Cerebrospinal fluid immunoglobulins in primary progressive multiple sclerosis are pathogenic.

Multiple sclerosis is clinically characterized by relapses and remissions (relapsing-remitting multiple sclerosis) that over time may evolve to a progressive course (secondary progressive multiple sclerosis) or as having a progressive course from disease onset (primary progressive multiple sclerosis). At present, it is not definitively known whether these clinical entities constitute a single pathological disease or whether these manifestations represent two distinct disease entities sharing inflammatory demyelination as a pathological feature. Here we show using a novel mouse model that CSF of primary progressive multiple sclerosis patients is unique in its capacity to induce motor disability and spinal cord pathology including demyelination, impaired remyelination, reactive astrogliosis and axonal damage. Notably, removal of immunoglobulin G from primary progressive multiple sclerosis CSF via filtration or immunodepletion attenuates its pathogenic capacity. Furthermore, injection of recombinant antibodies derived from primary progressive multiple sclerosis CSF recapitulates the pathology. Our findings suggest that the clinical and pathological features of primary progressive multiple sclerosis are antibody-mediated and pathogenically distinct from relapsing-remitting and secondary progressive multiple sclerosis. Our study has potentially important implications for the development of specific therapies for patients with primary progressive multiple sclerosis.

Murine cytomegalovirus infection exacerbates complex IV deficiency in a model of mitochondrial disease.

The influence of environmental insults on the onset and progression of mitochondrial diseases is unknown. To evaluate the effects of infection on mitochondrial disease we used a mouse model of Leigh Syndrome, where a missense mutation in the Taco1 gene results in the loss of the translation activator of cytochrome c oxidase subunit I (TACO1) protein. The mutation leads to an isolated complex IV deficiency that mimics the disease pathology observed in human patients with TACO1 mutations. We infected Taco1 mutant and wild-type mice with a murine cytomegalovirus and show that a common viral infection exacerbates the complex IV deficiency in a tissue-specific manner. We identified changes in neuromuscular morphology and tissue-specific regulation of the mammalian target of rapamycin pathway in response to viral infection. Taken together, we report for the first time that a common stress condition, such as viral infection, can exacerbate mitochondrial dysfunction in a genetic model of mitochondrial disease.

Helicobacter pylori Infection of the Gastric Mucosa and Ocular Adnexa-Lack of Association With Ocular Adnexal Lymphoma.

PURPOSE: Helicobacter pylori could theoretically induce ocular adnexal lymphoma (OAL) via 2 mechanisms: the first is that of infection within the ocular adnexa and the second is that of infection within the gastric mucosa, leading to the malignant transformation of lymphocytes that migrate to the ocular adnexa, forming a primary "ectopic" cancer. This study investigated if an association exists between gastric H. pylori or ocular adnexal H. pylori and OAL. METHODS: Prospective case-control study including cases with OAL and controls with nonlymphomatous pathologies. Gastric H. pylori infection was assessed via serologic antibody testing. Ocular adnexal infection was assessed via polymerase chain reaction testing for H. pylori and Chlamydia psittaci within ocular adnexal samples. RESULTS: Seventy-two patients were enrolled, of whom 18 had lymphoma and 54 nonlymphomatous pathologies. H. pylori antibodies were present in 5 cases (28%) and 18 controls (33%) (95% CI, 0.24%-2.50%, p = 0.78). All ocular adnexal specimens were negative for H. pylori and C. psittaci infection. The only relevant statistically significant difference between cases and controls was a history of gastric ulcer (95% CI, 1.23%-44.80%, p = 0.03). CONCLUSIONS: In the study's population, infection of gastric mucosa with H. pylori does not appear to influence the development of OAL. Also, H. pylori or C. psittaci infection within the ocular adnexa does not appear to influence the development of OAL. In the study's practice, authors do not recommend antibiotic administration or routine gastroscopy for patients with OAL. The authors do recommend referral of OAL patients with gastric symptoms to a gastroenterologist.

From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus.

Recent genome-wide association studies (GWASs) have identified a locus on chromosome 1p13 strongly associated with both plasma low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) in humans. Here we show through a series of studies in human cohorts and human-derived hepatocytes that a common noncoding polymorphism at the 1p13 locus, rs12740374, creates a C/EBP (CCAAT/enhancer binding protein) transcription factor binding site and alters the hepatic expression of the SORT1 gene. With small interfering RNA (siRNA) knockdown and viral overexpression in mouse liver, we demonstrate that Sort1 alters plasma LDL-C and very low-density lipoprotein (VLDL) particle levels by modulating hepatic VLDL secretion. Thus, we provide functional evidence for a novel regulatory pathway for lipoprotein metabolism and suggest that modulation of this pathway may alter risk for MI in humans. We also demonstrate that common noncoding DNA variants identified by GWASs can directly contribute to clinical phenotypes.

AMG 580: a novel small molecule phosphodiesterase 10A (PDE10A) positron emission tomography tracer.

Phosphodiesterase 10A (PDE10A) inhibitors have therapeutic potential for the treatment of psychiatric and neurologic disorders, such as schizophrenia and Huntington's disease. One of the key requirements for successful central nervous system drug development is to demonstrate target coverage of therapeutic candidates in brain for lead optimization in the drug discovery phase and for assisting dose selection in clinical development. Therefore, we identified AMG 580 [1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one], a novel, selective small-molecule antagonist with subnanomolar affinity for rat, primate, and human PDE10A. We showed that AMG 580 is suitable as a tracer for lead optimization to determine target coverage by novel PDE10A inhibitors using triple-stage quadrupole liquid chromatography-tandem mass spectrometry technology. [(3)H]AMG 580 bound with high affinity in a specific and saturable manner to both striatal homogenates and brain slices from rats, baboons, and human in vitro. Moreover, [(18)F]AMG 580 demonstrated prominent uptake by positron emission tomography in rats, suggesting that radiolabeled AMG 580 may be suitable for further development as a noninvasive radiotracer for target coverage measurements in clinical studies. These results indicate that AMG 580 is a potential imaging biomarker for mapping PDE10A distribution and ensuring target coverage by therapeutic PDE10A inhibitors in clinical studies.

Synthesis and SAR study of potent and selective PI3Kδ inhibitors.

2,3,4-Substituted quinolines such as (10a) were found to be potent inhibitors of PI3Kδ in both biochemical and cellular assays with good selectivity over three other class I PI3K isoforms. Some of those analogs showed favorable pharmacokinetic properties.

Epigenetic regulation of sensory axon regeneration after spinal cord injury.

Axon regeneration is hindered by a decline of intrinsic axon growth capability in mature neurons. Reversing this decline is associated with the induction of a large repertoire of regeneration-associated genes (RAGs), but the underlying regulatory mechanisms of the transcriptional changes are largely unknown. Here, we establish a correlation between diminished axon growth potential and histone 4 (H4) hypoacetylation. When neurons are triggered into a growth state, as in the conditioning lesion paradigm, H4 acetylation is restored, and RAG transcription is initiated. We have identified a set of target genes of Smad1, a proregenerative transcription factor, in conditioned DRG neurons. We also show that, during the epigenetic reprogramming process, histone-modifying enzymes work together with Smad1 to facilitate transcriptional regulation of RAGs. Importantly, targeted pharmacological modulation of the activity of histone-modifying enzymes, such as histone deacetylases, leads to induction of multiple RAGs and promotion of sensory axon regeneration in a mouse model of spinal cord injury. Our findings suggest epigenetic modulation as a potential therapeutic strategy to enhance axon regeneration.

Treatment of erythropoietin deficiency in mice with systemically administered siRNA.

Anemia linked to a relative deficiency of renal erythropoietin production is a significant cause of morbidity and medical expenditures in the developed world. Recombinant erythropoietin is expensive and has been linked to excess cardiovascular events. Moreover, some patients become refractory to erythropoietin because of increased production of factors such as hepcidin. During fetal life, the liver, rather than the kidney, is the major source of erythropoietin. In the present study, we show that it is feasible to reactivate hepatic erythropoietin production and suppress hepcidin levels using systemically delivered siRNAs targeting the EglN prolyl hydroxylases specifically in the liver, leading to improved RBC production in models of anemia caused by either renal insufficiency or chronic inflammation with enhanced hepcidin production.

Mapping sex and gender differences in falls among older adults: A scoping review.

BACKGROUND: There is growing recognition of the importance of sex and gender differences within falls literature, but the characterization of such literature is uncertain. The aim of this scoping review was to (1) map the nature and extent of falls literature examining sex or gender differences among older adults, and (2) identify gaps and opportunities for further research and practice. METHODS: We used a scoping review methodology. Eligible studies included participants with a mean age of ≥ 60 years and study aims specifying falls and either sex or gender concepts. MEDLINE, Embase, CINAHL, Ageline, and Psychinfo databases were searched from inception to March 2, 2022. Records were screened and charted by six independent reviewers. Descriptive and narrative reports were generated. RESULTS: A total of 15,266 records were screened and 74 studies were included. Most studies reported on sex and gender differences in fall risk factors (n = 52, 70%), incidence/prevalence (n = 26, 35%), fall consequences (n = 22, 30%), and fall characteristics (n = 15, 20%). The majority of studies (n = 70, 95%) found significant sex or gender differences in relation to falls, with 39 (53%) identifying significant sex differences and 31 (42%) identifying significant gender differences. However, only three (4%) studies defined sex or gender concepts and only nine (12%) studies used sex or gender terms appropriately. Fifty-six (76%) studies had more female participants than males. Four (5%) were intervention studies. Studies did not report falls in line with guidelines nor use common fall definitions. CONCLUSION: Sex and gender differences are commonly reported in falls literature. It is critical for future research to use sex and gender terms appropriately and include similar sample sizes across all genders and sexes. In addition, there is a need to examine more gender-diverse populations and to develop interventions to prevent falls that address sex and gender differences among older adults.

TCR-based lineage tracing: no evidence for conversion of conventional into regulatory T cells in response to a natural self-antigen in pancreatic islets.

Foxp3-expressing regulatory T (T reg) cells derive primarily from selection in the thymus. Yet conversion of mature conventional CD4(+) T (T conv) cell lymphocytes can be achieved in several conditions, such as transforming growth factor beta treatment, homeostatic expansion, or chronic exposure to low-dose antigen. Such conversion might provide a means to generate peripheral tolerance by "converting" potentially damaging T cells that react to self-antigens. We tested this hypothesis in mice transgenic for the BDC2.5 T cell receptor (TCR), which is representative of a diabetogenic specificity that is naturally present in NOD mice and reactive against a pancreatic self-antigen. In the thymus, before any exposure to antigen, clonotype-positive T reg and T conv cells express a second TCRalpha chain derived from endogenous loci. High-throughput single-cell sequencing of secondary TCRs of the Valpha2 family showed their joining CDR3alpha regions to be very different in T reg and T conv cell thymocytes. These specific CDR3alpha motifs, thus, provided a "tag" with which to test the actual impact of T conv to T reg cell conversion in response to peripheral self-antigen; should the autoreactive clonotypic TCR induce T conv to T reg cell conversion upon encounter of cognate antigen in the pancreas or draining lymph node, one would expect to detect tag CDR3alpha motifs from T conv cells in the T reg cell populations. Sequencing large numbers of peripheral BDC(+)Valpha2(+) cells showed that little to no conversion occurs in response to this pancreatic autoantigen.

Improving dendritic cell vaccine immunogenicity by silencing PD-1 ligands using siRNA-lipid nanoparticles combined with antigen mRNA electroporation.

Dendritic cell (DC)-based vaccination boosting antigen-specific immunity is being explored for the treatment of cancer and chronic viral infections. Although DC-based immunotherapy can induce immunological responses, its clinical benefit has been limited, indicating that further improvement of DC vaccine potency is essential. In this study, we explored the generation of a clinical-grade applicable DC vaccine with improved immunogenic potential by combining PD-1 ligand siRNA and target antigen mRNA delivery. We demonstrated that PD-L1 and PD-L2 siRNA delivery using DLin-KC2-DMA-containing lipid nanoparticles (LNP) mediated efficient and specific knockdown of PD-L expression on human monocyte-derived DC. The established siRNA-LNP transfection method did not affect DC phenotype or migratory capacity and resulted in acceptable DC viability. Furthermore, we showed that siRNA-LNP transfection can be successfully combined with both target antigen peptide loading and mRNA electroporation. Finally, we demonstrated that these PD-L-silenced DC loaded with antigen mRNA superiorly boost ex vivo antigen-specific CD8(+) T cell responses from transplanted cancer patients. Together, these findings indicate that our PD-L siRNA-LNP-modified DC are attractive cells for clinical-grade production and in vivo application to induce and boost immune responses not only in transplanted cancer patients, but likely also in other settings.

Medium Roasting and Brewing Methods Differentially Modulate Global Metabolites, Lipids, Biogenic Amines, Minerals, and Antioxidant Capacity of Hawai'i-Grown Coffee (Coffea arabica).

In the United States, besides the US territory Puerto Rico, Hawai'i is the only state that grows commercial coffee. In Hawai'i, coffee is the second most valuable agricultural commodity. Health benefits associated with moderate coffee consumption, including its antioxidant capacity, have been correlated to its bioactive components. Post-harvest techniques, coffee variety, degree of roasting, and brewing methods significantly impact the metabolites, lipids, minerals, and/or antioxidant capacity of brewed coffees. The goal of our study was to understand the impact of roasting and brewing methods on metabolites, lipids, biogenic amines, minerals, and antioxidant capacity of two Hawai'i-grown coffee (Coffea arabica) varieties, "Kona Typica" and "Yellow Catuai". Our results indicated that both roasting and coffee variety significantly modulated several metabolites, lipids, and biogenic amines of the coffee brews. Furthermore, regardless of coffee variety, the antioxidant capacity of roasted coffee brews was higher in cold brews. Similarly, total minerals were higher in "Kona Typica" cold brews followed by "Yellow Catuai" cold brews. Hawai'i-grown coffees are considered "specialty coffees" since they are grown in unique volcanic soils and tropical microclimates with unique flavors. Our studies indicate that both Hawai'i-grown coffees contain several health-promoting components. However, future studies are warranted to compare Hawai'i-grown coffees with other popular brand coffees and their health benefits in vivo.

Apolipoprotein B-100-mediated motor neuron degeneration in sporadic amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by motor neuron degeneration. Approximately 90% of cases occur sporadically with no known cause while 10% are familial cases arising from known inherited genetic mutations. In vivo studies have predominantly utilized transgenic models harbouring amyotrophic lateral sclerosis-associated gene mutations, which have not hitherto elucidated mechanisms underlying motor neuron death or identified therapeutic targets specific to sporadic amyotrophic lateral sclerosis. Here we provide evidence demonstrating pathogenic differences in CSF from patients with sporadic amyotrophic lateral sclerosis and familial amyotrophic lateral sclerosis patients with mutations in SOD1, C9orf72 and TARDBP. Using a novel CSF-mediated animal model, we show that intrathecal delivery of sporadic amyotrophic lateral sclerosis patient-derived CSF into the cervical subarachnoid space in adult wild-type mice induces permanent motor disability which is associated with hallmark pathological features of amyotrophic lateral sclerosis including motor neuron loss, cytoplasmic TDP-43 translocation, reactive astrogliosis and microglial activation. Motor impairments are not induced by SOD1, C9orf72 or TARDBP CSF, although a moderate degree of histopathological change occurs in C9orf72 and TARDBP CSF-injected mice. By conducting a series of CSF filtration studies and global proteomic analysis of CSF, we identified apolipoprotein B-100 in sporadic amyotrophic lateral sclerosis CSF as the putative agent responsible for inducing motor disability, motor neuron degeneration and pathological translocation of TDP-43. Apolipoprotein B-100 alone is sufficient to recapitulate clinical and pathological outcomes in vivo and induce death of human induced pluripotent stem cell-derived motor neurons in vitro. Targeted removal of apolipoprotein B-100 from sporadic amyotrophic lateral sclerosis CSF via filtration or immunodepletion successfully attenuated the neurotoxic capacity of sporadic amyotrophic lateral sclerosis CSF to induce motor disability, motor neuron death, and TDP-43 translocation. This study presents apolipoprotein B-100 as a novel therapeutic target specific for the predominant sporadic form of amyotrophic lateral sclerosis and establishes proof-of-concept to support CSF pheresis as a therapeutic strategy for mitigating neurotoxicity in sporadic amyotrophic lateral sclerosis.

Unexpected survival of neurons of origin of the pyramidal tract after spinal cord injury.

There is continuing controversy about whether the cells of origin of the corticospinal tract (CST) undergo retrograde cell death after spinal cord injury (SCI). All previous attempts to assess this have used imaging and/or histological techniques to assess upper motoneurons in the cerebral cortex. Here, we address the question in a novel way by assessing Wallerian degeneration and axon numbers in the medullary pyramid of Sprague Dawley rats after both acute SCI, either at cervical level 5 (C5) or thoracic level 9 (T9), and chronic SCI at T9. Our findings demonstrate that only a fraction of a percentage of the total axons in the medullary pyramid exhibit any sign of degeneration at any time after SCI--no more so than in uninjured control rats. Moreover, design-based counts of myelinated axons revealed no decrease in axon number in the medullary pyramid after SCI, regardless of injury level, severity, or time after injury. Spinal cord-injured rats had fewer myelinated axons in the medullary pyramid at 1 year after injury than aged matched controls, suggesting that injury may affect ongoing myelination of axons during aging. We conclude that SCI does not cause death of the CST cell bodies in the cortex; therefore, therapeutic strategies aimed at promoting axon regeneration of the CST in the spinal cord do not require a separate intervention to prevent retrograde degeneration of upper motoneurons in the cortex.

Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low density lipoprotein receptor (LDLR) protein levels and function. Loss of PCSK9 increases LDLR levels in liver and reduces plasma LDL cholesterol (LDLc), whereas excess PCSK9 activity decreases liver LDLR levels and increases plasma LDLc. Here, we have developed active, cross-species, small interfering RNAs (siRNAs) capable of targeting murine, rat, nonhuman primate (NHP), and human PCSK9. For in vivo studies, PCSK9 and control siRNAs were formulated in a lipidoid nanoparticle (LNP). Liver-specific siRNA silencing of PCSK9 in mice and rats reduced PCSK9 mRNA levels by 50-70%. The reduction in PCSK9 transcript was associated with up to a 60% reduction in plasma cholesterol concentrations. These effects were shown to be mediated by an RNAi mechanism, using 5'-RACE. In transgenic mice expressing human PCSK9, siRNAs silenced the human PCSK9 transcript by >70% and significantly reduced PCSK9 plasma protein levels. In NHP, a single dose of siRNA targeting PCSK9 resulted in a rapid, durable, and reversible lowering of plasma PCSK9, apolipoprotein B, and LDLc, without measurable effects on either HDL cholesterol (HDLc) or triglycerides (TGs). The effects of PCSK9 silencing lasted for 3 weeks after a single bolus i.v. administration. These results validate PCSK9 targeting with RNAi therapeutics as an approach to specifically lower LDLc, paving the way for the development of PCSK9-lowering agents as a future strategy for treatment of hypercholesterolemia.

A comparison of regional brain volumes and white matter connectivity in subjects with stimulant induced psychosis versus schizophrenia.

RATIONALE: Schizophrenia and stimulant-induced psychosis (SIP) represent two different forms of psychotic disorder, with different etiologies. While many of the symptoms of psychosis are common to both disorders, there have been few direct comparisons between these conditions, especially when controlling for stimulant use in individuals with schizophrenia. OBJECTIVES: We directly compared both psychotic disorders with a comprehensive battery of clinical, neurocognitive and neuroanatomical measures. This included one group with SIP (and concurrent stimulant dependence) and two groups with schizophrenia (either with or without concurrent stimulant dependence). METHODS: Ninety-six participants were recruited from a marginalized urban population, which included 39 with SIP (and concurrent stimulant dependence), 18 with schizophrenia (without stimulant dependence), and 39 with schizophrenia (with concurrent stimulant dependence). All subjects had extensive clinical and neurocognitive evaluations, complemented with structural MRI including diffusion tensor imaging (DTI) sequences to determine regional brain volumes and white matter connectivity. RESULTS: Both positive and negative symptoms were greater in the SZ-dependent group than the other two. Neurocognitive function was broadly similar. The structural brain imaging revealed lateralized changes to the left parietal/temporal lobe, in which regional volumes were smaller in the SZ-dependent than the SZ-non-dependent group. DTI analysis indicated extensive decreases in fractional anisotropy, with parallel increases in radial diffusivity, in the SIP group compared to the SZ-dependent group. CONCLUSIONS: These findings reveal both similarities and differences between SIP and schizophrenia. Furthermore, schizophrenia with concurrent stimulant dependence may be associated with a different clinical and neuroanatomical profile as compared to schizophrenia alone.

Prospective case-control trial evaluating silicone gel for the treatment of direct brow lift scars.

OBJECTIVE: To evaluate the effectiveness of a topical silicone gel on scars in patients who had undergone bilateral direct brow lift surgery. DESIGN: A randomized double-blind clinical trial with a placebo applied to one scar and topical silicone gel (Dermatix Ultra; Valeant Pharmaceuticals, Laval, Que.) used on the other scar for 2 months. PARTICIPANTS: Twelve patients (for a total of 24 surgical scars evaluated) were included in the study. METHODS: This study was performed in 2 academic hospitals of the University of Montreal in Montreal, Que. (Maisonneuve-Rosemont Hospital and Notre-Dame Hospital). Inclusion criteria were all bilateral direct brow lift surgeries performed in our hospitals. Exclusion criteria included revision surgery, silicone or latex allergy, and wound infection. Each patient received 2 tubes (1 with silicone gel and 1 with placebo) and applied 1 tube to their right brow scar and the other tube to their left brow scar, following the preassigned instructions. The patient and surgeon were blinded to the nature of the substance that was applied to each scar. At each visit, pictures of both scars were taken, and a questionnaire titled "The Patient and Observer Scar Assessment Scale" was filled out by the patient and the surgeon. A grade ranging from 0 to 10 was given on the multiple criteria in the questionnaire, and the sum of these grades was subsequently used for the data analysis. A lower sum was interpreted as improved scarring. At the end of the study, an independent evaluator graded both scars based on pictures. Follow-up visits were held on day 7, week 6, month 3, and month 6 after surgery. A comparison of the experimental and placebo group was performed with nonparametric tests of Wilcoxon signed rank. RESULTS: A total of 24 scars of 12 patients were analyzed (based on 4 follow-up visits). General improvement of scars was reported by the patient, the surgeon, and based on pictures. No statistically significant difference was found between the group treated with silicone gel and the group treated with placebo. All tests had a p value ≥0.08. CONCLUSIONS: We did not find a statistically significant difference between scars treated with silicone gel and scars treated with the placebo after direct brow lift surgery.

Author Correction: HDAC3 inhibition ameliorates spinal cord injury by immunomodulation.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Return of esophageal function after treatment for achalasia as determined by impedance-manometry.

BACKGROUND: Treatment for achalasia is aimed at the lower esophageal sphincter (LES), although little is known about the effect, if any, of these treatments on esophageal body function (peristalsis and clearance). We sought to measure the effect of various treatments using combined manometry (peristalsis) with Multichannel Intraluminal Impedance (MII) (esophageal clearance). METHODS: We enrolled 56 patients with Achalasia referred to the University of Washington Swallowing Center between January 2003 and January 2006. Each was grouped according to prior treatment: 38 were untreated (untreated achalasia), 10 had undergone botox injection or balloon dilation (endoscopic treatment), and 16 a laparoscopic Heller myotomy. The preoperative studies for 8 of the myotomy patients were included in the untreated achalasia group. Each patient completed a dysphagia severity questionnaire (scale 0-10). Peristalsis was analyzed by manometry and esophageal clearance of liquid and viscous material by MII. RESULTS: Mean dysphagia severity scores were significantly better in patients after Heller Myotomy than in either of the other groups (2.0 vs. 5.3 in the endoscopic group and 6.5 in untreated achalasia, p < 0.05). Peristaltic contractions were observed in 63% of patients in the Heller myotomy group, compared with 40% in the endoscopic group and 8% in untreated achalasia (p < 0.05 for both treatment groups vs. untreated achalasia). Liquid clearance rates were significantly better in both treatment groups: 28% in Heller myotomy and 16% in endoscopic treatment compared to only 5% in untreated achalasia (p < 0.05). Similarly, viscous clearance rates were 19% in Heller myotomy and 11% in endoscopic treatment, vs. 2% in untreated achalasia (p < 0.05). In the subset of patients who underwent manometry/MII both pre- and postoperatively, peristalsis was observed more frequently postoperatively than in preop studies (63% of patients exhibiting peristalsis vs. 12%), as was complete clearance of liquid (35% of swallows vs. 14%) and viscous boluses (22% of swallows vs. 14%). These differences were not significant, however. In the patients who had a myotomy the return of peristalsis correlates with effective esophageal clearance (liquid bolus: r = 0.46, p = 0.09 and viscous bolus: r = 0.63, p < 0.05). There is no correlation between peristalsis and bolus clearance in the endoscopic treatment group. CONCLUSIONS: With treatment Achalasia patients exhibit some restoration in peristalsis as well as improved bolus clearance. After Heller Myotomy, the return of peristalsis correlates with esophageal clearance, which may partly explain its superior relief of dysphagia.

HDAC3 inhibition ameliorates spinal cord injury by immunomodulation.

Following spinal cord injury (SCI), the innate immune response of microglia and infiltrating macrophages clears up cellular debris and promotes tissue repair, but it also inflicts secondary injury from inflammatory responses. Immunomodulation aimed at maximizing the beneficial effects while minimizing the detrimental roles of the innate immunity may aid functional recovery after SCI. However, intracellular drivers of global reprogramming of the inflammatory gene networks in the innate immune cells are poorly understood. Here we show that SCI resulted in an upregulation of histone deacetylase 3 (HDAC3) in the innate immune cells at the injury site. Remarkably, blocking HDAC3 with a selective small molecule inhibitor shifted microglia/macrophage responses towards inflammatory suppression, resulting in neuroprotective phenotypes and improved functional recovery in SCI model. Mechanistically, HDAC3 activity is largely responsible for histone deacetylation and inflammatory responses of primary microglia to classic inflammatory stimuli. Our results reveal a novel function of HDAC3 inhibitor in promoting functional recovery after SCI by dampening inflammatory cytokines, thus pointing towards a new direction of immunomodulation for SCI repair.