Microbial modulation via cross-fostering prevents the effects of pervasive environmental stressors on microglia and social behavior, but not the dopamine system.

Environmental toxicant exposure, including air pollution, is increasing worldwide. However, toxicant exposures are not equitably distributed. Rather, low-income and minority communities bear the greatest burden, along with higher levels of psychosocial stress. Both air pollution and maternal stress during pregnancy have been linked to neurodevelopmental disorders such as autism, but biological mechanisms and targets for therapeutic intervention remain poorly understood. We demonstrate that combined prenatal exposure to air pollution (diesel exhaust particles, DEP) and maternal stress (MS) in mice induces social behavior deficits only in male offspring, in line with the male bias in autism. These behavioral deficits are accompanied by changes in microglial morphology and gene expression as well as decreased dopamine receptor expression and dopaminergic fiber input in the nucleus accumbens (NAc). Importantly, the gut-brain axis has been implicated in ASD, and both microglia and the dopamine system are sensitive to the composition of the gut microbiome. In line with this, we find that the composition of the gut microbiome and the structure of the intestinal epithelium are significantly shifted in DEP/MS-exposed males. Excitingly, both the DEP/MS-induced social deficits and microglial alterations in males are prevented by shifting the gut microbiome at birth via a cross-fostering procedure. However, while social deficits in DEP/MS males can be reversed by chemogenetic activation of dopamine neurons in the ventral tegmental area, modulation of the gut microbiome does not impact dopamine endpoints. These findings demonstrate male-specific changes in the gut-brain axis following DEP/MS and suggest that the gut microbiome is an important modulator of both social behavior and microglia.

Quality of English inpatient mental health services for people with anxiety or depressive disorders: Findings and recommendations from the core audit of the National Clinical Audit of Anxiety and Depression.

BACKGROUND: Clinical audit is a sustained cyclical quality improvement process seeking to improve patient care and outcomes by evaluating services against explicit standards and implementing necessary changes. National audits aim to improve population-level clinical care by identifying unwarranted variations and making recommendations for clinicians, managers and service commissioners. The National Clinical Audit of Anxiety and Depression aimed to improve clinical care for people admitted to English hospitals for treatment of anxiety and depression, to provide comparative data on quality of care, and to support local quality improvement initiatives by identifying and sharing examples of best practice. PROCEDURES: Thirteen standards were developed based on NICE guidelines, literature review and feedback from a steering committee and reference group of service users and carers. All providers of NHS inpatient mental health services in England were asked to submit details of between 20 and 100 eligible service users/patients admitted between April 2017 and September 2018. To ascertain data reliability, participating services re-audited 5 sets of case-notes with a second auditor, and the coordinating team checked 10 randomly-selected sets of case-notes from 3 services, also selected at random. The reference group and steering committee identified key findings and developed a series of recommendations, which were discussed in regional quality improvement workshops and on-line webinars. FINDINGS: Data from 3795 case notes were analysed. A sizeable proportion of records indicated that at least one important aspect of initial assessment was not documented. Many service users/patients who could have benefited from an intervention targeted at optimising physical health did not receive it. Only a minority (39%) were referred for psychological therapy. Use of outcome measures varied considerably but no single outcome measure was being used routinely. Most individuals had a care plan recorded in the notes, but a review date was documented in only two-thirds, and almost half of individuals had not received a copy. CONCLUSIONS: There was considerable variation between English mental health services across many variables, and much scope for improvement. Clinicians should ensure that care plans are developed collaboratively with service users/patients and identified carers should be provided with information about support services. Health services should investigate the reasons for low referral rates for psychological therapies. Clinicians should ensure all service users have jointly developed crisis plans in place at discharge. Service managers should agree outcome measures to evaluate the treatment provided and clinicians should use these measures at initial assessment and review appointments. The implementation of such changes provides an opportunity for collaborative research into mental health service delivery and quality.

Reversibility and hysteresis of the sharp yielding transition of a colloidal glass under oscillatory shear.

The mechanical response of glasses remains challenging to understand. Recent results indicate that the oscillatory rheology of soft glasses is accompanied by a sharp non-equilibrium transition in the microscopic dynamics. Here, we use simultaneous x-ray scattering and rheology to investigate the reversibility and hysteresis of the sharp symmetry change from anisotropic solid to isotropic liquid dynamics observed in the oscillatory shear of colloidal glasses (D. Denisov, M.T. Dang, B. Struth, A. Zaccone, P. Schall, Sci. Rep. 5 14359 (2015)). We use strain sweeps with increasing and decreasing strain amplitude to show that, in analogy with equilibrium transitions, this sharp symmetry change is reversible and exhibits systematic frequency-dependent hysteresis. Using the non-affine response formalism of amorphous solids, we show that these hysteresis effects arise from frequency-dependent non-affine structural cage rearrangements at large strain. These results consolidate the first-order-like nature of the oscillatory shear transition and quantify related hysteresis effects both via measurements and theoretical modelling.

[Effects of mTOR-Cdc42 signaling pathway on phagocytosis of alveolar macrophages in chronic obstructive pulmonary disease mice].

Objective: To investigate effects of mammalian target of rapamycin (mTOR)- cell division cycle 42 (Cdc42) signaling pathway on phagocytosis of alveolar macrophages (AMs) in chronic obstructive pulmonary disease (COPD) mice. Methods: Forty mice were randomly divided into control group and model group. Each group contained 20 mice. COPD model group were established by cigarette smoking exposure. AMs were isolated from lung tissue by discontinuous density gradient centrifugation. AMs from control group were divided into health control group and rapamycin control group while AMs from model group were divided into COPD group and rapamycin COPD group. The AMs from rapamycin control group and rapamycin COPD group were incubated with a final concentration of 10 nmol/L rapamycin for 24 hours. Mean fluorescence intensity (MFI) and the positive percent of alveolar macrophage engulfed flurescein isothiocyanate-labeled Escherichina coli (FITC-E.coli) AM (AM%) were detected by flow cytometry. Real time PCR (RT-PCR) and Western blot were applied to detect mRNA and protein. The activity of Cdc42 was detected by G-LISA Small GTPase Activation Assays (G-LISA) Cdc42 Kit. The cytoskeleton structure of AM was observed by laser scanning confocal microscopy. Results: MFI and AM% in COPD group were decreased than those in health control group[4 060±590 vs 9 190±988 and (28.65±1.26)% vs (67.50±4.56)%]; Compared with COPD group, MFI and AM% in rapamycin COPD group[4 856±762, (38.31±1.71)%]were increased (all P<0.05). The expression of mRNA, protein and activity of mTOR in COPD group were increased than those in health control group[(2.62±0.46, 1.30±0.52, 1.46±0.43) vs (1.00±0.00, 0.48±0.27, 0.58±0.26)]; compared with COPD group, the expression of mRNA, protein and activity of mTOR in rapamycin COPD group (1.40±0.36, 0.90±0.66, 0.92±0.28) were decreased (all P<0.05). The Cdc42 mRNA, protein and activity in COPD group were higher than those in health control group[(2.56±0.50, 1.61±0.37, 0.46±0.09) vs (1.00±0.00, 0.67±0.22, 0.30±0.07)](all P<0.01); compared with COPD group, the expression of mRNA, protein and activity of Cdc42 in rapamycin COPD group (1.38±0.34, 0.91±0.48, 0.36±0.06) were decreased (all P<0.01). Filopodia protruding can not be seen in the cytoskeleton of AMs from health control group and rapamycin control group; some filopodia protruding can be seen in AM from COPD group; some long filopodia protruding can be seen in AM from rapamycin COPD group. Negative correlations were existed between the mRNA, protein and activity of mTOR, Cdc42 and MFI in all group. Conclusions: mTOR-Cdc42 signaling pathway is activated and related to phagocytosis deficiency of AM in COPD. It can be inferred that the pathway is involved in the pathogenesis of COPD.

Splenic CD11c+ cells derived from semi-immune mice protect naïve mice against experimental cerebral malaria.

BACKGROUND: Immunity to malaria requires innate, adaptive immune responses and Plasmodium-specific memory cells. Previously, mice semi-immune to malaria was developed. Three cycles of infection and cure ('three-cure') were required to protect mice against Plasmodium berghei (ANKA strain) infection. METHODS: C57BL/6 J mice underwent three cycles of P. berghei infection and drug-cure to become semi-immune. The spleens of infected semi-immune mice were collected for flow cytometry analysis. CD11c(+) cells of semi-immune mice were isolated and transferred into naïve mice which were subsequently challenged and followed up by survival and parasitaemia. RESULTS: The percentages of splenic CD4(+) and CD11c(+) cells were increased in semi-immune mice on day 7 post-infection. The proportion and number of B220(+)CD11c(+)low cells (plasmacytoid dendritic cells, DCs) was higher in semi-immune, three-cure mice than in their naïve littermates on day 7 post-infection (2.6 vs 1.1% and 491,031 vs 149,699, respectively). In adoptive transfer experiment, three months after the third cured P. berghei infection, splenic CD11c(+) DCs of non-infected, semi-immune, three-cure mice slowed Plasmodium proliferation and decreased the death rate due to neurological pathology in recipient mice. In addition, anti-P. berghei IgG1 level was higher in mice transferred with CD11c(+) cells of semi-immune, three-cure mice than mice transferred with CD11c(+) cells of naïve counterparts. CONCLUSION: CD11c(+) cells of semi-immune mice protect against experimental cerebral malaria three months after the third cured malaria, potentially through protective plasmacytoid DCs and enhanced production of malaria-specific antibody.

Shear banding of colloidal glasses: observation of a dynamic first-order transition.

We demonstrate that application of an increasing shear field on a glass leads to an intriguing dynamic first-order transition in analogy with equilibrium transitions. By following the particle dynamics as a function of the driving field in a colloidal glass, we identify a critical shear rate upon which the diffusion time scale of the glass exhibits a sudden discontinuity. Using a new dynamic order parameter, we show that this discontinuity is analogous to a first-order transition, in which the applied stress acts as the conjugate field on the system's dynamic evolution. These results offer new perspectives to comprehend the generic shear-banding instability of a wide range of amorphous materials.

Neuron Derived Cytokine Interleukin-34 Controls Developmental Microglia Function.

Neuron-microglia interactions dictate the development of neuronal circuits in the brain. However, the factors that support and broadly regulate these processes across developmental stages are largely unknown. Here, we find that IL34, a neuron-derived cytokine, is upregulated in development and plays a critical role in supporting and maintaining neuroprotective, mature microglia in the anterior cingulate cortex (ACC) of mice. We show that IL34 mRNA and protein is upregulated in neurons in the second week of postnatal life and that this increase coincides with increases in microglia number and expression of mature, homeostatic markers, e.g., TMEM119. We also found that IL34 mRNA is higher in more active neurons, and higher in excitatory (compared to inhibitory) neurons. Genetic KO of IL34 prevents the functional maturation of microglia and results in an anxiolytic phenotype in these mice by adulthood. Acute, low dose blocking of IL34 at postnatal day (P)15 in mice decreased microglial TMEM119 expression and increased aberrant microglial phagocytosis of thalamocortical synapses within the ACC. In contrast, viral overexpression of IL34 early in life (P1-P8) caused early maturation of microglia and prevented microglial phagocytosis of thalamocortical synapses during the appropriate neurodevelopmental refinement window. Taken together, these findings establish IL34 as a key regulator of neuron-microglia crosstalk in postnatal brain development, controlling both microglial maturation and synapse engulfment.

Pancreatobiliary cytology in the multidisciplinary setting.

This review article discusses the role of endoscopic ultrasound-guided fine needle aspiration (EUS FNA) cytology in the clinical management of patients with pancreatic tumours in the setting of a multidisciplinary team (MDT). The commonest diagnosis encountered is pancreatic adenocarcinoma, which is seldom diagnosed early enough for surgical resection. Thus, cytology is likely to be the only form of diagnosis in the majority of cases. Nevertheless, about half the lesions discussed at the MDT meeting are lesions other than primary adenocarcinoma and a wide differential diagnosis must be considered in order to identify tumours, including neuroendocrine tumours, that are amenable to surgical resection. Cytology is not always definitive and the diagnosis may be helped by categorizing results according to whether they are malignant, suspicious, atypical/indeterminate, benign or inadequate. Discussion at MDT meetings and correlation with clinical and imaging findings along with review of cytology slides may allow equivocal results to be clarified before treatment is decided. Inadequate cytology results are avoided by rapid on-site evaluation of slides; although this is cost-effective in terms of overall patient care, attendance of cytopathologists on-site may not be feasible. At Imperial College NHS Trust, specially trained biomedical scientists successfully carry out rapid on-site evaluation.

E-Selectin Targeted Gold Nanoshells to Inhibit Breast Cancer Cell Binding to Lung Endothelial Cells.

Extravasation of circulating tumor cells (CTCs) from the vasculature is a key step in cancer metastasis. CTCs bind to cell adhesion molecules (CAMs) expressed by endothelial cells (ECs) for flow arrest prior to extravasation. While a number of EC-expressed CAMs have been implicated in facilitating CTC binding, this work investigated the efficacy of inhibiting cancer cell binding to human lung microvascular ECs via antibody blocking of E-selectin using antibody-functionalized gold nanoshells (NS). The antibody-functionalized gold NS were synthesized using both directional and non-directional antibody conjugation techniques with variations in synthesis parameters (linker length, amount of passivating agents, and ratio of antibodies to NS) to gain a better understanding of these properties on the resultant hydrodynamic diameter, zeta potential, and antibody loading density. We quantified the ability of E-selectin antibody-functionalized NS to bind human lung microvascular endothelial cells (HMVEC-Ls) under non-inflamed and inflamed (TNF-α) conditions to inhibit binding of triple-negative MDA-MB-231s. E-selectin-targeted NS prepared using non-directional conjugation had higher antibody loading than those prepared via directional conjugation, resulting in the conjugates having similar overall binding to HMVEC-Ls at a given antibody concentration. E-selectin-targeted NS reduced MDA-MB-231 binding to HMVEC-Ls by up to 41% as determined using an in vitro binding assay. These results provide useful insights into the characteristics of antibody-functionalized NS prepared under different conditions while also demonstrating proof of concept that these conjugates hold potential to inhibit CTC binding to ECs, a critical step in extravasation during metastasis.

Structural modification enhances the optoelectronic properties of defect blue phosphorene thin films.

Active enhancement of the optical absorption coefficient to improve the light converting efficiency of thin-film solar cell materials is crucial to develop the next-generation solar cell devices. Here we report first-principles calculations with generalized gradient approximation to study the optoelectronic properties of pristine and divacancy (DV) blue phosphorene (BlueP) thin films under structural deformation. We show that instead of formingsp-like covalent bonds as in the pristine BlueP layer, a DV introduces two particular dangling bonds between the voids. Using a microscopic (non-) affine deformation model, we reveal that the orbital hybridization of these dangling bonds is strongly modified in both the velocity and vorticity directions depending on the type of deformation, creating an effective light trap to enhance the material absorption efficiency. Furthermore, this successful light trap is complemented by a clear signature ofσ+πplasmon when a DV BlueP layer is slightly compressive. These results demonstrate a practical approach to tailor the optoelectronic properties of low-dimensional materials and to pave a novel strategy to design functionalized solar cell devices from the bottom-up with selective defects.

Medications (NSAIDs, statins, proton pump inhibitors) and the risk of esophageal adenocarcinoma in patients with Barrett's esophagus.

BACKGROUND & AIMS: Limited evidence suggests that proton pump inhibitors (PPI), nonsteroidal anti-inflammatory drugs (NSAID)/aspirin, and statins may be associated with a low risk of esophageal neoplasia. However, the possible effect these medications may have on the risk of esophageal adenocarcinoma (EAC) in patients with existing Barrett's esophagus (BE) is unclear. METHODS: We conducted a nested case-control study in a cohort of patients with BE identified in the national Department of Veterans' Affairs computerized databases. Cases with incident EAC were matched by incidence density sampling to controls with BE who remained without EAC at the date of the EAC diagnosis for the corresponding case. We identified prescriptions for PPI, NSAIDs/aspirin, and statins that were filled between BE diagnosis and EAC diagnosis. Incidence density ratios were calculated using conditional logistic regression models that adjusted for race, outpatient encounters, a disease comorbidity index, and socioeconomic status. RESULTS: In a cohort of 11,823 patients with first-time BE diagnosis, we examined 116 EAC cases and 696 matched controls. Most cases and controls had at least one filled PPI prescription (95% vs 94%; P = .5). In this setting of almost universal PPI use, filled NSAID/aspirin prescriptions were associated with a reduced risk of EAC (adjusted incidence density ratio, 0.64; 95% confidence interval, 0.42-0.97). Filled statin prescriptions also were associated with a reduction in EAC risk (0.55; 95% confidence interval, 0.36-0.86), with a significant trend toward greater risk reduction with longer duration of statin use. However, the strong inverse associations with even short periods of use raise concerns of uncontrolled confounding. CONCLUSIONS: This observational study indicates that in patients with BE using PPI, NSAID/aspirin, or statin therapy might reduce the risk of developing EAC.

Barrett's esophagus in children and adolescents without neurodevelopmental or tracheoesophageal abnormalities: a prospective study.

BACKGROUND: Barrett's esophagus (BE) in children has been examined in retrospective studies, consisting of case series and cross-sectional studies. OBJECTIVE: To evaluate the prevalence and determinants of BE in children who are free from neurodevelopmental disorders and tracheoesophageal abnormalities. DESIGN: A prospective, cross-sectional study. SETTING: Three pediatric GI Centers in Houston, Texas; Phoenix, Arizona; and Portland, Maine between February 2006 and December 2007. PATIENTS: This study involved children and adolescents consecutively presenting for elective upper endoscopy. Patients with neurodevelopmental and tracheoesophageal disorders were excluded. INTERVENTION: Endoscopic pictures of all cases with suspected BE were independently reviewed and verified by two experienced investigators. Esophageal biopsy specimens were obtained in all patients, and targeted biopsy specimens also were obtained from suspected BE. MAIN OUTCOME MEASUREMENTS: Endoscopically suspected BE and histologically confirmed BE. RESULTS: A total of 840 patients (mean age 9.5 years) were enrolled and had complete questionnaire and endoscopic data. Twelve patients were suspected of having BE (prevalence of 1.43%; 95% confidence interval [CI], 0.73-2.45), and only 1 patient had intestinal metaplasia, for a prevalence of 0.12% (95% CI, 0-0.65), whereas the rest had gastric oxyntic glands (n=6) or squamous esophageal epithelium (n=5). Patients with suspected BE had a higher mean body mass index (23.0 vs 19.1, P=.05) and more chest pain (50% vs 13%, P<.01) than patients without BE or reflux esophagitis. There was a trend toward a higher frequency of dysphagia, heartburn, and regurgitation in patients with suspected BE. LIMITATIONS: The accuracy of BE prevalence estimates is limited by the small number of cases. CONCLUSION: BE is rare in children without neurodevelopmental delay or tracheoesophageal anomalies presenting for elective upper endoscopy.

Oral bisphosphonate prescriptions and the risk of esophageal adenocarcinoma in patients with Barrett's esophagus.

BACKGROUND: Recent case reports suggested a link between oral bisphosphonate use and esophageal cancer. We therefore examined the association between these medications and the risk of esophageal adenocarcinoma (EAC) in patients with Barrett's esophagus (BE). DESIGN: This was a nested, matched case-control study. Cases with incident EAC at least 6 months following BE index date were matched by incidence density sampling to controls with BE without EAC. Patients with BE were found in the national Department of Veterans Affairs computerized databases, and each filled prescriptions for oral bisphosphonates between BE diagnosis and EAC diagnosis (or corresponding dates in controls). Incidence density ratios were calculated using conditional logistic regression models. RESULTS: In a cohort of 11,823 patients with BE, we compared 116 cases and 696 controls. Most were men (97%). Most cases and controls had at least one filled proton pump inhibitor (PPI) prescription (95 vs. 94%, P = 0.5). Filled bisphosphonate prescriptions were very uncommon (1.7 vs. 1.9%) and were not associated with EAC; the incidence density ratio was 0.92 (95% CI, 0.21-4.15). CONCLUSION: In patients with BE, oral bisphosphonates were not associated with an increased risk of EAC.

Recall costs balanced against spoilage control in Dutch custard.

The relation between the moment at which a recall of Dutch custard is initiated and the direct costs of this recall was investigated. A simulation model of the custard supply chain was developed to compare scenarios with and without a quarantine of 48 h at the storage of the production plant. The model consists of 3 parts: 1) the distribution of a 24,000-L batch of custard over the supply chain over time is simulated; 2) the time to detect spoilage bacteria with a recontamination test procedure is simulated; and 3) the direct recall costs of custard over the different parts of the supply chain are calculated. Direct recall costs increase from about 25,000 euros/batch to 36,171 euros/batch from 57 to 135 h in the situation without quarantine and from 25,000 euros/batch to 36,648 euros/batch from 123 h to 163 h for the situation with quarantine. Then costs decrease because more and more custard is at the consumer level and only 0.13% of the consumers will ask for a refund. With low true contamination probabilities quarantine is not profitable, but at later detection moments with high probabilities it is. We conclude that a simulation model is a helpful tool to evaluate the efficiency of risk management strategies like end product testing and a quarantine situation.

Nanoparticles for Manipulation of the Developmental Wnt, Hedgehog, and Notch Signaling Pathways in Cancer.

The Wnt, Hedgehog, and Notch signaling pathways play a crucial role in early development and the maintenance of adult tissues. When dysregulated, these developmental signaling pathways can drive the formation and progression of cancer by facilitating cell survival, proliferation, and stem-like behavior. While this makes these pathways promising targets for therapeutic intervention, their pharmacological inhibition has been challenging due to the substantial complexity that exists within each pathway and the complicated crosstalk that occurs between the pathways. Recently, several small molecule inhibitors, ribonucleic acid (RNA) molecules, and antagonistic antibodies have been developed that can suppress these signaling pathways in vitro, but many of them face systemic delivery challenges. Nanoparticle-based delivery vehicles can overcome these challenges to enhance the performance and anti-cancer effects of these therapeutic molecules. This review summarizes the mechanisms by which the Wnt, Hedgehog, and Notch signaling pathways contribute to cancer growth, and discusses various nanoparticle formulations that have been developed to deliver small molecules, RNAs, and antibodies to cancer cells to inhibit these signaling pathways and halt tumor progression. This review also outlines some of the challenges that these nanocarriers must overcome to achieve therapeutic efficacy and clinical translation.

A Remarkable Response of Granulomatous Hypophysitis to Infliximab in a Patient With a Background of Crohn's Disease-A Case Report.

Background: Hypophysitis is primary or idiopathic or secondary to another disease process. The histologic subtypes of hypophysitis are lymphocytic, granulomatous, xanthomatous, xanthogranulomatous, or IgG4-related. Granulomatous hypophysitis is the second most common form and is characterized by multinucleated giant cells with granulomas and histiocytes. It can be idiopathic or secondary to another process such as infection, sarcoidosis, vasculitis, dendritic cell disorders, Crohn's disease (CD) or a reaction to rupture of a Rathke's cyst or pituitary adenoma. We present a case of granulomatous hypophysitis in a patient with CD who had resistance to corticosteroids but a dramatic response to immunosuppressive therapy with anti-tumor necrosis factor (TNF)-α therapy. Case description: A 43-year-old woman with a 9-year history of ileal and colonic CD presented to the Pituitary Center with headaches, visual disturbance, fatigue, nausea, and secondary amenorrhea. She was not on active therapy for her CD at the time of presentation and had no gastrointestinal symptoms. Hormonal evaluation revealed hyperprolactinemia, secondary hypothyroidism and adrenal insufficiency. MRI revealed a 12 × 12 × 19 mm sellar lesion abutting the optic chiasm, reported as a macroadenoma. The patient underwent endoscopic transsphenoidal biopsy of the pituitary mass. Pathology revealed granulomatous hypophysitis. Evaluation for secondary causes of hypophysitis, apart from CD, was negative. Despite a course of high dose prednisone, her symptoms and MRI findings worsened and she developed symptoms consistent with diabetes insipidus. Using a personalized medicine approach, she was started on anti-(TNF)-α therapy with infliximab combined with azathioprine, which are indicated for treatment of CD. Her headaches and polyuria resolved and her menstrual cycles resumed. MRI at 3 months and more than 1.5 years after initiation of anti-TNF-α therapy revealed durable resolution of the pituitary mass. Conclusion: To our knowledge, this is the first report of successful use of anti-TNF-α therapy for a patient with granulomatous hypophysitis, in this case associated with a previous diagnosis of CD. Although glucocorticoids are used frequently as first-line therapy for primary hypophysitis, granulomatous hypophysitis can be corticosteroid resistant and other immunosuppressive approaches may need to be considered within the context of the patient.

Diverse dystonin gene mutations cause distinct patterns of Dst isoform deficiency and phenotypic heterogeneity in Dystonia musculorum mice.

Loss-of-function mutations in dystonin (DST) can cause hereditary sensory and autonomic neuropathy type 6 (HSAN-VI) or epidermolysis bullosa simplex (EBS). Recently, DST-related diseases were recognized to be more complex than previously thought because a patient exhibited both neurological and skin manifestations, whereas others display only one or the other. A single DST locus produces at least three major DST isoforms: DST-a (neuronal isoform), DST-b (muscular isoform) and DST-e (epithelial isoform). Dystonia musculorum (dt) mice, which have mutations in Dst, were originally identified as spontaneous mutants displaying neurological phenotypes. To reveal the mechanisms underlying the phenotypic heterogeneity of DST-related diseases, we investigated two mutant strains with different mutations: a spontaneous Dst mutant (Dstdt-23Rbrc mice) and a gene-trap mutant (DstGt mice). The Dstdt-23Rbrc allele possesses a nonsense mutation in an exon shared by all Dst isoforms. The DstGt allele is predicted to inactivate Dst-a and Dst-b isoforms but not Dst-e There was a decrease in the levels of Dst-a mRNA in the neural tissue of both Dstdt-23Rbrc and DstGt homozygotes. Loss of sensory and autonomic nerve ends in the skin was observed in both Dstdt-23Rbrc and DstGt mice at postnatal stages. In contrast, Dst-e mRNA expression was reduced in the skin of Dstdt-23Rbrc mice but not in DstGt mice. Expression levels of Dst proteins in neural and cutaneous tissues correlated with Dst mRNAs. Because Dst-e encodes a structural protein in hemidesmosomes (HDs), we performed transmission electron microscopy. Lack of inner plaques and loss of keratin filament invasions underneath the HDs were observed in the basal keratinocytes of Dstdt-23Rbrc mice but not in those of DstGt mice; thus, the distinct phenotype of the skin of Dstdt-23Rbrc mice could be because of failure of Dst-e expression. These results indicate that distinct mutations within the Dst locus can cause different loss-of-function patterns among Dst isoforms, which accounts for the heterogeneous neural and skin phenotypes in dt mice and DST-related diseases.

Medication usage and the risk of neoplasia in patients with Barrett's esophagus.

BACKGROUND & AIMS: Experimental evidence indicates that proton pump inhibitors (PPIs), nonsteroidal anti-inflammatory drugs (NSAIDs)/aspirin, and statins can protect patients with Barrett's esophagus (BE) from developing neoplasias. However, only limited data are available on chemoprevention in patients with BE. METHODS: A retrospective observational study was performed using data from patients with documented BE. Prescription information was collected from pharmacy records. Cox regression analyses were performed to examine the association between prescriptions for PPIs, NSAIDs/aspirin, or statins and the risk of developing esophageal dysplasia or adenocarcinoma during follow-up (from 1982 to 2005). RESULTS: We examined 344 patients diagnosed with BE (mean age 61 years, 90.4% Caucasian, 94.2% male). After BE diagnosis, 67.2% of the patients were prescribed PPIs for a mean duration of 5.1 years; 49.1% were prescribed NSAIDs for a mean duration of 3.6 years, and 25.3% were prescribed statins for a mean duration of 2.8 years. During 2620 patient-years, high grade dysplasia or esophageal adenocarcinoma developed in 33 patients. PPI treatment after BE diagnosis was associated with a reduced risk of high grade dysplasia or cancer; this association persisted after adjustment for gender, age, and the length of BE. NSAID and/or aspirin therapy were associated with a nonsignificant trend toward lower incidence of high grade dysplasia or esophageal cancer. CONCLUSIONS: PPI therapy reduces the risk of neoplasms in patients with BE. NSAIDs/aspirin appear to reduce cancer risk whereas statin use is not significantly associated with the risk of neoplasia in patients with BE.

Expression of interleukin-10 activity by Epstein-Barr virus protein BCRF1.

Cytokine synthesis inhibitory factor (CSIF; interleukin-10), a product of mouse TH2 T cell clones that inhibits synthesis of cytokines by mouse TH1 T cell clones, exhibits extensive sequence similarity to an uncharacterized open reading frame in the Epstein-Barr virus BCRF1. Recombinant BCRF1 protein mimics the activity of interleukin-10, suggesting that BCRF1 may have a role in the interaction of the virus with the host's immune system.

Financial Impact of Alternative Pricing Benchmarks for Physician-Dispensed Drugs in the California Workers' Compensation System.

BACKGROUND: Pricing drugs in the California Workers' Compensation System (CAWCS) has become more difficult as there are increasingly fewer drugs listed in the Medi-Cal primary fee schedule, which is used as the source for CAWCS drug prices. This presents a challenge of providing timely and accurate CAWCS reimbursement. The objectives of this study are (1) to explore any trends in physician-dispensed drug prices; (2) to compare the proportion of drugs with and without a price and to determine the financial implications of repricing CAWCS physician-dispensed drugs with five alternative pricing benchmarks; and (3) to offer recommendations for the pricing benchmark to maximize pricing coverage and to remain budget neutral. METHODS: We evaluated physician-dispensed drugs at the transaction level, reimbursed in the CAWCS. Frequency, reimbursement rate, and total and average paid costs were reported. We matched each claim line in the CAWCS to the corresponding unit price of an alternative price benchmark including average wholesale price, wholesale acquisition cost, direct prices, national average drug acquisition cost, and Federal Upper Limit. RESULTS: Average wholesale price provided prices for 99.9% of physician-dispensed drug claims, while Medi-Cal, the current primary physician-dispensed drug benchmark provided prices for a lower percentage (92.7%) of claims. The CAWCS prices were equivalent to 49% of the average wholesale price, 95.5% of Medi-Cal, 126.7% of the wholesale acquisition cost, 266% of the Federal Upper Limit, 64.4% of direct prices, and 197% of national average drug acquisition cost-estimated prices. CONCLUSIONS: The CAWCS current Medi-Cal pricing for physician-dispensed drugs is better than all alternatives in terms of price availability, transparency, and budget neutrality, but pricing availability may decrease over time as Medi-Cal moves to managed care. National average drug acquisition cost is the next best alternative, but it requires combinations of pricing benchmarks to maximize its price availability.