Citations

Unilateral C2cervical spinal cord hemisection (SH) disrupts descending excitatory drive to phrenic motor neurons, thereby paralyzing the ipsilateral diaphragm muscle (DIAm) during ventilatory behaviors. Recovery of rhythmic DIAm activity ipsilateral to injury occurs over time, consistent with neuroplasticity and strengthening of spared synaptic inputs to phrenic motor neurons. Localized intrathecal delivery of brain-derived neurotrophic factor (BDNF) to phrenic motor neurons after SH enhances recovery of eupneic DIAm activity. However, the impact of SH and BDNF treatment on the full range of DIAm motor behaviors has not been fully characterized. We hypothesized that all DIAm motor behaviors are affected by SH and that intrathecal BDNF enhances the recovery of both ventilatory and higher force, nonventilatory motor behaviors. An intrathecal catheter was placed in adult, male Sprague-Dawley rats at C4to chronically infuse artificial cerebrospinal fluid (aCSF) or BDNF. DIAm electromyography (EMG) electrodes were implanted bilaterally to record activity across motor behaviors, i.e., eupnea, hypoxia-hypercapnia (10% O2and 5% CO2), sighs, airway occlusion, and sneezing. After SH, ipsilateral DIAm EMG activity was evident in only 43% of aCSF-treated rats during eupnea, and activity was restored in all rats after BDNF treatment. The amplitude of DIAm EMG (root mean square, RMS) was reduced following SH during eupnea and hypoxia-hypercapnia in aCSF-treated rats, and BDNF treatment promoted recovery in both conditions. The amplitude of DIAm RMS EMG during sighs, airway occlusion, and sneezing was not affected by SH or BDNF treatment. We conclude that the effects of SH and BDNF treatment on DIAm activity depend on motor behavior.NEW & NOTEWORTHY This study demonstrates that after unilateral C2spinal cord hemisection (SH), there are differences in the spontaneous recovery of diaphragm (DIAm) electromyographic activity during ventilatory compared with more forceful, nonventilatory motor behaviors. Furthermore, we show that intrathecal delivery of brain-derived neurotrophic factor (BDNF) at the level of the phrenic motor neuron pool enhances recovery of ipsilateral DIAm activity following SH, exerting main effects on recovery of ventilatory but not higher force, nonventilatory behaviors.

Abstract Xanthogranuloma (XG) of the sellar region is uncommon and is difficult to diagnose based on intraoperative frozen sections. This study is a case presentation and review of the literature, highlighting the need to explore underlying diseases in order to guarantee an accurate patient diagnosis. Herein, we presented the case of a 43-year-old woman who was afflicted with xanthogranuloma of the sellar region; the patient had a history of headache and lengthened menstrual cycles over the 6 months prior to presentation. Endocrinology tests revealed that the patient’s levels of prolactin were high and the MRI of the patient showed a clearly defined sellar mass. As a result, the patient was considered to have prolactinoma prior to undergoing surgery. The tumor was completely removed using a transsphenoidal approach, and intraoperative frozen section revealed histology similar to xanthogranuloma. When the tumor was removed by surgical operation, the patient’s visual field defects and headache were relieved. Although intraoperative frozen section should provide some guidance with regard to the diagnosis, a pathological study is conducted to confirm the actual diagnosis.

Terminal duct lobular units (TDLUs) are the predominant source of future breast cancers, and lack of TDLU involution (higher TDLU counts, higher acini count per TDLU and the product of the two) is a breast cancer risk factor. Numerous breast cancer susceptibility single nucleotide polymorphisms (SNPs) have been identified, but whether they are associated with TDLU involution is unknown. In a pooled analysis of 872 women from two studies, we investigated 62 established breast cancer SNPs and relationships with TDLU involution. Poisson regression models with robust variance were used to calculate adjusted per‐allele relative risks (with the non‐breast cancer risk allele as the referent) and 95% confidence intervals between TDLU measures and each SNP. All statistical tests were two‐sided; P < 0.05 was considered statistically significant. Overall, 36 SNPs (58.1%) were related to higher TDLU counts although this was not statistically significant (p = 0.25). Six of the 62 SNPs (9.7%) were nominally associated with at least one TDLU measure: rs616488 (PEX14), rs11242675 (FOXQ1) and rs6001930 (MKL1) were associated with higher TDLU count (p = 0.047, 0.045 and 0.031, respectively); rs1353747 (PDE4D) and rs6472903 (8q21.11) were associated with higher acini count per TDLU (p = 0.007 and 0.027, respectively); and rs1353747 (PDE4D) and rs204247 (RANBP9) were associated with the product of TDLU and acini counts (p = 0.024 and 0.017, respectively). Our findings suggest breast cancer SNPs may not strongly influence TDLU involution. Agnostic genome‐wide association studies of TDLU involution may provide new insights on its biologic underpinnings and breast cancer susceptibility.

AbstractBackgroundThe objective of this study was to characterize the degree, pattern, lesion site, and temporal evolution of sudomotor dysfunction in multiple system atrophy (MSA) and to evaluate differences by parkinsonian (MSA‐parkinsonism) and cerebellar (MSA‐cerebellar) subtypes.MethodsAll cases of MSA evaluated at Mayo Clinic Rochester between 2005 and 2010 with postganglionic sudomotor testing and thermoregulatory sweat test were reviewed. Pattern and lesion site (preganglionic, postganglionic, or mixed) were determined based on thermoregulatory sweat test and postganglionic sudomotor testing.ResultsThe majority of the 232 patients were MSA‐parkinsonism (145, 63%). Initial postganglionic sudomotor testing was abnormal in 59%, whereas thermoregulatory sweat test was abnormal in 95% of all patients. MSA‐parkinsonism patients were more likely to have an abnormal thermoregulatory sweat test compared with MSA‐cerebellar (98% versus 90%, P = 0.006) and had a higher mean percentage of anhidrosis (57%) compared with MSA‐cerebellar (48%; P = 0.033). Common anhidrosis patterns were regional (38%) and global (35%). The site of the lesion was preganglionic in 47% and mixed (preganglionic and postganglionic) in 41%. The increase in anhidrosis per year was 6.2% based on 70 repeat thermoregulatory sweat tests performed on 29 patients. The frequency of postganglionic sudomotor abnormalities increased over time.ConclusionsOur findings suggest: (1) sudomotor dysfunction is almost invariably present in MSA and even more common and severe in MSA‐parkinsonism than MSA‐cerebellar; (2) a preganglionic pattern of sweat loss is common in MSA; however, pre‐ and postganglionic abnormalities may coexist; and (3) the increasing frequency of postganglionic sudomotor dysfunction over time suggests involvement of postganglionic fibers or sweat glands later in the disease course. © 2016 International Parkinson and Movement Disorder Society

ObjectiveInterstitial lung disease (ILD) is associated with substantial morbidity in rheumatoid arthritis (RA), but very little is known about its long‐term progression. This study was undertaken to investigate the progression of pulmonary disease using a large single‐center cohort of patients with RA‐associated ILD.MethodsRecords of all patients with RA‐associated ILD seen at Mayo Clinic between 1998 and 2014, with at least 4 weeks follow‐up and at least 1 pulmonary function test, were identified and manually screened for study inclusion. Progression was defined as a diffusing capacity for carbon monoxide (DLco) <40% predicted (or patients whose illness was too advanced to undergo screening) or a forced vital capacity (FVC) <50% predicted. Time to progression was analyzed using the Kaplan‐Meier method.ResultsOf the 167 patients included in the study, 81 (49%) were female, with a mean ± SD age of 67 ± 10 years at diagnosis of ILD. Median follow‐up time from diagnosis of ILD was 3.3 years (range 0.01–14.8). One‐third of the patients required supplemental oxygen, 40% developed DLco <40% predicted, and 22% developed FVC <50% predicted within 5 years after ILD diagnosis. Usual interstitial pneumonia (UIP) versus nonspecific interstitial pneumonia (NSIP) was a risk factor for DLco progression (hazard ratio 3.29 [95% confidence interval 1.28–8.41]). Lower DLco and FVC at baseline increased the risk for progression to DLco <40% predicted and FVC <50% predicted, and higher rates of change in the first 6 months also increased the risk of progression.ConclusionProgressive loss of pulmonary function is common in RA‐associated ILD and is worse in patients with UIP than in those with NSIP. Predictors of progression in patients with RA‐associated ILD may aid clinicians in identifying patients at highest risk for progression of ILD.

ABSTRACTOsteogenic lineage commitment and progression is controlled by multiple signaling pathways (e.g., WNT, BMP, FGF) that converge on bone‐related transcription factors. Access of osteogenic transcription factors to chromatin is controlled by epigenetic regulators that generate post‐translational modifications of histones (“histone code”), as well as read, edit and/or erase these modifications. Our understanding of the biological role of epigenetic regulators in osteoblast differentiation remains limited. Therefore, we performed next‐generation RNA sequencing (RNA‐seq) and established which chromatin‐related proteins are robustly expressed in mouse bone tissues (e.g., fracture callus, calvarial bone). These studies also revealed that cells with increased osteogenic potential have higher levels of the H4K20 methyl transferase Suv420h2 compared to other methyl transferases (e.g., Suv39h1, Suv39h2, Suv420h1, Ezh1, Ezh2). We find that all six epigenetic regulators are transiently expressed at different stages of osteoblast differentiation in culture, with maximal mRNAs levels of Suv39h1 and Suv39h2 (at day 3) preceding maximal expression of Suv420h1 and Suv420h2 (at day 7) and developmental stages that reflect, respectively, early and later collagen matrix deposition. Loss of function analysis of Suv420h2 by siRNA depletion shows loss of H4K20 methylation and decreased expression of bone biomarkers (e.g., alkaline phosphatase/Alpl) and osteogenic transcription factors (e.g., Sp7/Osterix). Furthermore, Suv420h2 is required for matrix mineralization during osteoblast differentiation. We conclude that Suv420h2 controls the H4K20 methylome of osteoblasts and is critical for normal progression of osteoblastogenesis. J. Cell. Biochem. 118: 1262–1272, 2017. © 2016 Wiley Periodicals, Inc.