PD-L1 expression and infiltration by CD4+ and FoxP3+ T cells are increased in Xp11 translocation renal cell carcinoma and indicate poor prognosis.

AIMS: Interaction between programmed death-1 ligand (PD-L1) and its receptor programmed death 1 (PD-1) on T cells inactivates antitumour immune responses. PD-L1 expression has been associated with poor prognosis in renal cell carcinoma (RCC) and predicts adverse outcome. This study was designed to evaluate the impact of PD-L1 expression and the immune microenvironment on the clinical outcome in Xp11 translocation renal cell carcinoma (TRCC) and, therefore, their potential relevance as prognostic biomarkers. METHODS AND RESULTS: The present retrospective analysis investigated expression of PD-L1 and immune cells CD8, CD4, CD3, forkhead box protein 3 (FoxP3) and PD-1 in TRCC compared to other types of RCC. FFPE specimens were collected between 2011 and 2017 from 311 patients who underwent nephrectomy at our institution for RCC. Specimens were immunostained for PD-L1, CD8, CD4, CD3, FoxP3 and PD-1, and an outcome analysis was conducted. PD-L1 expression rate was highest in TRCC (68%, 16 of 25), followed by mucinous tubular and spindle cell RCC and collecting duct carcinoma (33%, one of three), papillary RCC (27%, seven of 26), clear cell RCC (16%, 29 of 233), chromophobe RCC (11%, two of 18) and multilocular cystic RCC (0%, none of three). In TRCC, PD-L1 expression was associated with poor recurrence-free survival (RFS) (P = 0.041). The CD4high and FoxP3high groups showed a significantly shorter RFS (P = 0.05 and P = 0.031, respectively) compared to CD4low and FOXPlow groups. CONCLUSION: PD-L1 expression was higher in TRCC than in other types of RCC. High PD-L1 tumour cell expression and tumour infiltration by CD4+ and FoxP3+ immune cells were associated with poor RFS in TRCC.

Potential Mechanisms Underlying Intercortical Signal Regulation via Cholinergic Neuromodulators.

The dynamical behavior of the cortex is extremely complex, with different areas and even different layers of a cortical column displaying different temporal patterns. A major open question is how the signals from different layers and different brain regions are coordinated in a flexible manner to support function. Here, we considered interactions between primary auditory cortex and adjacent association cortex. Using a biophysically based model, we show how top-down signals in the beta and gamma regimes can interact with a bottom-up gamma rhythm to provide regulation of signals between the cortical areas and among layers. The flow of signals depends on cholinergic modulation: with only glutamatergic drive, we show that top-down gamma rhythms may block sensory signals. In the presence of cholinergic drive, top-down beta rhythms can lift this blockade and allow signals to flow reciprocally between primary sensory and parietal cortex. SIGNIFICANCE STATEMENT: Flexible coordination of multiple cortical areas is critical for complex cognitive functions, but how this is accomplished is not understood. Using computational models, we studied the interactions between primary auditory cortex (A1) and association cortex (Par2). Our model is capable of replicating interaction patterns observed in vitro and the simulations predict that the coordination between top-down gamma and beta rhythms is central to the gating process regulating bottom-up sensory signaling projected from A1 to Par2 and that cholinergic modulation allows this coordination to occur.

Scrotal reconstruction using a superficial circumflex iliac artery perforator flap following Fournier's gangrene.

Fournier's gangrene is a type of necrotising fasciitis around the scrotum and perineum. Because of its aggressive nature, patients should be treated with broad-spectrum antibiotics and emergency, radical debridement during the acute phase. After recovering from the acute phase, reconstruction of the scrotal and perineal soft tissue defects is needed and is often challenging. Traditionally, various reconstruction methods have been used, including skin grafts, fasciocutaneous flaps and musculocutaneous flaps, each with its pros and cons. We successfully covered a wide scrotal defect using a superficial circumflex iliac artery perforator flap, which has not been previously reported for this indication. The design and operative technique are introduced in this study.

MUC5AC and MUC5B enhance the characterization of mucinous adenocarcinomas of the lung and predict poor prognosis.

AIMS: From the viewpoint of histogenesis, lung adenocarcinoma can be subdivided into two groups: terminal respiratory unit (TRU) and non-TRU types. We recently reported a non-TRU type adenocarcinoma designated as ciliated adenocarcinoma (we now prefer central type adenocarcinoma). We suggest reasons that mucinous adenocarcinoma should encompass central type adenocarcinoma to represent its biological characteristics as non-TRU type adenocarcinoma. METHODS AND RESULTS: Mucin (MUC)5AC and MUC5B were expressed more significantly in non-TRU type adenocarcinoma (P < 0.01). Thirty-five (76.1%) and 45 cases (97.8%) of 46 non-TRU type adenocarcinoma showed positivity for MUC5AC and MUC5B. Twelve (7.6%) and eight (5.1%) cases of 157 TRU type adenocarainoma showed positivity for MUC5B and MUC5AC. NKX2-1 gene expression was measured with quantitative reverse transcription-polymerase chain reaction (qRT-PCR). ΔΔCt of NKX2-1 gene expression was 6.79 for TRU type adenocarcinoma and 0.6 for non-TRU type adenocarcinoma. Overall survival and disease-free survival were poorer in non-TRU type adenocarcinoma (P = 0.02 and P = 0.03). A multivariate test also showed that non-TRU type adenocarcinoma is an independent prognostic factor (P = 0.04). CONCLUSION: MUC5AC and MUC5B were specific makers for non-TRU adenocarcinoma, including both central type adenocarcinoma and mucinous adenocarcinoma. We suggest that non-TRU type adenocarcinoma presents a poorer prognosis, so it should be regarded separately from TRU type adenocarcinoma.

The selective A3AR antagonist LJ-1888 ameliorates UUO-induced tubulointerstitial fibrosis.

Adenosine in the normal kidney significantly elevates in response to cellular damage. The renal A3 adenosine receptor (A3AR) is up-regulated under stress, but the therapeutic effects of A3AR antagonists on chronic kidney disease are not fully understood. The present study examined the effect of LJ-1888 [(2R,3R,4S)-2-[2-chloro-6-(3-iodobenzylamino)-9H-purine-9-yl]-tetrahydrothiophene-3,4-diol], a newly developed potent, selective, species-independent, and orally active A3AR antagonist, on unilateral ureteral obstruction (UUO)-induced renal fibrosis. Pretreatment with LJ-1888 inhibited UUO-induced fibronectin and collagen I up-regulation in a dose-dependent manner. Masson's trichrome staining confirmed that LJ-1888 treatment effectively reduced UUO-induced interstitial collagen accumulation. Furthermore, delayed administration of LJ-1888 showed an equivalent therapeutic effect on tubulointerstitial fibrosis to that of losartan. Small-interfering A3AR transfection effectively inhibited transforming growth factor-ß1 (TGF-ß1)-induced fibronectin and collagen I up-regulation in proximal tubular cells similar to LJ-1888, confirming that the renoprotective effect of LJ-1888 resulted from A3AR blockade. UUO- or TGF-ß1-induced c-Jun N-terminal kinase and extracellular signal-regulated kinase phosphorylation decreased significantly after LJ-1888 administration. A3AR blockade reduced UUO- or TGF-ß1-induced up-regulation of lysyl oxidase, which induces cross-linking of extracellular matrix, suggesting that LJ-1888 may also regulate extracellular matrix accumulation via post-translational regulation. In conclusion, the present data demonstrate that the A3AR antagonist, LJ-1888, blocked the development and attenuated the progression of renal fibrosis, and they suggest that LJ-1888 may become a new therapeutic modality for renal interstitial fibrosis.

Top-down beta rhythms support selective attention via interlaminar interaction: a model.

Cortical rhythms have been thought to play crucial roles in our cognitive abilities. Rhythmic activity in the beta frequency band, around 20 Hz, has been reported in recent studies that focused on neural correlates of attention, indicating that top-down beta rhythms, generated in higher cognitive areas and delivered to earlier sensory areas, can support attentional gain modulation. To elucidate functional roles of beta rhythms and underlying mechanisms, we built a computational model of sensory cortical areas. Our simulation results show that top-down beta rhythms can activate ascending synaptic projections from L5 to L4 and L2/3, responsible for biased competition in superficial layers. In the simulation, slow-inhibitory interneurons are shown to resonate to the 20 Hz input and modulate the activity in superficial layers in an attention-related manner. The predicted critical roles of these cells in attentional gain provide a potential mechanism by which cholinergic drive can support selective attention.

Differential representation of auditory categories between cell classes in primate auditory cortex.

A comprehensive understanding of the neural mechanisms of cognitive function requires an understanding of how neural representations are transformed across different scales of neural organization: from within local microcircuits to across different brain areas. However, the neural transformations within the local microcircuits are poorly understood. Particularly, the role that two main cell classes of neurons in cortical microcircuits (i.e. pyramidal neurons and interneurons) have in auditory behaviour and cognition remains unknown. In this study, we tested the hypothesis that pyramidal cells and interneurons in the auditory cortex play a differential role in auditory categorization. To test this hypothesis, we recorded single-unit activity from the auditory cortex of rhesus monkeys while they categorized speech sounds. Based on the spike-waveform shape, a neuron was classified as either a narrow-spiking putative interneuron or a broad-spiking putative pyramidal neuron. We found that putative interneurons and pyramidal neurons in the auditory cortex differentially coded category information: interneurons were more selective for auditory categories than pyramidal neurons. These differences between cell classes may be an essential property of the neural computations underlying auditory categorization within the microcircuitry of the auditory cortex.

Determination of CO2 solubility in semi-crystalline polylactic acid with consideration of rigid amorphous fraction.

Due to phase heterogeneity in semi-crystalline polymers, accurate determination of gas solubility has been a challenge. In this regard, PLA/CO2 was used as a case study to investigate the parameters governing formation of the rigid amorphous fraction (RAF) and its effect on the gas sorption behavior of the polymer. Six samples with different degrees of RAF were prepared through varying PLA tacticity and thermal history. Then, a gravimetric method involving a magnetic suspension balance and an in-house PVT visualization system was employed to experimentally determine the CO2 solubility at 70 °C under a pressure of 4.5 MPa. Furthermore, a theoretical CO2 solubility was calculated based on the Simha-Somcynski equation of state and was used in conjunction with the two-phase and three-phase models to describe the phase dependency of the gas solubility. The conventional two-phase model that considered the bulk amorphous phase consistently over-approximated the CO2 solubility compared to the measured data. On the other hand, the three-phase model that distinguished the rigid and the mobile amorphous phases well represented the experimental result. The analysis yielded CO2 solubility coefficients of 0.0375 ggas/gpoly for the RAF and 0.0817 ggas/gpoly for the mobile counterpart.

Determination of polyphenols in three Capsicum annuum L. (bell pepper) varieties using high-performance liquid chromatography-tandem mass spectrometry: their contribution to overall antioxidant and anticancer activity.

A mixture of polyphenol components was isolated from the fruits of C. annuum L. cv. Cupra, C. annuum L. cv. Orange glory, and C. annuum L. cv. ST4712 (CLST), via 70% methanol extraction followed by column chromatography over silica gel. The polyphenol components of the mixture were analyzed via HPLC-MS/MS and compared with the reported data. Three cinnamic acid derivatives and five flavonoid components in the fruits of the three varieties were identified for the first time in this study. The antioxidant activity and anticancer effect of the polyphenol mixtures of the three fruits were determined. The antioxidant and anticancer activities of CLST were substantially higher than those of C. annuum L. cv. Cupra and C. annuum L. cv. Orange glory. The high activities of CLST were attributed to the much higher concentration of quercetin derivatives in CLST.

Seven-year survival analysis in women with unsuspected uterine malignancy after laparotomic versus laparoscopic hysterectomy: A national claim data retrospective cohort study.

OBJECTIVE: The primary aim was to compare the overall survival of women with unsuspected uterine malignancy (UUM) diagnosed after laparotomic versus laparoscopic hysterectomy for benign gynecologic diseases. The secondary aim was to evaluate the incidence of UUM. METHODS: A national health insurance database was analyzed from 2006 to 2010. RESULTS: From the database (24 million women annually), 157 232 women who received hysterectomy for benign diseases were extracted. These women were divided into a laparotomic group (n = 103 631) and a laparoscopic group (n = 53 601). The overall incidences of UUM, unsuspected endometrial cancer, and unsuspected uterine malignancy other than endometrial cancer (UUMOEC) were 0.66%, 0.46%, and 0.19%, respectively. Kaplan-Meier survival analysis and Cox regression analysis showed that the laparoscopic group was associated with more favorable overall survival than the laparotomic group, especially in UUMOEC (P < 0.001). CONCLUSION: In women with UUM diagnosed after hysterectomy for benign diseases, overall survival up to 7 years favors laparoscopy over laparotomy, especially in UUMOEC and the incidence of UUM is relatively low. However, considering the devastating effect of intraperitoneal dissemination of UUM, surgeons should fully explain this issue to patients preoperatively and try to avoid intraperitoneal spread of tumor cells intraoperatively.

High-Condensed Tannin Diet and Transportation Stress in Goats: Effects on Physiological Responses, Gut Microbial Counts and Meat Quality.

Feeding condensed tannin (CT)-containing diets such as sericea lespedeza (Lespedeza cuneata) and reducing stress have been reported to improve meat quality and food safety in goats. In a completely randomized design with split-plot, thirty-six uncastrated male Spanish goats were assigned to 3 dietary treatments (n = 12/treatment): ground 'Serala' sericea lespedeza hay (SER), bermudagrass (Cynodon dactylon) hay (BG), or bermudagrass hay-dewormed goats (BG-DW; Control) at 75% of intake, with a corn-based supplementation (25%) for 8 weeks. Prior to slaughter, goats were either transported for 90 min to impose stress or held in pens. Basophil counts were lower (p < 0.01) in the SER group compared to BG or BG-DW groups suggesting a better anti-inflammatory capacity due to polyphenols in the SER diet. Compared to BG-DW group, cortisol level was higher (p < 0.05) and norepinephrine was lower (p < 0.05) in the SER group. The SER group had the lowest aerobic plate counts (APC) in both rumen and rectum (p < 0.01). Longissimus dorsi muscle initial pH was not affected by diet or stress. Feeding sericea hay to goats may have beneficial effects, such as enhanced antioxidant and anti-inflammatory properties during stress and reduced gut microbial counts, without changing meat quality characteristics.

Clinical effectiveness of botulinum toxin A compared to a mixture of steroid and local anesthetics as a treatment for sacroiliac joint pain.

OBJECTIVE: The sacroiliac joint (SIJ) is one of the sources of low back pain and referred pain to the lower limb. Steroid injections have been used to treat SIJ pain, but this frequently necessitates repeated injections. Botulinum toxin (BT) type A has been shown to provide significant reduction of joint pain, and functional improvements. This study investigated the efficacy of BT for reducing SIJ pain and maintaining a clinical effect, compared with steroid injections. DESIGN: Prospective case control study. SETTING: Spine hospital. PATIENTS: Patients who were diagnosed with SIJ syndrome based on physical examination and diagnostic SIJ injection were selected. INTERVENTIONS: Either Dysport (BT group) or a mixture of triamcinolone and lidocaine (triamcinolone and local anesthetics [TA] group) was injected into the posterior sacroiliac ligaments under C-arm fluoroscopy. OUTCOME MEASURES: Numeric Rating Scale (NRS) and Oswestry Disability Index (ODI) were used for evaluation at pretreatment, 1 month, 2 months, and 3 months after treatment. RESULTS: At 1 month, the BT and TA group showed no significant differences in NRS or ODI. However, at 2 and 3 months, the BT group had significantly lower scores in NRS and ODI than did the TA group. CONCLUSION: BT shows clinical usefulness in pain reduction and for functional improvement in patients with SIJ pain. This effect was maintained for 3 months following the injection, by which time the effects of TA had diminished.

Neurobehavioral performance in young adults living on a 28-h day for 6 weeks.

OBJECTIVES: Performance on many cognitive tasks varies with time awake and with circadian phase, and the forced desynchrony (FD) protocol can be used to separate these influences on performance. Some performance tasks show practice effects, whereas the Psychomotor Vigilance Task (PVT) has been reported not to show such effects. We aimed to compare performance on the PVT and on an addition test (ADD) across a 6-week FD study, to determine whether practice effects were present and to analyze the circadian and wake-dependent modulation of the 2 measures. DESIGN AND SETTING: A 47-day FD study conducted at the Brigham and Women's Hospital General Clinical Research Center. PARTICIPANTS: Eleven healthy adults (mean age: 24.4 years, 2 women). MEASUREMENTS AND RESULTS: For 2 baseline days and across 6 weeks of FD, we gave a test battery (ADD, PVT, self-rating of effort and performance) every 2 hours. During FD, there was a significant (P < 0.0001) improvement in ADD performance (more correct calculations completed), whereas PVT performance (mean reaction time, fastest 10% reaction times, lapses) significantly (P < 0.0001) declined week by week. Subjective ratings of PVT performance indicated that subjects felt their performance improved across the study (P < 0.0001), but their rating of whether they could have performed better with greater effort did not change across the study (P > 0.05). CONCLUSIONS: The decline in PVT performance suggests a cumulative effect of sleep loss across the 6-week study. Subjects did not accurately detect their declining PVT performance, and a motivational factor could not explain this decline.

Clinical or radiologic measurements and 3-D gait analysis in children with pes planus.

BACKGROUND: Static measurement in clinical and radiologic evaluation is often used in assessment of pes planus, but it is important to know whether pes planus leads to abnormal gait pattern. The purpose of the present study was to assess the clinical and radiologic findings of children with pes planus and the relationship between clinical, radiologic findings and parameters obtained in 3-D gait analysis. METHODS: Thirteen children with pes planus were selected. Physical measurements included femoral anteversion, internal and external rotation, thigh-foot angle (TFA), and resting calcaneal stance position (RCSP). Radiologic measurements included talo-calcaneal angle (TCA), talometatarsal angle (TMA), calcaneal pitch, and forefoot adduction on simple X-ray, and femoral anteversion, tibial torsion and rotation on computed tomography (CT). 3-D gait analysis was also performed and kinetic and kinematic data were obtained in sagittal, frontal, and transverse plane. The correlation between clinical, radiologic, and gait analysis data was investigated. RESULTS: RCSP was found to be significantly correlated with TMA. TMA was also correlated with TCA. TCA on simple X-ray was correlated with maximal internal and external rotation angle of the knee joint on gait analysis. CONCLUSION: TMA was the factor most related to degree of calcaneal valgus measured on physical exam. Larger TCA contributed to decreased maximal external rotation and increased maximal internal rotation in gait cycle. Clinical or radiological methods, however, had very limited ability to predict gait deviance of pes planus.

Characteristics of pediatric-onset spinal cord injury.

BACKGROUND: Although children rarely experience spinal cord injuries (SCI), those who do are subject to various lifelong disabilities and morbidities. The aim of the present study was to retrospectively assess the characteristics of pediatric onset SCI patients and their differences among age groups. METHODS: Clinical characteristics were compared in 48 patients who experienced SCI during childhood and adolescence and who underwent rehabilitation treatment. Clinical characteristics were compared in patients under 4 years old (group A), 4-12 years old (group B), and 13-18 years old (group C) at SCI onset. Radiological findings were compared in 20 patients who were examined on both plain radiograph and computed tomography. RESULTS: The overall male: female ratio was 3:2, with SCI due to non-traumatic causes more frequent overall. Of traumatic causes of SCI, vehicle accident was the most frequent. Of non-traumatic causes, congenital anomaly was most frequent in group A, but tumors became dominant as age increased. Overall, thoracic cord level of injury was most frequent. SCI without radiologic abnormalities (SCIWORA) was predominant in group A, but none was observed in group C. Spinal fractures with or without subluxation accounted for >60% of group C SCI. CONCLUSIONS: Non-traumatic, thoracic cord injury was frequent in the pediatric SCI population. SCIWORA was predominant in younger children.

Peanut skin in diet alters average daily gain, ruminal and blood metabolites, and carcass traits associated with Haemonchus contortus infection in meat goats.

The aim of this study was to determine the effects of tannin-rich peanut skin (PS) supplementation on growth performance, ruminal and blood metabolites, and carcass traits associated with internal parasite infection in meat goats under confined conditions. Twenty-one Kiko crossbred male goats were blocked by body weight (BW) and randomly assigned to one of 3 treatment groups. Experimental diets contained different levels of peanut (Arachis hypogaea) skin replacing alfalfa (Medicago sativa) pellets (ALP) in a control diet. Experimental treatments included: 30% ALP (control), 15% PS and 15% ALP, and 30% PS. Peanut skin was incorporated in the grain mix portion of the diets. Animals were fed once daily, and the intake was adjusted every 3 to 4 d. Each animal was each artificially infected with 5,000 larvae of the 3rd stage of barber's pole worm (Haemonchus contortus). Body weights, dry matter intake (DMI), and fecal samples for fecal egg counts (FEC) were taken at d 0, 12, 23, and 41. Rumen fluid and blood samples were collected at d 45. The performance period lasted 45 d and at the completion of the study, goats were harvested, and carcass characteristics, abomasal worm counts were measured. The results showed that DMI, BW, carcass traits, and meat color were not affected by PS supplementation, whereas average daily gain (ADG, P < 0.01), blood glucose (P < 0.001), phosphorus (P < 0.05), and cholesterol levels (P < 0.001) significantly increased with increasing levels of PS supplementation. There was a linear (P < 0.01) reduction in rumen acetate to propionate ratio, ammonia-nitrogen, FEC, and H. contortus worm counts, with increasing levels of PS supplementation. This study shows that PS supplementation up to 30% of the diet can improve ADG and rumen fermentation while reducing gastrointestinal parasite infection in meat goats.

Insight into the Directional Thermal Transport of Hexagonal Boron Nitride Composites.

Ideal dielectric materials for microelectronic devices should have high directionally tailored thermoconductivity with low dielectric constant and loss. Hexagonal boron nitride (hBN) with excellent thermal and dielectric properties shows a promise for the fabrication of thermoconductive dielectric polymer composites. Herein, a simple method for the fabrication of lightweight polymer/hBN composites with high directionally tailored thermoconductivity and excellent dielectric properties is presented. The solid polymer/hBN composites are manufactured by melt-compounding and injection molding. The porous composites are successfully manufactured in an injection molding process through supercritical fluid (SCF) foaming. X-ray tomography provides direct visualization of the internal microstructure and hBN orientation, leading to an in-depth understanding of the directionally dependent thermoconductivity of the polymer/hBN composite. Shear-induced orientation of hBN platelets in the solid HDPE/hBN composites leads to a significant anisotropic thermal conductivity. The solid HDPE/23.2 vol % hBN composites show an in-plane thermoconductivity as high as 10.1 W m-1 K-1, whereas the through-plane thermoconductivity is limited to 0.28 W m-1 K-1. However, the generation of a porous structure via SCF foaming imparts in situ exfoliation, random orientation, and interconnectivity of hBN platelets within the polymer matrix. This results in highly isotropic thermoconductivity with higher bulk thermal conductivity in the lightweight porous composites as compared to their solid counterparts. Furthermore, the electrically insulating composites developed in this study exhibit low dielectric constant and ultralow dielectric loss. Thus, this study presents a simple fabrication method to develop lightweight dielectric materials with tailored thermal conductivity for modern electronics.