Footprint evidence of early hominin locomotor diversity at Laetoli, Tanzania.

Bipedal trackways discovered in 1978 at Laetoli site G, Tanzania and dated to 3.66 million years ago are widely accepted as the oldest unequivocal evidence of obligate bipedalism in the human lineage1-3. Another trackway discovered two years earlier at nearby site A was partially excavated and attributed to a hominin, but curious affinities with bears (ursids) marginalized its importance to the paleoanthropological community, and the location of these footprints fell into obscurity3-5. In 2019, we located, excavated and cleaned the site A trackway, producing a digital archive using 3D photogrammetry and laser scanning. Here we compare the footprints at this site with those of American black bears, chimpanzees and humans, and we show that they resemble those of hominins more than ursids. In fact, the narrow step width corroborates the original interpretation of a small, cross-stepping bipedal hominin. However, the inferred foot proportions, gait parameters and 3D morphologies of footprints at site A are readily distinguished from those at site G, indicating that a minimum of two hominin taxa with different feet and gaits coexisted at Laetoli.

AAV5-miHTT-mediated huntingtin lowering improves brain health in a Huntington's disease mouse model.

Huntingtin (HTT)-lowering therapies show great promise in treating Huntington's disease. We have developed a microRNA targeting human HTT that is delivered in an adeno-associated serotype 5 viral vector (AAV5-miHTT), and here use animal behaviour, MRI, non-invasive proton magnetic resonance spectroscopy and striatal RNA sequencing as outcome measures in preclinical mouse studies of AAV5-miHTT. The effects of AAV5-miHTT treatment were evaluated in homozygous Q175FDN mice, a mouse model of Huntington's disease with severe neuropathological and behavioural phenotypes. Homozygous mice were used instead of the more commonly used heterozygous strain, which exhibit milder phenotypes. Three-month-old homozygous Q175FDN mice, which had developed acute phenotypes by the time of treatment, were injected bilaterally into the striatum with either formulation buffer (phosphate-buffered saline + 5% sucrose), low dose (5.2 × 109 genome copies/mouse) or high dose (1.3 × 1011 genome copies/mouse) AAV5-miHTT. Wild-type mice injected with formulation buffer served as controls. Behavioural assessments of cognition, T1-weighted structural MRI and striatal proton magnetic resonance spectroscopy were performed 3 months after injection, and shortly afterwards the animals were sacrificed to collect brain tissue for protein and RNA analysis. Motor coordination was assessed at 1-month intervals beginning at 2 months of age until sacrifice. Dose-dependent changes in AAV5 vector DNA level, miHTT expression and mutant HTT were observed in striatum and cortex of AAV5-miHTT-treated Huntington's disease model mice. This pattern of microRNA expression and mutant HTT lowering rescued weight loss in homozygous Q175FDN mice but did not affect motor or cognitive phenotypes. MRI volumetric analysis detected atrophy in four brain regions in homozygous Q175FDN mice, and treatment with high dose AAV5-miHTT rescued this effect in the hippocampus. Like previous magnetic resonance spectroscopy studies in Huntington's disease patients, decreased total N-acetyl aspartate and increased myo-inositol levels were found in the striatum of homozygous Q175FDN mice. These neurochemical findings were partially reversed with AAV5-miHTT treatment. Striatal transcriptional analysis using RNA sequencing revealed mutant HTT-induced changes that were partially reversed by HTT lowering with AAV5-miHTT. Striatal proton magnetic resonance spectroscopy analysis suggests a restoration of neuronal function, and striatal RNA sequencing analysis shows a reversal of transcriptional dysregulation following AAV5-miHTT in a homozygous Huntington's disease mouse model with severe pathology. The results of this study support the use of magnetic resonance spectroscopy in HTT-lowering clinical trials and strengthen the therapeutic potential of AAV5-miHTT in reversing severe striatal dysfunction in Huntington's disease.

PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington's disease.

DNA damage repair genes are modifiers of disease onset in Huntington's disease (HD), but how this process intersects with associated disease pathways remains unclear. Here we evaluated the mechanistic contributions of protein inhibitor of activated STAT-1 (PIAS1) in HD mice and HD patient-derived induced pluripotent stem cells (iPSCs) and find a link between PIAS1 and DNA damage repair pathways. We show that PIAS1 is a component of the transcription-coupled repair complex, that includes the DNA damage end processing enzyme polynucleotide kinase-phosphatase (PNKP), and that PIAS1 is a SUMO E3 ligase for PNKP. Pias1 knockdown (KD) in HD mice had a normalizing effect on HD transcriptional dysregulation associated with synaptic function and disease-associated transcriptional coexpression modules enriched for DNA damage repair mechanisms as did reduction of PIAS1 in HD iPSC-derived neurons. KD also restored mutant HTT-perturbed enzymatic activity of PNKP and modulated genomic integrity of several transcriptionally normalized genes. The findings here now link SUMO modifying machinery to DNA damage repair responses and transcriptional modulation in neurodegenerative disease.

Is Pain in the Uninjured Leg Associated With Unhelpful Thoughts and Distress Regarding Symptoms During Recovery From Lower Extremity Injury?

BACKGROUND: Patients recovering from lower extremity injuries often interpret discomfort associated with increased use of the uninjured leg as a potential indication of harm. If expressed concerns regarding contralateral leg pain are associated with unhelpful thinking regarding symptoms, they can signal orthopaedic surgeons to gently reorient these thoughts to help improve comfort and capability during recovery. QUESTIONS/PURPOSES: We asked: (1) Among people recovering from isolated traumatic lower extremity injury, is pain intensity in the uninjured leg associated with unhelpful thoughts and feelings of distress regarding symptoms, accounting for other factors? (2) Are pain intensity in the injured leg, magnitude of capability, and accommodation of pain associated with unhelpful thoughts and feelings of distress regarding symptoms? METHODS: Between February 2020 and February 2022, we enrolled 139 patients presenting for an initial evaluation or return visit for any traumatic lower extremity injury at the offices of one of three musculoskeletal specialists. Patients had the option to decline filling out our surveys, but because of the cross-sectional design, required fields on the electronic survey tools, and monitored completion, there were few declines and few incomplete surveys. The median age of participants was 41 years (IQR 32 to 58), and 48% (67 of 139) were women. Fifty percent (70 of 139) injured their right leg. Sixty-five percent (91 of 139) had operative treatment of their fracture. Patients completed measures of pain intensity in the uninjured leg, pain intensity in the injured leg, lower extremity-specific magnitude of capability, symptoms of depression, symptoms of health anxiety, catastrophic thinking, and accommodation of pain. Multivariable analysis sought factors independently associated with pain intensity in the uninjured leg, pain intensity in the injured leg, magnitude of capability, and pain accommodation, controlling for other demographic and injury-related factors. RESULTS: Greater pain intensity in the uninjured leg (regression coefficient [RC] 0.09 [95% CI 0.02 to 0.16]; p < 0.01) was moderately associated with more unhelpful thinking regarding symptoms. This indicates that for every one-unit increase in unhelpful thinking regarding symptoms on the 17-point scale we used to measure pain catastrophizing, pain intensity in the uninjured leg increases by 0.94 points on the 11-point scale that we used to measure pain intensity, holding all other independent variables constant. Greater pain intensity in the injured leg (RC 0.18 [95% CI 0.08 to 0.27]; p < 0.01) was modestly associated with more unhelpful thinking regarding symptoms. Greater pain accommodation (RC -0.25 [95% CI -0.38 to -0.12]; p < 0.01) was modestly associated with less unhelpful thinking regarding symptoms. Greater magnitude of capability was not independently associated with less unhelpful thinking regarding symptoms. CONCLUSION: A patient's report of concerns regarding pain in the uninjured limb (such as, "I'm overcompensating for the pain in my other leg") can be considered an indicator of unhelpful thinking regarding symptoms. Orthopaedic surgeons can use such reports to recognize unhelpful thinking and begin guiding patients toward healthier thoughts and behaviors. LEVEL OF EVIDENCE: Level II, prognostic study.

Is Pain in the Uninjured Arm Associated With Unhelpful Thoughts and Distress Regarding Symptoms During Recovery From Upper-Extremity Injury?

PURPOSE: During recovery from upper-extremity injury, patients sometimes express concerns regarding pain associated with increased use of the uninjured limb. Concerns about discomfort associated with increased use may represent a manifestation of unhelpful thoughts such as catastrophic thinking or kinesiophobia. We asked the following questions: (1) Among people recovering from an isolated unilateral upper-extremity injury, is pain intensity in the uninjured arm associated with unhelpful thoughts and feelings of distress regarding symptoms, accounting for other factors? (2) Is pain intensity in the injured extremity, magnitude of capability, or accommodation of pain associated with unhelpful thoughts and feelings of distress regarding symptoms? METHODS: In this cross-sectional study of new or returning patients presenting to a musculoskeletal specialist for care for an upper-extremity injury, the patients completed scales that were used to measure the following: pain intensity in the uninjured arm, pain intensity in the injured arm, upper-extremity-specific magnitude of capability, symptoms of depression, symptoms of health anxiety, catastrophic thinking, and accommodation of pain. Multivariable analysis was used to evaluate factors associated with pain intensity in the uninjured arm, pain intensity in the injured arm, magnitude of capability, and pain accommodation, controlling for other demographic and injury-related factors. RESULTS: Greater pain intensity in both uninjured and injured arms was independently associated with greater unhelpful thinking regarding symptoms. A greater magnitude of capability and pain accommodation were independently associated with less unhelpful thinking regarding symptoms. CONCLUSIONS: Given that greater pain intensity in the uninjured upper extremity is associated with greater unhelpful thinking, clinicians can be attuned to patient concerns about contralateral pain. Clinicians can facilitate recovery from upper-extremity injury by evaluating the uninjured limb as well as identifying and ameliorating unhelpful thinking regarding symptoms. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II.

Cooperative and Orthogonal Switching in the Solid State Enabled by Metal-Organic Framework Confinement Leading to a Thermo-Photochromic Platform.

Cooperative behavior and orthogonal responses of two classes of coordinatively integrated photochromic molecules towards distinct external stimuli were demonstrated on the first example of a photo-thermo-responsive hierarchical platform. Synergetic and orthogonal responses to temperature and excitation wavelength are achieved by confining the stimuli-responsive moieties within a metal-organic framework (MOF), leading to the preparation of a novel photo-thermo-responsive spiropyran-diarylethene based material. Synergistic behavior of two photoswitches enables the study of stimuli-responsive resonance energy transfer as well as control of the photoinduced charge transfer processes, milestones required to advance optoelectronics development. Spectroscopic studies in combination with theoretical modeling revealed a nonlinear effect on the material electronic structure arising from the coordinative integration of photoresponsive molecules with distinct photoisomerization mechanisms. Thus, the reported work covers multivariable facets of not only fundamental aspects of photoswitch cooperativity, but also provides a pathway to modulate photophysics and electronics of multidimensional functional materials exhibiting thermo-photochromism.

Confinement-Driven Photophysics in Hydrazone-Based Hierarchical Materials.

Confinement-imposed photophysics was probed for novel stimuli-responsive hydrazone-based compounds demonstrating a conceptual difference in their behavior within 2D versus 3D porous matrices for the first time. The challenges associated with photoswitch isomerization arising from host interactions with photochromic compounds in 2D scaffolds could be overcome in 3D materials. Solution-like photoisomerization rate constants were realized for sterically demanding hydrazone derivatives in the solid state through their coordinative immobilization in 3D scaffolds. According to steady-state and time-resolved photophysical measurements and theoretical modeling, this approach provides access to hydrazone-based materials with fast photoisomerization kinetics in the solid state. Fast isomerization of integrated hydrazone derivatives allows for probing and tailoring resonance energy transfer (ET) processes as a function of excitation wavelength, providing a novel pathway for ET modulation.

The effect of mindfulness-based stress reduction on the urinary microbiome in interstitial cystitis.

INTRODUCTION AND HYPOTHESIS: The objective was to investigate the impact of mindfulness-based stress reduction therapy on the urinary microbiome of patients with interstitial cystitis/bladder pain syndrome. METHODS: In this Institutional Review Board-approved prospective cohort study, patients with interstitial cystitis/bladder pain syndrome were recruited to attend an 8-week mindfulness-based stress reduction course involving yoga and meditation. Eligible participants were English-speaking women aged 18 or older with interstitial cystitis/bladder pain syndrome. All participants had a negative urinalysis within 2 months of enrollment and were currently undergoing first- or second-line treatment at the time of recruitment. The mindfulness-based stress reduction course met weekly for 1 h. A straight-catheter urine sample was obtained prior to and following the mindfulness-based stress reduction series. DNA from urine samples underwent bacterial 16S ribosomal gene sequencing at Johns Hopkins University Laboratories followed by taxonomic abundance and diversity analysis by Resphera Biosciences Laboratory. Participants completed validated symptom questionnaires pre- and post-intervention. RESULTS: A total of 12 participants completed the 8-week course and were included in the analysis. The average age was 59 and the majority identified as white. Patient symptoms, measured by the Urogenital Distress Inventory Short Form and Interstitial Cystitis Symptom and Pain Indices, improved significantly (all p < 0.05). Overall composition of the urinary microbiome changed significantly (p < 0.01) and demonstrated an increase in diversity following the intervention. CONCLUSIONS: Mindfulness-based stress reduction therapy improves patient symptoms and was associated with significant changes in the urinary microbiome in patients with interstitial cystitis/bladder pain syndrome.

Mutant huntingtin expression in microglia is neither required nor sufficient to cause the Huntington's disease-like phenotype in BACHD mice.

Huntington's disease (HD) is caused by a CAG repeat expansion in the HTT gene and is characterized by early and selective striatal neurodegeneration. The huntingtin (HTT) protein is ubiquitously expressed in many tissues and the cellular pathogenesis of the disease is not fully understood. Immune cell dysfunction due to mutant HTT (mHTT) expression and aberrant immune system activation in HD patients suggests that inflammatory processes may contribute to HD pathogenesis. Here we used the BACHD mouse model of HD, which carries a conditional transgene expressing full-length human mHTT, to selectively deplete mHTT expression in myeloid lineage cells, including microglia, and evaluated the effects on HD-related behavior and neuropathology. In the converse experiment, we depleted mHTT expression in the majority of cells in the brain but specifically excluding microglia and again evaluated behavior and neuropathology. In mice with myeloid-specific mHTT-depletion, we observed no significant rescue of any behavioral or neuropathological outcome measures, while neural-specific knockout mice showed significant rescue of body weight, rotarod performance and striatal volume. We conclude that mHTT expression in microglia, though clearly affecting specific aspects of microglia function, does not alter disease pathogenesis in the BACHD mouse model. This may have implications for current or future therapeutic trials testing immune-modulating drugs in HD patients.

Dynamic magnetic resonance imaging following native tissue vaginal reconstructive surgery; a prospective study.

INTRODUCTION AND HYPOTHESIS: To describe the impact of native tissue vaginal reconstruction on pelvic anatomy using dynamic magnetic resonance imaging. METHODS: This prospective single-cohort observational study involved women undergoing native tissue reconstruction with intraperitoneal vaginal vault suspension for pelvic organ prolapse. Concomitant procedures such as hysterectomy, midurethral sling, and anterior or posterior colporrhaphy were allowed. Enrolled participants underwent dynamic pelvic imaging pre- and postoperatively. Radiographic and anatomic measurements were compared. Secondary outcomes included validated patient questionnaires. RESULTS: Fourteen participants were included in the analysis. The mean age was 62 years; all participants were Caucasian. Most participants had stage III pelvic organ prolapse. Significant improvements were noted in several radiographic measurements. The average H-line (representing levator hiatus width) with straining maneuvers improved following surgery (7.2 cm preoperatively vs. 6.6 cm postoperatively, p = 0.015). The average M-line (representing levator muscular descent) improved significantly with both straining (4.0 cm preoperatively vs. 3.0 cm postoperatively, p < 0.001) and defecatory maneuvers (6.2 cm preoperatively vs. 5.2 cm postoperatively, p = 0.001). The average size of cystocele improved from 5.6 cm (moderate) preoperatively to 0.7 cm (absent descent) postoperatively (p < 0.001). The average descent of the vaginal apex with defecation preoperatively was 3.0 cm (moderate) and 0 cm (absent descent) postoperatively (p = 0.003). Posterior compartment descent with defecation did not change following surgical intervention (5.8 cm preoperatively vs. 5.2 cm postoperatively, p = 0.056). Pelvic Organ Prolapse Quantification measurements improved in all compartments, and Pelvic Floor Distress Inventory-20 scores improved significantly following surgery (102 preoperatively vs. 30 postoperatively, p < 0.001). CONCLUSIONS: Native tissue reconstruction with intraperitoneal vaginal vault suspension resulted in significant anatomic improvements, as defined by physical examination and dynamic magnetic resonance imaging.

A monumental cemetery built by eastern Africa's first herders near Lake Turkana, Kenya.

Monumental architecture is a prime indicator of social complexity, because it requires many people to build a conspicuous structure commemorating shared beliefs. Examining monumentality in different environmental and economic settings can reveal diverse reasons for people to form larger social units and express unity through architectural display. In multiple areas of Africa, monumentality developed as mobile herders created large cemeteries and practiced other forms of commemoration. The motives for such behavior in sparsely populated, unpredictable landscapes may differ from well-studied cases of monumentality in predictable environments with sedentary populations. Here we report excavations and ground-penetrating radar surveys at the earliest and most massive monumental site in eastern Africa. Lothagam North Pillar Site was a communal cemetery near Lake Turkana (northwest Kenya) constructed 5,000 years ago by eastern Africa's earliest pastoralists. Inside a platform ringed by boulders, a 119.5-m2 mortuary cavity accommodated an estimated minimum of 580 individuals. People of diverse ages and both sexes were buried, and ornaments accompanied most individuals. There is no evidence for social stratification. The uncertainties of living on a "moving frontier" of early herding-exacerbated by dramatic environmental shifts-may have spurred people to strengthen social networks that could provide information and assistance. Lothagam North Pillar Site would have served as both an arena for interaction and a tangible reminder of shared identity.

The influence of postoperative environment on patient pain and satisfaction: a randomized trial.

BACKGROUND: Improving the patient experience, controlling pain with nonopiate therapies, and preparing for value-based reimbursement are increasingly important foci for both physicians and hospitals. OBJECTIVE: We aimed to determine whether the addition of music and a natural landscape image to postoperative hospital rooms would result in improved pain and satisfaction scores among inpatients undergoing pelvic reconstructive surgery. STUDY DESIGN: This randomized controlled trial was approved by an Institutional Review Board. Eligible candidates were 18-85 years old, English speaking, and scheduled to undergo native tissue vaginal vault suspension for symptomatic pelvic organ prolapse. Patients with history of a chronic pain or substance abuse were excluded. Subjects were advised that the purpose of the study was to assess the effect of changes to the hospital environment on patient experience but were blinded to their group and intervention details. Changes included a landscape image mounted to the wall and access to a speaker with preprogrammed music selections. The intervention group was instructed to listen to their preferred music for a minimum of 2 30-minute sessions postoperatively. The control group had a standard hospital room, without music or landscape. All patient rooms were private. The primary outcome was the visual analog scale for pain in the morning of postoperative day 1. Secondary outcomes included narcotic use, likelihood to refer family to the same hospital facility, satisfaction with care and the hospital, and perception of a healing environment. A sample size of 43 subjects per arm was calculated to detect a difference of 10 mm in visual analog scale pain score. RESULTS: A total of 133 subjects were enrolled; primary outcome data were available for 92 (46 per arm). The mean age was 63.8 (standard deviation, 9.5) years, median Charlson comorbidity score was 2 (min, 0; max, 7), and 94.6% of subjects were white. On postoperative day 1, median visual analog scale pain scores were low (28.8 mm [0, 86]; 24.5 mm [0, 81]) and did not differ between intervention and control, respectively (P=.57). Total morphine equivalents (P=.817) and nursing pain scores (P=.774) were also similar. However, the intervention group displayed a higher likelihood to refer family members to the hospital (98 mm (47, 100); 96 mm (65, 100); P=.037). At postoperative 2 weeks, the intervention group indicated higher satisfaction with their care (98 mm, (34, 100); 95 mm (42, 100); P=.032), the hospital (98 mm (71, 100); 94 mm (6, 100); P=.004), and the healing environment provided during their stay (98 mm; 92 mm (19, 100); P=.020) than those in the standard hospital rooms. CONCLUSION: In this randomized trial, we found music and landscape imagery did not substantially affect postoperative pain scores; however, they had a positive effect on the postoperative experience. Furthermore, this effect appeared to broaden 2 weeks after surgery. Given the importance of value-based care, interventions such as these should be emphasized to enhance patient satisfaction, quality scores, and overall well-being.

Addressing apical support during hysterectomy for prolapse: a NSQIP review.

OBJECTIVE: To describe national practice patterns regarding apical support procedures at time of hysterectomy for prolapse prior to the American College of Obstetricians and Gynecologists (ACOG) 2017 Practice Bulletin on pelvic organ prolapse. METHODS: This retrospective descriptive study analyzed 24 months of data from the National Surgical Quality Improvement Program (NSQIP) database, from 2015 and 2016. Patients undergoing hysterectomy for the indication of pelvic organ prolapse were included. Surgical details, diagnostic codes, subspecialty, patient demographics, and postoperative complications were collected. Comparisons were conducted between those who did and did not undergo apical support procedures. Further comparisons, including logistic regressions, were performed using subspecialty designation. RESULTS: During the study period, 3458 hysterectomies were performed for the indication of pelvic organ prolapse. Of this population, 76% were White, with an average age of 61 years, BMI of 27.6, and parity of 2, and 90.5% carried the diagnosis of apical prolapse. Slightly over half (51.8%) had a concurrent procedure to support the vaginal apex. When performed by Female Pelvic Medicine and Reconstructive Surgery (FPMRS) physicians, 65.7% underwent an apical suspension at time of hysterectomy for prolapse compared with 40.2% of non-FPMRS (p < 0.001). Annual rates of apical support procedures showed significant improvement from 49.5% in 2015 to 55.2% in 2016 (P < 0.001). Regarding surgical data, addition of apical support procedures increased operative time by 33 min, and reoperation was 1.3% higher (0.3% vs 1.6%). CONCLUSION: Our results demonstrate that in the 2 years prior to ACOG's recommendation only 51.8% of women undergoing hysterectomy for pelvic organ prolapse received concurrent procedures to address apical support.

Associating genital hiatus size with long-term outcomes after apical suspension.

INTRODUCTION AND HYPOTHESIS: To describe associations between postoperative genital hiatus (GH) measurements and long-term anatomical and subjective outcomes following pelvic reconstructive surgery involving apical suspension. METHODS: This IRB-approved secondary analysis reports outcomes 3-7 years following robotic sacrocolpopexy (RSC) and uterosacral ligament suspension (USLS). Objective and subjective measures were obtained through clinical examinations and validated questionnaires. Subjective success was defined as the absence of a symptomatic bulge or retreatment. Objective success was defined as all Pelvic Organ Prolapse Quantification (POP-Q) points at or above -1 at the long-term examination. Postoperative GH measures were obtained at 6 weeks (early) and 3-7 years (long term) postoperatively. GH measurements were classified as either normal (<4 cm) or wide (≥4 cm). Logistic regression identified associations between postoperative GH measurements and long-term subjective and objective outcomes. RESULTS: A total of 154 subjects completed long-term POP-Q examinations (74 RSC and 80 USLS). The median time to follow-up (minimum, maximum) was 59 months (range 34-89); 97.4% were Caucasian. Subjective success was achieved in 134 (87%), and objective success in 139 (90.2%) subjects. The majority (79%) underwent a posterior repair during their index surgery. An early postoperative GH of less than 4 cm was associated with an 11-fold higher likelihood of subsequent objective success (11.8, 2.7-51.7; p = 0.001). Furthermore, a postoperative GH less than 4 cm was not associated with dyspareunia at long-term follow-up. CONCLUSIONS: Early postoperative GH <4 cm was associated with superior long-term objective success, without increasing dyspareunia. These data support correcting GH to <4 cm during prolapse repair with apical suspension to reduce objective long-term failure.

DNA methylation profiling in human Huntington's disease brain.

Despite extensive progress in Huntington's disease (HD) research, very little is known about the association of epigenetic variation and HD pathogenesis in human brain tissues. Moreover, its contribution to the tissue-specific transcriptional regulation of the huntingtin gene (HTT), in which HTT expression levels are highest in brain and testes, is currently unknown. To investigate the role of DNA methylation in HD pathogenesis and tissue-specific expression of HTT, we utilized the Illumina HumanMethylation450K BeadChip array to measure DNA methylation in a cohort of age-matched HD and control human cortex and liver tissues. In cortex samples, we found minimal evidence of HD-associated DNA methylation at probed sites after correction for cell heterogeneity but did observe an association with the age of disease onset. In contrast, comparison of matched cortex and liver samples revealed tissue-specific DNA methylation of the HTT gene region at 38 sites (FDR < 0.05). Importantly, we identified a novel differentially methylated binding site in the HTT proximal promoter for the transcription factor CTCF. This CTCF site displayed increased occupancy in cortex, where HTT expression is higher, compared with the liver. Additionally, CTCF silencing reduced the activity of an HTT promoter-reporter construct, suggesting that CTCF plays a role in regulating HTT promoter function. Overall, although we were unable to detect HD-associated DNA methylation alterations at queried sites, we found that DNA methylation may be correlated to the age of disease onset in cortex tissues. Moreover, our data suggest that DNA methylation may, in part, contribute to tissue-specific HTT transcription through differential CTCF occupancy.

Health Utility of Early Hemiarthroplasty vs Delayed Total Hip Arthroplasty for Displaced Femoral Neck Fracture in Elderly Patients: A Markov Model.

BACKGROUND: Treatment for femoral neck fracture among patients aged 65 years or older varies, with many surgeons preferring hemiarthroplasty (HA) over total hip arthroplasty (THA). There is evidence that THA may lead to better functional outcomes, although it also carries greater risk of mortality and dislocation rates. METHODS: We created a Markov decision model to examine the expected health utility for older patients with femoral neck fracture treated with early HA (performed within 48 hours) vs delayed THA (performed after 48 hours). Model inputs were derived from the literature. Health utilities were derived from previously fit patients aged more than 60 years. Sensitivity analyses on mortality and dislocation rates were conducted to examine the effect of uncertainty in the model parameters. RESULTS: In the base case, the average cumulative utility over 2 years was 0.895 for HA and 0.994 for THA. In sensitivity analyses, THA was preferred over HA until THA 30-day and 1-year mortality rates were increased to 1.3× the base case rates. THA was preferred over HA until the health utility for HA reached 98% that of THA. THA remained the preferred strategy when increasing the cumulative incidence of dislocation among THA patients from a base case of 4.4% up to 26.1%. CONCLUSION: We found that delayed THA provides greater health utility than early HA for older patients with femoral neck fracture, despite the increased 30-day and 1-year mortality associated with delayed surgery. Future studies should examine the cost-effectiveness of THA for femoral neck fracture.

Forkhead box protein p1 is a transcriptional repressor of immune signaling in the CNS: implications for transcriptional dysregulation in Huntington disease.

Forkhead box protein p1 (Foxp1), a transcription factor showing highly enriched expression in the striatum, has been implicated in central nervous system (CNS) development, but its role in the mature brain is unknown. In order to ascertain functional roles for Foxp1 in the CNS, we have identified gene targets for Foxp1 both in vitro and in vivo using genome-wide expression microarrays and chromatin-immunoprecipitation followed by high-throughput sequencing (ChIP-seq) assays. We found that mouse Foxp1 overexpression in striatal cells elicited expression changes of genes related to immune signaling, transcriptional regulation and a manually curated Huntington's disease (HD)-signaling pathway. Similar results were found when the gene expression data set was integrated with Foxp1-binding data determined from ChIP-seq analysis. In vivo lentiviral-mediated overexpression of human FOXP1 in the context of mutant huntingtin (Htt) protein resulted in a robust downregulation of glial cell-associated, immune genes, including those encoding a variety of cytokines and chemokines. Furthermore, Foxp1-induced expression changes were significantly negatively correlated with those changes elicited by mutant Htt protein in several different HD mouse models, and most significantly in post-mortem caudate from human HD subjects. We finally show that Foxp1 interacts with mutant Htt protein in mouse brain and is present in nuclear Htt aggregates in the striatum of R6/1 transgenic mice. These findings implicate Foxp1 as a key repressor of immune signaling in the CNS and suggest that the loss of Foxp1-mediated gene regulation in HD contributes to the immune dysfunction in this disease. We further suggest that Foxp1-regulated pathways might be important mediators of neuronal-glial cell communication.

Ureteropelvic junction obstruction secondary to parapelvic cyst encased ureter.

We present a 64-year-old male who presented with right-sided flank pain secondary to a parapelvic cyst impinging on the proximal ureter. However, intraoperative findings showed that the ureter was encased within the parapelvic cyst and secondarily obstructed at the UPJ rather than extrinsically compressed by the cyst. This specific anatomic variant is exceedingly rare as no published cases with similar anatomy could be identified.

Age-dependent neurovascular abnormalities and altered microglial morphology in the YAC128 mouse model of Huntington disease.

Central nervous system (CNS) inflammatory processes including microglial activation have been implicated in the pathogenesis of neurodegenerative diseases such as Huntington Disease (HD). We report age-dependent changes in striatal microglial morphology and vasculature in the YAC128 mouse model of HD. Decreases in microglial ramification along with a decrease in vessel diameter and increased vessel density and length suggest the presence of microgliosis and proangiogenic activity in YAC128 mice. Our hypothesis for this study was that the changes in microglial morphology and perturbations in vasculature may be involved in the pathogenesis of HD and that peripheral challenge with the bacterial endotoxin, lipopolysaccharide (LPS), will exacerbate these microglial and vascular changes as well as the HD phenotype in YAC128 mice at 12 months. Chronic peripheral LPS (1mg/kg) potentiated microglial activation indicated by an increase in microglial cell body size and retraction of processes. This potentiation in microglial activation with chronic peripheral LPS challenge was paralleled with vascular remodeling including dilatation, increased vessel wall thickness, increased BBB permeability and fibrinogen deposition in YAC128 striatum. Although peripheral LPS caused an increase in microglial activation and degenerative changes in cerebrovasculature, the phenotypic hallmarks of HD in YAC128 mice such as motor coordination deficits and decreased striatal volume were not exacerbated by chronic peripheral LPS exposure. This study identifies age-dependent increases in microglial activation and angiogenesis in YAC128 at 12 months. Peripheral inflammation induced by chronic LPS causes similar changes but does not influence the HD phenotype in YAC128 mice.

Synaptic dysfunction in progranulin-deficient mice.

Progranulin haploinsufficiency is a common cause of familial frontotemporal dementia (FTD), but the role of progranulin in the brain is poorly understood. To investigate the role of murine progranulin (Grn) in the CNS in vivo, we generated mice targeted at the progranulin locus (Grn) using a gene-trap vector. Constitutive progranulin knockout mice (GrnKO) show moderate abnormalities in anxiety-related behaviors, social interactions, motor coordination, and novel object recognition at 8months of age, many of which differ between males and females. Analysis of synaptic transmission in 10-12 month old GrnKO male mice indicates altered synaptic connectivity and impaired synaptic plasticity. Additionally, apical dendrites in pyramidal cells in the CA1 region of the hippocampus in GrnKO males display an altered morphology and have significantly decreased spine density compared to wild-type (WT) mice. The observed changes in behavior, synaptic transmission, and neuronal morphology in GrnKO mice occur prior to neuropathological abnormalities, most of which are apparent at 18 but not at 8 months of age. We conclude that progranulin deficiency leads to reduced synaptic connectivity and impaired plasticity, which may contribute to FTD pathology in human patients.