CoordenaÃÃo de AperfeÃoamento de Pessoal de NÃvel Superior / Oxaliplatina (OXL) à um composto de platina de terceira geraÃÃo com potente atividade citotÃxica contra vÃrios tipos de cÃncer, possuindo um efeito colateral de difÃcil tratamento, uma severa neuropatia perifÃrica. Estudos sugerem que o oxalato, metabÃlito da OXL, està envolvido no desenvolvimento dessa neuropatia sensitiva perifÃrica (NSP); de modo que foi publicada a sÃntese de um anÃlogo (LLC-1402) da OXL, livre de oxalato, tendo propriedades antitumorais (LIU et al., 2013). O objetivo do trabalho à estudar o papel do oxalato na neuropatia induzida por OXL em camundongos, comparando a OXL com LLC-1402. A NSP foi induzida por 2 injeÃÃes (iv.) por semana de OXL (2 mg/kg), em camundongos machos Swiss, durante 4  semanas, totalizando 9 injeÃÃes. LLC-1402 (7, 14 e 28 mg/kg) foi administrado (iv.) seguindo o mesmo esquema. Foram realizados testes nociceptivos (Von Frey eletrÃnico e TIC), semanalmente. Depois, foi escolhida a dose de 14 mg/kg do LLC-1402 para fazer um outro experimento, no qual foi acrescentada a injeÃÃo ip. de oxalato (1,7 mg/kg). No 28 dia, foi feita coleta de sangue para contagem total de leucÃcitos e dosagens bioquÃmicas. Nos 28 e 56 dias, foi feita a coleta de medula espinhal e GRD para imunofluorescÃncia para ATF-3, c-FOS, iNOS e NeuN. Os resultados mostraram que a OXL e o LLC-1402 foram capazes de diminuir o limiar de retirada da pata e o tempo de retirada da cauda significativamente (p<0,05), comparado ao grupo controle. A injeÃÃo de LLC-1402 junto com oxalato e somente oxalato tambÃm foi capaz de reduzir o limiar de retirada da pata e o tempo de retirada da cauda. Os grupos tratados com OXL, LLC-1402 e oxalato mostraram uma reduÃÃo significativa da contagem total de leucÃcitos. Para as dosagens bioquÃmicas (TGO, TGP, ureia, creatinina), nÃo houve diferenÃa estatÃstica entre os grupos. Houve um aumento da imunoexpressÃo de c-Fos no GRD nos grupos tratados com OXL, LLC-1402 e LLC-1402 junto com oxalato nos 28 e 56 dias, e somente oxalato no 28 dia. Foi observado esse aumento no corno dorsal da medula espinhal no 28 dia em todos os grupos tratados. Foi observado um aumento da imunoexpressÃo de ATF-3, no GRD e corno dorsal da medula espinhal, em todos os grupos tratados, nos 28 e 56 dias. NÃo houve diferenÃa significativa entre os grupos no GRD nem medula espinhal na imunoexpressÃo de iNOS no 56 dia; jÃ, no 28 dia, houve um aumento da imunoexpressÃo de iNOS no GRD. Os resultados mostraram que o oxalato pode estar envolvido parcialmente na NSP induzida por OXL. / Oxaliplatin (OXL) is a third generation platinum compound with potent cytotoxic activity against several types of cancers, having a side effect is difficult to treat, a severe peripheral neuropathy. Studies suggest that oxalate, OXL metabolite, is involved in the development of peripheral sensory neuropathy (PSN); so that was published the synthesis of an OXL analogue (LLC-1402), oxalate free, which has antitumor properties (LIU et al., 2013). The objective of this research is to study the role of oxalate in OXL induced neuropathy in mice, comparing OXL with LLC-1402. The PSN was induced by two injections (iv.) OXL (2 mg/ kg) per week, in male Swiss mice, for 4  weeks, totaling 9 injections. LLC-1402 (7, 14 and 28 mg / kg) was administered (iv.) following the same scheme. Nociceptive tests were performed (electronic von Frey and tail immersion test) weekly. After, it was chosen dose of 14 mg / kg of the LLC-1402 to perform another experiment, in which was added oxalate injection (1.7 mg/kg). In the 28th day, it was made blood collection for total leukocyte count and biochemical measurement. In the 28th and 56th days, spinal cord and DRG were removed for immunofluorescence for ATF-3, c-FOS, iNOS and NeuN. The results showed that both OXL and LLC-1402 were able to decrease the paw withdrawal threshold and tail withdrawal time significantly (p<0.05) compared to the control group. The injection of LLC-1402 together with oxalate and only oxalate was also able to reduce the paw withdrawal threshold and the tail withdrawal time. Moreover, all groups treated with OXL, LLC-1402 and oxalate showed a significant reduction in the total leukocyte count. The biochemical measurement (glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, urea, creatinine) showed no statistical difference between the groups. The results also showed increased c-Fos immunoexpression in GRD in groups treated with OXL, LLC-1402 and LLC-1402 together with oxalate in the 28 and 56 days, and only oxalate the 28th day. This increase was observed in the dorsal horn of the spinal cord at 28th day in all the treated groups. It was not observed this increase in the dorsal horn of the spinal cord in the 56th day. It was observed an increase in immunoexpression of ATF3 in DRG and spinal cord of dorsal horn in all treated groups in the 28th and 56th days. iNOS immunofluorescence showed no significant difference between groups in the DRG nor spinal cord, already in the 28th day, there was an increase in immunoexpression of iNOS in GRD. Thus, the results showed that the oxalate may be partially involved in PSN induced OXL.

Made available in DSpace on 2014-10-09T12:54:12Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T14:07:44Z (GMT). No. of bitstreams: 1 12697.pdf: 655472 bytes, checksum: 17722971c9d58d20dbb9095955c414c4 (MD5) / Dissertacao (Mestrado Profissionalizante em Lasers em Odontologia) / IPEN/D-MPLO / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP; Faculdade de Odontologia, Universidade de Sao Paulo , Sao Paulo

nÃo hà / A vincristina à um quimioterÃpico e seu uso à limitado devido a neuropatia perifÃrica, com acometimento autonÃmico, sensitivo e motor. Sulfato de vincristina ou salina foram injetados na veia da cauda, nas doses de 50 Âg/Kg (5 doses), 100 Âg/Kg (2-5 doses) ou 150 Âg/Kg (1, 2 ou 5 doses) a cada dois dias em 144 ratos Wistar machos (200-250 g). No dia seguinte, os animais receberam a refeiÃÃo-teste por gavagem e foram sacrificados 10 minutos apÃs. A recuperaÃÃo gÃstrica e intestinal de corante foi determinada por espectrofotometria. ConstipaÃÃo foi avaliada pelo peso colÃnico e neuropatia sensitiva pela latÃncia tÃrmica (51Â0,5ÂC). PressÃo arterial mÃdia (PAM) e freqÃÃncia cardÃaca (FC) basais e valores da PAM e FC apÃs a administraÃÃo de fenilefrina 5 Âg/Kg e atropina 0,5 mg/Kg foram usados para estudo dos baroreflexos. DiferenÃas foram avaliadas por One-Way ANOVA com P<0,05. Tratamentos crÃnicos com 5 doses de 50 Âg/Kg; 3, 4 e 5 doses de 100 Âg/Kg; 2 e 5 doses de 150 Âg/Kg causaram retardo do esvaziamento gÃstrico (EG) (P<0,05). Duas e 5 doses de 150 Âg/kg induziram constipaÃÃo e houve reduÃÃo da latÃncia tÃrmica apÃs 1 dose de 50 Âg/Kg, 100 Âg/Kg e 150 Âg/kg (P<0,05). O efeito da vincristina sobre o EG nÃo foi evidenciado uma e duas semanas apÃs o tratamento com 5 doses de 150 Âg/Kg (P>0,05). Houve reduÃÃo do tempo de latÃncia ao calor por atà duas semanas apÃs 5 doses de 150 Âg/Kg (P<0,05). Vincristina potencializou a reduÃÃo da FC induzida pela fenilefrina e aumentou a resposta cardÃaca à atropina (P<0,05). A neuropatia autonÃmica induzida pela vincristina cursa com retardo do EG, alteraÃÃes na resposta baroreflexa e aumento do peso colÃnico. A neuropatia sensitiva precede o surgimento das alteraÃÃes autonÃmicas e persiste apÃs a reversÃo destas. / Vincristine is a chemotherapy drug and its use is limited by peripheral neuropathy with autonomic, sensory and motor involvement. Vincristine sulphate or saline was injected into the tail vein at doses of 50 Âg/Kg (5 doses), 100 Âg/Kg (2-5 doses) or 150 Âg/Kg (1, 2 or 5 doses) QOD in 144 male Wistar rats (200-250g). Next day, they were gavage-fed with a test meal and sacrificed 10 minutes later. Gastric and intestinal dye recovery was determined by spectrophotometry. Basal mean arterial pressure (MAP) and heart rate (HR) and peak values of MAP and HR after i.v. phenylephrine 5 Âg/Kg and atropine 0.5 mg/Kg were used to evaluate the baroreflex responses. Differences were evaluated by One-Way ANOVA with P<0.05. Chronic treatment with 5 doses of 50 Âg/Kg; 3, 4 and 5 doses of 100 Âg/Kg; 2 and 5 doses of 150 Âg/Kg delayed gastric emptying (GE) (P<0.05). Two and 5 doses of 150 Âg/Kg induced constipation and reduction in withdrawal latencies occurred after 1 dose of 50 Âg/Kg, 100 Âg/Kg and 150 Âg/Kg (P<0.05). Vincristine (150 Âg/Kg) immediately decreased fecal output (P<0.05). The effect of vincristine on the GE was not present in rats treated with 5 doses of vincristine 150 Âg/kg one week and two weeks after the last dose (P>0.05). The withdrawal latency decrease lasted for at least 2 weeks after 5 doses of 150 Âg/Kg (P<0.05). Vincristine enhanced the HR reduction induced by phenylephrine and enhanced cardiac response to atropine (P<0.05). Vincristine-induced autonomic neuropathy courses with delayed GE, altered baroreflex responses and increased colonic weight. Sensory neuropathy preceded and outlasted these autonomic changes.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / Oxaliplatina (OXL) à um agente platÃnico de 3 geraÃÃo com potente atividade citotÃxica em diversos cÃnceres. Tem como toxicidade limitante uma neuropatia sensitiva perifÃrica (NSP) de inÃcio agudo, tornando-se crÃnica com doses cumulativas. Amifostina (AMF) à um agente antioxidante de largo espectro, que vem sendo atualmente estudado na citoproteÃÃo dos efeitos adversos da radioterapia e quimioterapia do cÃncer. Esta pesquisa objetivou avaliar o efeito da AMF sobre a hiperalgesia mecÃnica plantar e alodinia tÃrmica, assim como sobre as alteraÃÃes histopatolÃgicas e imunoexpressÃo de marcadores, tais como a proteÃna c-Fos, caspase 3, IL-1, nitrotirosina, NOSi, NOSn e NMDA, observadas na NSP experimental induzida por OXL. O estudo foi aprovado pelo Comità de Ãtica em Pesquisa Animal da Universidade Federal do CearÃ, com o protocolo 27/08. Camundongos Swiss machos (25-35g) foram tratados com OXL (1mg/kg, i.v.) e prÃ-tratados com AMF (1, 5, 25, 50 ou 100mg/kg, s.c.) por 4,5 semanas, paralelamente aos testes nociceptivos. A alodÃnia tÃrmica foi avaliada pelo teste de imersÃo da cauda em Ãgua fria (10ÂC) e a hiperalgesia mecÃnica plantar pelo teste do Von Frey EletrÃnico. Foi realizada a anÃlise histopatolÃgica e imunohistoquÃmica de amostras obtidas do corno dorsal da medula espinhal lombar dos animais em 24h, 7, 14, 21 e 28 dias. Demonstrou-se que a OXL diminuiu significativamente o limiar nociceptivo mecÃnico e tÃrmico, a partir do 21 dia (p<0,001) e 14 dia (p<0,01), respectivamente, quando comparados ao grupo controle. O tratamento com AMF inibiu esses efeitos em todas as doses testadas (p<0,001), sendo a dose de 25mg/kg aquela com efeito mais significativo. No teste do Rota-Rod nÃo foi observada variaÃÃo significativa entre os grupos, indicando ausÃncia de comprometimento motor. Na anÃlise histopatolÃgica foram observados edema do tecido nervoso e atrofia dos neurÃnios nos animais tratados com OXL, o que nÃo ocorreu nos animais prÃ-tratados com AMF. Observou-se a imunoexpressÃo importante de c-Fos, caspase 3, NOSn, NOSi e nitrotirosina nos animais tratados apenas com OXL, e uma imunoexpressÃo reduzida do receptor NMDA, quando comparado com o grupo controle. AMF reduziu a expressÃo de c-Fos e de nitrotrosina, mas nÃo da caspase 3, NOSn e NOSi, e aumentou a expressÃo do receptor NMDA. NÃo houve imunoexpressÃo de IL-1 nos grupos testados. Embora preliminares, os dados sugerem que a AMF promoveu uma importante proteÃÃo nas alteraÃÃes sensitivas da NSP induzida por OXL, desde que inibiu a hiperalgesia e a alodinia, alÃm da imunoexpressÃo de c-Fos. Adicionalmente AMF promoveu importante aÃÃo protetora nas lesÃes teciduais, sendo capaz de exercer aÃÃo antioxidante e antiapoptÃtica, atravÃs da inibiÃÃo da expressÃo de nitrotirosina e do aumento da expressÃo do receptor NMDA, respectivamente. / Oxaliplatin (OXP) is a third-generation platinum agent with potent cytotoxic activity in several cancers. Its limiting toxicity is a sensory peripheral neuropathy (SPN) of acute onset, which becomes chronic after cumulative doses. Amifostine (AMF) is a broad spectrum antioxidant and is currently being studied as a cell-protecting agent against the adverse effects of radiotherapy and chemotherapy in cancer patients. This study was aimed to evaluate the effect of AMF on plantar mechanical hyperalgesia and thermal allodynia, as well as on histopathological alterations and immune expression of markers such as c-Fos protein, caspase 3, IL-1, nitrotyrosine, iNOS, nNOS and NMDA, observed in experimental OXL-induced SPN. The study was approved by the Ethics Committee on Animal Research, Federal University of CearÃ, through protocol 27/08. Male Swiss mice (25-35g) were treated with OXL (1 mg/kg, i.v.) and pre-treated with AMF (1, 5, 25, 50 or 100 mg/kg, s.c.) for 4,5 weeks, in addition to the performance of nociceptive tests. Thermal allodynia was evaluated by tail immersion in cold water (10ÂC), and plantar mechanical hyperalgesia by the Electronic Von Frey test. The histopathological and immunohistochemical analysis of samples taken from the dorsal horn of the lumbar spinal cord of the animals was performed in 24 hours, 7, 14, 21 and 28 days. OXP significantly decreased mechanic and thermal nociceptive threshold since 21th day (p<0,001) and 14th day (p<0,01), respectively, when compared to control group. AMF treatment inhibited these effects in all doses tested (p<0,001), and the dose of 25mg/kg had the most significant effect. Locomotor impairment was not evidenced through Rota-Rod test. Furthermore, we observed edema and neurons atrophy in dorsal horn of OXP group, not showed in AMF group. OXP group had overexpression of c-Fos, caspase 3, nNOS, iNOS, and nitrotyrosine, but a reduced NMDA receptor expression when compared to control group. AMF group had hypoexpression of c-Fos and nitrotyrosine and increased NMDA receptor expression, but not altered caspase 3, nNOS and iNOS expression. There was no immunoexpression of IL-1 in the tested groups. Although preliminary, the data suggest that AMF promoted an important protection in OXL-induced SPN sensory changes, since it inhibited the hyperalgesia and allodynia, as well as the immunoexpression of c-Fos. Additionally AMF promoted significant protective action on tissue lesions, being able to exert antioxidant and antiapoptotic action by inhibiting the expression of nitrotyrosine and increasing expression of NMDA receptors, respectively.

Chronic traumatic encephalopathy is the neurodegenerative disease that is ascribed to the long term development of cognitive, behavioral, emotional, and motor deficits as a result of the exposure to high amounts of sub concussive traumatic brain injuries. The disease has gained recent popularity in the media for its prevalence in American football as a response to recent research that has suggested the prominence of the disease in nearly every NFL player that is examined post mortem. This has produced a growing concern for the consequences of head impact and participation in contact sports. Despite media attention, little is currently known about the specific causes of the disease and an in life diagnosis is still nonexistent. The present study proposes that the chemokine, CCL11, could prove to be a viable biomarker for recognizing the onset and progression of chronic traumatic encephalopathy. The results of our study suggest that football players who are clinically suspicious of CTE show significantly higher levels of CCL11 in their cerebrospinal fluid than do sedentary controls and noncontact athletes. Our results demonstrate that this increase in CCL11 is correlated with the number of years that a football player had participated in. We also suggest that this increase in CCL11 is associated with a unique immune response through results showing that the CCL11 expression increase is correlated with an increase in the expression of the cytokine IL-4 and substantial decrease in IFN-gamma. The analysis of CCL11 expression levels in the cerebrospinal fluid may prove to be a viable method of diagnosing and providing treatment for patients who may be at risk of chronic traumatic encephalopathy.

No description available.

Mutations in genes that cause transcriptional dysregulation, such as genes that encode DNA and RNA-binding proteins (RNABPs), are a well-described cause of neurodevelopmental syndromes such as autism and epilepsy. Heterozygous de novo mutations involving the gene HNRNPU, which encodes the heterogeneous nuclear ribonuclear protein U, have been implicated in a neurodevelopmental syndrome most commonly characterized by epileptic encephalopathy. Although hnRNP U is a highly-abundant and ubiquitously-expressed DNA- and RNA-binding protein involved in a variety of important nuclear processes—most notably gene expression regulation—the role it plays in neurological disease is unclear and has yet to be studied. The work presented here examines a precision medicine approach for epilepsies thought to have a transcriptomic basis, starting with a thorough neurophysiological characterization of a heterozygous loss-of-function Hnrnpu mouse model (Hnrnpu+/113DEL), followed by a comprehensive and region-specific single-cell transcriptomic study, and finally the validation of implicated brain regions. Characterization of the Hnrnpu+/113DEL mouse line revealed an increased susceptibility to seizures in Hnrnpu+/113DEL mice, along with an increased perinatal mortality, global developmental delay and gait abnormalities. Gene expression profiling, including bulk RNA-sequencing of neocortex and single cell RNA-sequencing of both neocortex and hippocampus, revealed widespread, yet modest, dysregulation of gene expression that was largely inversely correlated to gene-length, and involved important, neurodevelopmental disease genes. In particular, pyramidal neurons of the subiculum displayed greater transcriptional burden upon heterozygous loss of Hnrnpu, with the known epilepsy gene Mef2c as a clear outlier showing greater than 50% reduction in expression. Follow-up investigation into whether this region- and cell-type specific gene dysregulation correlated to differences in neuronal function using c-Fos immunostaining, revealed an overall decrease in neuronal activity within the ventral subiculum in Hnrnpu+/113DEL mice. In summary, our data validates the presence of neurodevelopmental defects upon heterozygous loss of Hnrnpu and supports the notion of transcriptional dysregulation as a likely contributing factor to hnRNP U-related disease, possibly through the dysfunction of subiculum-derived excitatory neurons. Future studies evaluating the relationship between reduced activity within the ventral subiculum and hnRNP U disease phenotypes are an important next step, and may serve as the basis for targeted therapeutic discovery.

Over 260,000 Americans are living with a traumatic spinal cord injury (SCI). Medical advances have increased the longevity of individuals living with SCI into middle age and beyond. The majority of these individuals are living with an incomplete SCI (NSCISC, 2012), and the proportion of incomplete injuries is rising (DeVivo, 2012). There is little research that specifically examines the changes in physical function experienced by individuals aging with a traumatic incomplete SCI. The purpose of this qualitative descriptive study was to describe the changes in physical function experienced by participants with a traumatic incomplete SCI aging through middle age. Data were collected through moderately structured individual interviews (N=17), in either a face-to-face (n=6) or an email (n=11) format. The seventeen participants ranged in age from 35 to 65 years, with a 16 to 36 year duration of injury. Participants described changes in various body systems and recalled the timing of those changes as they transitioned through their middle years. Qualitative content analysis revealed that participants described primarily gradual changes including decreased muscle strength, decreased endurance, weight gain, and wear and tear changes. When asked to identify sources of information about physical changes, participants predominantly emphasized their lack of knowledge about anticipated changes. Further content analysis revealed three themes related to this transition. Participants likened their experience to travelling through uncharted territory. They described strategies for living in uncharted territory that help them to prevent or manage changes in physical function, with sub-themes of being vigilant in their self-assessment and self-management practices, investing time in figuring out what changes they experienced and why those changes happened, and staying positive. They also described the importance of recognizing the impact of changes. These findings provide a foundation for understanding this age-related transition, and identify the need for further research to support effective self-management strategies and efficient mechanisms for disseminating this knowledge to people with SCI, their caregivers and families. In acute and chronic patient care settings, nurses are well-positioned to be a valuable support and information source for individuals living with an incomplete SCI.

Objective: The aims of this project were to (a) perform a systematic review and meta-analysis of the associations between multiple neurological disorders (or neurological diseases) and potential influencing factors, including the association between fine particulate matter (PM 2.5) and intestinal dysfunction, and (b) investigate the mechanisms and toxicological effects of PM 2.5 exposure in the brain and intestines using a mouse model of Alzheimer's disease (AD). Design: A systematic review and meta-analysis was conducted to assess the risks of PM 2.5 exposure, as manifested by the incidence of exposure-associate neurological disorders or intestinal dysfunction. An APP/PS1 transgenic mouse model for AD was used to study the brain damage resulting from PM 2.5 exposure, and the miRNA/mRNA regulatory mechanisms contributing to this damage. The inflammatory injuries and bacterial community changes in the intestines of AD mice exposed to PM 2.5 were also investigated. Data sources: Articles for systematic review and meta-analysis were obtained by searching PubMed and China National Knowledge Infrastructure (CNKI), which were published for more than ten years. Animal experiments were conducted at Shanxi University of Taiyuan in China, and toxicological tests were performed according to the stipulated methods and protocols. Review and experimental methods: Data on the risks of incidence of neurological disorders associated with the environmental factor (PM 2.5) and biological factors (intestinal disorders and bacteria) were obtained, and random- or fixed-effects models (depending on the I 2 value) were used to pool the odds ratios (OR) with the 95% confidence intervals (CI) from individual studies. In the animal experiments, mice were divided into four groups of five animals per group, as follows: normal control mice in filtered air, AD mice in filtered air, normal control mice in PM 2.5 air, and AD mice in PM 2.5 air. PM 2.5 mice were exposed to ambient PM 2.5 in a whole-body inhalation exposure device for 8 weeks in Taiyuan, China. Well-established methods were used to explore the toxicological mechanisms by which PM 2.5 exacerbated brain damage in AD mice, namely open-field testing, enzyme-linked immunosorbent assay (ELISA), real-time quantitative RT-PCR, hematoxylin-eosin (HE) staining, and transmission electron microscopy (TEM). Brain damage and related biomarkers in the brains were measured, and miRNA and mRNA profiles were detected using high-throughput sequencing methods. The signaling pathways of miRNAs or mRNAs were predicted and summarized, and specific miRNAs and mRNAs were screened to explore the possible regulatory mechanisms of PM 2.5 -induced brain damage in AD mice. Intestinal and fecal samples from these mice were also subjected to 16S rRNA gene sequencing. HE staining, ELISA, and metagenome bacterial diversity analyses were performed to investigate the effects of PM 2.5 inhalation on intestinal tissue damage, inflammatory responses, and changes of bacterial diversity and communities in AD mice. Results: Long-term PM 2.5 exposure has been associated with increased risks of stroke, dementia, AD, autism spectrum disorder (ASD), and Parkinson's disease (PD) in humans, with the risks of ischemic and hemorrhagic stroke being higher than that of stroke in general. Furthermore, a relatively higher risk of stroke has been observed in heavily polluted countries compared to less polluted countries. It is known that some intestinal disorders and related problems such as constipation, inflammatory bowel disease, irritable bowel syndrome, small intestinal bacterial overgrowth, and diarrhea significantly increase the risks of developing AD or PD. For example, the risk estimates of Helicobacter pylori infection were significantly associated with AD and PD. From another angle, preliminary animal experimental results showed that PM 2.5 promoted brain morphological damage and decreased spatial exploration ability in AD mice, and was concomitant with increases in the concentrations of amyloid-β-42, acetylcholinesterase, tumor necrosis factor-α, and interleukin-6 and decreases in the concentrations of choline acetyltransferase. High-throughput sequencing and bioinformatics analyses revealed that miRNAs and mRNA had differential expression profiles subsequent to PM 2.5 exposure, which suggested that these species are involved in the molecular regulatory mechanisms and possible signal pathways of PM 2.5 -aggravated brain injury in AD mice. These PM 2.5 -aggravated brain injuries were correlated with pathological intestinal injury, inflammatory responses, and changes in bacterial diversity in the intestines and feces of PM 2.5 -exposed AD mice, and decreases in predominant bacteria were identified. These data will assist in delineating the ability of PM 2.5 exposure to induce pathological changes in the brain and gut tissue via the brain-gut axis and thereby aggravate AD. Conclusions: A systematic review and meta-analysis showed that there is a significant association between PM 2.5 exposure and the occurrence of stroke, dementia, AD, ASD, and PD, and a strong association between intestinal disorders and the presence of certain bacteria and the development of AD and PD. PM 2.5 (environmental factors) and intestinal disorders accompanied by changes in bacterial diversity (internal biological factors) appeared to be the two most important factors that increase the risk of developing neurological disorders. Experimental animal data showed that PM 2.5 potently damaged the brain and intestines of AD mice, and that the toxicological mechanisms of this PM 2.5 -mediated brain injury led to morphological changes, inflammation, and perturbation of miRNA/mRNA regulation in the brain. These data suggest that PM 2.5 inhalation also have modulatory effects on the abundance and diversity of intestinal bacteria in AD mice. The findings of this study have clarified positive relationships between environmental and biological factors and neurological disorders and have elucidated the potential mechanisms by which PM 2.5 may mediate the initiation or exacerbation of AD

INTRODUCTION: HIV/AIDS is a global health problem, with Sub-Saharan Africa the most affected. “Neuro-AIDS” refers to the extensive neuropathological manifestations of the disease. Neuroimaging of the HIV-infected individual plays a fundamental role in their work-up. Limited resources, however, drive the development of imaging protocols based on clinical signs. ‘Confusion’ may or may not represent a significant presenting sign and needs to be investigated, as it is the basis of referral of a significant number of patients for CT scanning. AIM: To determine the frequency of positive findings of head CT in HIV-infected adults presenting with confusion with/without associated neurology, and correlate them with the degree of immunosuppression, presence of CSF abnormality and their ARV therapy status. METHOD: CT brain scans of adult patients, who were HIV-positive and presented with confusion in Johannesburg, Gauteng, were retrospectively reviewed. The neurological status, CD4 counts, LP results and their ARV therapy status were documented. RESULTS: 30% of our HIV-infected patients presented with confusion. There were 156 patients who were included. CT scans were abnormal in 81%. We found that ‘associated neurology’ was a weak predictor for abnormal CT, making it a poor screening tool. A positive LP was predictive of infection (p=0.04 for focal infection, p=0.03 for infected surface collection) and infarction (p<0.01) on CT. CD4 count, LP results and ARV therapy were found to be abnormal in the majority of patients. CONCLUSIONS: CT was abnormal in the majority of HIV-infected patients presenting with confusion. Neurology was an unreliable clinical indicator. A positive LP was a good predictor for CT evidence of infection and infarction. The clinical parameters such as CD4 counts, LP results and ARV therapy, were abnormal in the majority of patients. If any of these parameters are abnormal in a patient with a normal CT, we believe this should motivate for further imaging with MRI.