Impact of osteoporosis and osteoporosis medications on fracture healing: a narrative review.

Antiresorptive medications do not negatively affect fracture healing in humans. Teriparatide may decrease time to fracture healing. Romosozumab has not shown a beneficial effect on human fracture healing. BACKGROUND: Fracture healing is a complex process. Uncertainty exists over the influence of osteoporosis and the medications used to treat it on fracture healing. METHODS: Narrative review authored by the members of the Fracture Working Group of the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF), on behalf of the IOF and the Société Internationale de Chirurgie Orthopédique et de Traumatologie (SICOT). RESULTS: Fracture healing is a multistep process. Most fractures heal through a combination of intramembranous and endochondral ossification. Radiographic imaging is important for evaluating fracture healing and for detecting delayed or non-union. The presence of callus formation, bridging trabeculae, and a decrease in the size of the fracture line over time are indicative of healing. Imaging must be combined with clinical parameters and patient-reported outcomes. Animal data support a negative effect of osteoporosis on fracture healing; however, clinical data do not appear to corroborate with this. Evidence does not support a delay in the initiation of antiresorptive therapy following acute fragility fractures. There is no reason for suspension of osteoporosis medication at the time of fracture if the person is already on treatment. Teriparatide treatment may shorten fracture healing time at certain sites such as distal radius; however, it does not prevent non-union or influence union rate. The positive effect on fracture healing that romosozumab has demonstrated in animals has not been observed in humans. CONCLUSION: Overall, there appears to be no deleterious effect of osteoporosis medications on fracture healing. The benefit of treating osteoporosis and the urgent necessity to mitigate imminent refracture risk after a fracture should be given prime consideration. It is imperative that new radiological and biological markers of fracture healing be identified. It is also important to synthesize clinical and basic science methodologies to assess fracture healing, so that a convergence of the two frameworks can be achieved.

Carpogenic germination of Sclerotinia sclerotiorum sclerotia in Brassica oleracea var gemmifera (VN: Brussels sprouts) in North Patagonia, Argentina.

In August 2018, symptoms of apical and basal rot resembling those caused by Sclerotinia sclerotiorum infection were observed in a commercial Brussels sprouts field in North Patagonia, Argentina. The incidence of apical and basal rot was 23.30% and 2.30%, respectively. Carpogenic germination of sclerotia was detected in shaded, highly humid soil areas. To our knowledge, this is the first report of carpogenic germination of sclerotia from S. sclerotiorum in North Patagonia.

Resultados del primer programa para la reducción del tabaquismo en los trabajadores de un Hospital de agudos de segundo nivel en Huelva / [Results of the first program to reduce smoking in workers at a second level acute care hospital in Huelva]

Objetivos. El tabaquismo es el principal factor de riesgo en salud pública y una de las causas que ocasionan una mayor carga económica para la sociedad. El objetivo de nuestro estudio es aumentar el nivel de salud de los trabajadores del Hospital de segundo nivel, disminuyendo el consumo de tabaco y, por tanto, sus consecuencias, pero también, disminuir la prevalencia del hábito tabáquico entre los trabajadores del Hospital de Huelva y reducir las circunstancias de especial riesgo, personal y a terceros, como consecuencia del consumo de tabaco. Material y métodos. Se incluyeron en nuestro estudio a todo trabajador fumador, del Área Hospitalaria, motivado para la deshabituación tabáquica y a convivientes con algún trabajador que, a petición de este, desee abandonar el hábito, puesto que esta medida a prestar necesita apoyo familiar. El periodo de estudio abarcó desde enero a diciembre de 2021. Resultados. El número de pacientes fue de 136. Al año de tratamiento se observó una tasa de abandono del tabaco del 56% de los trabajadores que lo iniciaron. La población de pacientes estudiados presentó una edad media de 41 años; el rango abarca desde los 23 a los 63 años. La distribución según sexo fue: 83 mujeres (69% de los casos) y 37 hombres (31%). En cuanto al consumo diario su media fue de 24 cigarrillos/día y la media de comienzo del hábito tabáquico se sitúa en los 17 años. El 73% de los casos han intentado sin éxito dejar el hábito tabáquico al menos una vez. Con respecto a la categoría son los DUE los que fuman con más frecuencia con el 21% de los casos, seguidos de los auxiliares (19,8%), celadores (9,9%) y médicos (4,9%). La marca de cigarrillos más usada es LM (23,5%), Ducados (19,8%), Marlboro (7,4%), etc. El 85% de los fumadores toman café. En el 53% de los casos no fuman en su casa. Conclusiones. En nuestro estudio encontramos un porcentaje elevado de casos ... (AU)

Objetives.Smoking is the most important risk fac-tor for public health and one of the factors with thegreatest economic repercussions for society. Increasethe level of health of second level Hospital workers byreducing tobacco consumption and, therefore, its con-sequences. But also, reduce the prevalence of smokingamong workers at the Huelva ́s Hospital and reducecircumstances of special risk, both personally and tothird parties, as a consequence of tobacco consump-tion.Material and methods.We included in our studysmokers’ workers of area, motivated to lose the smok-ing habit and family living with workers, who at therequest of them want to leave the habit. Study periodwas collected from the 1st of January 2021 to 31st ofDecember 2021.Results.All cases were 136. Alter one year of treat-ment, 56% of the workers who had started the pro-gramme had dropped out. Average age populationwas 41 years old; rank include from 23 to 63 yearsold. Distribution by sex were: 83 women (69% ofcases) and 37 men (31%). Cigarettes average numberwas 24 cigarettes/day and beginning average was 17years old. 73% of cases have to intend to leave smok-ing habit once at least. In relation with the profes-sional categories, staff nurse are most smokers (21%of cases), followed by health auxiliary staff (19,8%),hospital porter staff (9,9%) and doctors’ staff (4,9%).Brand cigarettes more usual were L.M (23,5%), Duca-dos (19,8%), Marlboro (7,4%)... Otherwise, 85% ofsmokers usually drink coffee and 53% of cases don ́tsmoke in home.Conclusions.We find in our study a higher casespercent no smoking workers after one year beginningcomprehensive treatment. We conclude with this de-scriptive study we think necessary to developmentinterventions and coordinated programs with ex-tra-hospital care, and increase the activity to lose thehabit all rest of workers of our area (Hospital Area). (AU)

Endothelial cell CD36 regulates membrane ceramide formation, exosome fatty acid transfer and circulating fatty acid levels.

Endothelial cell (EC) CD36 controls tissue fatty acid (FA) uptake. Here we examine how ECs transfer FAs. FA interaction with apical membrane CD36 induces Src phosphorylation of caveolin-1 tyrosine-14 (Cav-1Y14) and ceramide generation in caveolae. Ensuing fission of caveolae yields vesicles containing FAs, CD36 and ceramide that are secreted basolaterally as small (80-100 nm) exosome-like extracellular vesicles (sEVs). We visualize in transwells EC transfer of FAs in sEVs to underlying myotubes. In mice with EC-expression of the exosome marker emeraldGFP-CD63, muscle fibers accumulate circulating FAs in emGFP-labeled puncta. The FA-sEV pathway is mapped through its suppression by CD36 depletion, blocking actin-remodeling, Src inhibition, Cav-1Y14 mutation, and neutral sphingomyelinase 2 inhibition. Suppression of sEV formation in mice reduces muscle FA uptake, raises circulating FAs, which remain in blood vessels, and lowers glucose, mimicking prominent Cd36-/- mice phenotypes. The findings show that FA uptake influences membrane ceramide, endocytosis, and EC communication with parenchymal cells.

Evidence on differential role for alpha 1 and alpha 2 subtypes of AP-2 adaptin in the central nervous system.

Two subtypes of alpha (α)subunits, α1and α2, belonging to AP-2 complex have been described in the central nervous system (CNS). The specific role of each subtype is still unclear. In this study, we evaluated the expression and interaction with cell membranes of both subtypes in the postnatal developing cerebral cortex and cerebellum in two rat strains that display distinct developmental features. We observed that α2 displays higher variations than α1 during development, and at lesser extent in the rats with delayed rate of development. Additionally, by in vitro binding assays we evaluated the interaction of α subunits with bovine brain membranes. Both subtypes displayed clear differences in their performance, maximum binding of α1 was higher and α2 reached it faster than α1. In addition, both subtypes displayed different binding to membranes when bivalent cations or nucleotides were added. We conclude that both subtypes interact differently with membranes and that they may play different roles in clathrin-mediated endocytosis in the CNS.

Continuous and binary sets of responses differ in the field.

This paper conducts a pre-registered study aimed to compare binary and continuous set of responses in survey questionnaires. Binary responses consist of two possible opposing response options (Yes/No). Continuous responses are numerical, where respondents can indicate an option on a 0-10 horizontal blind line. We study whether feasible sets of binary and continuous responses yield the same outcome (distribution) and have the same cost (duration in minutes). We collect data from 360 households in Honduras that were randomly assigned to Yes/No questions or given a slider (0-10 visual scale) to mark their responses, therefore, we provide causal evidence. We find that respondents are 13% more likely to respond "Yes" and spend 2.1 min less in the binary setting. Additionally, the results suggest that the type of question matters.

Enfermedad por arañazo de gato atípica: compromiso ocular y meníngeo por Bartonella henselae / Atypical cat scratch disease: Bartonella henselae ocular and meningeal involvement

Bartonella henselae es el agente etiológico de la enfermedad por arañazo de gato. Típicamente, se presenta como una linfadenopatía regional autolimitada y, con menor frecuencia, con compromiso sistémico y manifestaciones extraganglionares: hígado, bazo, hueso y ojo, entre otros. Se presenta un caso de enfermedad por arañazo de gato atípica en un paciente pediátrico inmunocompetente, en la que se evidenció compromiso meníngeo y ocular, este último como neurorretinitis. Se destaca la importancia de la búsqueda activa de complicaciones oculares en pacientes con compromiso sistémico por Bartonella henselae, que implica un cambio en el tratamiento y pronóstico de la enfermedad

Bartonella henselae is the etiologic agent of cat scratch disease. It typically presents as a self-limited regional lymphadenopathy and less frequently with systemic involvement and extranodal manifestations: liver, spleen, bone, eye, among others. A case of atypical cat scratch disease is presented in an immunocompetent pediatric patient, in which meningeal and ocular involvement was evidenced, the latter manifested as neuroretinitis. The importance of the active search for ocular complications in patients with systemic involvement by Bartonella henselae is highlighted, implying a change in the treatment and prognosis of the disease

[Atypical cat scratch disease: Bartonella henselae ocular and meningeal involvement]. / Enfermedad por arañazo de gato atípica: compromiso ocular y meníngeo por Bartonella henselae.

Bartonella henselae is the etiologic agent of cat scratch disease. It typically presents as a self-limited regional lymphadenopathy and less frequently with systemic involvement and extranodal manifestations: liver, spleen, bone, eye, among others. A case of atypical cat scratch disease is presented in an immunocompetent pediatric patient, in which meningeal and ocular involvement was evidenced, the latter manifested as neuroretinitis. The importance of the active search for ocular complications in patients with systemic involvement by Bartonella henselae is highlighted, implying a change in the treatment and prognosis of the disease.

Bartonella henselae es el agente etiológico de la enfermedad por arañazo de gato. Típicamente, se presenta como una linfadenopatía regional autolimitada y, con menor frecuencia, con compromiso sistémico y manifestaciones extraganglionares: hígado, bazo, hueso y ojo, entre otros. Se presenta un caso de enfermedad por arañazo de gato atípica en un paciente pediátrico inmunocompetente, en la que se evidenció compromiso meníngeo y ocular, este último como neurorretinitis. Se destaca la importancia de la búsqueda activa de complicaciones oculares en pacientes con compromiso sistémico por Bartonella henselae, que implica un cambio en el tratamiento y pronóstico de la enfermedad.

Is it time to consider population screening for fracture risk in postmenopausal women? A position paper from the International Osteoporosis Foundation Epidemiology/Quality of Life Working Group.

The IOF Epidemiology and Quality of Life Working Group has reviewed the potential role of population screening for high hip fracture risk against well-established criteria. The report concludes that such an approach should strongly be considered in many health care systems to reduce the burden of hip fractures. INTRODUCTION: The burden of long-term osteoporosis management falls on primary care in most healthcare systems. However, a wide and stable treatment gap exists in many such settings; most of which appears to be secondary to a lack of awareness of fracture risk. Screening is a public health measure for the purpose of identifying individuals who are likely to benefit from further investigations and/or treatment to reduce the risk of a disease or its complications. The purpose of this report was to review the evidence for a potential screening programme to identify postmenopausal women at increased risk of hip fracture. METHODS: The approach took well-established criteria for the development of a screening program, adapted by the UK National Screening Committee, and sought the opinion of 20 members of the International Osteoporosis Foundation's Working Group on Epidemiology and Quality of Life as to whether each criterion was met (yes, partial or no). For each criterion, the evidence base was then reviewed and summarized. RESULTS AND CONCLUSION: The report concludes that evidence supports the proposal that screening for high fracture risk in primary care should strongly be considered for incorporation into many health care systems to reduce the burden of fractures, particularly hip fractures. The key remaining hurdles to overcome are engagement with primary care healthcare professionals, and the implementation of systems that facilitate and maintain the screening program.

Sciatic nerve injury rebalances the hypothalamic-pituitary-adrenal axis in rats with persistent changes to their social behaviours.

Increased glucocorticoids characterise acute pain responses, but not the chronic pain state, suggesting specific modifications to the hypothalamic-pituitary-adrenal (HPA)-axis preventing the persistent nature of chronic pain from elevating basal glucocorticoid levels. Individuals with chronic pain mount normal HPA-axis responses to acute stressors, indicating a rebalancing of the circuits underpinning these responses. Preclinical models of chronic neuropathic pain generally recapitulate these clinical observations, but few studies have considered that the underlying neuroendocrine circuitry may be altered. Additionally, individual differences in the behavioural outcomes of these pain models, which are strikingly similar to the range of behavioural subpopulations that manifest in response to stress, threat and motivational cues, may also be reflected in divergent patterns of HPA-axis activity, which characterises these other behavioural subpopulations. We investigated the effects of sciatic nerve chronic constriction injury (CCI) on adrenocortical and hypothalamic markers of HPA-axis activity in the subpopulation of rats showing persistent changes in social interactions after CCI (Persistent Effect) and compared them with rats that do not show these changes (No Effect). Basal plasma corticosterone did not change after CCI and did not differ between groups. However, adrenocortical sensitivity to adrenocorticotropic hormone (ACTH) diverged between these groups. No Effect rats showed large increases in basal plasma ACTH with no change in adrenocortical melanocortin 2 receptor (MC2 R) expression, whereas Persistent Effect rats showed modest decreases in plasma ACTH and large increases in MC2 R expression. In the paraventricular nucleus of the hypothalamus of Persistent Effect rats, single labelling revealed significantly increased numbers of corticotropin releasing factor (CRF) +ve and glucocorticoid receptor (GR) +ve neurons. Double-labelling revealed fewer GR +ve CRF +ve neurons, suggesting a decreased hypothalamic sensitivity of CRF neurons to circulating corticosterone in Persistent Effect rats. We suggest that in addition to rebalancing the HPA-axis, the increased CRF expression in Persistent Effect rats contributes to changes in complex behaviours, and in particular social interactions.

Dosimetric analysis of graphitic carbon nitride quantum dots exposed to a gamma radiation for a low-dose applications.

In this study, graphitic carbon nitride quantum dots (g-C3N4QDs) were synthesized using different solvents, characterized, and then exposed to a gamma-ray source (137Cs) at irradiation doses of 0.1, 1.48, 2.05 and 3.25 Gy. The intensities of the emission bands progressively were attenuated as the received dose of gamma radiation increased. The changes were quantified with the help of a non-linear fit model. The material showed promising use as a dosimeter for low-dose radiation applications.

The First Record of Aedes vittatus (Diptera: Culicidae) in the Dominican Republic: Public Health Implications of a Potential Invasive Mosquito Species in the Americas.

Aedes vittatus Bigot is distributed throughout Africa, tropical Asia, and southern Europe and occurs in sylvatic as well as peridomestic environments where it readily feeds on humans. Although the vectorial capacity of Ae. vittatus is not well understood, this species is known to play a role in the maintenance and transmission of yellow fever, Zika, chikungunya, and dengue virus within its native range. In October 2019, after a routine inspection of mosquito-breeding containers in Jarabacoa, Dominican Republic, two Ae. vittatus females were captured via human landing catch method. After this finding, a CDC miniature light trap was deployed at the point of initial detection from 18:00 to 08:00 h, 2 d/wk from 3 to 31 October 2019. Potential larval habitats were also sampled via traditional dip method once per week spanning a 150 m radius from point of initial detection. In addition to the 2 adult females, 10 female and 2 male Ae. vittatus were captured. One Ae. vittatus larva also was found in a small puddle formed by an animal hoof print. Conventional PCR and Sanger sequencing were used to confirm morphological identification of collected specimens. This is the first detection of Ae. vittatus in the Dominican Republic as well as the Americas. Therefore, enhanced surveillance is needed to better understand the range and public health risks this potential invasive mosquito species may pose in the Dominican Republic, other Caribbean Islands, and/or the Americas.

Silver Nanoparticles Enhance Thermoluminescence and Photoluminescence Response in Li2B4O7 Glass Doped with Dy3+ and Yb3.

Lithium borate glass matrices doped with Dy3+ and Yb3+, containing silver nanoparticles in different concentrations are synthesized and characterized in this work. The Scanning Transmission Electron Microscopy confirms formation of silver nanoparticles in the samples. Absorption spectra of the samples show the presence of a broadband spectrum associated due to the surface plasmon effect of the silver nanoparticles. A strong surface plasmon band bellow 400 nm appears after the annealing process, due to the formation of silver nanoparticles with radius of 5-15 nm. The transition peaks of Dy3+ are also observed at 386, 446, 798, 917, 1088, 1265 and 1669 nm. Additionally, a large peak at 976 nm belonging to the absorption band corresponding to the Yb3+ is observed. Emission spectra under 406 nm pumping show two prominent bands at 506 and 590 nm belonging to the Dy3+ transitions 4F9/2 → 6H15/2 and 4F9/2 → 6H13/2, respectively. The fluorescence in the 480 nm and 525 nm spectral ranges enhanced with the silver nanoparticles contained in the samples. Is the first time, the luminescence studies of the lithium borate matrix doped with Dy3+ and Yb3+ containing silver nanoparticles is done. The basic parameters defining the lasing-amplifying potential of the glass matrices as a function of silver nanoparticles concentration are calculated. The Thermoluminescence response to UV irradiation also exhibits significant enhancement with the increment of silver nanoparticles in the samples.

[Comparison of surgical techniques for rotator cuff injury: cost-result]. / Comparación de técnicas quirúrgicas para la lesión del manguito de los rotadores: costo-resultado.

INTRODUCTION: Currently, to manage rotator cuff injury (RCI), there is a tendency to replace mini-open (MO) surgery with arthroscopy, but results and costs are controversial. OBJECTIVE: To analyze the cost-result of surgical techniques for RCI. MATERIAL AND METHODS: A partial economic evaluation of cost-result type was performed on 113 patients with RCI surgically operated by mini-open technique (n = 6), or arthroscopy (n = 91), or both (n = 16). Direct costs included: hospital stay, days of work disability, surgery, implants (anchors), medical assessments, laboratory and imaging. One-year shoulder functionality was evaluated with Constant-Murley scale (EscC-M). RESULTS: The MO technique was the most economical (X = $42,950.60 MXN) and the most expensive was the arthroscopy + MO with anchors (X = $89,594.80 MXN); with a non-significant difference in shoulder functionality (EscC-M = 56.33 ± 7.0 vs. 64.25 ± 9.0 points, respectively) (p 0.05; Kruskal-Wallis; post hoc Mann-Whitney). Difference of $46,644.1 MXN between techniques corresponded to 7.92 points. There was a mild relationship between the technique and the functionality of shoulder (rs = 0.26; p = 0.005; Spearman). CONCLUSION: The mini-open technique showed best cost-result, with similar functionality in shoulder to that obtained with the more expensive technique.

INTRODUCCIÓN: Actualmente, para manejar la ruptura del manguito de los rotadores (LMR), se prefiere la artroscopía sobre técnicas abiertas (mini-open [MO]), con resultados y costos controversiales. OBJETIVO: Analizar el costo-resultado de las técnicas quirúrgicas para la LMR. MATERIAL Y MÉTODOS: Se realizó una evaluación económica parcial de tipo costo-resultado a 113 pacientes con LMR intervenidos mediante técnica mini-open (n = 6) o artroscopía (n = 91) o ambas (n = 16). Los costos directos incluyeron: estancia, días de incapacidad laboral, cirugía, implantes (anclas), valoraciones médicas, laboratorio e imagen. Se evaluó la funcionalidad del hombro a un año mediante la escala de Constant-Murley (EscC-M). RESULTADOS: La técnica MO fue la más económica (X = $42,950.60 MXN) y la más costosa fue la artroscopía + MO con anclas (X = $89,594.80 MXN); con una diferencia no significativa en la funcionalidad del hombro (EscC-M = 56.33 ± 7 vs 64.25 ± 9 puntos, respectivamente) (p 0.05; Kruskal-Wallis; post hoc Mann-Whitney). Una diferencia de $46,644.10 MXN entre técnicas correspondió a 7.92 puntos. Hubo relación leve entre la técnica y la funcionalidad del hombro (rs = 0.26; p = 0.005; Spearman). CONCLUSIÓN: La técnica mini-open mostró mejor costo-resultado, con una ganancia en la funcionalidad de hombro similar a la que se obtiene con la técnica más costosa.

Cytotoxic and genotoxic effects in mechanics occupationally exposed to diesel engine exhaust.

Diesel engine exhaust (DEE), which is the product of diesel combustion, is considered carcinogenic in humans. It comprises toxic gases, polycyclic aromatic hydrocarbons (PAHs) and particulate matter which can reach the pulmonary parenchyma and trigger various diseases, including cancer. The aim of the present study was to evaluate the potential cytotoxic and genotoxic effects of DEE exposure on peripheral blood and buccal epithelial cells in mechanics occupationally exposed to DEE. We recruited 120 exposed mechanics and 100 non-exposed control individuals. Significant differences were observed between the two groups in terms of percentage of tail DNA and damage index (DI) in the alkaline comet assay; levels of biomarkers by cytokinesis-block micronucleus cytome (CBMN-Cyt) assay; frequency of micronucleus (MN), nucleoplasmic bridge (NPB), nuclear bud (NBUD) and apoptotic cells (APOP) and levels of biomarkers for micronucleus, karyorrhexis (KRX), karyolysis (KRL) and condensed chromatin (CC) by the buccal micronucleus cytome (BM-Cyt) assay. A significant and positive correlation was found between the frequency of MN in lymphocytes and buccal cells in the exposed group. Also, there was a significant correlation between age and percentage of tail DNA and DI in the comet assay, APOP and MN in the CBMN-Cyt assay and NBUD and MN in the BM-Cyt assay. Additionally, we found a positive and significant correlation of MN frequency in lymphocytes and buccal cells and age and MN frequency in lymphocytes with the time of service (years). Regarding lifestyle-related factors, a significant correlation was observed between meat and vitamin consumption and NBUD formation on CBMN-Cyt and between meat consumption and MN formation on CBMN-Cyt. Of the BM-Cyt biomarkers, there was a correlation between alcohol consumption and NBUD formation and between binucleated cell (BN), pyknosis (PYC), CC and KRL occurrence and family cancer history. These results are the first data in Colombia on the cytotoxic and genotoxic effects induced by continuous exposure to DEE and thus showed the usefulness of biomarkers of the comet, CBMN-Cyt and BM-Cyt assays for human biomonitoring and evaluation of cancer risk in the exposed populations.

PROPUESTA DE ESTRATEGIA PARA LA MEJORA DE LA SATISFACCIÓN LABORAL EN UNIDADES ASISTENCIALES ESTOMATOLÓGICAS. MUNICIPIO SANCTI SPÍRITUS, 2017. SOCIEDAD CON CALIDAD DE VIDA

ResumenLa satisfacción laboral es el grado de conformidad del empleado respecto a su entorno y condiciones de trabajo, es directamente proporcional al compromiso del trabajador con la institución, a la motivación y a la productividad. Según ubicación laboral, se comportó como sigue; los profesionales de la Clínica Estomatológica Docente Provincial fueron los más satisfechos con las dimensiones técnico-humano y entorno físico, respecto a la dimensión resultado de tratamiento, los del Policlínico Olivos fueron los de mayor satisfacción, los profesionales del Policlínico Sur están insatisfechos con las tres dimensiones. Así, el objetivo de este trabajo es identificar la satisfacción de los estomatólogos con los servicios de Estomatología General Integral en las unidades urbanas del municipio Sancti Spíritus en el periodo 2016-2018.[AU]

Parahippocampal gyrus expression of endothelial and insulin receptor signaling pathway genes is modulated by Alzheimer's disease and normalized by treatment with anti-diabetic agents.

A large body of literature links risk of cognitive decline, mild cognitive impairment (MCI) and dementia with Type 2 Diabetes (T2D) or pre-diabetes. Accumulating evidence implicates a close relationship between the brain insulin receptor signaling pathway (IRSP) and the accumulation of amyloid beta and hyperphosphorylated and conformationally abnormal tau. We showed previously that the neuropathological features of Alzheimer's disease (AD were reduced in patients with diabetes who were treated with insulin and oral antidiabetic medications. To understand better the neurobiological substrates of T2D and T2D medications in AD, we examined IRSP and endothelial cell markers in the parahippocampal gyrus of controls (N = 30), of persons with AD (N = 19), and of persons with AD and T2D, who, in turn, had been treated with anti-diabetic drugs (insulin and or oral agents; N = 34). We studied the gene expression of selected members of the IRSP and selective endothelial cell markers in bulk postmortem tissue from the parahippocampal gyrus and in endothelial cell enriched isolates from the same brain region. The results indicated that there are considerable abnormalities and reductions in gene expression (bulk tissue homogenates and endothelial cell isolates) in the parahippocampal gyri of persons with AD that map directly to genes associated with the microvasculature and the IRSP. Our results also showed that the numbers of abnormally expressed microvasculature and IRSP associated genes in diabetic AD donors who had been treated with anti-diabetic agents were reduced significantly. These findings suggest that anti-diabetic treatments may reduce or normalize compromised microvascular and IRSP functions in AD.

Hypoxia-ischemia alters distribution of lysosomal proteins in rat cortex and hippocampus.

Neuronal excitotoxicity induced by glutamatergic receptor overstimulation contributes to brain damage. Recent studies have shown that lysosomal membrane permeabilization (LMP) is involved in ischemia-associated neuronal death. In this study we evaluated the effect of neonatal hypoxia-ischemia (HI), as a model of excitotoxicity, on the lysosomal integrity throughout the distribution of the lysosomal proteins cathepsin D and prosaposin. Rat pups (7 days old) of the Wistar Kyoto strain were submitted to HI and they were euthanized 4 days after treatment and the cerebral cortex (Cx) and hippocampus (HIP) were processed for immunohistochemistry or immunoblotting. Treatment induced an increase of gliosis and also a redistribution of both prosaposin and cathepsin D (as intermediate and mature forms), into the cytosol of the HIP and Cx. In addition, HI induced a decrease of LAMP-1 in the membranous fraction and the appearance of a reactive band to anti-LAMP-1 in the cytosolic fraction, suggesting a cleavage of this protein. From these results, we propose that the abnormal release of Cat D and PSAP to the cytosol is triggered as a result of LAMP-1 cleavage in HI animals, which leads to cell damage. This could be a common mechanism in pathological conditions that compromises neuronal survival and brain function.

Cation-dependent mannose-6-phosphate receptor expression and distribution are influenced by estradiol in MCF-7 breast cancer cells.

Cancer cells secrete procathepsin D, and its secretion is enhanced by estradiol. Although alterations in the pro-enzyme intracellular transport have been reported, the mechanism by which it is secreted remains poorly understood. In this work, we have studied the influence of estradiol on the expression and distribution of the cation-dependent mannose-6-phosphate receptor (CD-MPR), which would be a key molecule to ensure the proper localization of the enzyme to lysosomes in breast cancer cells. Immunoblotting studies demonstrated that the expression of CD-MPR is higher in MCF-7 cells, as compared to other breast cancer and non-tumorigenic cells. This expression correlated with high levels of cathepsin D (CatD) in these cells. By immunofluorescence, this receptor mostly co-localized with a Golgi marker in all cell types, exhibiting an additional peripheral labelling in MCF-7 cells. In addition, CD-MPR showed great differences regarding to cation-independent mannose-6-phosphate receptor. On the other hand, the treatment with estradiol induced an increase in CD-MPR and CatD expression and a re-distribution of both proteins towards the cell periphery. These effects were blocked by the anti-estrogen tamoxifen. Moreover, a re-distribution of CD-MPR to plasma membrane-enriched fractions, analyzed by gradient centrifugation, was observed after estradiol treatment. We conclude that, in hormone-responsive breast cancer cells, CD-MPR and CatD are distributed together, and that their expression and distribution are influenced by estradiol. These findings strongly support the involvement of the CD-MPR in the pro-enzyme transport in MCF-7 cells, suggesting the participation of this receptor in the procathepsin D secretion previously reported in breast cancer cells.

Benzo[a]pyrene activates an AhR/Src/ERK axis that contributes to CYP1A1 induction and stable DNA adducts formation in lung cells.

Benzo[a]pyrene (B[a]P), the most extensively studied carcinogen in cigarette smoke, has been regarded as a critical mediator of lung cancer. It is known that B[a]P-mediated Aryl hydrocarbon Receptor (AhR) activation stimulates the mitogen activated protein kinases (MAPK) signaling cascade in different cell models. MAPK pathway disturbances drive alterations in cellular processes, such as differentiation, proliferation, and apoptosis, and the disturbances may also modify the AhR pathway itself. However, MAPK involvement in B[a]P metabolic activation and toxicity in lung tissues is not well understood. Here, we used a non-transformed human bronchial epithelial lung cell line, BEAS-2B, to study the participation of ERK 1/2 kinases in the metabolic activation of B[a]P and in its related genotoxic effects. Our results indicate that B[a]P is not cytotoxic to BEAS-2B cells at relatively low concentrations, but it enhances CYP1A1 gene transcription and protein induction. Additionally, B[a]P promotes Src and ERK 1/2 phosphorylation. Accordingly, inhibition of both Src and ERK 1/2 phosphorylation decreases CYP1A1 protein induction, AhR nuclear translocation and production of B[a]P adducts. Together, these data suggest a crosstalk between AhR and the members of the MAPK pathway, ERK 1/2 mediated by Src kinase. This interaction is important for the adequate AhR pathway signaling that in turn induces transcription and protein induction of CYP1A1 and B[a]P-induced DNA damage in BEAS-2B cells.