High TGM1 Allelic Heterogeneity causing Lamellar ichthyosis in a small geographic area in South Mexico: Another Example of the "Réunion Paradox".

Lamellar ichthyosis (LI) is an autosomal recessive congenital ichthyosis characterized by generalized dry skin and severe scaling. It is caused by biallelic mutations in the TGM1 gene, however molecular data from non-Caucasian populations are limited. Results of genetic-molecular analysis of a group of LI pedigrees originating from two close small populations from south Mexico are presented. LI affected individuals belonging to 9 apparently unrelated families were studied. Exome sequencing or Sanger sequencing in probands from each family was carried out. Furthermore, DNA from 294 unaffected subjects from one of the communities were Sanger sequenced to determine the carrier frequency of the c.427C > T TGM1 variant. Five different TGM1 pathogenic variants, either in homozygous or in compound heterozygous state, were demonstrated in affected subjects. The two most common variants were c.427C > T (p.Arg143Cys) and c.1159+1G > T. A novel c.1645+1G > T TGM1 pathogenic allele was recognized. Carrier frequency analysis identified a total of 23 individuals heterozygous for the c.427C > T variant, predicting a prevalence of 78 carriers per 1000 inhabitants in the community. A high TGM1 allelic heterogeneity with 5 different LI-causing alleles in a limited geographic area was demonstrated. While the occurrence of homozygosity for a founder mutation is expected in small populations with high frequency of a particular autosomal recessive disorder, the occurrence of multiple pathogenic alleles has been previously described, a situation known as the Reúnion paradox. Our results expand the current knowledge of the mutational spectrum of TGM1-linked LI.

Case report: Disease phenotype associated with simultaneous biallelic mutations in ABCA4 and USH2A due to uniparental disomy of chromosome 1.

Inherited retinal diseases (IRDs) represent a spectrum of clinically and genetically heterogeneous disorders. Our study describes an IRD patient carrying ABCA4 and USH2A pathogenic biallelic mutations as a result of paternal uniparental disomy (UPD) in chromosome 1. The proband is a 9-year-old girl born from non-consanguineous parents. Both parents were asymptomatic and denied family history of ocular disease. Clinical history and ophthalmologic examination of the proband were consistent with Stargardt disease. Whispered voice testing disclosed moderate hearing loss. Next-generation sequencing and Sanger sequencing identified pathogenic variants in ABCA4 (c.4926C>G and c.5044_5058del) and USH2A (c.2276G>T). All variants were present homozygously in DNA from the proband and heterozygously in DNA from the father. No variants were found in maternal DNA. Further analysis of single nucleotide polymorphisms confirmed paternal UPD of chromosome 1. This is the first known patient with confirmed UPD for two recessively mutated IRD genes. Our study expands on the genetic heterogeneity of IRDs and highlights the importance of UPD as a mechanism of autosomal recessive disease in non-consanguineous parents. Moreover, a long-term follow-up is essential for the identification of retinal features that may develop as a result of USH2A-related conditions.

Low muscle mass in COVID-19 critically-ill patients: Prognostic significance and surrogate markers for assessment.

INTRODUCTION: Low muscle mass is a common condition in the critically ill population and is associated with adverse clinical outcomes. The primary aim of this study was to analyze the prognostic significance of low muscle mass using computed tomography (CT) scans in COVID-19 critically ill patients. A second objective was to determine the accuracy and agreement in low muscle mass identification using diverse markers compared to CT as the gold standard. METHODS: This was a prospective cohort study of COVID-19 critically ill patients. Skeletal muscle area at the third lumbar vertebra was measured. Clinical outcomes (intensive care unit [ICU] and hospital length of stay [LOS], tracheostomy, days on mechanical ventilation [MV], and in-hospital mortality) were assessed. Phase angle, estimated fat-free mass index, calf circumference, and mid-upper arm circumference were measured as surrogate markers of muscle mass. RESULTS: Eighty-six patients were included (mean age ± SD: 48.6 ± 12.9; 74% males). Patients with low muscle mass (48%) had a higher rate of tracheostomy (50 vs 20%, p = 0.01), prolonged ICU (adjusted HR 0.53, 95%CI 0.30-0.92, p = 0.024) and hospital LOS (adjusted HR 0.50, 95% CI 0.29-0.86, p = 0.014). Bedside markers of muscle mass showed poor to fair agreement and accuracy compared to CT-assessed low muscle mass. CONCLUSION: Low muscle mass at admission was associated with prolonged length of ICU and hospital stays. Further studies are needed to establish targeted nutritional interventions to halt and correct the catabolic impact of COVID-19 in critically ill patients, based on standardized and reliable measurements of body composition.

Direct observation of endoglucanase fibrillation and rapid thickness identification of cellulose nanoplatelets using constructive interference.

Better understanding through direct observation of the mechanisms involved in chemical and enzymatic hydrolysis of biomass is of great importance, to implement a substitute for the common cellulose standards. We report the hydrolysis of biomass, using exclusively the parenchyma, to isolate cellulose nanoplatelets using a less harsh pretreatment. Then, we show direct evidence of the effect of endoglucanase on the structure of cellulose nanoplatelets, finding that amorphous cellulose is exclusively digested, loosening the cellulose nanofibrils in the process. The analysis of micrographs demonstrates that when cellulose nanoplatelets are deposited on a silicon wafer, its thickness can be qualitatively measured by the interference color detected using an optical microscope. This finding facilitates further studies of mechanisms involved in lignin removal and cellulose nanofibrils production by specific enzymatic digestion.

Oxígeno hiperbárico para la cistitis inducida por radioterapia: un seguimiento a largo plazo / Hyperbaric oxygen for radiation-induced cystitis: A long-term follow-up

INTRODUCCIÓN Y OBJETIVOS: Alrededor del 12% de los pacientes tratados con radioterapia pélvica desarrollan complicaciones en la vejiga. La terapia de oxígeno hiperbárico (TOHB) es una opción para el manejo de la cistitis hemorrágica inducida por radioterapia (CHIR). El objetivo de este estudio fue evaluar la eficacia de la TOHB para tratar la cistitis por radioterapia e identificar factores predictivos para un resultado exitoso. MATERIAL Y MÉTODOS: Revisamos retrospectivamente a 105 pacientes diagnosticados de CHIR que recibieron un tratamiento de TOHB entre 2007 y 2016 en nuestro centro. Los pacientes recibieron oxígeno al 100% en una cámara hiperbárica multiplaza a 2,4 ATA durante 80 min. Todos los pacientes cumplimentaron un cuestionario en el que se documentaba la gravedad de los síntomas previos a la TOHB y tras el período de seguimiento. RESULTADOS: Después de una media de 40 sesiones de TOHB, hubo una tasa de éxito del 92,4% en el control de la hematuria. Durante el período de seguimiento (mediana de 63 meses), el 24,7% de los pacientes presentaron recurrencia de la hematuria. La puntuación media de las variables evaluadas en el cuestionario -disuria, frecuencia urinaria y hematuria- fue significativamente menor después del período de seguimiento (p <0,05). Nuestros datos muestran que cuanto antes se administre la TOHB después del primer episodio de hematuria, se logran mejores tasas de respuesta y se registran menores recurrencias en relación con la hematuria (p <0,05). No se observaron complicaciones graves. CONCLUSIONES: Nuestros resultados apoyan la seguridad y los beneficios a largo plazo de la TOHB para la CHIR y otros síntomas molestos de la vejiga, lo que supondría una mejora en la calidad de vida de nuestros pacientes

INTRODUCTION AND OBJECTIVES: Bladder complications may be seen in up to 12% of patients treated with pelvic irradiation. Hyperbaric oxygen therapy (HBOT) is an option for the management of radiation-induced hemorrhagic cystitis (RIHC). The aim of this study was to evaluate the efficacy of HBOT in radiation cystitis and to identify the predictive factors for a successful outcome. MATERIAL AND METHODS: We retrospectively reviewed 105 patients diagnosed with RIHC which were treated with HBOT between 2007 and 2016 in our institution. Patients received 100% oxygen in a multiplace hyperbaric chamber at 2.4atm for 80minutes. All patients fulfilled a questionnaire documenting symptom severity pre-HBOT and at the end of the follow-up period. RESULTS: After a median of 40 HBOT sessions, there was success rate of 92,4% in the control of hematuria. During our follow-up period (median of 63 months) 24,7% patients presented with recurrence of hematuria. The mean score of the questionnaire-assessed variables: dysuria, urinary frequency and hematuria, was significantly lower after the follow-up period (P<.05). Our data shows that the sooner HBOT is delivered after the first episode of hematuria, better response rates are achieved and lower recurrences concerning hematuria were registered (P<.05). No serious complications were observed. CONCLUSIONS: Our results support the safety and long-term benefits of HBOT on RIHC and other distressful bladder symptoms, which represents an expected improvement of quality of life in our patients

Hyperbaric oxygen for radiation-induced cystitis: A long-term follow-up. / Oxígeno hiperbárico para la cistitis inducida por radioterapia: un seguimiento a largo plazo.

INTRODUCTION AND OBJECTIVES: Bladder complications may be seen in up to 12% of patients treated with pelvic irradiation. Hyperbaric oxygen therapy (HBOT) is an option for the management of radiation-induced hemorrhagic cystitis (RIHC). The aim of this study was to evaluate the efficacy of HBOT in radiation cystitis and to identify the predictive factors for a successful outcome. MATERIAL AND METHODS: We retrospectively reviewed 105 patients diagnosed with RIHC which were treated with HBOT between 2007 and 2016 in our institution. Patients received 100% oxygen in a multiplace hyperbaric chamber at 2.4atm for 80minutes. All patients fulfilled a questionnaire documenting symptom severity pre-HBOT and at the end of the follow-up period. RESULTS: After a median of 40 HBOT sessions, there was success rate of 92,4% in the control of hematuria. During our follow-up period (median of 63 months) 24,7% patients presented with recurrence of hematuria. The mean score of the questionnaire-assessed variables: dysuria, urinary frequency and hematuria, was significantly lower after the follow-up period (P<.05). Our data shows that the sooner HBOT is delivered after the first episode of hematuria, better response rates are achieved and lower recurrences concerning hematuria were registered (P<.05). No serious complications were observed. CONCLUSIONS: Our results support the safety and long-term benefits of HBOT on RIHC and other distressful bladder symptoms, which represents an expected improvement of quality of life in our patients.

Eco-friendly isolation of cellulose nanoplatelets through oxidation under mild conditions.

Agave is recognized as a low recalcitrant material, which makes it a potential source to obtain nanocellulose. Aqueous dispersions (in water, H2O2, H2O2/H2SO4) of agave powder were heated at 120°C under vapor pressure (1kg/cm2). The resultant materials were observed with an optical microscope (OM), a laser scanning microscope (LSM) to obtain the thickness measurement and a scanning electron microscope (SEM) to observe morphology. Raman spectroscopy, X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) were used to obtain the chemical structure. Cellulose nanoplatelets (CNPs) from Agave salmiana were successfully isolated under mild conditions. Physicochemical analysis indicates that lignin was removed in a single step oxidation with hydrogen peroxide in presence of sulfuric acid at low concentration (0.17M). The CNPs images revealed the presence of entangled cellulose nanofibrils (Ø≈14nm) along the nanoplatelets (thickness ≈80nm).

The influence of hyperbaric environment on the skeletal muscle mitochondrial energetic of rats after induced muscle contusion.

OBJECTIVE: Analyze the influence of the hyperbaric environment on skeletal muscle mitochondrial bioenergetic end-points of rats submitted to muscle contusion. METHODS: Twelve female Wistar rats were randomly assigned to three groups. All rats were submitted to muscle contusion in the right gastrocnemius through a standard protocol. The control group (C) remained under normobaric conditions without any treatment. The hyperbaric air (HB) and the hyperbaric oxygen (HBO2) groups had four sessions of HBO2 therapy 60 minutes, six, 12, 24 and 48 hours after the injury at 253.25 kPa (2.5 atmospheres absolute/ATA) with air or 100% oxygen, respectively. The animals were sacrificed 48 hours after muscle injury, and both muscles (injured and non-injured) were analyzed. Muscle mitochondrial bioenergetics and mitochondrial permeability transition pore (MPTP) susceptibility were evaluated. RESULTS: Significant differences were found in all parameters between the injured and the non-injured gastrocnemius in the C group. In the HB group, significantly better results concerning bioenergetics-related end points with complex I and II substrates where found in the right gastrocnemius, whereas in the HBO2 group the time to Vmax (time that elapsed until the faster swelling kinetics starts) was significantly higher and the swelling amplitude was significantly smaller than in other groups, which suggest a lower susceptibility to MPTP opening. CONCLUSION: The present data suggest that hyperbaric exposure, particularly with oxygen, positively modulates the efficiency of skeletal muscle mitochondria after muscle contusion.

Expression of metallothionein type 2 and 3 genes in Prosopis glandulosa leaves treated with copper.

For a better understanding of the strategies that are used by Prosopis glandulosa in heavy metal tolerance, the present study evaluated the gene expression of three metallothioneins (MTs; PgMt2-1, PgMt2, and PgMt3) in plants exposed to sub-lethal concentrations of copper. The PgMt2-1, PgMt2, and PgMt3 sequences were homologous to the MT type 2 (isoform 1), Mt2, and Mt3 sequences of other plant species found in GenBank. A reverse transcriptase-polymerase chain reaction showed that treatment with 100 mM Cu2+ induced a significant increase in PgMt2 and PgMt3 expression during the first 4 h of exposure compared to that of PgMt2-1. However, after 8 h of exposure, the expression levels of PgMt2 and PgMt3 were significantly lower than those of PgMt2-1. PgMt transcript levels only increased significantly during the first hour after exposure to copper, suggesting that PgMts could play a key role in the plant's detoxification mechanism. However, additional studies are required to confirm MTs as a mechanism of heavy metal tolerance and accumulation in this species.

Clinical, imaging, and molecular findings in a sample of Mexican families with pantothenate kinase-associated neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder characterized by iron accumulation in the brain, because of mutations in the PANK2 gene. Phenotypic and genotypic characteristics of 11 patients from five Mexican families with PKAN disease are reported. Sequencing of PANK2 confirmed the diagnosis. The 11 patients had dysarthria associated with dystonia and Parkinsonism in six. Brain magnetic resonance imaging (MRI) showed the 'eye-of-the-tiger' sign in all patients. Three different mutations were identified, a novel one (p.A469P) and two (p.G219V and p.N404I) very rare. Homozygous sibs for the p.G219V mutation had a severe disease progression with early death. Dystonia predominated in the p.A469P/p.N404I compound heterozygous patients. Homozygous for p.N404I showed Parkinsonism, tics and personality and speech disorders. Early and late disease onset and variable expression was present in carriers of the different identified mutations. The 'eye-of-the-tiger' is an excellent neuroimaging hallmark to predict PANK2 mutations. We detected a 'cluster' of patients harboring the p.N404I mutation, strongly suggesting a founder effect for this mutation. This is the first familial clinical-genetic PKAN disease study accomplished in Mexico.

A novel gene mutation in PANK2 in a patient with an atypical form of pantothenate kinase-associated neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) disease is an autosomal recessive neurodegenerative disorder with iron storage in the brain due to PANK2 gene mutations. Brain magnetic resonance imaging (MRI) shows the typical "eye-of-the-tiger" sign. The aim of the present study was to describe clinical, MRI and molecular findings in a 26-year-old male with atypical PKAN disease in whom, brain MRI scans showed bilateral pallidal T2-hypointensity with a small central region of T2-hyperintensity, resembling the "eye-of-the-tiger" typical image. Genetic analysis identified two mutations in PANK2: c.1561G>A and c.1663G>A, being the latter never described before. Due to limited phenotype-genotype correlation among patients with movement disorders, if "eye-of-the-tiger" brain MRI is present, PANK2 mutations investigation are needed to confirm PKAN disease.

A Novel De Novo EFNB1 Gene Mutation in a Mexican Patient with Craniofrontonasal Syndrome.

Craniofrontonasal syndrome (CNFS) is an X-linked disorder caused by mutations in the EFNB1 gene in which, paradoxically, heterozygous females are more severely affected than hemizygous males. In this paper, the clinical and molecular studies of a female subject with CFNS are described. A novel de novo c.473T>C (p.M158T) mutation in exon 3 of EFNB1 was demonstrated in this patient. The M158 residue of the Ephrin-B1 protein is highly conserved between species. Our results expand the mutational spectrum exposed by CNFS.

The resolving power of in vitro genotoxicity assays for cigarette smoke particulate matter.

In vitro genotoxicity assays are often used to compare tobacco smoke particulate matter (PM) from different cigarettes. The quantitative aspect of the comparisons requires appropriate statistical methods and replication levels, to support the interpretation in terms of power and significance. This paper recommends a uniform statistical analysis for the Ames test, mouse lymphoma mammalian cell mutation assay (MLA) and the in vitro micronucleus test (IVMNT); involving a hierarchical decision process with respect to slope, fixed effect and single dose comparisons. With these methods, replication levels of 5 (Ames test TA98), 4 (Ames test TA100), 10 (Ames test TA1537), 6 (MLA) and 4 (IVMNT) resolved a 30% difference in PM genotoxicity.

Clinical effectiveness of hyperbaric oxygen therapy for BK-virus-associated hemorrhagic cystitis after allogeneic bone marrow transplantation.

Late-onset hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (HSCT) has been associated with BK virus (BKV). Antiviral drugs are of limited efficacy and the optimal treatment for HC has not yet been established. Hyperbaric oxygen (HBO) may benefit these patients. We, therefore, retrospectively evaluated the effectiveness of HBO therapy in 16 patients with HC after allogeneic HSCT. All 16 patients had macroscopic hematuria and BKV infection. Patients received 100% oxygen in a hyperbaric chamber at 2.1 atmospheres for 90 min, 5 days per week, with a median 13 treatments (range, 4-84). Fifteen patients (94%) showed complete resolution of hematuria. Median urinary DNA BKV titers declined after HBO (P<0.05). Patients started on HBO earlier after diagnosis of HC responded sooner (P<0.05). HBO was generally well tolerated and proved to be a reliable option for this difficult to manage condition.

Divertículo de meckel gigante necrosado por torsión axial / Giant meckel’s diverticula with necrosis due to axial torsion

El presente artículo reporta el caso de un paciente masculino de 73 años que ingresa por cuadro de abdomen agudo y es llevado laparotomía donde se encuentra divertículo de Meckel gigante complicado con necrosis del tejido por torsión axial sobre pedículo de unión al íleon, una de las complicaciones más raras que se ha descrito en la literatura.

This article presents the case of a 73 year old patient who was admitted to the hospital with acute abdominal pain. A midline laparotomy was performed in which a giant Meckel’s Diverticulum was found. It was complicated by necrosis of the diverticular tissue due to axial torsion over its base. This is one of the rarest complications reported in the literature.

Fuzzy surface-based sliding mode control.

A new controller based on a combination of Sliding Mode Control and Fuzzy Logic is proposed. The conventional sliding surface is modified using a set of fuzzy rules. This combination confers controller robustness and flexibility. A neutralization process and a mixing process are used to compare the performance of the new controller to that of a conventional sliding mode controller and a PID controller.

[Geriatric physical performance assessment in an emergency department]. / Valoración geriátrica de la función física en un Servicio de Urgencias.

BASIS: Premorbid situation with regard to daily life activities is an important prognostic factor in elderly people who needs medical care. This work analyzes the way the parameter evaluation of core processes of daily life (CPDL) is made in patients over 70 years cared in an Emergency Service because of diverse medical conditions. PATIENTS AND METHODS: A prospective study, carried out in a third level medical institution, on 200 patients over 70 years cared in the Emergency medical Service, with questioning a group of 60 physicians on duty (POD) about the informal or subjective assessments of five parameters of CPDL (to get dressed, to be fed, sphincter control, walking, and transfer). POD evaluation is compared with evaluation carried out formally by the research physician. Assessments are evaluated, grouping the patients according to the degree of dependency, age, or sex. RESULTS: 82% of most dependent patients and 53% of those older than 80 years were poorly assessed, and both parameters were statistically significant. The analysis with multiple linear regression showed that the intensity of these errors is only determined by a variable: the greater degree of dependency. CONCLUSIONS: Correct performance assessment of elderly patients in emergency services, especially of those older and most dependent, requires a specific training of professionals in this regard and the use of formal instruments of evaluation.

[Prevalence of cognitive decline in people older than 70 years admitted in an internal medicine service]. / Prevalencia de deterioro cognitivo en mayores de 70 años ingresados en un Servicio de Medicina Interna.

BACKGROUND: Cognitive decline in older people is an important cause of burden for caregivers and assistance staff. It is a poor prognosis marker that favors the onset of different geriatric syndromes and increases the risk of institutionalization. As some causes of cognitive decline can be treated, its early diagnosis is fundamental for patients and caregivers. This, help us to design a care plan and a future follow up. The objective of this article is to measure the prevalence of Cognitive Decline before the onset of the acute disease that led patients older than 70 years, to an admission at the Internal Medicine Service. PATIENTS AND METHODS: A prospective randomized study was performed in the Internal Medicine Service of the Hospital de Mataro, which included 100 patients older than 70 years. Presence of Cognitive Decline was evaluated through the Blessed Scale during the previous month of the onset of the disease that motivated the admission. RESULTS: 43% of the patients had Cognitive Decline (42% male and 44% female). The prevalence of CD in patients older than 80 years was over 60%. CONCLUSIONS: Many of the admitted patients of an Internal Medicine Service older than 70 years had criteria for Cognitive Decline before the onset of the acute disease. Its diagnosis, study and therapeutic plan before the patient's discharge is a great opportunity to improve the quality of assistance.

Prevalencia de deterioro cognitivo en mayores de 70 años ingresados en un Servicio de Medicina Interna / Prevalence of cognitive decline in people older than 70 years admitted in an Internal Medicine Service

Fundamento: El deterioro cognitivo (DC) de los ancianos es una causa importante de sobrecargas de los cuidadores y del personal asistencial. Por otro lado es un marcador de mal pronóstico, favorece diferentes síndromes geriátricos e incrementa el riesgo de institucionalización. Su detección precoz puede ser beneficiosa, tanto para el enfermo como para sus familiares, ya que algunas causas de DC tienen tratamiento y además permite planificar la atención y seguimiento futuros. El objetivo de este trabajo es medir la prevalencia de DC, antes del comienzo de la patologia aguda que motiva su ingreso hospitalario, en pacientes mayores de 70 años ingresados en un Servicio de Medicina Interna de un hospital comarcal. Pacientes y métodos: Estudio prospectivo realizado en el Servicio de Medicina Interna del Hospital de Mataró, en 100 pacientes mayores de 70 años, elegidos de forma aleatoria. Se evalúa la presencia de DC, con la escala de Blessed, durante el mes previo al inicio de la enfermedad que motiva el ingreso. Resultados: el 43 por ciento de los pacientes tenían DC (42 por ciento de los hombres y 44 por ciento de las mujeres). En los mayores de 80 años la prevalencia de DC era superior al 60 por ciento. Conclusiones: A partir de los 70 años muchos de los pacientes ingresados en un Servicio de Medicina Interna tienen criterios de DC, previo al inicio de la enfermedad aguda. Su diagnóstico, estudio y tratamiento precoz permitiría mejorar la calidad asistencial en estos pacientes (AU)