Evaluation of the introduction of novel potassium binders in routine care; the Stockholm CREAtinine measurements (SCREAM) project.

BACKGROUND: The pharmacological management of hyperkalemia traditionally considered calcium or sodium polystyrene sulfonate and, since recently, the novel binders patiromer and sodium zirconium cyclosilicate. We evaluated their patterns of use, duration of treatment and relative effectiveness/safety in Swedish routine care. METHODS: Observational study of adults initiating therapy with sodium polystyrene sulfonate or a novel binder (sodium zirconium cyclosilicate or patiromer) in Stockholm 2019-2021. We quantified treatment duration by repeated dispensations, compared mean achieved potassium concentration within 60 days, and potential adverse events between treatments. RESULTS: A total of 1879 adults started treatment with sodium polystyrene sulfonate, and 147 with novel binders (n = 41 patiromer and n = 106 sodium zirconium cyclosilicate). Potassium at baseline for all treatments was 5.7 mmol/L. Sodium polystyrene sulfonate patients stayed on treatment a mean of 61 days (14% filled ≥3 consecutive prescriptions) compared to 109 days on treatment (49% filled ≥3 prescriptions) for novel binders. After 15 days of treatment, potassium similarly decreased to 4.6 (SD 0.6) and 4.8 (SD 0.6) mmol/L in the sodium polystyrene sulfonate and novel binder groups, respectively, and was maintained over the 60 days post-treatment. In multivariable regression, the odds ratio for novel binders (vs sodium polystyrene sulfonate) in reaching potassium ≤ 5.0 mmol/L after 15 days was 0.65 (95% CI 0.38-1.10) and after 60 days 0.89 (95% CI 0.45-1.76). Hypocalcemia, hypokalemia, and initiation of anti-diarrheal/constipation medications were the most-commonly detected adverse events. In multivariable analyses, the OR for these events did not differ between groups. CONCLUSION: We observed similar short-term effectiveness and safety for all potassium binders. However, treatment duration was longer for novel binders than for sodium polystyrene sulfonate.

Alzheimer and Parkinson diseases, frontotemporal lobar degeneration and amyotrophic lateral sclerosis overlapping neuropathology start in the first two decades of life in pollution exposed urbanites and brain ultrafine particulate matter and industrial nanoparticles, including Fe, Ti, Al, V, Ni, Hg, Co, Cu, Zn, Ag, Pt, Ce, La, Pr and W are key players. Metropolitan Mexico City health crisis is in progress.

The neuropathological hallmarks of Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS) are present in urban children exposed to fine particulate matter (PM2.5), combustion and friction ultrafine PM (UFPM), and industrial nanoparticles (NPs). Metropolitan Mexico City (MMC) forensic autopsies strongly suggest that anthropogenic UFPM and industrial NPs reach the brain through the nasal/olfactory, lung, gastrointestinal tract, skin, and placental barriers. Diesel-heavy unregulated vehicles are a key UFPM source for 21.8 million MMC residents. We found that hyperphosphorylated tau, beta amyloid1-42, α-synuclein, and TAR DNA-binding protein-43 were associated with NPs in 186 forensic autopsies (mean age 27.45 ± 11.89 years). The neurovascular unit is an early NPs anatomical target, and the first two decades of life are critical: 100% of 57 children aged 14.8 ± 5.2 years had AD pathology; 25 (43.9%) AD+TDP-43; 11 (19.3%) AD + PD + TDP-43; and 2 (3.56%) AD +PD. Fe, Ti, Hg, Ni, Co, Cu, Zn, Cd, Al, Mg, Ag, Ce, La, Pr, W, Ca, Cl, K, Si, S, Na, and C NPs are seen in frontal and temporal lobes, olfactory bulb, caudate, substantia nigra, locus coeruleus, medulla, cerebellum, and/or motor cortical and spinal regions. Endothelial, neuronal, and glial damages are extensive, with NPs in mitochondria, rough endoplasmic reticulum, the Golgi apparatus, and lysosomes. Autophagy, cell and nuclear membrane damage, disruption of nuclear pores and heterochromatin, and cell death are present. Metals associated with abrasion and deterioration of automobile catalysts and electronic waste and rare earth elements, i.e., lanthanum, cerium, and praseodymium, are entering young brains. Exposure to environmental UFPM and industrial NPs in the first two decades of life are prime candidates for initiating the early stages of fatal neurodegenerative diseases. MMC children and young adults-surrogates for children in polluted areas around the world-exhibit early AD, PD, FTLD, and ALS neuropathological hallmarks forecasting serious health, social, economic, academic, and judicial societal detrimental impact. Neurodegeneration prevention should be a public health priority as the problem of human exposure to particle pollution is solvable. We are knowledgeable of the main emission sources and the technological options to control them. What are we waiting for?

Phytochemicals That Interfere With Drug Metabolism and Transport, Modifying Plasma Concentration in Humans and Animals.

Phytochemicals (Pch) present in fruits, vegetables and other foods, are known to inhibit or induce drug metabolism and transport. An exhaustive search was performed in five databases covering from 2000 to 2021. Twenty-one compounds from plants were found to modulate CYP3A and/or P-gp activities and modified the pharmacokinetics and the therapeutic effect of 27 different drugs. Flavonols, flavanones, flavones, stilbenes, diferuloylmethanes, tannins, protoalkaloids, flavans, hyperforin and terpenes, reduce plasma concentration of cyclosporine, simvastatin, celiprolol, midazolam, saquinavir, buspirone, everolimus, nadolol, tamoxifen, alprazolam, verapamil, quazepam, digoxin, fexofenadine, theophylline, indinavir, clopidogrel. Anthocyanins, flavonols, flavones, flavanones, flavonoid glycosides, stilbenes, diferuloylmethanes, catechin, hyperforin, alkaloids, terpenes, tannins and protoalkaloids increase of plasma concentration of buspirone, losartan, diltiazem, felodipine, midazolam, cyclosporine, triazolam, verapamil, carbamazepine, diltiazem, aripiprazole, tamoxifen, doxorubicin, paclitaxel, nicardipine. Interactions between Pchs and drugs affect the gene expression and enzymatic activity of CYP3A and P-gp transporter, which has an impact on their bioavailability; such that co-administration of drugs with food, beverages and food supplements can cause a subtherapeutic effect or overdose. Therefore, it is important for the clinician to consider these interactions to obtain a better therapeutic effect.

Environmental Fe, Ti, Al, Cu, Hg, Bi, and Si Nanoparticles in the Atrioventricular Conduction Axis and the Associated Ultrastructural Damage in Young Urbanites: Cardiac Arrhythmias Caused by Anthropogenic, Industrial, E-Waste, and Indoor Nanoparticles.

Air pollution exposure is a risk factor for arrhythmia. The atrioventricular (AV) conduction axis is key for the passage of electrical signals to ventricles. We investigated whether environmental nanoparticles (NPs) reach the AV axis and whether they are associated with ultrastructural cell damage. Here, we demonstrate the detection of the shape, size, and composition of NPs by transmission electron microscopy (TEM) and energy-dispersive X-ray spectrometry (EDX) in 10 subjects from Metropolitan Mexico City (MMC) with a mean age of 25.3 ± 5.9 and a 71-year-old subject without cardiac pathology. We found that in every case, Fe, Ti, Al, Hg, Cu, Bi, and/or Si spherical or acicular NPs with a mean size of 36 ± 17 nm were present in the AV axis in situ, freely and as conglomerates, within the mitochondria, sarcomeres, lysosomes, lipofuscin, and/or intercalated disks and gap junctions of Purkinje and transitional cells, telocytes, macrophages, endothelium, and adjacent atrial and ventricular fibers. Erythrocytes were found to transfer NPs to the endothelium. Purkinje fibers with increased lysosomal activity and totally disordered myofilaments and fragmented Z-disks exhibited NP conglomerates in association with gap junctions and intercalated disks. AV conduction axis pathology caused by environmental NPs is a plausible and modifiable risk factor for understanding common arrhythmias and reentrant tachycardia. Anthropogenic, industrial, e-waste, and indoor NPs reach pacemaker regions, thereby increasing potential mechanisms that disrupt the electrical impulse pathways of the heart. The cardiotoxic, oxidative, and abnormal electric performance effects of NPs in pacemaker locations warrant extensive research. Cardiac arrhythmias associated with nanoparticle effects could be preventable.

Combustion- and friction-derived magnetic air pollution nanoparticles in human hearts.

Air pollution is a risk factor for cardiovascular and Alzheimer's disease (AD). Iron-rich, strongly magnetic, combustion- and friction-derived nanoparticles (CFDNPs) are abundant in particulate air pollution. Metropolitan Mexico City (MMC) young residents have abundant brain CFDNPs associated with AD pathology. We aimed to identify if magnetic CFDNPs are present in urbanites' hearts and associated with cell damage. We used magnetic analysis and transmission electron microscopy (TEM) to identify heart CFDNPs and measured oxidative stress (cellular prion protein, PrPC), and endoplasmic reticulum (ER) stress (glucose regulated protein, GRP78) in 72 subjects age 23.8 ±â€¯9.4y: 63 MMC residents, with Alzheimer Continuum vs 9 controls. Magnetite/maghemite nanoparticles displaying the typical rounded crystal morphologies and fused surface textures of CFDNPs were more abundant in MMC residents' hearts. NPs, ∼2-10 × more abundant in exposed vs controls, were present inside mitochondria in ventricular cardiomyocytes, in ER, at mitochondria-ER contact sites (MERCs), intercalated disks, endothelial and mast cells. Erythrocytes were identified transferring 'hitchhiking' NPs to activated endothelium. Magnetic CFDNP concentrations and particle numbers ranged from 0.2 to 1.7 µg/g and ∼2 to 22 × 109/g, respectively. Co-occurring with cardiomyocyte NPs were abnormal mitochondria and MERCs, dilated ER, and lipofuscin. MMC residents had strong left ventricular PrPC and bi-ventricular GRP78 up-regulation. The health impact of up to ∼22 billion magnetic NPs/g of ventricular tissue are likely reflecting the combination of surface charge, ferrimagnetism, and redox activity, and includes their potential for disruption of the heart's electrical impulse pathways, hyperthermia and alignment and/or rotation in response to magnetic fields. Exposure to solid NPs appears to be directly associated with early and significant cardiac damage. Identification of strongly magnetic CFDNPs in the hearts of children and young adults provides an important novel layer of information for understanding CVD pathogenesis emphasizing the urgent need for prioritization of particulate air pollution control.

Tracheal growth assessment in mongrel puppies (dogs) through multidetector CT.

The aim of this study was to describe the tracheal growth pattern and its zoometric relationship in related medium-sized mongrel puppies through adulthood. Fourteen puppies were studied. CT monitoring was performed monthly, starting in the 1st month of life through the 7th month and subsequently at the 9th and 12th months. Additionally, six zoometric measurements were performed. Dorsoventral (DV) and transverse (TV) diameters and the luminal area from C1 to T2 were obtained. The global tracheal growth pattern revealed an increase up to 13 times its initial size, reaching a plateau phase during the last trimester. The relationship between the DV and the TV internal diameters of the tracheal lumen did not change during growth. As previously reported, the cranial tracheal area was wider, while the caudal part gradually decreased towards T1-T2; this consideration is important since the more distal an endotracheal tube is inserted, the greater the risk that injury may occur. The linear correlation between the zoometric measurements and the tracheal ring areas was positive. This study provides evidence for the evaluation of the morphometry of the canine trachea during physiological growth using helicoidal CT as a non-invasive, accurate tool.

Combustion-derived nanoparticles, the neuroenteric system, cervical vagus, hyperphosphorylated alpha synuclein and tau in young Mexico City residents.

Mexico City (MC) young residents are exposed to high levels of fine particulate matter (PM2.5), have high frontal concentrations of combustion-derived nanoparticles (CDNPs), accumulation of hyperphosphorylated aggregated α-synuclein (α-Syn) and early Parkinson's disease (PD). Swallowed CDNPs have easy access to epithelium and submucosa, damaging gastrointestinal (GI) barrier integrity and accessing the enteric nervous system (ENS). This study is focused on the ENS, vagus nerves and GI barrier in young MC v clean air controls. Electron microscopy of epithelial, endothelial and neural cells and immunoreactivity of stomach and vagus to phosphorylated ɑ-synuclein Ser129 and Hyperphosphorylated-Tau (Htau) were evaluated and CDNPs measured in ENS. CDNPs were abundant in erythrocytes, unmyelinated submucosal, perivascular and intramuscular nerve fibers, ganglionic neurons and vagus nerves and associated with organelle pathology. ɑSyn and Htau were present in 25/27 MC gastric,15/26 vagus and 18/27 gastric and 2/26 vagus samples respectively. We strongly suggest CDNPs are penetrating and damaging the GI barrier and reaching preganglionic parasympathetic fibers and the vagus nerve. This work highlights the potential role of CDNPs in the neuroenteric hyperphosphorylated ɑ-Syn and tau pathology as seen in Parkinson and Alzheimer's diseases. Highly oxidative, ubiquitous CDNPs constitute a biologically plausible path into Parkinson's and Alzheimer's pathogenesis.

Exposures to fine particulate matter (PM2.5) and ozone above USA standards are associated with auditory brainstem dysmorphology and abnormal auditory brainstem evoked potentials in healthy young dogs.

BACKGROUND: Delayed central conduction times in the auditory brainstem have been observed in Mexico City (MC) healthy children exposed to fine particulate matter (PM2.5) and ozone (O3) above the current United States Environmental Protection Agency (US-EPA) standards. MC children have α synuclein brainstem accumulation and medial superior olivary complex (MSO) dysmorphology. The present study used a dog model to investigate the potential effects of air pollution on the function and morphology of the auditory brainstem. METHODOLOGY: Twenty-four dogs living in clean air v MC, average age 37.1 ± 26.3 months, underwent brainstem auditory evoked potential (BAEP) measurements. Eight dogs (4 MC, 4 Controls) were analysed for auditory brainstem morphology and histopathology. RESULTS: MC dogs showed ventral cochlear nuclei hypotrophy and MSO dysmorphology with a significant decrease in cell body size, decreased neuronal packing density with regions in the nucleus devoid of neurons and marked gliosis. MC dogs showed significant delayed BAEP absolute wave I, III and V latencies compared to controls. CONCLUSIONS: MC dogs show auditory nuclei dysmorphology and BAEPs consistent with an alteration of the generator sites of the auditory brainstem response waveform. This study puts forward the usefulness of BAEPs to study auditory brainstem neurodegenerative changes associated with air pollution in dogs. Recognition of the role of non-invasive BAEPs in urban dogs is warranted to elucidate novel neurodegenerative pathways link to air pollution and a promising early diagnostic strategy for Alzheimer's Disease.

Prefrontal white matter pathology in air pollution exposed Mexico City young urbanites and their potential impact on neurovascular unit dysfunction and the development of Alzheimer's disease.

Millions of urban children are chronically exposed to high concentrations of air pollutants, i.e., fine particulate matter (PM2.5) and ozone, associated with increased risk for Alzheimer's disease. Compared with children living with clear air those in Mexico City (MC) exhibit systemic, brain and intrathecal inflammation, low CSF Aß42, breakdown of the BBB, attention and short-term memory deficits, prefrontal white matter hyperintensities, damage to epithelial and endothelial barriers, tight junction and neural autoantibodies, and Alzheimer and Parkinson's hallmarks. The prefrontal white matter is a target of air pollution. We examined by light and electron microscopy the prefrontal white matter of MC dogs (n: 15, age 3.17±0.74 years), children and teens (n: 34, age: 12.64±4.2 years) versus controls. Major findings in MC residents included leaking capillaries and small arterioles with extravascular lipids and erythrocytes, lipofuscin in pericytes, smooth muscle and endothelial cells (EC), thickening of cerebrovascular basement membranes with small deposits of amyloid, patchy absence of the perivascular glial sheet, enlarged Virchow-Robin spaces and nanosize particles (20-48nm) in EC, basement membranes, axons and dendrites. Tight junctions, a key component of the neurovascular unit (NVU) were abnormal in MC versus control dogs (χ(2)<0.0001), and white matter perivascular damage was significantly worse in MC dogs (p=0.002). The integrity of the NVU, an interactive network of vascular, glial and neuronal cells is compromised in MC young residents. Characterizing the early NVU damage and identifying biomarkers of neurovascular dysfunction may provide a fresh insight into Alzheimer pathogenesis and open opportunities for pediatric neuroprotection.

Bioabsorbable implant as a tracheal wall substitute in young developing canines.

This study evaluated a polylactic and polyglycolic acid (PLA/PGA) implant as a partial tracheal substitute in young developing canines. This experimental and longitudinal study included local stray pups that received substitution of a short cervical tracheal segment with a PLA 85%/PGA 15% plaque. We measured clinical, endoscopic, and tomographic variables for 1 year, at which time we performed histomorphological evaluations of the implant using light and electron microscopy. There were no adverse events throughout the clinical progression. On endoscopic evaluation, the implant was covered with mucosal tissue beginning in the first month, without granulation or stenosis, and the circular shape of the trachea was altered. Tomographic images of the tracheal area at the implant site were similar to adjacent healthy areas (p = 0.423). At the end of the follow-up period, the plaque had biodegraded, and the space was covered by pseudostratified epithelium and ciliated cells similar to the neighboring tissue. Implantation of a PLA/PGA plaque constituted an effective (functional) replacement of a short semicircular cervical tracheal segment without limiting the growth of the recipient. Additional studies are required to prove the efficacy of these implants for larger tracheal segment replacements and in subjects at different stages of development.

Up-regulation of mRNA ventricular PRNP prion protein gene expression in air pollution highly exposed young urbanites: endoplasmic reticulum stress, glucose regulated protein 78, and nanosized particles.

Mexico City Metropolitan Area children and young adults exposed to high concentrations of air pollutants including fine and ultrafine particulate matter (PM) vs. clean air controls, exhibit myocardial inflammation and inflammasome activation with a differential right and left ventricular expression of key inflammatory genes and inflammasomes. We investigated the mRNA expression levels of the prion protein gene PRNP, which plays an important role in the protection against oxidative stress and metal toxicity, and the glucose regulated protein 78, a key protein in endoplasmic reticulum (ER) stress signaling, in ventricular autopsy samples from 30 children and young adults age 19.97 ± 6.8 years with a lifetime of low (n:4) vs. high (n:26) air pollution exposures. Light microscopy and transmission electron microscopy studies were carried out in human ventricles, and electron microscopy studies were also done in 5 young, highly exposed Mexico City dogs. There was significant left ventricular PRNP and bi-ventricular GRP78 mRNA up-regulation in Mexico City young urbanites vs. controls. PRNP up-regulation in the left ventricle was significantly different from the right, p < 0.0001, and there was a strong left ventricular PRNP and GRP78 correlation (p = 0.0005). Marked abnormalities in capillary endothelial cells, numerous nanosized particles in myocardial ER and in abnormal mitochondria characterized the highly exposed ventricles. Early and sustained cardiac ER stress could result in detrimental irreversible consequences in urban children, and while highly complex systems maintain myocardial homeostasis, failure to compensate for chronic myocardial inflammation, oxidative and ER stress, and particles damaging myocardial organelles may prime the development of pathophysiological cardiovascular states in young urbanites. Nanosized PM could play a key cardiac myocyte toxicity role.

[Experimental bacterial contamination of bile and liver in mongrel dogs: an alternative treatment with cephalone, a hybrid of cephalosporine fluoroquinolone]. / Contaminación bacteriana experimental de bilis e hígado en perros criollos. Tratamiento alternativo con (cefalona), un híbrido de cefalosporina y fluoroquinolona.

OBJECTIVES: A longitudinal, randomized, single blind study was done to evaluate the efficacy of an antibacterial hybrid molecule (beta-lactamic-fluoroquinolone) named cephalone after biliary-enteric-bypass (BEB). MATERIAL AND METHODS: Four groups of mongrel dogs were operated on three consecutive periods. Cultures of bile and liver were obtained and assessed, followed by obliteration of common bile duct and BEB to groups A, B and C. Group D served as a control. Ten days later the group A received conventional treatment based on ampicillin/gentamicin and groups B and C, cephalone in two different concentration schemes during 10 consecutive days. Further samples were processed for bacteria and additional liver biopsies were obtained for histopathological analysis. RESULTS: All three treatments reverted bacterial contamination in the liver and most of the bile samples were negative or showed a significant decrease in the number of colony forming units (p = 0.002). Histopathological analysis proved no lesions. CONCLUSIONS: Comparison of efficacy among antibacterial treatments revealed undistinguishable efficacy in this short-term assessment of bacterial contamination after BEB in dogs. The use of cephalone could be considered as a viable treatment or prophylaxis in bacterial infections occurring after BEB. Further studies are needed to assess long-term impact of the cephalone in this setting.

Urban air pollution targets the dorsal vagal complex and dark chocolate offers neuroprotection.

Mexico City (MC) residents exposed to fine particulate matter and endotoxin exhibit inflammation of the olfactory bulb, substantia nigra, and vagus nerve. The goal of this study was to model these endpoints in mice and examine the neuroprotective effects of chocolate. Mice exposed to MC air received no treatment or oral dark chocolate and were compared to clean-air mice either untreated or treated intraperitoneally with endotoxin. Cyclooxygenase-2 (COX-2), interleukin 1 beta (IL-1ß), and CD14 messenger RNA (mRNA) were quantified after 4, 8, and 16 months of exposure in target brain regions. After 16 months of exposure, the dorsal vagal complex (DVC) exhibited significant inflammation in endotoxin-treated and MC mice (COX-2 and IL-1ß P<.001). Mexico City mice had olfactory bulb upregulation of CD14 (P=.002) and significant DVC imbalance in genes for antioxidant defenses, apoptosis, and neurodegeneration. These findings demonstrate sustained DVC inflammation in mice exposed to MC air, which is mitigated by chocolate administration.

Fibrocollagen-covered prosthesis for a noncircumferential segmental tracheal replacement.

OBJECTIVE: Fibrocollagen-covered polyester meshes can be used as possible substitutions for tracheal segments if they become integrated into the tissue without complications. The aim of this study was to assess a fibrocollagen-covered polyester prosthesis to be used as a substitution for a tracheal segment. METHODS: We performed a blind, randomized experimental assay. Adult Wistar rats were assigned to one of 2 groups. Prostheses were made by implanting polyester tubing in a group of animals to cover them with homologous collagen. They were implanted as substitutions of tracheal segments in the experimental group after creating a defect in the anterior wall of the trachea. Clinical, histomorphologic, and immunohistochemical assessments were made at 4 different time points. RESULTS: The experimental group presented some respiratory distress signs during the first 7 to 10 days, such as stertors, hissing, and low motor activity. After this initial period, the symptoms subsided progressively and disappeared at the end of the first month. These respiratory symptoms caused no mortality. Initially undifferentiated monolayer cells predominated on the implant's surface, but during the last 2 months, the proportion of epithelial and ciliated cells was similar to that seen in control animals. Types I, III, and V collagen fibers were identified around the mesh. The intraluminal area of the tracheas with prostheses and prosthesis thickness were larger during the 4 months of the experiment. The increase in thickness was due to angiogenesis without evidence of fibrosis or chronic inflammation. CONCLUSIONS: Polyester-collagen prostheses used as substitutions of tracheal segments in rats enabled the proliferation of normal respiratory epithelium and maintained tracheal function without collapse, inflammatory reaction, or secondary stenosis.

Effects of a cyclooxygenase-2 preferential inhibitor in young healthy dogs exposed to air pollution: a pilot study.

Residency in cities with high air pollution is associated with neuroinflammation and neurodegeneration in healthy children, young adults, and dogs. Nonsteroidal anti-inflammatory drugs may offer neuroprotection. The authors measured the plasma concentrations of 3-nitrotyrosine and the cerebro-spinal-fluid concentrations of prostaglandin E2 metabolite and the oligomeric form of amyloid derived diffusible ligand; measured the mRNA expression of cyclooxygenase-2, interleukin 1beta, CD14, and Aquaporin-4 in target brain areas; and evaluated brain MRI, cognition, and neuropathology in 8 dogs treated with a preferential cyclooxygenase-2 inhibitor (Nimesulide) versus 7 untreated litter-matched Mexico City dogs. Nimesulide significantly decreased nitrotyrosine in plasma (p < .0001), frontal gray IL1beta (p = .03), and heart IL1beta (p = .02). No effect was seen in mRNA COX2, amyloid, and PGE2 in CSF or the MRI white matter lesions. All exposed dogs exhibited olfactory bulb and frontal accumulation of Abeta(42) in neurons and blood vessels and frontal vascular subcortical pathology. White matter hyperintense MRI frontal lesions were seen in 4/6 non-treated and 6/8 treated dogs. Nonsteroidal anti-inflammatory drugs may offer limited neuroprotection in the setting of severe air pollution exposures. The search for potentially beneficial drugs useful to ameliorate the brain effects of pollution represents an enormous clinical challenge.

Neuro-protective effects of carbamazepine on sleep patterns and head and body shakes in kainic acid-treated rats.

UNLABELLED: The aim of this work was to analyze the effect of carbamazepine (CBZ) on sleep patterns and on "head and body shakes" and to determine the role of serotonin (5-HT) in a model of kainic-induced seizures. Thirty male Wistar rats (280-300 g) were used for polygraphic sleep recording. After a basal recording, the rats were allocated into three groups: kainic acid-treated animals (KA; 10 mg/kg; n=10), carbamazepine-treated animals (CBZ; 30 mg/kg; n=10) and animals injected with KA 30 min after pretreatment with CBZ (CBZ+KA; n=10). Polygraphic recordings were performed for 10 h for 3 days, with the exception of the CBZ group, which were observed for 1 day. In order to measure the head and body shakes that occurred over that time, a behavioral assessment was performed in two additional groups of KA (n=10) and CBZ+KA (n=10) animals. After 10 h of behavioral assessment, the rats were sacrificed, and the levels of 5-HT and 5-hydroxy-indol-acetic acid (5-HIAA) were analyzed. We compared these findings with the results from a group of rats without pharmacological intervention (n=10). All of the recordings were performed from 08:00 to 18:00 h. DATA ANALYSIS: the electrographic parameters, head and body shake counting and monoamine concentrations were analyzed by an ANOVA test. Differences of *p < or = 0.01 and **p < or = 0.001 were considered statistically significant. Our results showed that CBZ exerted a protective effect on sleep pattern alterations induced by KA, which when administered alone caused a complete inhibition of sleep for the first 10 h after administration. Although there was a reduction in the amount of sleep after the administration of KA in CBZ-pretreated animals, sleep inhibition was incomplete. In addition, CBZ decreased the frequency of head and body shakes by 60% as compared to KA. The 5-HT and 5-HIAA levels in the pons were increased in the KA and KA+CBZ groups. Our conclusion is that in addition to decreasing seizure intensity, CBZ facilitates the partial recovery of sleep. These results suggest that CBZ provides neuro-protective effects on sleep and against seizures.

Air pollution, cognitive deficits and brain abnormalities: a pilot study with children and dogs.

Exposure to air pollution is associated with neuroinflammation in healthy children and dogs in Mexico City. Comparative studies were carried out in healthy children and young dogs similarly exposed to ambient pollution in Mexico City. Children from Mexico City (n: 55) and a low polluted city (n:18) underwent psychometric testing and brain magnetic resonance imaging MRI. Seven healthy young dogs with similar exposure to Mexico City air pollution had brain MRI, measurement of mRNA abundance of two inflammatory genes cyclooxygenase-2, and interleukin 1 beta in target brain areas, and histopathological evaluation of brain tissue. Children with no known risk factors for neurological or cognitive disorders residing in a polluted urban environment exhibited significant deficits in a combination of fluid and crystallized cognition tasks. Fifty-six percent of Mexico City children tested showed prefrontal white matter hyperintense lesions and similar lesions were observed in dogs (57%). Exposed dogs had frontal lesions with vascular subcortical pathology associated with neuroinflammation, enlarged Virchow-Robin spaces, gliosis, and ultrafine particulate matter deposition. Based on the MRI findings, the prefrontal cortex was a target anatomical region in Mexico City children and its damage could have contributed to their cognitive dysfunction. The present work presents a groundbreaking, interdisciplinary methodology for addressing relationships between environmental pollution, structural brain alterations by MRI, and cognitive deficits/delays in healthy children.

Kainic acid does not modify the oral pharmacokinetics of carbamazepine in rats.

Carbamazepine (CBZ) is a widely used antiepileptic agent that frequently interacts with other drugs. Recently, it has been reported that CBZ is able to modify the disturbed sleep patterns induced by kainic acid in epileptics. As a pharmacokinetic-pharmacodynamic characterization in the same animal is not possible due to the stress induced by blood sampling, it is important to establish if kainic acid is able to modify the pharmacokinetics of CBZ. Two groups of seven rats were used in this study. Animals received an oral dose of 50 mg/kg of CBZ alone or with 10 mg/kg of kainic acid. Blood samples (0.1 mL) were obtained at selected times for 12 hr and stored frozen until analyzed by HPLC. Pharmacokinetic parameters were: Cmax 6.51 +/- 1.32 and 6.63 +/- 0.95 microg/mL, tmax 3.55 +/- 0.98 and 1.82 +/- 0.59 hr, AUC 66.61 +/- 28.16 and 73.54 +/- 15.35 microg x h/mL and t1/2 7.16 +/- 2.55 and 5.80 +/- 1.37 hr. No statistically significant difference was observed in any parameter indicating that kainic acid is not able to modify oral pharmacokinetics of CBZ and pharmacokinetic-pharmacodynamic studies may be carried out using two groups of animals, one for the pharmacodynamics and another for the pharmacokinetic evaluation.

Difusión de cotrimoxazol a través de un expansor tisular: Estudio in vitro / Cotrimoxazole diffusion through a tissue expanders: In vitro study

Introducción: La principal complicación del uso de los expansores titulares (ET) son las infecciones. Una alternativa para evitarla, es agregar antibióticos que se difundan a través de la pared de un ET y eviten la colonización bacteriana. El objetivo de este trabajo fue evaluar la eficacia de una presentación nacional de cotrimoxazol, para difundirse a través de un ET en diferentes volúmenes de expansión. Material y método: Se realizó un experimento longitudinal con 12 ET, llenados a 50,100, 150 o 200% de su capacidad nominal, con solución fisiológica y cotrimoxazol a una concentración de 800/4000 ug/mL de trimetoprin/sulfametoxazol (TMX/SMX), sumergidos posteriormente en un sistema cerrado. Se midió la presión en el interior del ET, al inicio y al final del experimento. En los cuatro grupos se cuantificó la concentración de cotrimoxazol en la solución del contenedor, durante nueve días consecutivos. Los resultados se compararon mediante ANOVA de dos vías. Resultados: El SMX se precipitó dentro del ET. Las concentraciones de TMX en la solución del contenedor fueron diferentes en función del tiempo y el porcentaje de expansión. No hubo correlación entre el porcentaje de expansión y la presión dentro del ET. Conclusiones: La sinergia de cotrimoxazol de uso endovenoso disponible en nuestro país, no es una buena opción a emplearse en un ET a las dosis utilizadas, ya que el coeficiente de solubilidad de SMX se saturó y se formaron cristales. El incremento de difusión de TMX estuvo asociado con un mayor porcentaje de expansión, lo que es una ventaja, considerando que las infecciones son más frecuentes al final del proceso de expansión.

Introduction: Infection associated with tissue expansion is one of the main complications and force to take away the tissue expander. An alternative to avoid this action is to dilute antibiotics inside it. The aim of this experiment was to quantify the concentration of cotrimoxazole diffused through a tissue expander at different expansion and pressure volumes. Material and methods: A test was performed with 12 tissue expanders immersed in a closed system. These were divided in 4 sets according to the introduced expansion rate. Three independent variables were considered: percentage of lumen volume introduced into the expander, pressure inside the expander, and experiment duration. The concentration of the drug diffused through the expander was taken as dependent variable. The solution in which the expander was immersed was continuously sampled and drug concentration was determined by High Performance Liquid Chromatography (HPLC). ANOVA was used to determine differences between concentrations measured of every variable applied. Results: Only trimethoprim (TMX) diffused. No lineal correlation was observed between expansion rate and pressure inside the expander. The difference with respect to time and concentration of the drug outside the expander was statistically significant among the 4 sets of expanders (p = 0.0000). Conclusion: Sulfametoxazole (SMX) did not diffuse and crystallized inside the expander because of the different pk of the two drugs (SMX-TMX) respect to pH of dilution which was similar to pK of trimethoprim. The expansion rate had a proportional effect on TMX concentration outside the expander: an over-expansion of the system greater than 200% increases diffusion highly.

[Publication profile (1991-2002) of a group of Mexican pediatric surgeons]. / Perfil de las publicaciones efectuadas por cirujanos pediatras mexicanos (1991-2002).

INTRODUCTION: This study was undertaken to determine the characteristics of scientific articles published by Mexican pediatric surgeons (MPS) available in the major electronic databases for international and national medical information. MATERIAL AND METHODS: An observational, descriptive and transversal study was performed. Articles written by pediatric surgeons were localized in the most frequently accessed electronic searches: Medline, EMBASE, LILACS, and ARTEMISA, in the period from January 1991 to December 2002. Articles were grouped into three categories. RESULTS: A total of 247 publications were analyzed, 199 devoted to clinical research, 11 to basic research, and 37 reviews. Of the clinical research studies, 189 were observational-descriptive studies, and 151 of these were retrospective. Only 7.6% of the pediatric surgeons certified by the Mexican Council for Pediatric Surgery published an article (61 authors). Most studies (80%) was performed at Mexico City institutions. CONCLUSIONS: Most studies published by pediatric surgeons describe common problems of the Mexican pediatric population. A smaller percentage focus on comparing therapeutic actions or diagnostic strategies; however, result reliability is questionable due to experimental design. The contribution by MPS to the generation of medical publications during the last decade has been sparse, and more so from places other than Mexico City.