system of permissible culture. Numerous attempts have been reported to establish an in vitro system for the study of HCV. Recently, a system of efficient culture was established that allows replication of subgenomic molecules of HCV in a cell line of human hepatoma. In this revision, after a brief description of the molecular biology, means of transmission and clinical characteristics of hepatitis C, some of the experimental models are described that have been developed to date, focusing mainly on the subgenomic replicon system and their use in the development of new antiviral treatments.