Patients suffering from dystrophic epidermolysis bullosa are prone to developing autoantibodies against skin proteins: A longitudinal confirmational study.

Epidermolysis bullosa (EB) is a heritable skin blistering disease caused by variants in genes coding for proteins that secure cell-cell adhesion and attachment of the epidermis to the dermis. Interestingly, several proteins involved in inherited EB are also associated with autoimmune blistering diseases (AIBD). In this study, we present a long-term follow-up of 15 patients suffering from recessive dystrophic or junctional EB. From these patients, 62 sera were analysed for the presence of autoantibodies associated with AIBD. We show that patients suffering from recessive dystrophic EB (RDEB) are more susceptible to developing autoantibodies against skin proteins than patients suffering from junctional EB (70% vs. 20%, respectively). Interestingly, no correlation with age was observed. Most patients showed reactivity to Type XVII collagen/linear IgA bullous dermatosis autoantigen (n = 5; 33%), followed by BP230 (n = 4; 27%), Type VII collagen (n = 4; 27%) and laminin-332 (n = 1; 7%). The pathogenicity of these autoantibodies remains a subject for future experiments.

Resistance Exercise Program in Cognitively Normal Older Adults: CERT-Based Exercise Protocol of the AGUEDA Randomized Controlled Trial.

OBJECTIVES: To provide a comprehensive CERT (Consensus on Exercise Reporting Template)-based description of the resistance exercise program implemented in the AGUEDA (Active Gains in brain Using Exercise During Aging) study, a randomized controlled trial investigating the effects of a 24-week supervised resistance exercise program on executive function and related brain structure and function in cognitively normal older adults. DESIGN AND PARTICIPANTS: 90 cognitively normal older adults aged 65 to 80 were randomized (1:1) to a: 1) resistance exercise group; or a 2) wait-list control group. Participants in the exercise group (n = 46) performed 180 min/week of resistance exercise (3 supervised sessions per week, 60 min/session) for 24 weeks. INTERVENTION: The exercise program consisted of a combination of upper and lower limb exercises using elastic bands and the participant's own body weight as the main resistance. The load and intensity were based on the resistance of the elastic bands (7 resistances), number of repetitions (individualized), motor complexity of exercises (3 levels), sets and rest (3 sets/60 sec rest), execution time (40-60 sec) and velocity (as fast as possible). SETTINGS: The maximum prescribed-target intensity was 70-80% of the participants' maximum rate of perceived exertion (7-8 RPE). Heart rate, sleep quality and feeling scale were recorded during all exercise sessions. Those in the wait-list control group (n = 44) were asked to maintain their usual lifestyle. The feasibility of AGUEDA project was evaluated by retention, adherence, adverse events and cost estimation on the exercise program. RESULTS AND CONCLUSIONS: This study details the exercise program of the AGUEDA trial, including well-described multi-language manuals and videos, which can be used by public health professionals, or general public who wish to implement a feasible and low-cost resistance exercise program. The AGUEDA exercise program seems to be feasible by the high retention (95.6%) and attendance rate (85.7%), very low serious adverse event (1%) and low economic cost (144.23 € /participant/24 weeks). We predict that a 24-week resistance exercise program will have positive effects on brain health in cognitively normal older adults.

[Health implications of the finding of Angiostrongylus cantonensis, the main cause of eosinophilic meningoencephalitis, in continental Europe (Valencia, Spain)]. / Implicaciones sanitarias del hallazgo de Angiostrongylus cantonensis, causa principal de la meningoencefalitis eosinofílica, en Europa continental (València, España).

The rat pulmonary artery nematode, Angiostrongylus cantonensis (discovered in rats from the province of Canton, southern China, in 1933 ) is the main cause in humans of what is known as eosinophilic meningoencephalitis (EEM), with around of 3,000 confirmed cases in various parts of the world.

El nematodo de las arterias pulmonares de las ratas, Angiostrongylus cantonensis (descubierto en ratas de la provincia de Cantón, en el sur de China, en 1933  es el principal responsable en el ser humano de la conocida como meningoencefalitis eosinofílica (MEE), con alrededor de 3.000 casos confirmados en diversas partes del mundo.

Eficacia y seguridad del implante XEN45 en la cirugía de glaucoma. Estudio retrospectivo de nuestros primeros 73 casos / Efficacy and safety of the XEN45 implant in glaucoma surgery: Retrospective study of our first 73 cases

Objetivo Analizar los resultados del implante XEN45 en nuestro centro hospitalario, tanto en términos de eficacia como en cuanto a seguridad. Método Estudio observacional, retrospectivo y monocéntrico de los pacientes intervenidos de XEN45 en el Hospital Universitario de Jaén entre el 1 de enero de 2018 y el 31 de junio de 2021. Resultados Se implantó el dispositivo XEN45 a un total de 73 pacientes (48 cirugía combinada con facoemulsificación del cristalino y 25 de forma aislada). La PIO disminuyó de 19,9±4,9mmHg en la primera visita hasta una media de 17,1±5,3 (p=0,001) en el sexto mes. Se redujo de 2,1±0,9 a 0,6 el uso de fármacos necesarios entre la primera visita y el mes tras el implante XEN (p<0,000). Fue necesaria una segunda cirugía en 18 pacientes (26,6%) en los 6 primeros meses. Conclusiones La cirugía de glaucoma mediante implante XEN45, en solitario o combinado con la cirugía de catarata, es un procedimiento eficaz y seguro para la disminución de la PIO (AU)

Objective To analyze the results of the XEN45 implant in our hospital center, both in terms of efficacy and safety. Methods Observational, retrospective, single-center study of patients undergoing XEN45 surgery at the University Hospital of Jaén between January 1, 2018 and June 31, 2021. Results A total of 73 patients were implanted with the XEN45 device (48 with in combined surgery with phacoemulsification of the crystalline lens and 25 standalone XEN45 surgery). IOP decreased from 19.9±4.9mmHg at the first visit to a mean of 17.1±5.3 (P=.001) at the sixth month. Drug use required between the first visit and XEN implantation was reduced from 2.1±0.9 to 0.6 (P<.000). A second surgery was necessary in 18 patients (26.6%) in the first 6 months. Conclusions Glaucoma surgery by XEN45 implant, alone or combined with cataract surgery, is an effective and safe procedure for IOP lowering (AU)

Efficacy and safety of the XEN45 implant in glaucoma surgery: Retrospective study of our first 73 cases.

OBJECTIVE: To analyze the results of the Xen45 implant in our hospital center, both in terms of efficacy and safety. METHODS: Observational, retrospective, single-center study of patients undergoing Xen45 surgery at the University Hospital of Jaén between January 1, 2018 and June 31, 2021. RESULTS: A total of 73 patients were implanted with the Xen45 device (48 with in combined surgery with phacoemulsification of the crystalline lens and 25 standalone Xen45 surgery). IOP decreased from 19.9 ±â€¯4.9 mmHg at the first visit to a mean of 17.1 ±â€¯5.3 (P = .001) at the sixth month. Drug use required between the first visit and Xen implantation was reduced from 2.1 ±â€¯0.9 to 0.6 (P < .000). A second surgery was necessary in 18 patients (26.6%) in the first 6 months. CONCLUSIONS: Glaucoma surgery by Xen45 implant, alone or combined with cataract surgery, is an effective and safe procedure for IOP lowering.

Risk associations for intestinal parasites in symptomatic and asymptomatic schoolchildren in central Mozambique.

OBJECTIVES: Chronic infections by enteric parasites including protist and helminthic species produce long-term sequelae on the health status of infected children. This study assesses potential associations linked with enteric parasite infections in symptomatic and asymptomatic children in Zambézia province, Mozambique. METHODS: In this prospective cross-sectional study, stool samples and epidemiological questionnaires on demographics and risk associations were collected from symptomatic children (n = 286) from clinical settings and asymptomatic (n = 807) children from 17 schools and creches aged 3‒14 years. We detected enteric parasites using PCR-based methods. We calculated prevalence (adjusted for age, sex, house construction, drinking water, and latrine use) and odds ratios (ORs) for risk associations with logistic regression, after adjusting for district, neighbourhood and symptoms. RESULTS: Numbers and adjusted prevalence (95% confidence intervals in parentheses) for the symptomatic and asymptomatic populations were Giardia duodenalis 120, 52% (22-82), 339, 42% (25-59); followed by Strongyloides stercoralis 52, 14% (9‒20), 180, 20% (15-25). Risk associations for G. duodenalis included drinking untreated river/spring water, OR 2.91 (1.80-4.70); contact with ducks, OR 14.96 (2.93‒76.31); dogs, OR 1.92 (1.04-3.52); cats, OR 1.73 (1.16-2.59), and a relative with diarrhoea, OR 2.59 (1.54‒4.37). Risk associations for S. stercoralis included having no latrine, OR 2.41 (1.44-4.02); drinking well water, OR 1.82 (1.02-3.25), and increasing age, OR 1.11 (1.04-1.20). CONCLUSIONS: We found a high prevalence of intestinal parasites regardless of the children's symptoms. Drinking well or river water, domestic animals, and latrine absence were contributing factors of human infections.

Generation and characterization of human induced pluripotent stem cells (iPSCs) from hand osteoarthritis patient-derived fibroblasts.

Knowledge and research results about hand osteoarthritis (hOA) are limited due to the lack of samples and animal models of the disease. Here, we report the generation of two induced pluripotent stem cell (iPSC)-lines from patients with radiographic hOA. Furthermore, we wondered whether these iPSC-lines carried single nucleotide polymorphisms (SNPs) within genes that have been associated with hOA. Finally, we performed chondrogenic differentiation of the iPSCs in order to prove their usefulness as cellular models of the disease. We performed a non-integrative reprogramming of dermal fibroblasts obtained from two patients with radiographic rhizarthrosis and non-erosive hOA by introducing the transcriptional factors Oct4, Sox2, Klf4 and c-Myc using Sendai virus. After reprogramming, embryonic stem cell-like colonies emerged in culture, which fulfilled all the criteria to be considered iPSCs. Both iPSC-lines carried variants associated with hOA in the four studied genes and showed differences in their chondrogenic capacity when compared with a healthy control iPSC-line. To our knowledge this is the first time that the generation of iPSC-lines from patients with rhizarthrosis and non-erosive hOA is reported. The obtained iPSC-lines might enable us to model the disease in vitro, and to deeper study both the molecular and cellular mechanisms underlying hOA.

Eosinophilic cholecystitis: a retrospective study spanning a fourteen-year period. / Colecistitis eosinofílica: estudio retrospectivo de 14 años.

INTRODUCTION AND AIMS: Eosinophilic cholecystitis is a rare entity that was first described in 1949 and is clinically indistinguishable from calculous cholecystitis. Histologically, there is transmural inflammatory infiltration of the gallbladder wall, more than 90% of which is composed of eosinophils. The aim of the present article was to review the prevalence of eosinophilic cholecystitis and analyze the clinical and surgical characteristics of patients diagnosed with the disease that were operated on at our hospital. MATERIALS AND METHODS: A retrospective study was conducted on patients that underwent cholecystectomy and whose postoperative histopathologic diagnosis was eosinophilic cholecystitis, within the time frame of January 2000 and August 2014. The demographic, clinical, paraclinical, surgical, and histopathologic variables were described. RESULTS: Over a period of 14 years, a total of 7,494 patients underwent cholecystectomy. Of those patients, 12 had a postoperative histologic diagnosis of eosinophilic cholecystitis. Mean patient age for disease presentation was 39 years (±11 years), and female sex was predominant, with 7 cases. All the patients had concomitant gallstones and 10 patients presented with acute cholecystitis that required urgent cholecystectomy. All the cases were considered idiopathic. We found a prevalence of 0.16%, corresponding to 1 case for every 625 cholecystectomies performed at our hospital. CONCLUSION: We found a low prevalence of eosinophilic cholecystitis (0.16%) in our study population. The clinical manifestations were similar to those of calculous cholecystitis. Cholecystectomy is adequate treatment in patients with idiopathic disease.

Tratamiento de fracturas supracondíleas de húmero mediante osteosíntesis con doble placa / Double plating as treatment for supracondylar humeral fractures

Introducción y objetivos. Las fracturas supracondíleas de húmero representan el 0,5-1%. El objetivo de nuestro estudio es evaluar retrospectivamente el resultado funcional y la calidad de vida de los pacientes intervenidos quirúrgicamente por fractura supracondílea de húmero mediante osteosíntesis con doble placa. Material y métodos. Presentamos un estudio descriptivo retrospectivo de 27 fracturas supracondíleas de húmero tratadas quirúrgicamente mediante reducción abierta y osteosíntesis con 2 placas anatómicas, entre enero de 2005 y septiembre de 2012. La edad media de los pacientes fue de 56±22,9 años, 14 mujeres y 13 hombres. Todas las fracturas fueron tipificadas según la clasificación de la AO. El seguimiento medio fue de 41±23,9 meses. Se evaluó la consolidación de la fractura por medio de estudio radiológico y el resultado funcional mediante el Mayo Elbow Performance Score. La calidad de vida fue evaluada mediante el cuestionario SF 36. Resultados. El 96% de las fracturas consolidaron antes de 6 meses. El rango de movimiento medio fue de 102° (70-140°) y el Mayo Elbow Performance Score fue de 86 puntos (60-100). La puntuación media en el SF-36 fue de 54,87 (8,66-89,22), siendo las puntuaciones menores en pacientes de mayor edad. El 60% de los pacientes (15 de 25) se incorporaron a la misma actividad que realizaban antes del accidente. No hubo ningún caso de infección. Dos pacientes fueron reintervenidos por rigidez de codo. Conclusiones. La reducción abierta y osteosíntesis con doble placa de las fracturas supracondíleas de húmero permite obtener la consolidación de la fractura en un porcentaje elevado, con buenos resultados funcionales y radiológicos (AU)

Introduction and objectives. Supracondylar humeral fractures represent only about 0.5-1% of all fractures in adults. The objective of this study is to evaluate functional outcome and quality of life in patients treated with open reduction and internal fixation using double plates. Material and methods. We designed a retrospective descriptive study including 27 supracondylar humeral fractures treated with open reduction and internal fixation using two anatomic plates from January 2005 to September 2012. Mean age was 56 ± 22.9 years including 14 female and 13 male. All fractures were classified using the AO classification. Average follow-up was of 41 ± 23.9 months. Fracture union was evaluated with x-ray exams and functional outcome using the Mayo Elbow Performance Score (MEPS). Quality of life was evaluated using the Short Form-36 survey. Results. Union at 6 months was achieved in 96% of all fractures. Average range of motion was 102° (70°-140°) and average MEPS 86 points (60-100). Mean score on SF-36 was 54.87 (8.66-89.22) the older patients had lower scores. Sixty percent of patients (15 of 25) were able to return to previous activity. No infection was reported. Two patients required surgical treatment due to a stiff elbow. Conclusions. Open reduction and internal fixation using double plates in supracondylar humeral fractures obtains a high union rate allowing excellent functional and radiological outcomes (AU)

Isolation and molecular characterization of Acanthamoeba from patients with keratitis in Spain.

In order to improve our knowledge on the epidemiology of amoebic keratitis, as well as the identification of Acanthamoeba isolates, we have isolated Acanthamoeba spp. from five symptomatic patients in Spain in the present study. All isolates were grown in axenic liquid medium, with only one exception. The morphology of these isolates were characterized by optical and scanning electron microscopy. Their structural features corresponded to those of amphizoic amoebae (namely Acanthamoeba spp.). The molecular characterization of the five Acanthamoeba isolates yielded six sequences. Almost complete 18S rRNA gene sequences (>2000bp) were obtained from three isolates and partial sequences (∼1500bp) from the other two. A robust phylogenetic analysis based on the almost complete 18S rRNA sequence showed that four isolates belonged to the T4 genotype and the other one to the T3 genotype. However, all isolates were identified as T4 genotype using the ASA.S1 fragment. As previously suggested by other researchers, only a robust phylogenetic approach may be helpful in identifying Acanthamoeba genotypes. In addition, new data on the phylogenetic relationships among the Acanthamoeba genotypes is provided and discussed.

Double plating as treatment for supracondylar humeral fractures. / Tratamiento de fracturas supracondíleas de húmero mediante osteosíntesis con doble placa.

INTRODUCTION AND OBJECTIVES: Supracondylar humeral fractures represent only about 0.5-1% of all fractures in adults. The objective of this study is to evaluate functional outcome and quality of life in patients treated with open reduction and internal fixation using double plates. MATERIAL AND METHODS: We designed a retrospective descriptive study including 27 supracondylar humeral fractures treated with open reduction and internal fixation using two anatomic plates from January 2005 to September 2012. Mean age was 56 ± 22.9 years including 14 female and 13 male. All fractures were classified using the AO classification. Average follow-up was of 41 ± 23.9 months. Fracture union was evaluated with x-ray exams and functional outcome using the Mayo Elbow Performance Score (MEPS). Quality of life was evaluated using the Short Form-36 survey. RESULTS: Union at 6 months was achieved in 96% of all fractures. Average range of motion was 102° (70°-140°) and average MEPS 86 points (60-100). Mean score on SF-36 was 54.87 (8.66-89.22) the older patients had lower scores. Sixty percent of patients (15 of 25) were able to return to previous activity. No infection was reported. Two patients required surgical treatment due to a stiff elbow. CONCLUSIONS: Open reduction and internal fixation using double plates in supracondylar humeral fractures obtains a high union rate allowing excellent functional and radiological outcomes.

Correlation between peak systolic velocity and diameter of cavernosal arteries in flaccid versus dynamic state for the evaluation of erectile dysfunction.

Previous studies have suggested that parameters measured in the flaccid state (FS) by penile duplex Doppler ultrasound (PDDU) may predict the outcome after intracavernosal injection (ICI). The aim of this study was to evaluate the association between peak systolic velocity (PSV) and cavernosal artery diameter (CAD) in the FS with PSV and clinical assessment of erection hardness (CAEH) after ICI. Fifty patients who underwent PDDU for erectile dysfunction were prospectively enrolled. PSV and CAD were measured in FS and then correlated with PSV and CAEH after ICI of 20 µg of e1 prostaglandin (PGe1). Even though PSV in FS demonstrated a significant correlation with PSV after ICI (P=0.04, r=0.21), none of the cutoff values tested (10, 13 and 15 cm s-1 in FS) had a combined sensitivity and specificity >80% to predict a PSV after ICI ⩾30 cm s-1. No correlation was observed between CAD in FS and PSV after ICI. Also, no association was observed between PSV in FS and development of a complete full rigid erection after ICI. Although PSV in FS statistically correlates with PSV after ICI, predictive values are low, making it non-reliable to predict accurately the response to ICI of 20 µg PGe1.

Hierarchical organization of the hemostatic response to penetrating injuries in the mouse macrovasculature.

Essentials Methods were developed to image the hemostatic response in mouse femoral arteries in real time. Penetrating injuries produced thrombi consisting primarily of platelets. Similar to arterioles, a core-shell architecture of platelet activation occurs in the femoral artery. Differences from arterioles included slower platelet activation and reduced thrombin dependence. SUMMARY: Background Intravital studies performed in the mouse microcirculation show that hemostatic thrombi formed after penetrating injuries develop a characteristic architecture in which a core of fully activated, densely packed platelets is overlaid with a shell of less activated platelets. Objective Large differences in hemodynamics and vessel wall biology distinguish arteries from arterioles. Here we asked whether these differences affect the hemostatic response and alter the impact of anticoagulants and antiplatelet agents. Methods Approaches previously developed for intravital imaging in the mouse microcirculation were adapted to the femoral artery, enabling real-time fluorescence imaging despite the markedly thicker vessel wall. Results Arterial thrombi initiated by penetrating injuries developed the core-and-shell architecture previously observed in the microcirculation. However, although platelet accumulation was greater in arterial thrombi, the kinetics of platelet activation were slower. Inhibiting platelet ADP P2Y12 receptors destabilized the shell and reduced thrombus size without affecting the core. Inhibiting thrombin with hirudin suppressed fibrin accumulation, but had little impact on thrombus size. Removing the platelet collagen receptor, glycoprotein VI, had no effect. Conclusions These results (i) demonstrate the feasibility of performing high-speed fluorescence imaging in larger vessels and (ii) highlight differences as well as similarities in the hemostatic response in the macro- and microcirculation. Similarities include the overall core-and-shell architecture. Differences include the slower kinetics of platelet activation and a smaller contribution from thrombin, which may be due in part to the greater thickness of the arterial wall and the correspondingly greater separation of tissue factor from the vessel lumen.

Ion channels, ion channel receptors, and visceral hypersensitivity in irritable bowel syndrome.

Ion channels are expressed throughout the gastrointestinal system and regulate nearly every aspect of digestion, including fluid secretion and absorption, motility, and visceral sensitivity. It is therefore not surprising that in the setting of functional bowel disorders, such as irritable bowel syndrome (IBS), ion channels are often altered in terms of expression level and function and are a target of pharmacological intervention. This is particularly true of their role in driving abdominal pain through visceral hypersensitivity (VH), which is the main reason IBS patients seek medical care. In the study by Scanzi et al., in the current issue of this journal, they provide evidence that the T-type voltage-gated calcium channel (Cav ) Cav 3.2 is upregulated in human IBS patients, and is necessary for the induction of an IBS-like disease state in mice. In this mini-review, we will discuss the contribution of specific ion channels to VH in IBS, both in human patients and rodent models. We will also discuss how Cav 3.2 may play a role as an integrator of multiple environmental stimuli contributing toward VH.

Tumor miofibroblástico de laringe: reporte de caso clínico y revisión de literatura / Miofibroflástico larynx tumor: case report and literature review

El tumor miofibroblástico inflamatorio de laringe es una patología rara dentro de los tumores de cabeza, cuello y de vía aérea, con una baja prevalencia, existiendo escasa literatura al respecto. Corresponde a un tumor benigno que generalmente se presenta como hallazgo incidental en relación a cuerdas vocales con mayor frecuencia, que puede ser de carácter asintomático o presentarse con clínica de obstrucción de vía aérea como estridor y disnea progresiva, además de disfonía. Puede afectar a pacientes de cualquier edad, siendo más frecuentes en adultos en edad media. El diagnóstico se hace a través de radiología y visualización directa mediante laringoscopía con la consiguiente obtención de muestra y estudio histopatológico. El tratamiento consta en la resección quirúrgica completa de la lesión, asociado o no a terapia esteroidal, sin embargo la curación completa no se logra en todos los casos producto de la naturaleza recidivante de la lesión.

The inflammatory myofibroblastic umor of the larynx is a rare condition in tumors of head, neck and airway, with a low prevalence, and scarce existing literature. It corresponds to a benign tumor that usually occurs as an incidental finding in relation to vocal cords more frequently, which can be asymptomatic or present with clinical character of airway obstruction, as progressive stridor and dyspnea, plus dysphonia. It can affect patients of any age are more common in adults in middle age. The diagnosis is made by radiology and direct laryngoscopy with visualization by obtaining sample and histology. Treatment consists of surgical removal of the entire lesion with or without steroid therapy, however complete healing is not achieved in all the cases product of the recurrent nature of the patology.

Detection of Zoonotic Protozoa Toxoplasma gondii and Sarcocystis suihominis in Wild Boars from Spain.

Food safety regulations require the control of the presence of protozoa in meats destined for human consumption. Wild boar (Sus scrofa) meat may constitute a source of zoonoses. A 23.8% (688/2881) seroprevalence of anti-Toxoplasma gondii antibodies and 72.2% (662/910) Sarcocystis sarcocysts prevalence were detected among wild boars hunted in Southwestern areas of Spain. Identity of Sarcocystis spp. was performed by RFLP-PCR and sequencing, detecting S. miescheriana (7/8) and the zoonotic S. suihominis (1/8). Risk assessment studies of these coccidian in meats destined to human consumption are needed.

Influence of age on rat bone-marrow mesenchymal stem cells potential.

Mesenchymal stem cells promising role in cell-based therapies and tissue engineering appears to be limited due to a decline of their regenerative potential with increasing donor age. Six age groups from bone marrow mesenchymal stem cells of Wistar rats were studied (newborn, infant, young, pre-pubertal, pubertal and adult). Quantitative proteomic assay was performance by iTRAQ using an 8-plex iTRAQ labeling and the proteins differentially expressed were grouped in pluripotency, proliferative and metabolism processes. Proliferation makers, CD117 and Ki67 were measure by flow cytometry assay. Real time polymerase chain reaction analysis of pluripotency markers Rex1, Oct4, Sox2 and Nanog were done. Biological differentiation was realized using specific mediums for 14 days to induce osteogenesis, adipogenesis or chondrogenesis and immunostain analysis of differentiated cell resulting were done. Enzimoimmunoassay analysis of several enzymes as L-lactate dehydrogenase and glucose-6-phosphate isomerase were also done to validate iTRAQ data. Taking together these results indicate for the first time that mesenchymal stem cells have significant differences in their proliferative, pluripotency and metabolism profiles and those differences are age depending.