RESUMO
Prolonged exposure to HIV-1 transactivator of transcription (Tat) protein dysregulates monoamine transmission, a physiological change implicated as a key factor in promoting neurocognitive disorders among people living with HIV. We have demonstrated that in vivo expression of Tat in Tat transgenic mice decreases dopamine uptake through both dopamine transporter (DAT) and norepinephrine transporter (NET) in the prefrontal cortex. Further, our novel allosteric inhibitor of monoamine transporters, SRI-32743, has been shown to attenuate Tat-inhibited dopamine transport through DAT and alleviates Tat-potentiated cognitive impairments. The current study reports the pharmacological profiles of SRI-32743 in basal and Tat-induced inhibition of human NET (hNET) function. SRI-32743 exhibited less affinity for hNET binding than desipramine, a classical NET inhibitor, but displayed similar potency for inhibiting hDAT and hNET activity. SRI-32743 concentration-dependently increased hNET affinity for [3H]DA uptake but preserved the Vmax of dopamine transport. SRI-32743 slowed the cocaine-mediated dissociation of [3H]Nisoxetine binding and reduced both [3H]DA and [3H]MPP+ efflux but did not affect d-amphetamine-mediated [3H]DA release through hNET. Finally, we determined that SRI-32743 attenuated a recombinant Tat1-86-induced decrease in [3H]DA uptake via hNET. Our findings demonstrated that SRI-32743 allosterically disrupts the recombinant Tat1-86-hNET interaction, suggesting a potential treatment for HIV-infected individuals with concurrent cocaine abuse.
Assuntos
Cocaína , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Produtos do Gene tat do Vírus da Imunodeficiência Humana , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/química , Cocaína/farmacologia , Cocaína/metabolismo , Humanos , HIV-1/metabolismo , HIV-1/efeitos dos fármacos , Quinazolinas/farmacologia , Quinazolinas/química , Animais , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Ligação Proteica , CamundongosRESUMO
BACKGROUND & AIMS: A recent panel of international experts proposed the disease acronym metabolic (dysfunction)-associated fatty liver disease (MAFLD) in lieu of nonalcoholic fatty liver disease (NAFLD). We aimed to estimate the burden of and risk factors for NAFLD and MAFLD, and to examine the concordance between definitions in a Veterans population. METHODS: We conducted a cross-sectional study among randomly selected patients within primary care at the Houston Veterans Affairs (VA) facility. Participants completed a survey, provided blood, and underwent Fibroscan. In the absence of heavy alcohol, hepatitis C virus and hepatitis B virus, a controlled attenuation parameter median ≥290 dB/m was used to define NAFLD, whereas MAFLD was defined as controlled attenuation parameter median ≥290 dB/m and either body mass index ≥25 kg/m2 or diabetes, or 2 or more of the following: hypertension, high triglycerides, low high-density lipoprotein cholesterol, and high low-density lipoprotein cholesterol. RESULTS: The mean age of participants was 50.9 years, 55.4% were women, 42.8% were white, and 43.8% were Black. The prevalence of NAFLD was 40.6% (82/202). All 82 patients with NAFLD had a body mass index ≥25 kg/m2, and therefore met our criteria for MAFLD (ie, 100% concordance). Compared with patients with no metabolic trait, patients with ≥3 traits had a 48-fold (adjusted odds ratio, 47.6; 95% confidence interval, 11.3-200) higher risk of NAFLD/MAFLD. Overall, 19 participants (9.4% of the total, 15.9% of those with NAFLD) had at least moderate fibrosis. CONCLUSIONS: NAFLD was present in 40% of Veterans registered in primary care; 9.4% of veterans had at least moderate hepatic fibrosis, with most having concurrent NAFLD. There was perfect concordance between NAFLD and the alternative MAFLD definition.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Prevalência , Estudos Transversais , Fatores de Risco , Atenção Primária à SaúdeRESUMO
BACKGROUND: Screening for gastric cancer is not recommended despite rising rates in certain U.S. POPULATIONS: We determined possible missed opportunities for the detection and surveillance of preneoplastic lesions among gastric cancer patients in a VA hospital. METHODS: This retrospective cohort study included consecutive, newly diagnosed non-cardia gastric adenocarcinoma patients from 11/2007 to 10/2018 at the Houston VA Hospital. We identified missed opportunities for screening based on risk factors (non-White race, smoking, alcohol, Helicobacter pylori infection, gastric ulcers, family history of gastric cancer). We additionally determined missed opportunities for surveillance of known high-risk lesions. Associations between receipt of prior endoscopy for screening or surveillance and cancer-related outcomes (stage, treatment, survival) were determined using logistic regression models. RESULTS: Among 91 gastric cancer patients, 95.6% were men, 51.6% were black, 12.1% were Hispanic, with mean age of 68.0 years (standard deviation 10.8 years). The most common risk factors included non-white race (68.1%), smoking (76.9%), alcohol use (59.3%) and prior H. pylori (12.1%). Most patients had ≥ 1 risk factor for gastric cancer (92.6%), and 76.9% had ≥ 2 risk factors. Only 25 patients (27.5%) had undergone endoscopy prior to cancer diagnosis. Of 14 with known high-risk lesions (i.e., gastric intestinal metaplasia, dysplasia, ulcer), only 2 (14.3%) underwent surveillance endoscopy. Receipt of prior endoscopy was not associated with differences in cancer outcomes. CONCLUSIONS: Most patients with newly diagnosed gastric cancer had ≥ 2 known risk factors for gastric cancer but never received prior screening endoscopy. Among the few with known prior preneoplastic lesions, endoscopic surveillance was not consistently performed.
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Adenocarcinoma , Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Masculino , Humanos , Idoso , Feminino , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/patologia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Adenocarcinoma/diagnóstico , Adenocarcinoma/epidemiologia , Adenocarcinoma/complicações , Metaplasia/complicaçõesRESUMO
BACKGROUND & AIMS: Limitations of endoscopic sampling may result in missed dysplasia at the diagnosis of Barrett's esophagus (BE). However, the role of close follow-up endoscopy is unclear. The aim was to evaluate the proportion of patients diagnosed with "missed" dysplasia within 18 months of their index nondysplastic BE (NDBE) diagnosis. METHODS: This was a retrospective analysis of a cohort of BE patients diagnosed during 1990-2019 at the Houston VA. Patients with BE on index esophagogastroduodenoscopy (EGD) were classified as NDBE, indefinite dysplasia, or dysplastic (low- or high-grade dysplasia) based on initial biopsies. We identified NDBE patients who had follow-up EGD within 3-18 months after index EGD. We used logistic regression models to estimate odds ratios and 95% confidence intervals for risk factors of dysplasia on follow-up EGD. RESULTS: We identified 614 patients who had BE on index EGD. Among those with NDBE and follow-up EGD within 3-18 months (n = 271), 4.1% had definite dysplasia on follow-up, and an additional 14.0% had indefinite dysplasia. Proportions of definite or indefinite dysplasia at follow-up within 3-18 months significantly decreased from 32.6% among patients with index EGD before 2009 to 11.7% among patients with index EGD after 2013 (P for trend = .068). Those with any indefinite or definite dysplastic BE at follow-up within 3-18 months after index EGD (n = 49) were more likely to have BE length ≥3 cm on index EGD (odds ratio, 3.39; 95% confidence interval, 1.63-7.08) than those with persistent NDBE or no BE on follow-up. CONCLUSIONS: The occurrence of missed dysplasia on an index EGD has decreased over time. However, those with long segment BE were more than 3 times as likely to have missed dysplasia, and this group could benefit from dysplasia surveillance within 18 months of BE diagnosis.
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Adenocarcinoma , Esôfago de Barrett , Neoplasias Esofágicas , Veteranos , Adenocarcinoma/patologia , Esôfago de Barrett/diagnóstico , Esôfago de Barrett/epidemiologia , Esôfago de Barrett/patologia , Progressão da Doença , Endoscopia Gastrointestinal , Neoplasias Esofágicas/diagnóstico , Humanos , Prevalência , Estudos RetrospectivosRESUMO
INTRODUCTION: Several US subgroups have increased risk of gastric cancer and gastric intestinal metaplasia (GIM) and may benefit from targeted screening. We evaluated demographic and clinical risk factors for GIM and examined the interaction between race/ethnicity and birthplace on GIM risk. METHODS: We identified patients who had undergone esophagogastroduodenoscopy with gastric biopsy from 3/2006-11/2016 using the pathology database at a safety net hospital in Houston, Texas. Cases had GIM on ≥1 gastric biopsy histopathology, whereas controls lacked GIM on any biopsy. We estimated odds ratios and 95% confidence intervals (CI) for associations with GIM risk using logistic regression and developed a risk prediction model of GIM risk. We additionally examined for associations using a composite variable combining race/ethnicity and birthplace. RESULTS: Among 267 cases with GIM and 1,842 controls, older age (vs <40 years: 40-60 years adjusted odds ratios (adjORs) 2.02; 95% CI 1.17-3.29; >60 years adjOR 4.58; 95% CI 2.61-8.03), Black race (vs non-Hispanic White: adjOR 2.17; 95% CI 1.31-3.62), Asian race (adjOR 2.83; 95% CI 1.27-6.29), and current smoking status (adjOR 2.04; 95% CI 1.39-3.00) were independently associated with increased GIM risk. Although non-US-born Hispanics had higher risk of GIM (vs non-Hispanic White: adjOR 2.10; 95% CI 1.28-3.45), we found no elevated risk for US-born Hispanics (adjOR 1.13; 95% CI 0.57-2.23). The risk prediction model had area under the receiver operating characteristic of 0.673 (95% CI 0.636-0.710) for discriminating GIM. DISCUSSION: We found that Hispanics born outside the United States were at increased risk of GIM, whereas Hispanics born in the United States were not, independent of Helicobacter pylori infection. Birthplace may be more informative than race/ethnicity when determining GIM risk among US populations.
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Entorno do Parto/estatística & dados numéricos , Etnicidade , Vigilância da População , Lesões Pré-Cancerosas , Grupos Raciais , Neoplasias Gástricas/etnologia , Estômago/patologia , Adulto , Biópsia , Estudos Transversais , Humanos , Incidência , Metaplasia/etnologia , Metaplasia/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Estômago/microbiologia , Neoplasias Gástricas/diagnóstico , Texas/epidemiologiaRESUMO
BACKGROUND AND AIMS: Risk of esophageal adenocarcinoma (EAC) in those with Barrett's esophagus (BE) is 11-fold greater than the general population. It remains unclear which BE patients are at highest risk of progression to EAC. We aimed to validate a predictive model risk-stratifying BE patients. METHODS: We conducted a retrospective cohort study at the Houston Veteran Affairs Medical Center of consecutive patients with a new diagnosis of BE from November 1990 to January 2019. Study follow-up was through February 2020. Patients were excluded if they had no follow-up EGD with esophageal biopsy sampling after the initial BE-diagnosing EGD or evidence of high-grade dysplasia (HGD) or EAC on initial EGD. We performed an external validation study of a risk model containing sex, smoking, BE length, and low-grade dysplasia (LGD) status and assessed discriminatory ability using the area under the receiver operating characteristic curve (AUROC). RESULTS: Among 608 BE patients, 24 progressed to HGD/EAC. The points-based model discriminated well with an AUROC of .72 (95% confidence interval [CI], .63-.82). When categorized into low-, intermediate-, and high-risk groups according to published cutoffs, the AUROC was poor at .57. Restructured into low-risk versus high-risk groups, the AUROC was .72 (95% CI, .64-.80). Excluding baseline LGD did not reduce discriminatory ability (AUROC, .73; 95% CI, .64-.82). CONCLUSIONS: This external validation provides further evidence that the model including sex, LGD status, smoking status, and BE length may help to risk stratify BE patients. A simplified version excluding LGD status and/or reducing the number of risk groups has increased utility in clinical practice without loss of discriminatory ability.
Assuntos
Esôfago de Barrett , Neoplasias Esofágicas , Lesões Pré-Cancerosas , Veteranos , Adenocarcinoma , Esôfago de Barrett/patologia , Progressão da Doença , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/etiologia , Humanos , Hiperplasia , Lesões Pré-Cancerosas/patologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND/AIMS: Screening for gastric intestinal metaplasia (GIM) may lead to early gastric cancer detection. We developed and validated a pre-endoscopy risk prediction model for detection of GIM based on patient-level risk factors in a U.S. METHODS: We used data from 423 GIM cases and 1796 controls from a cross-sectional study among primary care and endoscopy clinic patients at the Houston VA. We developed the model using backwards stepwise regression and assessed discrimination using area under the receiver operating characteristic (AUROC). The model was internally validated using cross-validation and bootstrapping. The final expanded model was compared to a model including H. pylori infection alone and a baseline model including remaining terms without H. pylori. RESULTS: Male sex, older age, non-white race/ethnicity, smoking status, and H. pylori were associated with GIM risk. The expanded model including these terms had AUROC 0.73 (95%CI 0.71-0.76) for predicting GIM and AUROC 0.82 (95%CI 0.79-0.86) for extensive GIM. This model discriminated better than a model including only H. pylori (AUROC 0.66; 95%CI 0.63-0.68) and the baseline model (AUROC 0.67; 95%CI 0.64-0.70). The expanded model performed similarly among primary care (AUROC 0.75) and endoscopy (AUROC 0.73) patients. The expanded model showed sufficient internal validity (cross-validation AUROC 0.72) with little evidence of over-fitting. CONCLUSIONS: We develop and validate a non-invasive risk model for GIM detection in a U.S. population that included terms for sex, age, race/ethnicity, smoking status, and H. pylori infection. Validated risk models would identify individuals with GIM who should be referred for endoscopic screening.
Assuntos
Infecções por Helicobacter , Helicobacter pylori , Lesões Pré-Cancerosas , Neoplasias Gástricas , Estudos Transversais , Demografia , Endoscopia Gastrointestinal , Infecções por Helicobacter/complicações , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/epidemiologia , Humanos , Masculino , Metaplasia/complicações , Metaplasia/epidemiologia , Fatores de Risco , Neoplasias Gástricas/epidemiologiaRESUMO
Venezuelan equine encephalitis virus (VEEV) is a reemerging alphavirus that can cause encephalitis resulting in severe human morbidity and mortality. Using a high-throughput cell-based screen, we identified a quinolinone compound that protected against VEEV-induced cytopathic effects. Analysis of viral replication in cells identified several quinolinone compounds with potent inhibitory activity against vaccine and virulent strains of VEEV. These quinolinones also displayed inhibitory activity against additional alphaviruses, such as Mayaro virus and Ross River virus, although the potency was greatly reduced. Time-of-addition studies indicated that these compounds inhibit the early-to-mid stage of viral replication. Deep sequencing and reverse genetics studies identified two unique resistance mutations in the nsP2 gene (Y102S/C; stalk domain) that conferred VEEV resistance on this chemical series. Moreover, introduction of a K102Y mutation into the nsP2 gene enhanced the sensitivity of chikungunya virus (CHIKV) to this chemical series. Computational modeling of CHIKV and VEEV nsP2 identified a highly probable docking alignment for the quinolinone compounds that require a tyrosine residue at position 102 within the helicase stalk domain. These studies identified a class of compounds with antiviral activity against VEEV and other alphaviruses and provide further evidence that therapeutics targeting nsP2 may be useful against alphavirus infection.
Assuntos
Vírus Chikungunya , Vírus da Encefalite Equina Venezuelana , Quinolonas , Animais , Antivirais/farmacologia , Vírus da Encefalite Equina Venezuelana/genética , Cavalos , Humanos , Quinolonas/farmacologia , Replicação ViralRESUMO
BACKGROUND & AIMS: There is a need to identify individuals with gastric intestinal metaplasia, a precursor to gastric cancer, so they can be offered screening and surveillance. We examined the prevalence of gastric intestinal metaplasia, detected by upper endoscopy biopsy analysis, in different race and ethnic subgroups. We also investigated the extent to which Helicobacter pylori infection, with or without acute and chronic gastritis, accounts for observed associations between race or ethnicity and risk of gastric intestinal metaplasia. METHODS: We used data from a cross-sectional study of consecutively recruited patients at the Michael E. DeBakey Veterans Affairs Medical Center in Houston, Texas, from February 2008 to August 2013. All participants completed a study questionnaire on sociodemographic and clinical characteristics and underwent upper endoscopy with gastric mapping (7 biopsy sites). Cases were classified as having gastric intestinal metaplasia if intestinal metaplasia was detected in 1 or more noncardia gastric biopsies; noncases were participants without evidence of gastric intestinal metaplasia. We used logistic regression models to estimate odds ratios (ORs) and 95% CI values to examine the association between race or ethnicity and gastric intestinal metaplasia and performed a mediation analysis to determine whether H pylori and gastritis affected observed associations. RESULTS: We included 415 cases with gastric intestinal metaplasia and 1764 noncases. The prevalence of gastric intestinal metaplasia was highest among Hispanic patients (29.5%; 95% CI, 23.7%-36.1%), followed by African American (25.5%; 95% CI, 22.4%-28.9%) and non-Hispanic white patients (13.7%; 95% CI, 11.9%-15.7%). After we adjusted for age, sex, and smoking, African American (OR, 1.87; 95% CI, 1.44-2.44) and Hispanic race or ethnicity (OR, 2.32; 95% CI, 1.61-3.34) and H pylori infection (OR, 3.65; 95% CI, 2.79-4.55) were associated with an increased risk of gastric intestinal metaplasia. H pylori infection alone accounted for 33.6% of the association of race or ethnicity with gastric intestinal metaplasia, and 55.5% of the association when combined with acute and chronic gastritis. CONCLUSIONS: Hispanic and African American patients have an increased risk for gastric intestinal metaplasia, determined by upper endoscopy biopsy analysis, compared with non-Hispanic white patients. This increase in risk was partially independent of H pylori infection.
Assuntos
Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Veteranos , Estudos Transversais , Mucosa Gástrica , Infecções por Helicobacter/complicações , Infecções por Helicobacter/epidemiologia , Humanos , Metaplasia , Prevalência , Fatores de RiscoRESUMO
BACKGROUND AND AIMS: Less than 10% of patients diagnosed with esophageal adenocarcinoma have a pre-existing Barrett's esophagus (BE) diagnosis, possibly because of suboptimal performance of guidelines. We examined the prevalence of BE in a previously unscreened primary care population and the potential yield of practice BE screening guidelines. METHODS: This was a retrospective analysis of a prospective cross-sectional study of consecutively recruited unreferred patients from primary care clinics who underwent study upper endoscopy. We examined the performance of BE screening guidelines of the European Society of Gastrointestinal Endoscopy (ESGE), British Society of Gastroenterology (BSG), American Society for Gastrointestinal Endoscopy (ASGE), American College of Gastroenterology (ACG), American Gastroenterological Association (AGA), and our own modification of guidelines. RESULTS: We identified 44 BE cases and 469 control subjects (prevalence, 8.6%). Among 371 patients without GERD symptoms, 25 (6.7%) had BE. The AGA guidelines requiring ≥2 BE risk factors had sensitivity of 100% and specificity of only .2%, whereas ACG, ASGE, ESGE, and BSG guidelines (all requiring GERD first) had low sensitivities (38.6%-43.2%), specificities ranging from 67.4% to 76.5%, and area under the receiver operating curve (AUROC) of .50 to .60. Our 2-pronged approach depending on presence or absence of GERD symptoms but with other risk factors achieved sensitivity of 81.8%, specificity of 51.2%, and AUROC of .66. CONCLUSIONS: Over half of BE cases were without frequent GERD symptoms, but virtually all had at least 1 known BE risk factor. Practice guidelines requiring GERD symptoms have low sensitivity, whereas those not requiring GERD have low specificity. We have proposed a screening guideline with better use of known risk factors.
Assuntos
Esôfago de Barrett , Refluxo Gastroesofágico , Veteranos , Esôfago de Barrett/diagnóstico , Esôfago de Barrett/epidemiologia , Estudos Transversais , Refluxo Gastroesofágico/diagnóstico , Refluxo Gastroesofágico/epidemiologia , Humanos , Prevalência , Atenção Primária à Saúde , Estudos Prospectivos , Estudos Retrospectivos , Fatores de RiscoRESUMO
PURPOSE OF REVIEW: Low anterior resection syndrome is a highly prevalent condition that can develop after anal sphincter-sparing surgery for rectal cancer and impair quality of life. In this review, we summarize the major features and pathophysiology of this syndrome and discuss treatment approaches. RECENT FINDINGS: Quality of life correlates significantly with severity of low anterior resection syndrome. Prompt assessment and initiation of therapy are essential to rehabilitating damaged mechanical and neural structures. Anorectal manometry demonstrates a global decrease in sphincteric function postoperatively, though in many patients, function does recover. Transanal irrigation, pelvic floor rehabilitation, and biofeedback are the mainstays of the treatment of major LARS. Definitive stoma can be considered in therapy refractory LARS > 2 years. The development of low anterior resection syndrome likely involves an interplay between mechanical and neural pathways. Clinically, patients present at varying levels of severity, and scoring systems are available to help assess patient symptoms and guide therapy. Treatment approaches range from conservative therapies to biofeedback and sacral nerve stimulation. Future randomized controlled trials aimed at risk stratification of patients and development of severity-based treatment algorithms are warranted.
Assuntos
Constipação Intestinal/terapia , Incontinência Fecal/terapia , Neoplasias Retais/cirurgia , Canal Anal , Biorretroalimentação Psicológica , Constipação Intestinal/etiologia , Dieta , Incontinência Fecal/etiologia , Humanos , Manometria , Tratamentos com Preservação do Órgão/efeitos adversos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/terapia , Qualidade de Vida , Neoplasias Retais/terapia , Fatores de Risco , Síndrome , Irrigação TerapêuticaRESUMO
BACKGROUND: Helicobacter pylori infection is an established causal factor for non-cardia gastric cancer. H. pylori negative gastric cancer prevalence among US patients is unclear. METHODS: This retrospective cohort study examined H. pylori prevalence among consecutive patients with incident non-cardia gastric adenocarcinoma at the Houston VA Hospital (11/2007-10/2018). H. pylori positivity was defined by H. pylori on histopathology, positive antibody serology, stool antigen, or urea breath testing. We examined for trends in H. pylori negative gastric cancer based on year of diagnosis. Associations between histopathologic and cancer-related outcomes with H. pylori positivity were determined using regression models. RESULTS: Of 91 patients with gastric adenocarcinoma, most were men (N = 87, 95.6%), black (N = 47, 51.6%), with mean age at diagnosis of 68.0 years (SD 10.8). In addition to gastric cancer biopsy histopathology, 74 patients (81.3%) had ≥ 1 testing for H. pylori, including antibody serology (n = 34), non-cancer gastric biopsy histopathology (n = 63), or stool antigen (n = 1). The overall prevalence of H. pylori infection was 38.5% and 45.9% among patients with ≥ 2 H. pylori tests. The proportions of H. pylori positive gastric cancer decreased from 50.0% (2007-2010) to 43.4% (2011-2014) and 29.3% (2015-2018) (p = 0.096). Active/acute gastritis (adjOR 3.74), atrophic gastritis (adjOR 15.30), and gastric intestinal metaplasia (adjOR 3.65) were associated with H. pylori positive gastric cancer. DISCUSSION: The prevalence of H. pylori infection among patients with non-cardia gastric adenocarcinoma is relatively low (38.5-45.9%) and decreasing over time. This finding suggests there may be other important causal factors apart from H. pylori for gastric adenocarcinoma.
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Adenocarcinoma/microbiologia , Gastrite/complicações , Infecções por Helicobacter/complicações , Helicobacter pylori , Neoplasias Gástricas/microbiologia , Adenocarcinoma/epidemiologia , Idoso , Feminino , Gastrite/epidemiologia , Infecções por Helicobacter/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Neoplasias Gástricas/epidemiologia , Estados Unidos/epidemiologiaRESUMO
The synthesis of fused N-arylindolines using visible light photoredox catalysis has been developed. We previously described that photogenerated amine radical cations generate substituted indoles through an intermediate benzylic carbocation. Herein, we expand the application of this chemistry by trapping the benzylic carbocation with tethered heteronucleophiles. The reactivity of the photogenerated benzylic carbocation is explored and applied to a range of substrates with various electronic characters and ring constraints. The method described provides C2 and C3 fused indolines bearing a tetrasubstituted carbon stereocenter with greater than 99:1 diastereoselectivity in moderate to good yields.
RESUMO
OBJECTIVES: Esophageal adenocarcinoma is more common among non-Hispanic Whites (NHWs) than African Americans (AAs). It is unclear whether its precursor, Barrett's esophagus (BE), is also less common among AAs, and whether differences in risk factor profiles explain the racial disparity. METHODS: Data were from a case-control study among eligible Veterans Affairs patients scheduled for an upper endoscopy, and a sample identified from primary care clinics. Participants completed a questionnaire on sociodemographic and clinical factors and underwent a study esophagogastroduodenoscopy. We calculated race-specific BE prevalence rates and used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for BE. RESULTS: There were 301 BE cases and 1,651 controls. BE prevalence was significantly higher among NHWs than AAs (21.3 vs. 5.0%; P<0.001). NHWs were more likely than AAs to be male, have a high waist-to-hip ratio (WHR), hiatal hernia, and use proton-pump inhibitors (PPIs), but less likely to have Helicobacter pylori (P<0.001). Among cases, NHWs were more likely to have long-segment BE and dysplasia than AAs. Independent BE risk factors for AAs included a hiatus hernia ≥3 cm (OR 4.12; 95% CI, 1.57-10.81) and a history of gastroesophageal reflux disease or PPI use (OR, 3.70; 95% CI, 1.40-9.78), whereas high WHR (OR, 2.82; 95% CI, 1.41-5.63), hiatus hernia ≥3 cm (OR, 4.95; 95% CI, 3.05-8.03), PPI use (OR, 1.88; 95% CI, 1.33-2.66), and H. pylori (OR, 0.64; 95% CI, 0.41-0.99) were statistically significantly associated with BE risk for NHWs. Among all cases and controls, race was a risk factor for BE, independent of other BE risk factors (OR for AAs, 0.26; 95% CI, 0.17-0.38). CONCLUSIONS: Among veterans, the prevalence of BE was lower in AAs compared with NHWs. This disparity was not accounted for by differences in risk estimates or prevalence of risk factors between NHWs and AAs.
Assuntos
Esôfago de Barrett/etnologia , Negro ou Afro-Americano/estatística & dados numéricos , Refluxo Gastroesofágico/etnologia , Infecções por Helicobacter/etnologia , Hérnia Hiatal/etnologia , Sobrepeso/etnologia , Lesões Pré-Cancerosas/etnologia , População Branca/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Esôfago de Barrett/epidemiologia , Esôfago de Barrett/patologia , Endoscopia do Sistema Digestório , Feminino , Refluxo Gastroesofágico/tratamento farmacológico , Refluxo Gastroesofágico/epidemiologia , Infecções por Helicobacter/epidemiologia , Helicobacter pylori , Hérnia Hiatal/epidemiologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Sobrepeso/epidemiologia , Lesões Pré-Cancerosas/epidemiologia , Lesões Pré-Cancerosas/patologia , Inibidores da Bomba de Prótons/uso terapêutico , Fatores de Risco , Fatores Sexuais , Fumar/epidemiologia , Fumar/etnologia , Estados Unidos/epidemiologia , Veteranos/estatística & dados numéricos , Relação Cintura-Quadril/estatística & dados numéricosRESUMO
One-step synthesis of carbocycles substituted with amines from simple starting materials remains rare. We recently developed intermolecular [3+2] annulation of cyclopropylanilines with alkenes and alkynes that enable this one-step synthesis. Herein, we report our findings for a fullscale study of the annulation. Significant expansion of the substrate scope for both cyclopropylanilines and alkynes is achieved. A range of structurally diverse carbocycles substituted with amines is prepared.
RESUMO
Intermolecular [3 + 2] annulation of cyclopropylanilines with alkynes is realized using visible light photoredox catalysis, yielding a variety of cyclic allylic amines in fair to good yields. This method exhibits significant group tolerance particularly with heterocycles. It can also be used to prepare complex heterocycles such as fused indolines.
RESUMO
Amine radical cations are highly useful reactive intermediates in amine synthesis. They have displayed several modes of reactivity leading to some highly sought-after synthetic intermediates including iminium ions, α-amino radicals, and distonic ions. One appealing method to access amine radical cations is through one-electron oxidation of the corresponding amines under visible light photoredox conditions. This approach and subsequent chemistries are emerging as a powerful tool in amine synthesis. This article reviews synthetic applications of amine radical cations produced by visible light photocatalysis.
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Veterans with difficult-to-diagnose conditions who receive care in the Department of Veterans Affairs (VA) healthcare system can be referred for evaluation at one of three specialty VA War-Related Illness and Injury Study Centers (WRIISC). Veterans of the 1990−1991 Gulf War have long experienced excess rates of chronic symptoms associated with the condition known as Gulf War Illness (GWI), with hundreds evaluated at the WRIISC. Here we provide the first report from a cohort of 608 Gulf War Veterans seen at the WRIISC who completed questionnaires on chronic symptoms (>6 months) consistent with GWI as well as prominent exposures during Gulf War deployment. These included veterans' reports of hearing chemical alarms/donning Military-Ordered Protective Posture Level 4 (MOPP4) gear, pesticide use, and use of pyridostigmine bromide (PB) pills as prophylaxis against the effects of nerve agents. Overall, veterans in the cohort were highly symptomatic and reported a high degree of exposures. In multivariable models, these exposures were significantly associated with moderate-to-severe chronic symptoms in neurocognitive/mood, fatigue/sleep, and pain domains. Specifically, exposure to pesticides was associated with problems with concentration and memory, problems sleeping, unrefreshing sleep, and joint pain. Use of MOPP4 was associated with light sensitivity and unrefreshing sleep and use of PB was associated with depression. We also evaluated the association of exposures with symptom summary scores based on veterans' severity of symptoms in four domains and overall. In multivariable modeling, the pain symptom severity score was significantly associated with pesticide use (Odds ratio (OR): 4.13, 95% confidence intervals (CI): 1.78−9.57) and taking PB pills (OR: 2.28, 95% CI: 1.02−5.09), and overall symptom severity was significantly associated with use of PB pills (OR: 2.41, 95% CI: 1.01−5.75). Conclusion: Decades after deployment, Gulf War veterans referred to a VA tertiary evaluation center report a high burden of chronic symptoms, many of which were associated with reported neurotoxicant exposures during the war.
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Cocaine abuse increases the incidence of HIV-1-associated neurocognitive disorders. We have demonstrated that HIV-1 transactivator of transcription (Tat) allosterically modulates dopamine (DA) reuptake through the human DA transporter (hDAT), potentially contributing to Tat-induced cognitive impairment and potentiation of cocaine conditioned place preference (CPP). This study determined the effects of a novel allosteric modulator of DAT, SRI-32743, on the interactions of HIV-1 Tat, DA, cocaine, and [3H]WIN35,428 with hDAT in vitro. SRI-32743 (50 nM) attenuated Tat-induced inhibition of [3H]DA uptake and decreased the cocaine-mediated dissociation of [3H]WIN35,428 binding in CHO cells expressing hDAT, suggesting a SRI-32743-mediated allosteric modulation of the Tat-DAT interaction. In further in vivo studies utilizing doxycycline-inducible Tat transgenic (iTat-tg) mice, 14 days of Tat expression significantly reduced the recognition index by 31.7% in the final phase of novel object recognition (NOR) and potentiated cocaine-CPP 2.7-fold compared to responses of vehicle-treated control iTat-tg mice. The Tat-induced NOR deficits and potentiation of cocaine-CPP were not observed in saline-treated iTat-tg or doxycycline-treated G-tg (Tat-null) mice. Systemic administration (i.p.) of SRI-32743 prior to behavioral testing ameliorated Tat-induced impairment of NOR (at a dose of 10 mg/kg) and the Tat-induced potentiation of cocaine-CPP (at doses of 1 or 10 mg/kg). These findings demonstrate that Tat and cocaine interactions with DAT may be regulated by compounds interacting at the DAT allosteric modulatory sites, suggesting a potential therapeutic intervention for HIV-infected patients with concurrent cocaine abuse.
Assuntos
Transtornos Relacionados ao Uso de Cocaína , Cocaína , HIV-1 , Animais , Cocaína/metabolismo , Cocaína/farmacologia , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Cricetinae , Cricetulus , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Doxiciclina , Humanos , Camundongos , Camundongos Transgênicos , Recompensa , Transativadores , Fator de Transcrição DP1/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genéticaRESUMO
In the United States, the incidence of gastric cancer has decreased over the past five decades. However, despite overall decreasing trends in incidence rates of gastric cancer, rates of noncardia gastric cancer among adults aged less than 50 years in the United States are increasing, and most cases of gastric cancer still present with advanced disease and poor resultant survival. Epidemiologic studies have identified the main risk factors for gastric cancer, including increasing age, male sex, non-White race, Helicobacter pylori infection, and smoking. This article summarizes the current epidemiologic evidence with implications for primary and secondary prevention of gastric cancer.