The Role of Gender Differences and Menopause in Obesity-Related Renal Disease, Renal Inflammation and Lipotoxicity.

The pathogenesis of obesity-related-renal disease is unknown. Menopause can promote renal disease in obese women, but this interaction is unclear. In a previous study, we observed that obese male and female mice developed albuminuria, hyperfiltration, and glomerulomegaly, and these changes were more severe in those obese ovariectomized females. In this study, we also evaluated renal inflammation and lipotoxicity in that animal model. For six months, 43 males and 36 females C57BL6/J mice were randomized to standard diet (SD) or high fat diet (HFD). A group of female animals on SD or HFD was ovariectomized to simulate menopause. We evaluated cytokines: NF-κß p65, IL-1ß, MCP-1, TNF-α, total lipid content, lipid classes, and fatty acid profile in total lipid and individual lipid classes in renal tissue and urine. We found that obese males and females showed higher NF-kß p-65, TNF-α and MCP-1 in renal tissue, and obese females ovariectomized had higher IL-1ß and TNF-α compared with not-ovariectomized. Also, obese animals showed lower proinflammatory and higher anti-inflammatory fatty acids in kidney total lipids, while obese females ovariectomized had a more exacerbated pattern. In brief, obesity induces inflammation and an unbalanced lipidic profile in renal tissue. This pattern seems to be enhanced in obesity after menopause.

Pulmonary Function and Respiratory Diseases in Different Genotypes of Alpha-1 Antitrypsin Deficiency.

OBJECTIVE: Respiratory disease is the major cause of morbidity and mortality in patients with alpha-1 antitrypsin deficiency, mainly in homozygous PI*ZZ individuals. However, this association is uncertain in subjects with other deficiency genotypes. The objective of this study was to assess, in the context of alpha-1 antitrypsin deficiency, the existence of further risk factors that have been associated with respiratory diseases. MATERIAL AND METHODS: Lung function was assessed by spirometry in a sample of 1334 patients with a known genotype for the SERPINA1 gene whose serum alpha-1 antitrypsin levels had been previously determined. Patients with a normal genotype (PI*MM) were compared to 389 patients carrying a deficiency allele. RESULTS: Statistically significant associations were detected between (i) PI*ZZ genotype and abnormal FEV1 values (χ2 = 26.45; P <.0002), FEV1/FVC (χ2 = 14.8; P < .02) or forced mid-expiratory flow 25%-75% (χ2 =22.66; P < .0009); (ii) chronic obstructive pulmonary disease and PI*ZZ odds ratio: 26.5; 95% CI: (2.6-265.9); P <.005 and or PI*SS genotype odds ratio: 9; 95% CI: (2-40.1); P < .004; (iii) prevalence of COPD in PI*MZ subjects and smoking habit (P < .01), low body weight (P < .01) or older age (P < .0001). CONCLUSION: The PI*ZZ and PI*SS genotypes seem to be associated with the prevalence of chronic obstructive pulmonary disease. Tobacco use, low body weight, and older age are risk factors that increase the probability of prevalence of chronic obstructive pulmonary disease by up to 70% in PI*MZ individuals.

Obesity and metabolic syndrome induce hyperfiltration, glomerulomegaly, and albuminuria in obese ovariectomized female mice and obese male mice.

OBJECTIVE: Obese patients with metabolic syndrome have a high risk of chronic kidney disease. The prevalence of obesity, metabolic syndrome, and insulin resistance increase in women after menopause, as does the risk of chronic kidney disease. This may indicate an interaction between obesity, metabolic syndrome, and menopause in the induction of renal damage. However, the pathogenesis of kidney disease in postmenopausal obese women is poorly understood. METHODS: We investigated the interaction of an obesogenic diet and menopause on renal dysfunction in ovariectomized and non-ovariectomized lean (n = 8 and 17) and obese (n = 12 and 20) female mice. Obese (n = 12) and lean (n = 10) male mice were also studied. Glucose metabolism, insulin resistance, and kidney function were evaluated with gold standards procedures. Changes in kidney histology and lipid deposition were analyzed. Females had a lower number of glomeruli than males at baseline. RESULTS: Only female ovariectomized obese animals developed insulin resistance, hyperglycemia, and kidney damage, evidenced as glomerulomegaly, glomerular hyperfiltration, and increased urinary albumin excretion, despite a similar increase in weight than obese non-ovariectomized female mice. Male obese mice developed hyperglycemia, insulin resistance, and hyperfiltration without major renal histological changes. Males on high fat diet showed higher renal lipid content and females on high fat diet (ovariectomized or non-ovariectomized) showed higher total cholesterol content than males. CONCLUSIONS: In mice, there is a clear interplay between obesity, metabolic syndrome, and menopause in the induction of kidney damage.

Video Summary : http://links.lww.com/MENO/A803 .

Las alteraciones en el pico de fusión de las sondas de hibridación usadas para el genotipado en la deficiencia de alfa-1 antitripsina no siempre implican errores / Changes in the Melting Point of Hybridization Probes Used for Genotyping in Alpha-1 Antitrypsin Deficiency Do Not Always Imply Errors

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Efecto de los polimorfismos en UGT, SLCO, ABCB y ABCC en la toxicidad del tratamiento con irinotecán / Effect of UGT, SLCO, ABCB and ABCC polymorphisms on irinotecan toxicity

Antecedentes y objetivos: Evaluar la relación entre la presencia de polimorfismos en los genes implicados en la farmacodinamia del irinotecán (UGT1A, SLCO1B1, ABCB1 y ABCC2) y la seguridad asociada al mismo en el tratamiento del cáncer colorrectal metastásico (CCRm). Pacientes y métodos: Estudio prospectivo observacional y unicéntrico de 30 meses de duración, en el que se incluyeron los pacientes diagnosticados de CCRm tratados con el esquema FOLFIRI. La toxicidad fue evaluada en cada ciclo de tratamiento según la Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 NCI. La obtención del ADN genómico se realizó mediante una muestra de sangre periférica a partir de un método de extracción basado en lisis alcalina. La caracterización genética se realizó empleando la plataforma LigthCycler®480 y sondas fluorescentes HybProbe® específicas de alelo. Los polimorfismos analizados fueron: UGT1A1*28, UGT1A1*60, UGT1A7*1,*2,*3,*4, UGT1A7*12, UGT1A9*22, SLCO1B1 (rs11045879), ABCC2 (rs717620) y ABCB1 (rs1045642). Resultados: Fueron incluidos 34 pacientes (el 73,5% eran hombres, con una edad media de 59,9 años [27-81]). Los polimorfismos: rs8175347, rs17868323, rs3832043, rs11692021 y rs7577677 se relacionaron con una mayor incidencia de efectos adversos. Por otro lado, se observó que aquellos pacientes wild-type, en la serie de genes de la familia UGT analizada, presentan unas menores tasas de toxicidad asociada al tratamiento con irinotecán que aquellos que poseen alguno de los polimorfismos analizados (p=0,010). Conclusiones: Estos resultados sugieren que la presencia de determinados polimorfismos en la familia de genes UGT1A se encuentra relacionada con el desarrollo de toxicidad en el tratamiento con irinotecán en dosis para el esquema FOLFIRI

Background and objectives: Evaluate the relationship between the presence of polymorphisms in genes involved in the pharmacodynamics of irinotecan (UGT1A, SLCO1B1, ABCB1 and ABCC2) and the safety of irinotecan in the treatment of metastatic colorectal cancer (mCRC). Patients and methods: Prospective observational, single-centre study of 30 months duration, which included patients diagnosed with mCRC treated with FOLFIRI was carried out. Toxicity was evaluated in each treatment cycle according to the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 NCI. Genomic DNA was obtained with a peripheral blood sample from an extraction method based on alkaline lysis. Genetic characterisation was performed using the LigthCycler®480 platform and allele-specific HybProbe® fluorescent probes. Analysed polymorphisms were: UGT1A1*28, UGT1A1*60, UGT1A7*1,*2,*3,*4, UGT1A7*12, UGT1A9*22, SLCO1B1 (rs11045879), ABCC2 (rs717620) and ABCB1 (rs1045642). Results: Thirty-four patients were included (73.5% were male, mean age 59.9 years [27-81]) in the study. Polymorphisms rs8175347, rs17868323, rs3832043, rs11692021 and rs7577677 were associated with a higher incidence of adverse effects. Furthermore, it was observed that those patients with wild-type in UGT family genes analysed have lower rates of toxicity associated with irinotecan treatment than those with certain mutated allele (P=.010). Conclusions: These results suggest that the presence of certain polymorphisms in the UGT1A family of genes is related to the development of toxicity during treatment with irinotecan

Effect of UGT, SLCO, ABCB and ABCC polymorphisms on irinotecan toxicity. / Efecto de los polimorfismos en UGT, SLCO, ABCB y ABCC en la toxicidad del tratamiento con irinotecán.

BACKGROUND AND OBJECTIVES: Evaluate the relationship between the presence of polymorphisms in genes involved in the pharmacodynamics of irinotecan (UGT1A, SLCO1B1, ABCB1 and ABCC2) and the safety of irinotecan in the treatment of metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Prospective observational, single-centre study of 30 months duration, which included patients diagnosed with mCRC treated with FOLFIRI was carried out. Toxicity was evaluated in each treatment cycle according to the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 NCI. Genomic DNA was obtained with a peripheral blood sample from an extraction method based on alkaline lysis. Genetic characterisation was performed using the LigthCycler®480 platform and allele-specific HybProbe® fluorescent probes. Analysed polymorphisms were: UGT1A1*28, UGT1A1*60, UGT1A7*1,*2,*3,*4, UGT1A7*12, UGT1A9*22, SLCO1B1 (rs11045879), ABCC2 (rs717620) and ABCB1 (rs1045642). RESULTS: Thirty-four patients were included (73.5% were male, mean age 59.9 years [27-81]) in the study. Polymorphisms rs8175347, rs17868323, rs3832043, rs11692021 and rs7577677 were associated with a higher incidence of adverse effects. Furthermore, it was observed that those patients with wild-type in UGT family genes analysed have lower rates of toxicity associated with irinotecan treatment than those with certain mutated allele (P=.010). CONCLUSIONS: These results suggest that the presence of certain polymorphisms in the UGT1A family of genes is related to the development of toxicity during treatment with irinotecan.

Importancia de una correcta determinación de la glucemia capilar en el diagnóstico: resultados engañosos en manipuladores de Opuntia ficus-indica (higos chumbos) / Importance of accurate assessment of capillary blood glucose level in diagnosis: misleading results in handlers of prickly pears (Opuntia ficus-indica)

La hipoglucemia puede provocar síntomas neuroglucopénicos que fácilmente pueden confundirse con los ocasionados por patologías con otra repercusión clínica como son los accidentes cerebrovasculares (ACV). Un correcto diagnóstico diferencial entre ambos procesos será fundamental a la hora de determinar estrategias terapéuticas adecuadas. Presentamos un caso donde la incorrecta técnica de determinación de glucemia capilar (GC) en un vendedor ambulante de higos chumbos (Opuntia ficus-indica) enmascaró una hipoglucemia y motivó la sospecha inicial de un ACV. Se estudió la GC en 11 vendedores de estos frutos, antes y después de su manipulación. En todos los casos, las glucemias posteriores fueron notablemente superiores. Los resultados obtenidos evidenciaron la necesidad de realizar correctamente la técnica de determinación de GC y la importancia de descartar la hipoglucemia con doble medición (capilar y venosa), en pacientes con sintomatología neurológica aguda (AU)

Hypoglycemia can cause symptoms of neuroglycopenia that can be easily confused with symptoms of greater clinical importance such as stroke. Appropriate differential diagnosis between these 2 processes will be essential for guiding the treatment approach. We report a case in which stroke was initially suspected because hypoglycemia was masked by the incorrect capillary blood glucose (CBG) measurement technique used in treating an itinerant vendor of prickly pears (Opuntia ficus-indica). We studied the effects of prickly pear handling on the CBG levels in 11 vendors before and after they handled the fruit. CBG levels were noticeably higher after the fruit was handled in all cases. Our observations reveal the need to measure both capillary and venous blood glucose levels to rule out hypoglycemia in patients with acute neurological symptoms (AU)

Reducing the degree of colonisation of venous access catheters by continuous passive disinfection.

INTRODUCTION: The advent of Luer-type needleless venous access catheters has been accompanied by a growing number of catheter-related bloodstream infections. Our main objective was to compare rates of colonisation and phlebitis between our standard of care and the new passive disinfection system, using a Luer SwabCap bearing a sponge impregnated with 70% isopropyl alcohol. METHODS: We performed a prospective experimental study involving patients attending our day hospital oncology unit, with central venous (CV) or peripheral venous (PV) access lines with needleless connectors for antineoplastic treatment delivery. We assessed the colonisation rate by culture of the inside of the hubs (qualitative culture) and also assessed the possible appearance of phlebitis and the extra cost of introducing the new system in our oncology day hospital; nurse satisfaction was evaluated by a questionnaire. The effectiveness of the isopropyl alcohol disinfection cap was evaluated by analysing rates of catheter colonisation and phlebitis between two groups: group 1 comprised of patients receiving the standard disinfection method and group 2 comprised of patients receiving SwabCaps on any venous access connectors. Samples were taken from the catheter lumen through a sterile swab seeded in Luria Bertani-rich broth and cultivated for at least 48 h at 37°C. We also assessed the extra cost of introducing the new system in our oncology day hospital, and nurse satisfaction was evaluated by a questionnaire. RESULTS: 29 patients were included (13 in group 1 and 16 in group 2). In group 1, 56% of the samples were taken from CV access connectors versus 40% in group 2. Bacterial growth was detected in 43.7% of group 1 samples versus 0% in group 2 (p=0.006). No differences in the degree of contamination were found between CV and PV access connectors. No cases of phlebitis were observed. Nurse satisfaction with the new system was 9.2 out of a maximum score of 10. The incremental cost of incorporating the new system in our oncology unit was estimated at €1.87 836. CONCLUSION: Passive disinfection systems help reduce colonisation of venous access catheters without requiring large economic investment or special training of health personnel.

[Importance of accurate assessment of capillary blood glucose level in diagnosis: misleading results in handlers of prickly pears (Opuntia ficus-indica)]. / Importancia de una correcta determinación de la glucemia capilar en el diagnóstico: resultados engañosos en manipuladores de Opuntia ficus-indica (higos chumbos).

OBJECTIVES: Hypoglycemia can cause symptoms of neuroglycopenia that can be easily confused with symptoms of greater clinical importance such as stroke. Appropriate differential diagnosis between these 2 processes will be essential for guiding the treatment approach. We report a case in which stroke was initially suspected because hypoglycemia was masked by the incorrect capillary blood glucose (CBG) measurement technique used in treating an itinerant vendor of prickly pears (Opuntia ficus-indica). We studied the effects of prickly pear handling on the CBG levels in 11 vendors before and after they handled the fruit. CBG levels were noticeably higher after the fruit was handled in all cases. Our observations reveal the need to measure both capillary and venous blood glucose levels to rule out hypoglycemia in patients with acute neurological symptoms.

OBJETIVO: La hipoglucemia puede provocar síntomas neuroglucopénicos que fácilmente pueden confundirse con los ocasionados por patologías con otra repercusión clínica como son los accidentes cerebrovasculares (ACV). Un correcto diagnóstico diferencial entre ambos procesos será fundamental a la hora de determinar estrategias terapéuticas adecuadas. Presentamos un caso donde la incorrecta técnica de determinación de glucemia capilar (GC) en un vendedor ambulante de higos chumbos (Opuntia ficus-indica) enmascaró una hipoglucemia y motivó la sospecha inicial de un ACV. Se estudió la GC en 11 vendedores de estos frutos, antes y después de su manipulación. En todos los casos, las glucemias posteriores fueron notablemente superiores. Los resultados obtenidos evidenciaron la necesidad de realizar correctamente la técnica de determinación de GC y la importancia de descartar la hipoglucemia con doble medición (capilar y venosa), en pacientes con sintomatología neurológica aguda.

Description of alpha-1-antitrypsin deficiency associated with PI*Q0ourém allele in La Palma Island (Spain) and a genotyping assay for its detection.

By analysis of a case of discrepancy between serum alpha-1-antitrypsin (AAT) level and genotype for the most common defective alleles associated with AAT deficiency (PI*S and PI*Z), a patient carrying the allele PI*Q0ourém has been identified for the first time outside of Portugal. This null allele has been implicated in cases of severe pulmonary emphysema. After developing a clinical assay for detection of c.1130insT mutation, based on fluorescent probes (HybProbe®), another 4 carriers of PI*Q0ourém allele were identified among 43 patients with abnormally low serum AAT levels based on their genotypes for PI*S and PI*Z alleles. Since 4 out 5 cases are from the same locality (La Palma Island, Spain), it is advisable to conduct genetic analyses of affected families and, possibly, a focused population screening.