Reverse TAR may be added when necessary in open preperitoneal repair of lateral incisional hernias: a retrospective multicentric cohort study.

BACKGROUND: The best approach for lateral incisional hernia is not known. Posterior component separation (reverse TAR) offers the possibility of using the retromuscular space for medial extension of the challenging preperitoneal plane. The aim of our multicenter study was to compare the operative and patient-reported outcomes measures (PROMs) using two open surgical techniques from the lateral approach: a totally preperitoneal vs a reverse TAR. METHODS: A retrospective cohort study was performed since 2012 to 2020. Patients with lateral incisional hernia treated through a lateral approach were identified from a prospectively maintained multicenter database. Reverse TAR was added when the preperitoneal plane could not be safely dissected. The results obtained using these two lateral approaches were compared, including short- and long-term complications, as well as PROMs, using the specific tool EuraHSQoL. RESULTS: A total of 61 patients were identified. Reverse TAR was performed in 33 patients and lateral retromuscular preperitoneal approach in 28 patients. Both groups were comparable in terms of sociodemographic and comorbidities variables. Surgical site occurrences occurred in 13 cases (21.3%), with 8 patients (13.1%) requiring procedural intervention. During a median follow-up of 34 months, no incisional hernia recurrence was registered. There was a case (1.6%) of symptomatic bulging that required reoperation. Also 12 patients (19.7%) presented an asymptomatic bulging. No statistically significant difference was identified in the complications and PROMs between the two procedures. CONCLUSION: The open lateral retromuscular reconstruction using very large meshes that reach the midline has excellent long-term results with acceptable postoperative complications, including PROMs. A reverse TAR may be added, when necessary, without increasing complications and obtaining similar long-term results.

Increase in C-reactive protein as early predictor of anastomotic leakage in abdominal surgery.

OBJECTIVES: The aim of this study was to evaluate the role of the C-reactive protein (CRP) and white cell count (WC) in the prediction of anastomotic leakage (AL) in major abdominal surgery. METHODS: Multicenter, prospective, and observational study of adult patients who underwent major abdominal surgery. CRP and hemogram were measured after post-operative day (POD) 3 and POD 5. Complications were classified according to the Clavien-Dindo classification. Diagnostic accuracy was evaluated by the area under the receiver operating characteristic curve (AUC). RESULTS: A total of 97 patients were included in the study. The mean age was 63 ± 12 years and 47 (48%) were male. Colorectal (56%) and gastric cancer (36%) were the most frequent diagnoses. About 23% had post-operative complications, of which 5% had AL. The most significant predictive factor was the increase in CRP ≥ 2.84 mg/L among POD 3 and 5 (AUC, 0.99, sensitivity, 95.6%, specificity, 100%, positive likelihood ratio, 23.0). The accuracy of the other biomarkers was lower, CRP on POD 3 (AUC, 0.55), on POD 5 (AUC, 0.93), WC on POD 3 (AUC, 0.33), and POD 5 (AUC, 0.35). CONCLUSION: The increase of CRP among POD 3 and 5 was an early predictor of AL in adult patients with major abdominal surgery.

OBJETIVO: El objetivo de este estudio fue evaluar el papel de la proteína C-reactiva (PCR) y el recuento de glóbulos blancos (RGB) en la predicción de la Fuga Anastomotica (FA) en la cirugía abdominal mayor. MÉTODO: Estudio multicéntrico, prospectivo y observacional de pacientes adultos sometidos a cirugía abdominal mayor. Se midieron la PCR y el hemograma después del día postoperatorio (DPO) 3 y DPO 5. Las complicaciones se categorizaron según la clasificación de Clavien-Dindo y la precisión diagnóstica se evaluó mediante el área bajo la curva (AUC). RESULTADOS: Se incluyeron un total de 97 pacientes. La edad media era de 63 ± 12 años y 47 (48%) eran hombres. El factor predictivo más significativo fue el aumento de la PCR ≥ 2,84 mg/L entre los DPO 3 y 5 (AUC, 0,99, sensibilidad, 95,6%, especificidad, 100%, ratio de probabilidad positiva, 23,0). La precisión de los demás biomarcadores fue menor, la PCR en el DPO 3 (AUC, 0,55), en el DPO5 (AUC, 0,93), el RGB en el DPO 3 (AUC, 0,33) y en el DPO 5 (AUC, 0,35). CONCLUSIONES: El aumento de la PCR entre los DPO 3 y 5 fue un predictor temprano de FA en pacientes adultos con cirugía abdominal mayor.

Etiology and Risk Factors for Admission to the Pediatric Intensive Care Unit in Children With Encephalitis in a Developing Country.

OBJECTIVE: To describe a cohort of pediatric patients with encephalitis and their risk factors for admission to the pediatric intensive care unit (PICU). STUDY DESIGN: Children (<18 years old), with encephalitis evaluated by conventional microbiology and syndromic, multiplex test in cerebrospinal fluid (CSF) between July 2017 and July 2020, were recruited from 14 hospitals that comprise the Colombian Network of Encephalitis in Pediatrics. Multivariate analyses were used to evaluate risk factors associated with the need for PICU admission. RESULTS: Two hundred two children were included, of which 134 (66.3%) were male. The median age was 23 months (IQR 5.7-73.2). The main etiologies were bacteria (n = 55, 27%), unspecified viral encephalitis (n = 44, 22%) and enteroviruses (n = 27, 13%), with variations according to age group. Seventy-eight patients (38.6%) required management in the PICU. In multivariate analysis, factors associated with admission to the PICU were the presence of generalized seizures (OR 2.73; 95% CI: 1.82-4.11), status epilepticus (OR 3.28; 95% CI: 2.32-4.62) and low leukocyte counts in the CSF (OR 2.86; 95% CI: 1.47-5.57). Compared with enterovirus, bacterial etiology (OR 7.50; 95% CI: 1.0-56.72), herpes simplex encephalitis (OR 11.81; 95% CI: 1.44-96.64), autoimmune encephalitis (OR 22.55; 95% CI: 3.68-138.16) and other viral infections (OR 5.83; 95% CI: 1.09-31.20) increased the risk of PICU admission. CONCLUSIONS: Data from this national collaborative network of pediatric patients with encephalitis allow early identification of children at risk of needing advanced care and can guide the risk stratification of admission to the PICU.

Nonylphenol-mediated CYP induction is PXR-dependent: The use of humanized mice and human hepatocytes suggests that hPXR is less sensitive than mouse PXR to nonylphenol treatment.

Nonylphenol (NP), a by-product of alkylphenol ethoxylates, is a pervasive surfactant that activates the xenosensing nuclear receptor, the pregnane X-receptor (PXR) in transactivation assays in vitro. We are interested in determining if NP activates PXR in vivo, determining if hPXR and mPXR act similarly, and investigating the role of PXR in protecting individuals from NP. Wild-type (WT), PXR-null, and humanized PXR (hPXR) mice were treated with NP at 0, 50 or 75mg/kg/day for one week, and cytochrome P450 (CYP) induction, liver histopathology, and serum NP concentrations were examined. WT mice treated with NP showed induction of Cyp2b, and male-specific induction of Cyp2c and Cyp3a. CYPs were not induced in PXR-null mice, demonstrating that PXR is necessary for NP-mediated CYP induction. CAR-mediated CYP induction was not observed in the PXR-null mice despite previous data demonstrating that NP is also a CAR activator. hPXR mice only showed moderate Cyp induction, suggesting that hPXR is not as sensitive to NP as mPXR in vivo. NP-mediated Cyp3a induction from three human hepatocyte donors was not significant, confirming that hPXR is not very sensitive to NP-mediated CYP induction. Lastly, mice with PXR (mPXR and hPXR) showed lower NP serum concentrations than PXR-null mice treated with NP suggesting that PXR plays a role in decreasing liver toxicity by basally regulating phase I-III detoxification enzymes that promote the metabolism and elimination of NP. In summary, PXR is required for NP-mediated CYP-induction, mPXR mediates greater CYP induction than hPXR in vivo, and the presence of PXR, especially mPXR, is associated with altered histopathology and increased clearance of NP.

Ortho-aminoazotoluene activates mouse constitutive androstane receptor (mCAR) and increases expression of mCAR target genes.

2'-3-dimethyl-4-aminoazobenzene (ortho-aminoazotoluene, OAT) is an azo dye and a rodent carcinogen that has been evaluated by the International Agency for Research on Cancer (IARC) as a possible (class 2B) human carcinogen. Its mechanism of action remains unclear. We examined the role of the xenobiotic receptor Constitutive Androstane Receptor (CAR, NR1I3) as a mediator of the effects of OAT. We found that OAT increases mouse CAR (mCAR) transactivation in a dose-dependent manner. This effect is specific because another closely related azo dye, 3'-methyl-4-dimethyl-aminoazobenzene (3'MeDAB), did not activate mCAR. Real-time Q-PCR analysis in wild-type C57BL/6 mice revealed that OAT induces the hepatic mRNA expression of the following CAR target genes: Cyp2b10, Cyp2c29, Cyp3a11, Ugt1a1, Mrp4, Mrp2 and c-Myc. CAR-null (Car(-/-)) mice showed no increased expression of these genes following OAT treatment, demonstrating that CAR is required for their OAT dependent induction. The OAT-induced CAR-dependent increase of Cyp2b10 and c-Myc expression was confirmed by Western blotting. Immunohistochemistry analysis of wild-type and Car(-/-) livers showed that OAT did not acutely induce hepatocyte proliferation, but at much later time points showed an unexpected CAR-dependent proliferative response. These studies demonstrate that mCAR is an OAT xenosensor, and indicate that at least some of the biological effects of this compound are mediated by this nuclear receptor.

Cavernous Sinus Meningioma: Tumor Decompression for Trigeminal Neuralgia and Anterior Tibial Artery Graft High-Flow Bypass for Brain Ischemia: 2-Dimensional Operative Video.

A 62-yr-old man with left cavernous sinus tumor presented with atypical trigeminal neuralgia refractory to medical treatment. He received Gamma Knife (Elekta) radiation for the tumor. However, the facial pain worsened after radiation. Neuropsychological testing done for memory problems had revealed mild neurocognitive disorder. Neurological examination showed trigeminal distribution numbness and partial abducens nerve paralysis. Imaging revealed an enhancing left cavernous sinus and supra-cavernous mass. Angiography revealed severe stenosis of the left cavernous internal carotid artery (ICA). Computed tomography (CT) perfusion study showed diminished blood flow on the left side, and ischemic changes were seen in fluid-attenuated inversion-recovery (FLAIR) magnetic resonance imaging (MRI). Surgical resection of the tumor was preferred over ablative treatment for trigeminal neuralgia because of its effectiveness in improving cranial nerve (CN) function.1 The patient underwent staged surgeries. In the first stage, the tumor was partially excised with decompression of the trigeminal ganglion and nerve root in the lateral cavernous sinus wall, Meckel's cave. Postoperatively, MR angiography revealed worsening of the left ICA caliber. Therefore, a high-flow bypass from the external carotid artery to the middle cerebral artery (MCA) was performed with an anterior tibial artery graft. The patient recovered initially but developed enterococcus meningitis postoperatively, which was promptly identified and treated with antibiotics. At 1-yr follow-up, the graft was patent, and the patient had significant relief of his facial pain and cognitively improved. This 2-dimensional video demonstrates the technique of partial excision of cavernous sinus meningioma with CN decompression, and the technique of a high-flow bypass from the external carotid artery to M2 MCA segment using an anterior tibial artery graft. The patient gave informed consent for surgery and video recording. All relevant patient identifiers have been removed from the video and accompanying radiology slides.

Hypoglossal Nerve Schwannoma With Severe Brainstem Compression: Microsurgical Excision by Extreme Lateral Approach: 2-Dimensional Operative Video.

A 37-yr-old male presented with a history of left-sided tongue atrophy and fasciculations and weakness of upper limbs for 3 mo. Magnetic resonance imaging (MRI) revealed a large, partially cystic tumor with severe compression of the brainstem and spinal cord, with expansion and erosion of the hypoglossal canal. Computed tomography (CT) angiography showed the left vertebral artery to be anteriorly displaced by the tumor. A retrosigmoid craniotomy and craniectomy were performed followed by mastoidectomy with unroofing the posterior aspect of the sigmoid sinus. The foramen magnum was completely unroofed. The hypoglossal canal was exposed with a diamond drill and an ultrasonic bone curette, and a tumor was seen within the expanded canal. C1 lamina was removed partially in the lateral aspect, and the occipital condyle was partially removed. After opening the dura mater, the tumor was found to be stretching the eleventh cranial nerve. The tumor was debulked, and dissected from the cranial nerve fibers. The vertebral artery, anterior spinal artery, and other branches displaced by the tumor were carefully preserved. The tumor was removed from the hypoglossal canal with a curette. The patient recovered well, with the resolution of his upper limb weakness. Patient modified Rankin Scale was 1 at 6-mo follow-up. The postoperative MRI showed a small remnant inside the hypoglossal canal, and it was treated by radiosurgery. This 2-dimensional video demonstrates the technique of complete microsurgical removal of a complex tumor with preservation of cranial nerves and vertebral artery. Informed consent was obtained from the patient prior to the surgery, which included videotaping of the procedure and its distribution for educational purposes. Also, all relevant patient identifiers have been removed from the video and accompanying radiology slides.

Constitutive androstane receptor -null mice are sensitive to the toxic effects of parathion: association with reduced cytochrome p450-mediated parathion metabolism [corrected].

Constitutive androstane receptor [corrected](CAR) is activated by several chemicals and in turn regulates multiple detoxification genes. Our research demonstrates that parathion is one of the most potent, environmentally relevant CAR activators with an EC(50) of 1.43 microM. Therefore, animal studies were conducted to determine whether CAR was activated by parathion in vivo. Surprisingly, CAR-null mice, but not wild-type (WT) mice, showed significant parathion-induced toxicity. However, parathion did not induce Cyp2b expression, suggesting that parathion is not a CAR activator in vivo, presumably because of its short half-life. CAR expression is also associated with the expression of several drug-metabolizing cytochromes P450 (P450). CAR-null mice demonstrate lower expression of Cyp2b9, Cyp2b10, Cyp2c29, and Cyp3a11 primarily, but not exclusively in males. Therefore, we incubated microsomes from untreated WT and CAR-null mice with parathion in the presence of esterase inhibitors to determine whether CAR-null mice show perturbed P450-mediated parathion metabolism compared with that in WT mice. The metabolism of parathion to paraoxon and p-nitrophenol (PNP) was reduced in CAR-null mice with male CAR-null mice showing reduced production of both paraoxon and PNP, and female CAR-null mice showing reduced production of only PNP. Overall, the data indicate that CAR-null mice metabolize parathion slower than WT mice. These results provide a potential mechanism for increased sensitivity of individuals with lower CAR activity such as newborns to parathion and potentially other chemicals due to decreased metabolic capacity.

Bow Hunter's Syndrome: Complete Microsurgical Decompression of Vertebral Artery by Far Lateral Retrocondylar Approach: 3-Dimensional Operative Video.

This 50-yr-old man had a 15-yr history of presyncopal episodes that were precipitated by turning his head to the right, and had worsened recently. Cerebral angiogram demonstrated complete cessation of anterograde flow in left vertebral artery (VA) at the level of the C1 sulcus arteriosus while turning head to right, indicating dynamic compression at the C1 level. Patient underwent left extreme lateral retrocondylar approach, partial C1 laminectomy and opening of the C1 foramen with complete microsurgical decompression of the VA. After skin incision, meticulous muscle dissection was performed and superior and inferior oblique muscles were disconnected from the tubercle of C1. The VA was exposed, and three areas of constriction were visible, first at the atlanto-occipital membrane laterally; second, located more medially as the artery curved around the occipital condyle to enter the posterior fossa; and third, located anterior to C2 nerve root. The artery was dissected from all the surrounding tissues, preserving the C2 nerve root, and the Cl foramen was opened completely. The Cl lamina was also partially resected and grooved to allow free placement of the VA. The VA was also decompressed near the C2 foramen. Postoperative computed tomography angiogram of the head and neck showed complete decompression of VA. The patient had no episodes of presyncope or dizziness while turning head to right and his mRs was 0 at 8 mo follow up. This 3D video shows the technical nuances of decompression of V3 segment of VA in bow hunters's syndrome. Informed consent was obtained from the patient prior to the surgery that included videotaping of the procedure and its distribution for educational purposes. All relevant patient identifiers have also been removed from the video and accompanying radiology slides.

Localization and Microsurgical Resection of Left Postcentral Gyrus Spetzler-Martin Grade 3 Arteriovenous Malformation by Intraoperative Neuronavigation and Tracing of Subcortical Draining Vein: 3-Dimensional Operative Video.

This 42-yr-old man presented with a history of sudden right-sided facial and right arm weakness and dysarthria. Head computed tomography showed a left frontal-parietal blood clot. An intra-arterial digital subtraction angiography demonstrated a left subcortical postcentral, Spetzler-Martin Grade 3 arteriovenous malformation (AVM) with a diffuse nidus, measuring 2.1 × 1.5 cm, supplied by branches of the left MCA, and draining into a cortical vein and a deep vein, which was going toward the ventricle. Preoperative embolization was not possible. The patient underwent left frontal-parietal craniotomy with intraoperative motor and sensory mapping. No arterialized veins were visible on the cortical surface. Neuronavigation localized the AVM in the subcortical postcentral gyrus. Through an incision in the postcentral sulcus, microdissection led to a yellowish gliotic plane. The large cortical vein was in the gliotic area and traced to the AVM. Circumferential microdissection was performed around the AVM. It had a very diffuse nidus; the arterial feeders were cauterized and divided, and the superior superficial and inferior deep draining veins were finally occluded, and AVM was removed. Postoperative angiogram showed total removal of the AVM. At discharge, his right arm weakness had improved (power 5/5), and facial weakness and dysarthria were improving (modified Rankin Scale (mRS) 2). At 1-yr follow-up, facial weakness and dysarthria had improved considerably, and patient returned to work (mRS 1). This video shows microsurgical resection of an AVM by neuronavigation and tracing of the subcortical draining vein. The technique of cauterizing the perforating arteries after temporary clipping with flow arrest is shown in the video. Informed consent was obtained from the patient prior to the surgery that included videotaping of the procedure and its distribution for educational purposes. All relevant patient identifiers have also been removed from the video and accompanying radiology slides.

Complete Microsurgical Resection of Large Retrochiasmatic Hypothalamic Craniopharyngioma by Transpetrosal Approach: 2-Dimensional Operative Video.

This two-dimensional video shows the technical nuances of complete microsurgical resection of a hypothalamic craniopharyngioma located in the retrochiasmatic region by the transpetrosal approach. This 49-yr-old man presented with progressive fatigue, excessive sleepiness, and difficulty in vision in both eyes. He was found to have right CN 3 paralysis and bitemporal hemianopsia on neurological examination. Further workup revealed panhypopituitarism. Brain magnetic resonance imaging (MRI) demonstrated a large solid retrochiasmatic hypothalamic lesion with homogeneous contrast enhancement, measuring 2.1 × 2.6 × 2.4 cm. Optic chiasm was prefixed, and the tumor was just posterior to the pituitary stalk area. The preoperative differential diagnosis included hypothalamic astrocytoma, craniopharyngioma, germinoma, and histiocytosis. Because of the prefixed chiasm, a presigmoid, transpetrosal approach was performed. Our initial plan was a large biopsy, but based on frozen section histology, we decided to excise the tumor completely. The tumor had a pseudocapsule, which was firm and yellowish. It was debulked, dissected from the surrounding hypothalamus, and removed completely. The pituitary stalk was found at the anterior and inferior ends of the tumor and was preserved. Postoperatively, the patient developed diabetes insipidus and requires desmopressin replacement, which was gradually tapered. For panhypopituitarism, he is receiving thyroxine, hydrocortisone, and testosterone. Postoperatively, patient had an improvement in vision in his left eye and ptosis was improving in the right eye with mRs 1- at 10-wk follow-up. An informed consent was obtained from the patient prior to the surgery, which included videotaping of the procedure and its distribution for educational purposes. All relevant patient identifiers have also been removed from the video and accompanying radiology slides.

Microsurgical Resection of Recurrent Cavernous Sinus Hemangioma by Superior and Lateral Approach: 2-Dimensional Operative Video.

This video shows the technical nuances of microsurgical resection of recurrent cavernous sinus (CS) hemangioma by superior and lateral approach. A 77-yr-old woman presented with headache and difficulty in vision in right eye for 6 mo. She had previously undergone attempted resection of a right CS tumor in another hospital with partial removal, and the tumor had grown significantly. Neurological examination revealed proptosis, cranial nerve 3 palsy, and loss of vision in right eye (20/200). Left side visual acuity was 20/20. Brain magnetic resonance imaging (MRI) demonstrated a large CS mass with homogeneous enhancement, measuring 3.3 × 3.3 × 2.6 cm, extending into the suprasellar cistern with mass effect on the right optic nerve. It extended anteriorly to the region of the right orbital apex and abuted the basilar artery posteriorly. She underwent right frontotemporal craniotomy, posterolateral orbitotomy and anterior clinoidectomy as well as optic nerve decompression, and the CS tumor was removed by superior and lateral approach. An incision was made into the superior wall of the CS medial to the third nerve. On lateral aspect the tumor had extended outside the CS through the Parkinson's triangle. Posteriorly it extended through the clival dura. Anteriorly tumor encased the carotid artery and it was gradually dissected away. At the end of the operation, all of the cranial nerves were intact. Postoperative MRI showed near complete tumor resection with preservation of the internal carotid artery. At 6 mo follow-up her modified Rankin Scale was 1 and vision in left eye was normal. Informed consent was obtained from the patient prior to the surgery that included videotaping of the procedure and its distribution for educational purposes. All relevant patient identifiers have also been removed from the video and accompanying radiology slides.

The environmental estrogen, nonylphenol, activates the constitutive androstane receptor.

Nonylphenol (NP) and its parent compounds, the nonylphenol ethoxylates are some of the most prevalent chemicals found in U.S. waterways. NP is also resistant to biodegradation and is a known environmental estrogen, which makes NP a chemical of concern. Our data show that NP also activates the constitutive androstane receptor (CAR), an orphan nuclear receptor important in the induction of detoxification enzymes, including the P450s. Transactivation assays demonstrate that NP increases murine CAR (mCAR) transcriptional activity, and NP treatment can overcome the inhibitory effects of the inverse agonist, androstanol, on mCAR activation. Treatment of wild-type (CAR +/+) mice with NP at 50 or 75 mg/kg/day increases Cyp2b protein expression in a dose-dependent manner as demonstrated by Western blotting, and was confirmed by quantitative reverse transcription-PCR of Cyp2b10 transcript levels. CAR-null (CAR -/-) mice show no increased expression of Cyp2b following NP treatment, indicating that CAR is required for NP-mediated Cyp2b induction. In addition, NP increases the translocation of CAR into the nucleus, which is the key step in the commencement of CAR's transcriptional activity. NP also induced CYP2B6 in primary human hepatocytes, and increased Cyp2b10 messenger RNA and protein expression in humanized CAR mice, indicating that NP is an activator of human CAR as well. In conclusion, NP is a CAR activator, and this was demonstrated in vitro with transactivation assays and in vivo with transgenic CAR mouse models.

[Histological alterations in the liver and increased serum proteins in chickens fed with diet containing Saccharomyces cerevisiae]. / Alteraciones histológicas hepáticas e incremento de proteínas séricas en pollos de engorde alimentados con dietas suplementadas con Saccharomyces cerevisiae.

The aim of this study was to determine the effect of diet supplemented with Saccharomyces cerevisiae (SC), on the liver morphology, serum activities of aspartateaminotrasferase (AST) and alanineaminotransferase (ALT), and the serum concentration of total proteins, albumin and the different fractions (alpha, beta, gamma) of globulin in chickens. Two groups of Hubbar x Hubbar strain chickens (each = 16), were fed with a diet T1 (commercial food without SC) and T2 (commercial food with SC) for 42 days. Thereafter, animals were sacrificed and samples of blood and liver were obtained. Macroscopic features and relative weight of livers remained in the normal ranges in both groups. High percent of T2 chickens (p < 0.05) showed hepatic alterations with proliferation/dilation of biliary ducts and increased degree of vacuolization. Tricromic stain showed elevated perivascular fibrosis in T2. The ultrastructural study showed fibroblast like cells, increased amount of collagen fibers, cytoplasm vacuolization of hepatocytes and loss of cellular and mitochondrial integrates. No significant differences were observed in the activities of AST and ALT between groups. Increased concentrations of total proteins and alpha2, beta and gamma globulins and decreased albumin were observed in the serum of T2 group. These findings may be related to a hepatotoxic effect of SC and chickens could have the risk of further increased hepatic failure with a prolonged exposition to this diet.

Compensatory changes in CYP expression in three different toxicology mouse models: CAR-null, Cyp3a-null, and Cyp2b9/10/13-null mice.

Targeted mutant models are common in mechanistic toxicology experiments investigating the absorption, metabolism, distribution, or elimination (ADME) of chemicals from individuals. Key models include those for xenosensing transcription factors and cytochrome P450s (CYP). Here we investigated changes in transcript levels, protein expression, and steroid hydroxylation of several xenobiotic detoxifying CYPs in constitutive androstane receptor (CAR)-null and two CYP-null mouse models that have subfamily members regulated by CAR; the Cyp3a-null and a newly described Cyp2b9/10/13-null mouse model. Compensatory changes in CYP expression that occur in these models may also occur in polymorphic humans, or may complicate interpretation of ADME studies performed using these models. The loss of CAR causes significant changes in several CYPs probably due to loss of CAR-mediated constitutive regulation of these CYPs. Expression and activity changes include significant repression of Cyp2a and Cyp2b members with corresponding drops in 6α- and 16ß-testosterone hydroxylase activity. Further, the ratio of 6α-/15α-hydroxylase activity, a biomarker of sexual dimorphism in the liver, indicates masculinization of female CAR-null mice, suggesting a role for CAR in the regulation of sexually dimorphic liver CYP profiles. The loss of Cyp3a causes fewer changes than CAR. Nevertheless, there are compensatory changes including gender-specific increases in Cyp2a and Cyp2b. Cyp2a and Cyp2b were down-regulated in CAR-null mice, suggesting activation of CAR and potentially PXR following loss of the Cyp3a members. However, the loss of Cyp2b causes few changes in hepatic CYP transcript levels and almost no significant compensatory changes in protein expression or activity with the possible exception of 6α-hydroxylase activity. This lack of a compensatory response in the Cyp2b9/10/13-null mice is probably due to low CYP2B hepatic expression, especially in male mice. Overall, compensatory and regulatory CYP changes followed the order CAR-null > Cyp3a-null > Cyp2b-null mice.

Neutropenia febril asociada a quimioterapia en pacientes con neoplasias hematológicas de un centro de referencia en Colombia: características clínicas y desenlaces / Febrile neutropenia in patients with hematological malignancies at a reference center in Colombia

RESUMEN Objetivo: analizar las características epidemiológicas, clínicas y bacteriológicas que influyen en la supervivencia de los pacientes con neoplasias hematológicas que desarrollaron neutropenia febril posterior a quimioterapia. Materiales y métodos: estudio de corte transversal que incluyó adultos con diagnóstico de neoplasias hematológicas que presentaron neutropenia febril durante la hospitalización en 2014 en las sedes de Oncólogos de Occidente en Pereira, Manizales y Armenia (Colombia). Se realizaron análisis univariados y multivariados; la supervivencia se estableció según el método de Kaplan-Meier. Se estableció un valor de p <0.05. Se usó el software STATA. Se tuvo aval de bioética de la Universidad Tecnológica de Pereira. Resultados: se incluyó a 55 pacientes. La mediana de edad fue de 48 años (31-63), 27(49 %) fueron hombres. Los diagnósticos oncológicos más frecuentes fueron el linfoma no Ho-dgkin (29 %), leucemia mieloide aguda (24%) y leucemia linfoblástica aguda (20 %). La mayor letalidad se presentó en los días 21, 32 y 48. La mortalidad general fue del 9 % y la mortalidad por neutropenia profunda fue del 18 %. Conclusión: el número de neutropenias febriles, mayor tiempo de duración de la neutropenia febril, índice de Charlson y el antecedente de ingreso a UCI son factores de riesgo para mortalidad, mientras que el uso de piperacilina-tazobactam y el incremento en la puntuación del índice de MASCC son factores protectores.

ABSTRACT Objective: analyze the epidemiological, clinical and bacteriological characteristics that influence the survival of patients with haematological malignancies who developed febrile neutropenia after chemotherapy. Materials and methods: cross-sectional study of adult patients diagnosed with hema-tologic malignancies who presented febrile neutropenia during hospitalization in 2014 at Oncólogos de Occidente in Pereira, Manizales and Armenia (Colombia). Univariate and multivariate analyzes were performed. The survival analysis was established according to the Kaplan-Meier method. A value of p<0.05 was established for it. The STATA software was used. This study was endorsed by the bioethics committee of the Universidad Tecnológica de Pereira. Results: 55 patients were included. The median age was 48 years (31-63), 27 (49%) were men. The most frequent oncological diagnoses were non-Hodgkin's lymphoma (29 %), acute myeloid leukemia (24 %) and acute lymphoblastic leukemia (20 %). The highest lethality occurred on days 21, 32 and 48. Overall mortality was 9 %, mortality due to deep neutro-penia was 18 %. Conclusion: the number of febrile neutropenia, longer duration of febrile neutropenia, Charlson index and the history of admission to the ICU are risk factors for mortality, while the use of piperacillin-tazobactam and the increase in the score of the MASCC index are protective factors.

Percepciones y actitudes de los pacientes frente a la cirugía de la epilepsia: conceptos equivocados en Colombia / Patients' perceptions of and attitudes towards epilepsy surgery: mistaken concepts in Colombia

Introducción. Los pacientes con epilepsia focal farmacorresistente se podrían beneficiar de la cirugía de la epilepsia; sin embargo, existen demoras en la realización del procedimiento. El objetivo de este estudio fue evaluar el conocimiento y las actitudes de los pacientes hacia la cirugía de epilepsia e identificar barreras que pudieran retrasar el tratamiento. Pacientes y métodos. Se aplicó un cuestionario de 10 minutos a pacientes con epilepsia en Colombia. La encuesta evaluó el conocimiento de la opción quirúrgica, las percepciones sobre el riesgo de la cirugía frente al riesgo de crisis no controladas, la discapacidad producida por la enfermedad, las metas del tratamiento y las variables demográficas y socioeconómicas. Resultados. Se seleccionaron 88 pacientes con epilepsia focal. El 56% de los pacientes no sabía que la cirugía podría ser una opción terapéutica. El 60% consideró que la cirugía de la epilepsia es muy o moderadamente peligrosa. Una gran proporción pensaba que la muerte (41%), el ictus (47%), la pérdida visual (56%), los cambios en la personalidad (56%), la parálisis (61%), las dificultades para hablar (69%) y la pérdida de la memoria (60%) eran efectos secundarios comunes. La mayoría (62%) consideraba el procedimiento como la última opción de tratamiento. Conclusiones. Existe una actitud negativa por parte de los pacientes frente a la cirugía de la epilepsia fundamentada en la sobreestimación del riesgo de adquirir déficits neurológicos secundarios al procedimiento, lo que refleja la falta de conocimiento hacia este tratamiento. Estas percepciones erróneas pueden contribuir a demoras en la atención quirúrgica

Introduction. Selected patients with drug-resistant focal epilepsy benefit from epilepsy surgery, however significant delays remain. The aim of this study was to assess knowledge and attitudes toward epilepsy surgery among patients with epilepsy and identify barriers that might delay the treatment. Patients and methods. A 10-minute questionnaire was administered to patients with epilepsy in Colombia. Survey assessed the following: knowledge of surgical options, perceptions about the risks of surgery vs. ongoing seizures, disease disability, treatment goals, and demographic and socioeconomic variables. Results. We recruited 88 patients with focal epilepsy. More than half of patients (56%) were not aware that surgery might be an option. Apprehension about epilepsy surgery was evident, 60% of patients perceived epilepsy surgery to be very or moderately dangerous. A large proportion of patients believe death (41%), stroke (47%), vision loss (56%), personality change (56%), paralysis (62%), difficulties in speaking (69%), and memory loss (60%) were frequent side effects. The majority of patients (62%) consider the surgical procedure as the last option of treatment. Conclusions. There is a negative attitude toward epilepsy surgery based on the patients' misperceptions of suffering neurological deficits during the surgery, reflecting lack of knowledge toward this type of treatment. These perceptions can contribute to delays in surgical care

Factores de riesgo para mortalidad en la infección por Pseudomonas aeruginosa en pacientes oncológicos hospitalizados en tres ciudades de Colombia / Risk Factors for Mortality Caused by Pseudomonas Aeruginosa Infection in Hospitalized Patients with Oncologic Diagnosis in three Cities of Colombia

Introducción: Pseudomonas aeruginosa es una bacteria oportunista Gram negativa particularmente eficiente en la adquisición de mecanismos de resistencia y de alta prevalencia en infecciones nosocomiales en pacientes oncológicos. Objetivo: identificar los factores de riesgo para mortalidad en pacientes oncológicos con aislamiento de P. aeruginosa. Metodología: estudio descriptivo, la población de estudio fueron los casos reportados con aislamiento de P. aeruginosa en el servicio de hospitalización de Oncólogos de Occidente en Pereira, Armenia y Manizales durante el año 2015. Se realizaron análisis univariados y multivariados; la supervivencia se estableció según el método de Kaplan-Meier. Se estableció un valor de p <0.05. Se usó el software STATA. Se tuvo aval de bioética de la Universidad Tecnológica de Pereira. Resultados: se estudió 41 casos confirmados de cultivos positivos de P. aeruginosa. El sexo masculino (46.3%), anemia (46.3%), neutropenia febril (41%), trombocitopenia (29.3%) y haber sido hospitalizado en la unidad de cuidados intensivos (29.3%) fueron asociados estadísticamente con mayor mortalidad (p=0.019); con estos resultados se diseñó una escala de riesgo (alfa de Cronbach =0.72). Los pacientes con cuatro de estas exposiciones mostraron mayor riesgo de mortalidad al egreso hospitalario con una sensibilidad del 68% y especificidad del 90%. La P. aeruginosa presentó resistencia a cefepime (36.6%) y a aztreonam (34.1%), mientras que la letalidad global fue del 26.8%. Conclusión: El sexo masculino, la coexistencia de anemia, trombocitopenia, y neutropenia febril, así como la estancia en la unidad de cuidados intensivos aumentan la mortalidad en los pacientes oncológicos infectados con P. aeruginosa...(AU)

Introduction: Pseudomonas aeruginosa is a Gram-negative and rod-shape opportunistic bacterium that is particularly efficient in the acquisition of resistance mechanisms and its high prevalence in nosocomial infections in cancer patients. Objective: To identify risk factors for mortality in cancer patients with P. aeruginosa infection. Methodology: A descriptive study was carried out in patients with P. aeruginosa infection during the hospitalization service of "Oncólogos de Occidente" in Pereira, Armenia and Manizales during 2015. Univariate and multivariate analyzes were performed. The survival analysis was established according to the Kaplan-Meier method. A value of p<0.05 was established for it. The analyses were examined with the STATA software. This study was endorsed by the bioethics committee of the "Universidad Tecnológica de Pereira". Results: Fourty-one patients with positive culture for P. aeruginosa were studied. Males (46.3%), anemia (46.3%), febrile neutropenia (41%), thrombocytopenia (29.3%) and previous hospitalization in an intensive care unit (29.3%) were associated with higher mortality risk (p = 0.019); a risk scale was designed with these factors (Cronbach´s alpha = 0.72). Patients who presented four of these exposures were at higher risk of mortality with a sensitivity of 68% and specificity of 90% at the moment of discharge. P. aeruginosa showed 36.6% of resistance to cefepime, 34.1% to aztreonam, the mortality rate was 26.8%. Conclusion: Male sex, anemia, thrombocytopenia, febrile neutropenia and previous hospitalization in an intensive care unit increase the mortality rate in patients with cancer who were infected by P. aeruginosa...(AU)

Introdução: Pseudomonas aeruginosa é uma bactéria oportunista Gram-negativa particularmente eficiente na aquisição de mecanismos de resistência e alta prevalência em infecções nosocomiais em pacientes com câncer. Objetivo: identificar os fatores de risco para mortalidade em pacientes oncológicos com isolamento de P. aeruginosa. Materiais e métodos: estudo descritivo, a população estudada foram os casos relatados com isolamento de P. aeruginosa ao serviço da hospitalização de Oncologistas do Ocidente em Pereira, Armênia e Manizales durante o ano de 2015. Foram realizadas análises univariadas e multivariadas; a sobrevivência foi estabelecida de acordo com o método de Kaplan-Meier. Foi estabelecido um valor de p. <0,05 y se utilizou o software STATA, aprovada pelo Comité de Bioética da Universidade Tecnológica de Pereira. Resultados: 41 casos confirmados de P. aeruginosa culturas positivas foram estudadas. A anemia (46,3%), a neutropenia febril (41%), a trombocitopenia (29,3%) e a hospitalização na unidade de terapia intensiva (29,3%) foram associadas estatisticamente com maior mortalidade (p. = 0,019); Com esses resultados, foi elaborada uma escala de risco (Alfa de Cronbach = 0,72). Os pacientes com quatro dessas exposições apresentaram maior risco de mortalidade na alta hospitalar com uma sensibilidade de 68% e uma especificidade de 90%. P. aeruginosa apresentou resistência ao cefepima (36,6%) e aztreonam (34,1%), enquanto a letalidade global foi de 26,8%. Conclusão: o sexo masculino, a coexistência de anemia, trombocitopenia e neutropenia febril, além de permanecer na unidade de terapia intensiva, aumentam a mortalidade em pacientes oncológicos infectados com P. aeruginosa...(Au)