The Impact of Low Workplace Support During Pregnancy on Surgeon Distress and Career Dissatisfaction.

OBJECTIVE: To describe the impact of lack of workplace support (LOWS) for obstetric health on surgeon distress and career satisfaction. BACKGROUND: Although most pregnant surgeons desire clinical duty reductions to mitigate obstetric risk, few modify their schedules due to low workplace support. METHODS: US surgeons with at least one live birth completed an electronic survey. LOWS during pregnancy was defined as (1) disagreeing that colleagues/leadership were supportive of obstetric-mandated bedrest; (2) feeling unable to reduce clinical duties despite health concerns due to risk of financial penalties, requirement to make up missed call shifts, being perceived as "weak", burdening colleagues, or accommodations being denied by the workplace. Multivariate logistic regression determined the association between LOWS and burnout, low quality of life, plans to leave clinical practice or to reduce work hours, and likelihood of recommending a surgical career to one's child. RESULTS: Of 557 surgeons, the 360 (64.6%) who reported LOWS during pregnancy were more likely to report burnout (OR:2.57; 95%CI:1.60-4.13), low quality of life (OR:1.57; 95%CI:1.02-2.41), a desire to leave their practice (OR:2.74; 95%CI: 1.36-5.49), plans to reduce clinical hours in the next year (OR:4.25; 95%CI:1.82-9.90), and were less likely to recommend their career to their child (OR:0.44; 95%CI:0.28-0.70). CONCLUSIONS: LOWS for maternal-fetal health concerns is associated with burnout, low quality of life, and career dissatisfaction. The work environment is a modifiable factor requiring system-level interventions to limit clinical work during pregnancy and provide fair compensation for covering surgeons. Supporting surgeons during pregnancy is a short-term investment with long-term implications for improving longevity and diversity of the workforce.

A Randomized Crossover Trial Evaluating the Impact of Cultural Dexterity Training on Surgical Residents' Knowledge, Cross-Cultural Care, Skills, and Beliefs: The Provider Awareness and Cultural dexterity Training for Surgeons (PACTS) Trial.

OBJECTIVES: This trial examines the impact of the Provider Awareness and Cultural dexterity Toolkit for Surgeons (PACTS) curriculum on surgical residents' knowledge, cross-cultural care, skills, and beliefs. SUMMARY BACKGROUND DATA: Cross-cultural training of providers may reduce healthcare outcome disparities, but its effectiveness in surgical trainees is unknown. METHODS: PACTS focuses on developing skills needed for building trust, working with patients with limited English proficiency, optimizing informed consent, and managing pain. The PACTS trial was a randomized crossover trial of 8 academic general surgery programs in the United States: The Early group ("Early") received PACTS between Periods 1 and 2, while the Delayed group ("Delayed") received PACTS between Periods 2 and 3. Residents were assessed pre- and post-intervention on Knowledge, Cross-Cultural Care, Self-Assessed Skills, and Beliefs. Chi-square and Fisher's exact tests were conducted to evaluate within- and between-intervention group differences. RESULTS: Of 406 residents enrolled, 315 were exposed to the complete PACTS curriculum. Early residents' Cross-Cultural Care (79.6% to 88.2%, P<0.0001), Self-Assessed Skills (74.5% to 85.0%, P<0.0001), and Beliefs (89.6% to 92.4%, P=0.0028) improved after PACTS; Knowledge scores (71.3% to 74.3%, P=0.0661) were unchanged. Delayed resident scores pre- to post-PACTS showed minimal improvements in all domains. When comparing the two groups at Period 2, Early residents had modest improvement in all 4 assessment areas, with statistically significant increase in Beliefs (92.4% vs 89.9%, P=0.0199). CONCLUSION: The PACTS curriculum is a comprehensive tool that improved surgical residents' knowledge, preparedness, skills, and beliefs, which will help with caring for diverse patient populations.

Experimental laboratory models as tools for understanding modifiable dementia risk.

Experimental laboratory research has an important role to play in dementia prevention. Mechanisms underlying modifiable risk factors for dementia are promising targets for dementia prevention but are difficult to investigate in human populations due to technological constraints and confounds. Therefore, controlled laboratory experiments in models such as transgenic rodents, invertebrates and in vitro cultured cells are increasingly used to investigate dementia risk factors and test strategies which target them to prevent dementia. This review provides an overview of experimental research into 15 established and putative modifiable dementia risk factors: less early-life education, hearing loss, depression, social isolation, life stress, hypertension, obesity, diabetes, physical inactivity, heavy alcohol use, smoking, air pollution, anesthetic exposure, traumatic brain injury, and disordered sleep. It explores how experimental models have been, and can be, used to address questions about modifiable dementia risk and prevention that cannot readily be addressed in human studies. HIGHLIGHTS: Modifiable dementia risk factors are promising targets for dementia prevention. Interrogation of mechanisms underlying dementia risk is difficult in human populations. Studies using diverse experimental models are revealing modifiable dementia risk mechanisms. We review experimental research into 15 modifiable dementia risk factors. Laboratory science can contribute uniquely to dementia prevention.

Sarm1 knockout modifies biomarkers of neurodegeneration and spinal cord circuitry but not disease progression in the mSOD1G93A mouse model of ALS.

The mechanisms underlying the loss of motor neuron axon integrity in amyotrophic lateral sclerosis (ALS) are unclear. SARM1 has been identified as a genetic risk variant in sporadic ALS, and the SARM1 protein is a key mediator of axon degeneration. To investigate the role of SARM1 in ALS-associated axon degeneration, we knocked out Sarm1 (Sarm1KO) in mSOD1G93ATg (mSOD1) mice. Animals were monitored for ALS disease onset and severity, with motor function assessed at pre-symptomatic and late-stage disease and lumbar spinal cord and sciatic nerve harvested for immunohistochemistry at endpoint (20 weeks). Serum was collected monthly to assess protein concentrations of biomarkers linked to axon degeneration (neurofilament light (NFL) and tau), and astrogliosis (glial fibrillary acidic protein (GFAP)), using single molecule array (Simoa®) technology. Overall, loss of Sarm1 in mSOD1 mice did not slow or delay symptom onset, failed to improve functional declines, and failed to protect motor neurons. Serum NFL levels in mSOD1 mice increased between 8 -12 and 16-20 weeks of age, with the later increase significantly reduced by loss of SARM1. Similarly, loss of SARM1 significantly reduced an increase in serum GFAP between 16 and 20 weeks of age in mSOD1 mice, indicating protection of both global axon degeneration and astrogliosis. In the spinal cord, Sarm1 deletion protected against loss of excitatory VGluT2-positive puncta and attenuated astrogliosis in mSOD1 mice. In the sciatic nerve, absence of SARM1 in mSOD1 mice restored the average area of phosphorylated neurofilament reactivity towards WT levels. Together these data suggest that Sarm1KO in mSOD1 mice is not sufficient to ameliorate functional decline or motor neuron loss but does alter serum biomarker levels and provide protection to axons and glutamatergic synapses. This indicates that treatments targeting SARM1 could warrant further investigation in ALS, potentially as part of a combination therapy.

Lack of Workplace Support for Obstetric Health Concerns is Associated With Major Pregnancy Complications: A National Study of US Female Surgeons.

OBJECTIVE: We sought to assess whether lack of workplace support for clinical work reductions during pregnancy was associated with major pregnancy complications. BACKGROUND: Surgeons are at high risk of major pregnancy complications. Although rigorous operative schedules pose increased risk, few reduce their clinical duties during pregnancy. METHODS: An electronic survey was distributed to US surgeons who had at least 1 live birth. Lack of workplace support was defined as: (1) desiring but feeling unable to reduce clinical duties during pregnancy due to failure of the workplace/training program to accommodate and/or concerns about financial penalties, burden on colleagues, requirement to make up missed call, being perceived as weak; (2) disagreeing colleagues and/or leadership were supportive of obstetrician-prescribed bedrest. Multivariate logistic regression determined the association between lack of workplace support and major pregnancy complications. RESULTS: Of 671 surgeons, 437 (65.13%) reported lack of workplace support during pregnancy and 302 (45.01%) experienced major pregnancy complications. Surgeons without workplace support were at higher risk of major pregnancy complications than those who had workplace support (odds ratio: 2.44; 95% confidence interval: 1.58-3.75). Bedrest was prescribed to 110/671 (16.39%) surgeons, 38 (34.55%) of whom disagreed that colleagues and/or leadership were supportive. Of the remaining surgeons, 417/560 (74.5%) desired work reductions but were deterred by lack of workplace support. CONCLUSIONS: Lack of workplace support for reduction in clinical duties is associated with adverse obstetric outcomes for surgeons. This is a modifiable workplace obstacle that deters surgeons from acting to optimize their infant's and their own health. To ensure the health of expectant surgeons, departmental policies should support reduction of clinical workload in an equitable manner without creating financial penalties, requiring payback for missed call duties, or overburdening colleagues.

The Long Road to Parenthood: Assisted Reproduction, Surrogacy, and Adoption Among US Surgeons.

OBJECTIVE: We sought to characterize demographics, costs, and workplace support for surgeons using assisted reproductive technology (ART), adoption, and surrogacy to build their families. SUMMARY BACKGROUND DATA: As the surgical workforce diversifies, the needs of surgeons building a family are changing. ART, adoption, and surrogacy may be used with greater frequency among female surgeons who delay childbearing and surgeons in same-sex relationships. Little is known about costs and workplace support for these endeavors. METHODS: An electronic survey was distributed to surgeons through surgical societies and social media. Rates of ART use were compared between partners of male surgeons and female surgeons and multivariate analysis used to assess risk factors. Surgeons using ART, adoption, or surrogacy were asked to describe costs and time off work to pursue these options. RESULTS: Eight hundred and fifty-nine surgeons participated. Compared to male surgeons, female surgeons were more likely to report delaying children due to surgical training (64.9% vs. 43.5%, P < 0.001), have fewer children (1.9 vs. 2.4, p < 0.001), and use ART (25.2% vs. 17.4%, P = 0.035). Compared to non-surgeon partners of male surgeons, female surgeons were older at first pregnancy (33 vs 31 years, P < 0.001) with age > 35 years associated with greater odds of ART use (odds ratio 3.90; 95% confidence interval 2.74-5.55, P < 0.001). One-third of surgeons using ART spent >$40,000; most took minimal time off work for treatments. Forty-five percent of same-sex couples used adoption or surrogacy. 60% of surgeons using adoption or surrogacy spent >$40,000 and most took minimal paid parental leave. CONCLUSIONS: ART, adoption, or surrogacy is costly and lacks strong workplace support in surgery, disproportionately impacting women and same-sex couples. Equitable and inclusive environments supporting all routes to parenthood ensure recruitment and retention of a diverse workforce. Surgical leaders must enact policies and practices to normalize childbearing as part of an early surgical career, including financial support and equitable parental leave for a growing group of surgeons pursuing ART, surrogacy, or adoption to become parents.

Perceived Discrimination Among Surgical Residents at Academic Medical Centers.

BACKGROUND: Residents of color experience microaggressions in the work environment, are less likely to feel that they fit into their training programs, and feel less comfortable asking for help. Discrimination has been documented among surgical residents, but has not been extensively studied and largely remains unaddressed. We sought to determine the extent of perceived discrimination among general surgery residents. MATERIALS AND METHODS: Residents who were enrolled in a randomized controlled trial investigating a cultural dexterity curriculum completed baseline assessments prior to randomization that included demographic information and the Everyday Discrimination Scale (EDS). Data from the baseline assessments were analyzed for associations of EDS scores with race, ethnicity, sex, socioeconomic level, language ability, and training level. RESULTS: Of 266 residents across seven residency programs, 145 (55%) were men. Racial breakdown was 157 (59%) White, 45 (17%) Asian, 30 (11%) Black, and 12 (5%) Multiracial. The median EDS score was seven (range: 0-36); 58 (22%) fell into the High EDS score group. Resident race, fluency in a language other than English, and median household income were significantly associated with EDS scores. When controlling for other sociodemographic factors, Black residents were 4.2 (95% CI 1.62-11.01, P = 0.003) times as likely to have High EDS scores than their White counterparts. CONCLUSIONS: Black surgical residents experience high levels of perceived discrimination on a daily basis. Institutional leaders should be aware of these findings as they seek to cultivate a diverse surgical training environment.

Effects of TDP-43 overexpression on neuron proteome and morphology in vitro.

TDP-43 is pathologically and genetically with associated amyotrophic lateral sclerosis and frontotemporal lobar degeneration. These diseases are characterized by significant neurite defects, including cytoskeletal pathology. The involvement of TDP-43 in the degeneration of neurons in these diseases are not yet well understood, however accumulating evidence shows involvement in neurite outgrowth, remodelling and in regulation of many components of the neuronal cytoskeleton. In order to investigate how alterations to TDP-43 expression levels may exert effects on the neuronal cytoskeleton, primary cortical neurons from transgenic mice overexpressing one or two copies of human wildtype TDP-43 under the prion promoter were examined. Label-free quantitative proteomic analysis, followed by functional annotation clustering to identify protein families that clustered together within up- or down-regulated protein groups, revealed that actin-binding proteins were significantly more abundant in neurons overexpressing TDP-43 compared to wildtype neurons. Morphological analysis demonstrated that during early development neurons expressing one copy of human TDP-43 had an increased number of neurite branches and alterations to growth cone morphology, while no changes were observed in neurons expressing two copies of TDP-43. These developmental processes require specific expression and organization of the cytoskeleton. The results from these studies provide further insight into the normal function of TDP-43 and how alterations in TDP-43 expression may impact the cytoskeleton.

Mapping tree species vulnerability to multiple threats as a guide to restoration and conservation of tropical dry forests.

Understanding the vulnerability of tree species to anthropogenic threats is important for the efficient planning of restoration and conservation efforts. We quantified and compared the effects of future climate change and four current threats (fire, habitat conversion, overgrazing and overexploitation) on the 50 most common tree species of the tropical dry forests of northwestern Peru and southern Ecuador. We used an ensemble modelling approach to predict species distribution ranges, employed freely accessible spatial datasets to map threat exposures, and developed a trait-based scoring approach to estimate species-specific sensitivities, using differentiated trait weights in accordance with their expected importance in determining species sensitivities to specific threats. Species-specific vulnerability maps were constructed from the product of the exposure maps and the sensitivity estimates. We found that all 50 species face considerable threats, with an average of 46% of species' distribution ranges displaying high or very high vulnerability to at least one of the five threats. Our results suggest that current levels of habitat conversion, overexploitation and overgrazing pose larger threats to most of the studied species than climate change. We present a spatially explicit planning strategy for species-specific restoration and conservation actions, proposing management interventions to focus on (a) in situ conservation of tree populations and seed collection for tree planting activities in areas with low vulnerability to climate change and current threats; (b) ex situ conservation or translocation of populations in areas with high climate change vulnerability; and (c) active planting or assisted regeneration in areas under high current threat vulnerability but low climate change vulnerability, provided that interventions are in place to lower threat pressure. We provide an online, user-friendly tool to visualize both the vulnerability maps and the maps indicating priority restoration and conservation actions.

Surgeon presence and utilization of bariatric surgery in the United States.

BACKGROUND: Bariatric surgery is the most effective long-term treatment for morbid obesity; however, it is under-utilized. This study examines the association between morbid obesity rates, bariatric surgeon presence, and utilization of bariatric surgery in the United States. METHODS: Healthcare Cost and Utilization Project's 2013 National Inpatient Sample was used to determine the incidence of inpatient bariatric procedures using ICD-9 codes. The Center for Disease Control's 2013 Behavioral Risk Factor Surveillance System survey was analyzed to determine estimates of bariatric surgery qualified adults, aged 18-70, with BMI ≥ 40 or ≥ 35 with diabetes. The number of bariatric surgeons was determined from four online sources: searches of Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program accredited bariatric programs, American Society for Metabolic and Bariatric Surgery membership, and two adjustable gastric band manufacturer "find a surgeon" search tools. Correlations between rates of morbid obesity, bariatric surgeon presence, and incidence of inpatient bariatric surgery were determined. RESULTS: The defined bariatric surgery eligible population comprised between 3.6% (New England) to 6.8% (East South Central) of the total division population (p < 0.001). Incident rates of bariatric surgery ranged from 0.9% in East South Central to 2.2% in New England (p < 0.001). 2124 bariatric surgeons were identified. The rate of bariatric surgery by division was negatively correlated with division morbid obesity rates (r = - 0.65) and strongly positively correlated with surgeon presence (r = 0.91). After adjusting for demographic differences between divisions, surgeon presence remained highly associated with surgery utilization (p < 0.001). CONCLUSIONS: Rates of bariatric surgery procedures in the U.S. are minimally correlated with rates of morbid obesity and are strongly correlated with the number of available bariatric surgeons. Effective therapy for the morbidly obese may be limited by the lack of qualified surgeons.

Mammary stem cell and macrophage markers are enriched in normal tissue adjacent to inflammatory breast cancer.

INTRODUCTION: We hypothesized that breast tissue not involved by tumor in inflammatory breast cancer (IBC) patients contains intrinsic differences, including increased mammary stem cells and macrophage infiltration, which may promote the IBC phenotype. MATERIALS AND METHODS: Normal breast parenchyma ≥ 5 cm away from primary tumors was obtained from mastectomy specimens. This included an initial cohort of 8 IBC patients and 60 non-IBC patients followed by a validation cohort of 19 IBC patients and 25 non-IBC patients. Samples were immunostained for either CD44+CD49f+CD133/2+ mammary stem cell markers or the CD68 macrophage marker and correlated with IBC status. Quantitation of positive cells was determined using inForm software from PerkinElmer. We also examined the association between IBC status and previously published tumorigenic stem cell and IBC tumor signatures in the validation cohort samples. RESULTS: 8 of 8 IBC samples expressed isolated CD44+CD49f+CD133/2+ stem cell marked cells in the initial cohort as opposed to 0/60 non-IBC samples (p = 0.001). Similarly, the median number of CD44+CD49f+CD133/2+ cells was significantly higher in the IBC validation cohort as opposed to the non-IBC validation cohort (25.7 vs. 14.2, p = 0.007). 7 of 8 IBC samples expressed CD68 + histologically confirmed macrophages in initial cohort as opposed to 12/48 non-IBC samples (p = 0.001). In the validation cohort, the median number of CD68 + cells in IBC was 3.7 versus 1.0 in the non-IBC cohort (p = 0.06). IBC normal tissue was positively associated with a tumorigenic stem cell signature (p = 0.02) and with a 79-gene IBC signature (p < 0.001). CONCLUSIONS: Normal tissue from IBC patients is enriched for both mammary stem cells and macrophages and has higher association with both a tumorigenic stem cell signature and IBC-specific tumor signature. Collectively, these data suggest that IBC normal tissue differs from non-IBC tissue. Whether these changes occur before the tumor develops or is induced by tumor warrants further investigation.

α-Methyl phenylglycines by asymmetric α-arylation of alanine and their effect on the conformational preference of helical Aib foldamers.

α-Arylated alanine derivatives were made enantioselectively by migratory rearrangement of a urea derivative using (R,R)-pseudoephedrine as a chiral auxiliary. Incorporation of a single residue of the product α-methyl phenylglycine into an otherwise achiral oligomer of aminoisobutyric acid oligomer induced a preferred screw sense, detectable by a NMR reporter located at the remote terminus of the oligomer. The magnitude of the screw sense induction was greater when the chiral residue was located at the N-terminus of the foldamer, and in some cases the sense of induction was opposite to that of related α-methylated amino acids with α-substituents other than aryl.

Repeat propofol anesthesia does not exacerbate plaque deposition or synapse loss in APP/PS1 Alzheimer's disease mice.

BACKGROUND: There is increasing interest in whether anesthetic agents affect the risk or progression of Alzheimer's disease (AD). To mitigate many of the methodological issues encountered in human retrospective cohort studies we have used a transgenic model of AD to investigate the effect of propofol on AD pathology. METHODS: Six month-old amyloid precursor protein/presenilin 1 (APP/PS1) transgenic AD mice and control mice were exposed to 3 doses of propofol (200 mg/kg) or vehicle, delivered at monthly intervals. RESULTS: There was no difference in the extent of ß-amyloid (Aß) immunolabeled plaque deposition in APP/PS1 mice in vehicle versus propofol treatment groups. We also detected no difference in plaque-associated synapse loss in APP/PS1 mice following repeat propofol exposure relative to vehicle. Western blotting indicated that there was no difference in post-synaptic density protein 95, synaptophysin or glutamic acid decarboxylase 65/67 expression in control or APP/PS1 mice subjected to repeat propofol treatment relative to vehicle. CONCLUSIONS: These data suggest that repeat propofol anesthesia may not exacerbate plaque deposition or associated synapse loss in AD. Interestingly, this data also provides some of the first evidence suggesting that repeat propofol exposure in adult wild-type mice does not result in robust long-term alterations in the levels of key excitatory and inhibitory synaptic markers.

C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking.

Intronic expansion of a hexanucleotide GGGGCC repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene is the major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. However, the cellular function of the C9ORF72 protein remains unknown. Here, we demonstrate that C9ORF72 regulates endosomal trafficking. C9ORF72 colocalized with Rab proteins implicated in autophagy and endocytic transport: Rab1, Rab5, Rab7 and Rab11 in neuronal cell lines, primary cortical neurons and human spinal cord motor neurons, consistent with previous predictions that C9ORF72 bears Rab guanine exchange factor activity. Consistent with this notion, C9ORF72 was present in the extracellular space and as cytoplasmic vesicles. Depletion of C9ORF72 using siRNA inhibited transport of Shiga toxin from the plasma membrane to Golgi apparatus, internalization of TrkB receptor and altered the ratio of autophagosome marker light chain 3 (LC3) II:LC3I, indicating that C9ORF72 regulates endocytosis and autophagy. C9ORF72 also colocalized with ubiquilin-2 and LC3-positive vesicles, and co-migrated with lysosome-stained vesicles in neuronal cell lines, providing further evidence that C9ORF72 regulates autophagy. Investigation of proteins interacting with C9ORF72 using mass spectrometry identified other proteins implicated in ALS; ubiquilin-2 and heterogeneous nuclear ribonucleoproteins, hnRNPA2/B1 and hnRNPA1, and actin. Treatment of cells overexpressing C9ORF72 with proteasome inhibitors induced the formation of stress granules positive for hnRNPA1 and hnRNPA2/B1. Immunohistochemistry of C9ORF72 ALS patient motor neurons revealed increased colocalization between C9ORF72 and Rab7 and Rab11 compared with controls, suggesting possible dysregulation of trafficking in patients bearing the C9ORF72 repeat expansion. Hence, this study identifies a role for C9ORF72 in Rab-mediated cellular trafficking.

Epidemiological risk factors associated with inflammatory breast cancer subtypes.

BACKGROUND: In this single-institution case-control study, we identified risk factors associated with inflammatory breast cancer (IBC) subtypes based on staining of estrogen receptor (ER), progesterone receptor (PR) and expression of human epidermal growth factor 2 (HER2neu) to determine distinct etiologic pathways. METHODS: We identified 224 women with IBC and 396 cancer-free women seen at the MD Anderson Cancer Center. Multinomial logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for associations between breast cancer risk factors and the IBC tumor subtypes: luminal (ER+ and/or PR+/HER2neu-), HER2neu+ (any ER and PR, HER2neu+), and triple-negative (ER-/PR-/HER2neu-). RESULTS: In multivariable analysis, compared with women age ≥26 at first pregnancy, women age <26 had a higher risk of triple-negative IBC (OR 3.32, 95% CI 1.37-8.05). Women with a history of breast-feeding had a lower risk of triple-negative (OR 0.30; 95% CI 0.15-0.62) and luminal IBC (OR 0.35, 95% CI 0.18-0.68). A history of smoking was associated with an increased risk of luminal IBC (OR 2.37; 95% CI 1.24-4.52). Compared with normal-weight women, those who were overweight or obese (body mass index ≥25 kg/m(2)) had a higher risk of all three tumor subtypes (p < 0.01 for all subtypes). CONCLUSION: Overweight or obese status is important modifiable risk factor for IBC of any subtype. Modifiable risk factors, age at first pregnancy (≥26), breast-feeding, and smoking may be associated with specific IBC subtypes. These results highlight the importance of evaluating epidemiologic risk factors for IBC for the identification of subtype-specific prevention strategies.

Pseudoephedrine-Directed Asymmetric α-Arylation of α-Amino Acid Derivatives.

Available α-amino acids undergo arylation at their α position in an enantioselective manner on treatment with base of N'-aryl urea derivatives ligated to pseudoephedrine as a chiral auxiliary. In situ silylation and enolization induces diastereoselective migration of the N'-aryl group to the α position of the amino acid, followed by ring closure to a hydantoin with concomitant explulsion of the recyclable auxiliary. The hydrolysis of the hydantoin products provides derivatives of quaternary amino acids. The arylation avoids the use of heavy-metal additives, and is successful with a range of amino acids and with aryl rings of varying electronic character.

Alterations to metabolic hormones in amyotrophic lateral sclerosis and frontotemporal dementia postmortem human tissue.

Metabolic changes are observed in patients with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although regulation of metabolic processes in the CNS is predominantly carried out within the hypothalamus, extra-hypothalamic CNS areas contain metabolic hormone receptors, including those for leptin (LEPR), insulin (INSR), and neuropeptide Y (NPY), indicating that they may play a role in biological processes underlying pathogenic disease processes. The status of these hormones within regions vulnerable in ALS/FTD is not well described. This study sought to determine whether the expression of these hormones and their receptors is altered in pathology-rich regions in cases of human FTD (superior frontal gyrus and insular cortex) and ALS (primary motor cortex and lumbar spinal cord) with TDP-43 pathology compared to matched healthy controls. LEPR mRNA was increased within the superior frontal gyrus of FTD cases and within primary motor cortex and lumbar spinal cord of ALS cases; INSR mRNA was increased in superior frontal gyrus and insular cortex of FTD cases. NPY protein was decreased in primary motor cortex and lumbar spinal cord of ALS cases. Our results demonstrate that metabolic hormones undergo complex alterations in ALS and FTD and suggest that these hormones could play critical roles in the pathogenesis of these diseases.

HDAC6 inhibition as a mechanism to prevent neurodegeneration in the mSOD1G93A mouse model of ALS.

The loss of upper and lower motor neurons, and their axons is central to the loss of motor function and death in amyotrophic lateral sclerosis (ALS). Due to the diverse range of genetic and environmental factors that contribute to the pathogenesis of ALS, there have been difficulties in developing effective therapies for ALS. One emerging dichotomy is that protection of the neuronal cell soma does not prevent axonal vulnerability and degeneration, suggesting the need for targeted therapeutics to prevent axon degeneration. Post-translational modifications of protein acetylation can alter the function, stability and half-life of individual proteins, and can be enzymatically modified by histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs), which add, or remove acetyl groups, respectively. Maintenance of post-translational microtubule acetylation has been suggested as a mechanism to stabilize axons, prevent axonal loss and neurodegeneration in ALS. This study used an orally dosed potent HDAC6 inhibitor, ACY-738, prevent deacetylation and stabilize microtubules in the mSOD1G93A mouse model of ALS. Co-treatment with riluzole was performed to determine any effects or drug interactions and potentially enhance preclinical research translation. This study shows ACY-738 treatment increased acetylation of microtubules in the spinal cord of mSOD1G93A mice, reduced lower motor neuron degeneration in female mice, ameliorated reduction in peripheral nerve axon puncta size, but did not prevent overt motor function decline. The current study also shows peripheral nerve axon puncta size to be partially restored after treatment with riluzole and highlights the importance of co-treatment to measure the potential effects of therapeutics in ALS.