Prospective assessment of disease-specific quality of life in adults with eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is an important cause of upper gastrointestinal dysfunction in children and adults. The EoE-quality of life (QOL)-A was validated as a disease-specific measure of quality of life in EoE. This study characterized the extent of QOL concerns in a cohort of adult EoE patients and delineated the relationships between QOL and other disease activity measures. One hundred sixty-seven patients enrolled in this prospective cohort study. Patients with established and suspected EoE undergoing endoscopy at a single university-based medical center were recruited. EoE was diagnosed on the basis of the clinical criteria and histologic demonstration of ≥15 eos/hpf while on proton pump inhibition therapy. Sixty five patients undergoing repeat endoscopy during the enrollment period participated twice. Patients provided demographic information and completed symptom assessments and the EoE-QOL-A. Analyses included comparisons with overall QOL as well as QOL subscales. Outcome measures included endoscopic activity using a validated instrument, the EoE Endoscopic Reference Score, and histology. Overall QOL was significantly correlated with dysphagia frequency, intensity, and severity (P < 0.001). Patients who experienced a food impaction in the last 30 days had significantly worse overall QOL (P = 0.009). There was no correlation between overall QOL and years since diagnosis, symptom duration, endoscopic features, or histologic findings. Patient symptoms correlated with endoscopic features of edema, rings, and stricture severity. Histologic activity was highly correlated with severity of endoscopic features. Patients who underwent repeat endoscopy with histologic response demonstrated improved eating and social QOL; however, overall QOL was unchanged. In adults with EoE, patient reported QOL is associated with symptom severity but not endoscopic or histologic features. Disease-specific QOL may complement parameters of biologic activity in the assessment of overall disease burden in EoE.

Systematic review: methodological flaws in racial/ethnic reporting for gastroesophageal reflux disease.

Health care disparities affecting the care of multiple disease groups are of growing concern internationally. Research guidelines, governmental institutions, and scientific journals have attempted to minimize disparities through policies regarding the collection and reporting of racial/ethnic data. One area where shortcomings remain is in gastroesophageal reflux disease (GERD). This systematic review, which adheres to the PRISMA statement, focuses on characterizing existing methodological weaknesses in research focusing on studies regarding the assessment, prevalence, treatment, and outcomes of GERD patients. Search terms included GERD and typical symptoms of GERD in ethnic groups or minorities. We reviewed 62 articles. The majority of studies did not report the race/ethnicity of all participants, and among those who did, very few followed accepted guidelines. While there were diverse participants, there was also diversity in the manner in which groups were labeled, making comparisons difficult. There appeared to be a disparity with respect to countries reporting race/ethnicity, with certain countries more likely to report this variable. Samples overwhelmingly consisted of the study country's majority population. The majority of studies justified the use of race/ethnicity as a study variable and investigated conceptually related factors such as socioeconomic status and environment. Yet, many studies wrote as if race/ethnicity reflected biological differences. Despite recommendations, it appears that GERD researchers around the world struggle with the appropriate and standard way to include, collect, report, and discuss race/ethnicity. Recommendations on ways to address these issues are included with the goal of preventing and identifying health care disparities.

Analysis of variants and mutations in the human winged helix FOXA3 gene and associations with metabolic traits.

BACKGROUND/OBJECTIVES: The forkhead factor Foxa3 is involved in the early transcriptional events controlling adipocyte differentiation and plays a critical function in fat depot expansion in response to high-fat diet regimens and during aging in mice. No studies to date have assessed the potential associations of genetic variants in FOXA3 with human metabolic outcomes. SUBJECTS/METHODS: In this study, we sequenced FOXA3 in 392 children, adolescents and young adults selected from several cohorts of subjects recruited at the National Institute of Child Health and Human Development of the National Institutes of Health based on the availability of dual-energy X-ray absorptiometry data, magnetic resonance imaging scans and DNA samples. We assessed the association between variants present in these subjects and metabolic traits and performed in vitro functional analysis of two novel FOXA3 missense mutations identified. RESULTS: Our analysis identified 14 novel variants and showed that the common single-nucleotide polymorphism (SNP) rs28666870 is significantly associated with greater body mass index, lean body mass and appendicular lean mass (P values 0.009, 0.010 and 0.013 respectively). In vitro functional studies showed increased adipogenic function for the FOXA3 missense mutations c.185C>T (p.Ser62Leu) and c.731C>T (p.Ala244Val) compared with FOXA3-WT. CONCLUSIONS: Our study identified novel FOXA3 variants and mutations, assessed the adipogenic capacity of two novel missense alterations in vitro and demonstrated for the first time the associations between FOXA3 SNP rs28666870 with metabolic phenotypes in humans.

Effect of propofol on the medial temporal lobe emotional memory system: a functional magnetic resonance imaging study in human subjects.

BACKGROUND: Subclinical doses of propofol produce anterograde amnesia, characterized by an early failure of memory consolidation. It is unknown how propofol affects the amygdala-dependent emotional memory system, which modulates consolidation in the hippocampus in response to emotional arousal and neurohumoral stress. We present an event-related functional magnetic resonance imaging study of the effects of propofol on the emotional memory system in human subjects. METHODS: Thirty-five healthy subjects were randomized to receive propofol, at an estimated brain concentration of 0.90 µg ml(-1), or placebo. During drug infusion, emotionally arousing and neutral images were presented in a continuous recognition task, while blood-oxygen-level-dependent activation responses were acquired. After a drug-free interval of 2 h, subsequent memory for successfully encoded items was assessed. Imaging analysis was performed using statistical parametric mapping and behavioural analysis using signal detection models. RESULTS: Propofol had no effect on the stereotypical amygdalar response to emotional arousal, but caused marked suppression of the hippocampal response. Propofol caused memory performance to become uncoupled from amygdalar activation, but it remained correlated with activation in the posterior hippocampus, which decreased in proportion to amnesia. CONCLUSIONS: Propofol is relatively ineffective at suppressing amygdalar activation at sedative doses, but abolishes emotional modulation and causes amnesia via mechanisms that commonly involve hyporesponsiveness of the hippocampus. These findings raise the possibility that amygdala-dependent fear systems may remain intact even when a patient has diminished memory of events. This may be of clinical importance in the perioperative development of fear-based psychopathologies, such as post-traumatic stress disorder. CLINICAL TRIAL REGISTRATION: NCT00504894.

Children's binge eating and development of metabolic syndrome.

BACKGROUND: Binge eating predisposes children to excessive weight gain. However, it is unknown if pediatric binge eating predicts other obesity-associated adverse health outcomes. OBJECTIVE: The objective of this study was to investigate the relationship between binge eating and metabolic syndrome (MetS) in children. METHOD: Children aged 5-12 years at high risk for adult obesity, either because they were overweight/obese when first examined or because their parents were overweight/obese, were recruited from Washington, DC and its suburbs. Children completed a questionnaire assessment of binge eating at baseline and underwent measurements of MetS components at baseline and at a follow-up visit approximately 5 years later. Magnetic resonance imaging was used to measure the visceral adipose tissue (VAT) in a subset. RESULTS: In all, 180 children were studied between July 1996 and August 2010. Baseline self-reported binge eating presence was associated with a 5.33 greater odds of having MetS at follow-up (95% confidence interval (CI): 1.47, 19.27, P=0.01). The association between binge eating and body mass index (BMI) only partially explained changes in MetS components: baseline binge eating predicted higher follow-up triglycerides, even after accounting for baseline triglycerides, baseline BMI, BMI change, sex, race, baseline age and time in study (P = 0.05). Also, adjusting for baseline VAT and demographics, baseline binge eating predicted greater follow-up L(2-3) VAT (P = 0.01). DISCUSSION: Children's reports of binge eating predicted development of MetS, worsening triglycerides and increased VAT. The excessive weight gain associated with children's binge eating partly explained its adverse metabolic health outcomes. Reported binge eating may represent an early behavioral marker upon which to focus interventions for obesity and MetS.

Quantitative SPECT/CT parameters of myocardial 99mTechnetium-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) uptake in suspected cardiac transthyretin amyloidosis.

BACKGROUND: 99mTc-labelled bisphosphonates are used for imaging assessment of patients with transthyretin cardiac amyloidosis (ATTR). Present study evaluates whether quantitative SPECT/CT measurement of absolute myocardial 99mTc-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (Tc-DPD) uptake can diagnose patients with suspected ATTR. METHODS: Twenty-eight patients (25 male, age 80.03 ± 6.99 years) with suspected ATTR referred for Tc-DPD imaging had planar and SPECT/CT imaging of the chest. Three operators independently obtained Tc-DPD myocardial SUVmax and SUVmean above threshold (SMaT) (20, 40 and 60% of SUVmax), using a semi-automated threshold segmentation method. Results were compared to visual grading (0-3) of cardiac uptake. RESULTS: Twenty-two patients (78%) had cardiac uptake (2 grade 1, 15 grade 2, 5 grade 3). SUVmax and SMaT segmentation thresholds enabled separating grades 2/3 from 0/1 with excellent inter- and intra-reader correlation. Cut-off values 6.0, 2.5, 3 and 4 for SUVmax, SMaT20,40,60, respectively, separated between grades 2/3 and 0 /1 with PPV and NPV of 100%. SMaT20,40,60(cardiac)/SUVmean (liver) and SMaT20,40,60(cardiac)/SUVmean(liver/lung) separated grades 2 and 3. CONCLUSION: Quantitative SPECT/CT parameters of cardiac Tc-DPD uptake are robust, enabling separation of patients with grades 2 and 3 cardiac uptake from grades 0 and 1. Larger patient cohorts will determine the incremental value of SPECT/CT quantification for ATTR management.

Axon reflexes evoked by transient receptor potential vanilloid 1 activation are mediated by tetrodotoxin-resistant voltage-gated Na+ channels in intestinal afferent nerves.

Capsaicin-sensitive nerves mediate axon vasodilator reflexes in the intestine, but the ion channels underlying action potential (AP) propagation are poorly understood. To examine the role of voltage-gated Na(+) channels underlying these reflexes, we measured vasomotor and electrophysiological responses elicited by capsaicin in guinea pig and mouse dorsal root ganglia (DRG) neurons, submucosal arterioles, and mesenteric arteries in vitro. Transient receptor potential vanilloid 1 (TRPV1) agonists dilated guinea pig ileal submucosal arterioles and were blocked by capsazepine and ruthenium red. In double-chamber baths, capsaicin-evoked activation of TRPV1 on proximal perivascular nerves in the left chamber evoked dilations of the distal segment of the submucosal arteriole in the right chamber. Dilations were tetrodotoxin (TTX) (1 microM)-resistant, but reducing extracellular Na(+) (10% solution) or applying the Na(v) 1.8 antagonist A-803467 [5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide] (1 microM) in the proximal chamber blocked capsaicin-evoked dilations in the distal chamber (88%; P = 0.01 and 75% and P < 0.02, respectively). In mouse mesenteric arteries, electrical field stimulation and capsaicin (2 microM) evoked dilations that were also TTX-resistant. In perforated patch-clamp recordings, APs in mouse and guinea pig capsaicin-sensitive DRG neurons were TTX-resistant but blocked by 10% extracellular Na(+). When capsaicin-evoked AP conduction was studied in in vitro ileal multiunit afferent nerve preparations, capsaicin responses were elicited in the presence of TTX, whereas distention-evoked responses were almost completely blocked by TTX. Together, these data provide evidence for TTX-resistant AP conduction in extrinsic sensory neurons that innervate guinea pig and mouse intestine and suggest this neural propagation is sufficient to mediate axon reflexes in the intestine.

Contraceptives and dysplasia: higher rate for pill choosers.

Among women choosing the pill in preference to other contraceptive methods there is a higher rate of the cancer precursor, dysplasia of the cervix, before any possible effect of the pill.

Steroid contraceptive use and cervical dysplasia: increased risk of progression.

In a prospective study of women with dysplasia of the cervix, there was an increase in severity of dysplasia and of conversion to cancer in situ in users of the contraceptive pill compared with users of other contraceptive methods. There was a delay in this adverse response. Nonreversal of dysplasia within the first 6 months of pill use is predictive of progression after prolonged exposure.

Pulmonary artery intimal injury associated with blunt trauma.

In recent years, intimal injuries to the aorta (minimal aortic injuries) have been diagnosed more frequently. We report the first case of pulmonary artery intimal injury in the setting of blunt trauma. We propose a number of theories regarding the pathogenesis, outcome, and treatment of pulmonary artery intimal injuries, drawing inferences from aortic intimal injuries. We conclude with a discussion on differentiating pulmonary artery intimal injury from the more common (but still rare) pulmonary artery dissection, using our case as an example.

Rapid development and plasticity of layer 2/3 maps in rat barrel cortex in vivo.

Cortical synaptic circuitry develops rapidly in the second postnatal week, simultaneous with experience-dependent turnover of dendritic spines. To relate the emergence of sensory maps to synaptogenesis, we recorded synaptic potentials evoked by whisker deflection in layer 2/3 neurons from postnatal day (P) 12 to 20. At P12, synaptic responses were undetectable. Only 2 days later in life (P14), receptive fields had mature organization. Sensory deprivation, if initiated before P14, disrupted receptive field structure. In layer 4, responses and maps were already mature by P12 and insensitive to deprivation, implying that barrel cortex develops from layer 4 to layer 2/3. Thus, P12-14 is a critical period shared by layer 2/3 synapses and their spines, suggesting that spine plasticity is involved in the refinement of maps.

Chiral resolution of the enantiomers of new selective CB(2) receptor agonists by liquid chromatography on amylose stationary phases.

Analytical HPLC methods using derivatized amylose chiral stationary phases, Chiralpak AD-H and Chiralpak AS, were developed for the direct enantioseparation of eight substituted 4-oxo-1,4-dihydroquinoline-3-carboxamide derivatives with one stereogenic center. Baseline separation (Rs>1.5) was always achieved on amylose based Chiralpak AD-H column to the difference with Chiralpak AS. Using UV detection, a linear response was observed within a 180-420 micromol L(-1) concentration range (r2>0.991) for three racemic compounds 1, 3 and 4 with best pharmacological potentials; repeatability, limit of detection (LD) and quantification (LQ) were also determined: LD varied, for the solutes, from 0.36 to 2.56 micromol L(-1). Finally, the enantiopurity of these compounds was determined. Additionally, the effect of temperature variations upon isomer separations was investigated.

Abnormal esophageal acid exposure on high-dose proton pump inhibitor therapy is common in systemic sclerosis patients.

BACKGROUND: Esophageal dysfunction and gastro-esophageal reflux disease (GERD) are common among patients with systemic sclerosis (SSc). Although high-dose proton pump inhibitors (PPIs) typically normalize esophageal acid exposure, the effectiveness of PPI therapy has not been systematically studied in SSc patients. The aim of this study was to characterize reflux in SSc patients on high-dose PPI using esophageal pH-impedance testing. METHODS: In this case-controlled retrospective analysis, 38 patients fulfilling 2013 American College of Rheumatology SSc criteria who underwent esophageal pH-impedance testing on twice-daily PPI between January 2014 and March 2017 at a tertiary referral center were compared with a control-cohort of 38 non-SSc patients matched for PPI formulation and dose, hiatal hernia size, age, and gender. Patient clinical characteristics, including endoscopy and high-resolution manometry findings, were assessed via chart review. KEY RESULTS: On pH-impedance, SSc patients had higher acid exposure times (AETs) than controls. Sixty-one percent of the SSc patients and 18% of the control patients had a total AET ≥4.5% (P < .001). Systemic sclerosis patients also had significantly longer AETs, longer median bolus clearance, and lower nocturnal impedance values. CONCLUSIONS & INFERENCES: Abnormal esophageal acid exposure despite high-dose PPI therapy was common among patients with SSc. The lack of increased reflux episodes in the SSc patients, and longer bolus clearance times and lower nocturnal impedance, supports ineffective clearance as the potential mechanism. Systemic sclerosis patients may require adjunctive therapies to PPIs to control acid reflux.

Human fear-related motor neurocircuitry.

Using functional magnetic resonance imaging and an experimental paradigm of instructed fear, we observed a striking pattern of decreased activity in primary motor cortex with increased activity in dorsal basal ganglia during anticipation of aversive electrodermal stimulation in 42 healthy participants. We interpret this pattern of activity in motor neurocircuitry in response to cognitively-induced fear in relation to evolutionarily-conserved responses to threat that may be relevant to understanding normal and pathological fear in humans.

Four novel mutations, including the first gross deletion in TCF1, identified in HNF-4alpha, GCK and TCF1 in patients with MODY in Israel.

Maturity onset diabetes of the young (MODY) is characterized by a primary defect in insulin secretion with non-ketotic hyperglycemia, monogenic autosomal dominant mode of inheritance, age at onset less than 25 years, and lack of autoantibodies. The aim of this study was to characterize the genetic basis of MODY in different ethnic groups in the Israeli population. Fifty-nine unrelated Israeli patients with MODY were assessed for mutations in the three common MODY genes: hepatocyte nuclear factor (HNF)-4alpha, glucokinase (GCK), and transcription factor 1 (TCF1). Overall, 11 mutations in 12 unrelated families were found (20.3% of patients), for a relative frequency of 1.7% for MODY1, 8.5% for MODY2, and 10.1% for MODY3. Four mutations were novel, including the first gross deletion ever described in the TCF1 gene. The low overall mutation frequency found here may suggest the involvement of other, yet unidentified, genes in the etiology of MODY in Israel.

Evaluation of Papanicolaou smear and effect of sample biopsy in follow-up of cervical dysplasia.

In a prospective study of women with dysplasia, a superficial sampling biopsy of the cervix was carried out as a periodic check of the cytological findings. The relationship of smear and biopsy results was evaluated, as well as the effect of the biopsy procedure on the subsequent course of dysplasia. We found sufficiently close agreement between smear and biopsy results to conclude that smears and biopsies measure similar aspects of dysplasia. It would appear unwise, however, to rely on Papanicolaou smears exclusively in following women with a history of dysplasia, since negative smears in such women may occasionally show dysplasia in the corresponding biopsy. Periodic corroborative biopsy procedures are therefore indicated in the follow-up care of women with a history of dysplasia. There was no evidence that a superficial sampling biopsy significantly altered the short-term course of dysplasia. There was also no evidence of a cumulative effect of repeated sampling biopsies. These results do not rule out possible effects of other forms of biopsy procedures and schedules on the subsequent course of dysplasia.

Mechanistic studies of a novel class of trisubstituted platinum(II) antitumor agents.

Chemical and biological studies are presented for a new series of platinum(II) antitumor agents that violate the classical structure-activity relationships established for platinum complexes. These new agents, which have demonstrated activity against murine and human tumor systems, are cis-[Pt(NH3)2(Am)Cl]+ cations, in which Am is a derivative of pyridine, pyrimidine, purine, or aniline. Members from this series block simian virus 40 DNA replication in vitro and inhibit the action of DNA polymerases at individual guanine residues in replication mapping experiments. Monoclonal antibodies that bind selectively to cisplatin lesions on calf thymus DNA were used in a competitive enzyme-linked immunosorbent assay study to show that the platinum-triamine complexes do not produce the type of intrastrand cross-links on DNA that are characteristics of cisplatin and analogues with the general formula cis-[Pt(amine)2X2]. These results indicate that cis-[Pt(NH3)2(Am)Cl]+ cations form monofunctional adducts on DNA rather than eliminate NH3 or Am to afford bifunctional lesions. This conclusion is further supported by nuclear magnetic resonance spectroscopic and enzymatic digestion analyses of the products of the reactions of these triamine complexes with d(GpG) and dG, which also reveal monofunctional binding. When cis-[Pt(NH3)2(4-Br-pyridine)Cl]+ was allowed to stand in phosphate-buffered saline at 37 degrees C for 14 days, however, NH4+ was released and trans-[Pt(NH3)(4-Br-pyridine)Cl2] formed concomitantly. This compound was characterized by a single crystal X-ray diffraction study, the details of which are reported. The fact that trans-[Pt(NH3)(4-Br-pyridine)Cl2] displays no anticancer activity, however, indicates that its formation from cis-[Pt(NH3)2(4-Br-pyridine)Cl]+ is not a significant component of the mechanism of action of this platinum-triamine complex. Taken together, these findings indicate that the cytotoxicity of cis-[Pt(NH3)2(Am)Cl]+ complexes most likely arises from the formation of monofunctional adducts. The DNA binding properties associated with this new class of antitumor agents suggest that they may display an activity profile different from that of cisplatin and related analogues.

Reed-Sternberg cells in Hodgkin's lymphoma present features of cellular senescence.

Hodgkin's Lymphoma (HL) is one of the most prevailing malignancies in young adults. Reed-Sternberg (RS) cells in HL have distinctive large cell morphology, are characteristic of the disease and their presence is essential for diagnosis. Enlarged cells are one of the hallmarks of senescence, but whether RS cells are senescent has not been previously investigated. Here we show that RS cells have characteristics of senescent cells; RS cells in HL biopsies specifically express the senescence markers and cell cycle inhibitors p21Cip1 and p16INK4a and are negative for the proliferation marker Ki-67, suggesting that these cells have ceased to proliferate. Moreover, the RS-like cells in HL lines, stained specifically for senescence-associated ß-galactosidase (SA-ß-gal). Oxidative stress promoted senescence in these cells as demonstrated by their staining for p21Cip1, p16INK4a, p53 and γH2AX. Senescent cells produce copious amounts of inflammatory cytokines termed 'senescence-associated secretory phenotype' (SASP), primarily regulated by Nuclear Factor κB (NF-κB). Indeed, we show that NF-κB activity and NF-κB-dependent cytokines production (e.g., IL-6, TNF-α, GM-CSF) were elevated in RS-like cells. Furthermore, NF-κB inhibitors, JSH-23 and curcumin reduced IL-6 secretion from RS-like cells. Thus, defining RS cells as senescent offers new insights on the origin of the proinflammatory microenvironment in HL.

High prevalence of diabetes in young adult Ethiopian immigrants to Israel.

We performed oral glucose tolerance tests in 158 Ethiopian immigrants to Israel. The subjects were less than 30 yr of age, had lived in Israel less than or equal to 4 yr, and originated from villages in the Gondar and Ambovar regions of Ethiopia. Most had been subjected to famine conditions in Ethiopia and/or extreme hardship in Sudan before or during immigration. All were lean. They revealed a profound change in dietary habits since their arrival in Israel, with consumption of large amounts of refined carbohydrate in place of spicy stews and injura (Ethiopian pita) that had constituted dietary staples in better times in Ethiopia. According to National Diabetes Data Group criteria, 14 (8.9%) of the subjects had diabetes, and another 14 (8.9%) had impaired glucose tolerance. In addition, 13 subjects had a dramatic increase in capillary blood glucose levels (greater than 300 mg/dl) 1 h after ingestion of 75 g glucose, despite fasting and 2-h values well within the normal range, and they complained of associated symptoms during the 1st h of testing. Eleven of 137 men and 3 of 21 women had diabetes; 7 (5.1%) of the men and 7 (33%) of the women had impaired glucose tolerance. These results indicate a high prevalence of diabetes among young adult Ethiopian immigrants of relatively short residency in Israel, for which the factors responsible warrant further investigation.

Prevalence of diabetes in Israel. Epidemiologic survey.

A survey of 4660 Israeli adults aged 30-65 yr revealed an overall diabetes prevalence of 4.1%. Prevalence was slightly lower in women (3.5%) than in men (4.3%), rose with age, and was highest in the group greater than 60 yr old (10.3%). In approximately 40% of the diabetic subjects, the diagnosis of diabetes was made as a result of the screening program. Association with a family history of diabetes, obesity, and the presence of other diseases was greater in diabetic than in nondiabetic subjects. The prevalence of diabetes differed among different segments of the survey population when classified according to country of origin, being lowest in African and Asian (1.2%), intermediate in American and European (4.9%), and highest in Israeli born (5.5%); this order of prevalence is the reverse of that reported in earlier surveys. The results indicate that the overall diabetes prevalence in Israel, and that within the European- and American-born segment, is comparable to that reported in other westernized societies. The findings also suggest that environmental factors contribute to the phenotypic expression of the non-insulin-dependent genotype(s) but that the influence of such factors varies with different genetic backgrounds.