Deep Learning for Perfusion Cerebral Blood Flow (CBF) and Volume (CBV) Predictions and Diagnostics.

Dynamic susceptibility contrast magnetic resonance perfusion (DSC-MRP) is a non-invasive imaging technique for hemodynamic measurements. Various perfusion parameters, such as cerebral blood volume (CBV) and cerebral blood flow (CBF), can be derived from DSC-MRP, hence this non-invasive imaging protocol is widely used clinically for the diagnosis and assessment of intracranial pathologies. Currently, most institutions use commercially available software to compute the perfusion parametric maps. However, these conventional methods often have limitations, such as being time-consuming and sensitive to user input, which can lead to inconsistent results; this highlights the need for a more robust and efficient approach like deep learning. Using the relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) perfusion maps generated by FDA-approved software, we trained a multistage deep learning model. The model, featuring a combination of a 1D convolutional neural network (CNN) and a 2D U-Net encoder-decoder network, processes each 4D MRP dataset by integrating temporal and spatial features of the brain for voxel-wise perfusion parameters prediction. An auxiliary model, with similar architecture, but trained with truncated datasets that had fewer time-points, was designed to explore the contribution of temporal features. Both qualitatively and quantitatively evaluated, deep learning-generated rCBV and rCBF maps showcased effective integration of temporal and spatial data, producing comprehensive predictions for the entire brain volume. Our deep learning model provides a robust and efficient approach for calculating perfusion parameters, demonstrating comparable performance to FDA-approved commercial software, and potentially mitigating the challenges inherent to traditional techniques.

Role of Lymphovascular Invasion in Oral Cavity Squamous Cell Carcinoma Regional Metastasis and Prognosis.

OBJECTIVE: The overall 5-year survival for oral squamous cell carcinoma (OSCC) has not changed in the last 20 years despite advances in treatment. Lymphovascular invasion (LVI) has been shown to be a negative prognostic factor in other cancers, however its role in the prognosis of OSCC remains unclear. This study aims to determine if LVI is a predictor of cervical lymph node metastasis and/or recurrence in OSCC. METHODS: We conducted a retrospective cohort review of patients from our institutional cancer registry who were treated for OSCC between 2004 and 2018. Patient demographics, surgical pathology results, and clinical outcome data were collected. A multivariable logistic regression analysis was performed to determine if LVI was an independent predictor of cervical lymph node metastasis and/or recurrence. RESULTS: 442 patients were included, 32.8% were female and median age at time of diagnosis was 61.2 years. LVI was present in 32.8% of patients. When controlled for age, sex, t-classification, perineural invasion, depth of invasion (DOI), and margin status, LVI was a significant predictor of the presence of cervical node metastasis (OR: 3.42, CI: 2.17-5.39, P < .001). There was no significant association found between LVI and local recurrence (OR: 1.03, CI: 0.57-1.84, P = .92), regional recurrence (OR: 1.10, CI: 0.57-2.11, P = .78), or distant recurrence (OR: 1.59, CI: 0.87-2.94, P = .13). CONCLUSION: The results of this study suggest that LVI is a significant predictor of the presence of cervical lymph node metastasis at presentation independent of other known prognostic factors. LVI, however, was not found to be a significant independent predictor of locoregional or distant recurrence.Level of Evidence: Level III.

Association of Core Biopsy With Extranodal Extension in Surgically Treated Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma.

Importance: Extranodal extension (ENE) is an adverse feature in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) and is an indication for adjuvant treatment escalation. Preoperative core needle biopsy (CNB) may cause lymph node capsule disruption related to ENE development; however, evidence regarding this association in OPSCC is lacking. Objective: To assess whether preoperative nodal CNB is associated with presence of ENE in final pathology findings among patients with HPV-associated OPSCC targeted for primary surgical resection. Design, Setting, and Participants: This retrospective cohort study was conducted at a single academic tertiary care center from 2012 to 2022. All patients with OPSCC treated with transoral robotic surgery were assessed for eligibility, and primary surgical patients with HPV-associated OPSCC and node-positive disease confirmed on neck dissection were included in analyses. Data were analyzed from November 28, 2022, to May 21, 2023. Exposure: Preoperative nodal CNB. Main Outcomes and Measures: The primary outcome was presence of ENE in final pathology findings. Secondary outcomes included adjuvant chemotherapy and recurrence rates. Outcomes of interest were investigated against patient demographic, clinical, and pathologic features. Results: Of 106 patients (mean [SD] age, 60.2 [10.9] years; 99 [93.4%] men) included in analyses, 23 patients (21.7%) underwent CNB. Mean (range) preoperative node size was 3.0 (0.9-6.0) cm. Pathologic node class was pN1 in 97 patients (91.5%) and pN2 in 9 patients (8.5%). A total of 49 patients (46.2%) had ENE identified in final pathology analysis. Of 94 patients who received adjuvant therapy, 58 (61.7%) underwent radiation therapy and 36 (38.3%) underwent chemoradiation therapy. There were 9 recurrences (8.5%). In univariate analysis, CNB was associated with ENE (odds ratio [OR], 2.70; 95% CI, 1.03-7.08), but there was no association in a multivariable model including pN class and preoperative node size (OR, 2.56; 95% CI, 0.97-7.27). Compared with pN1 class, pN2 class was associated with ENE (OR, 10.93; 95% CI, 1.32-90.80). There were no associations of ENE with preoperative node size, presence of cystic or necrotic nodes, fine needle aspiration, tobacco or alcohol exposure, pathologic T class, prior radiation, or age. Furthermore, use of CNB was not associated with macroscopic ENE, adjuvant chemotherapy, or recurrence. Conclusions and Relevance: This cohort study of patients with HPV-associated OPSCC found that preoperative nodal CNB was strongly associated with ENE in final pathology, supporting the possibility of an artifactual ENE component in this population.

Exploring the Role of External Beam Radiation Therapy in Osteosarcoma Treatment: Impact of Diagnostic Imaging Delays and Innovative Techniques.

Osteosarcomas are a type of bone cancer that typically affect young adults, often in the bones of the arms and legs. To treat osteosarcoma, doctors typically use a combination of chemotherapy, radiotherapy, and surgery, with External Beam Radiation Therapy (EBRT) being the most commonly used form of radiotherapy. EBRT involves directing high-energy photons, X-rays, gamma rays, protons, and electrons at the tumor to induce cancer cell death. Additionally, healthcare providers use imaging techniques to monitor treatment success. This literature review aims to explore the relationship between osteosarcomas and EBRT, investigate the impact of the delayed diagnosis on survival rates, and examine the effectiveness of innovative uses of EBRT for treating osteosarcomas in unusual locations using comprehensive diagnostic techniques. To achieve these objectives, the review examines case studies and literary analyses and categorizes them based on the delay between symptom onset and diagnosis. The null hypothesis is that the presence or absence of a delay in diagnosis does not significantly impact outcomes for the "Delay" category. A lack of delay results in a more favorable outcome in the "Lack of Delay" category. However, the data and statistical results suggest that additional follow-up care in patients with rare or commonly recurring cancers could benefit outcomes. It is important to note that due to the rarity of osteosarcoma with EBRT, the small sample size in the studies warrants further investigation. Interestingly, many patients presented with head and neck tumors despite the most common location of osteosarcoma being in the long bones.

Presentation and outcomes of patients with clinically T1-2, N0 oropharynx squamous cell carcinoma: The interplay of primary treatment modality and human papillomavirus status.

BACKGROUND: To examine the pattern of utilization and outcomes of definitive radiotherapy (RT) versus primary robotic-assisted surgery in patients with early-stage oropharyngeal squamous cell carcinoma (OPSCC). METHODS: A retrospective cohort analysis of patients with clinically T1-2, N0 OPSCC was performed using the National Cancer Database, 2010-2016. RESULTS: A total of 1451 patients were included. Prevalence of human papillomavirus (HPV)-positive tumors was 58.30%. Primary surgery was performed in 30.25% of the sample. Tongue base and clinically T1 tumors were each associated with a higher likelihood of undergoing surgery (p < 0.05). Histopathology of patients who underwent surgery demonstrated a prevalence of 15.95% with lymphovascular invasion, 16.67% with extranodal extension, 19.36% were T updated, and 30.00% were N upstaged. Improved survival was observed in the surgery + adjuvant RT group compared to RT alone for HPV-positive tumors (HR: 0.27; 95%CI: 0.12, 0.62; p = 0.002). CONCLUSION: This study provides epidemiological perspective regarding management pattern and outcomes of patients with early-stage OPSCC.

Upgrading Carbonate Electrolytes for Ultra-stable Practical Lithium Metal Batteries.

LiNO3 is a widely used salt-additive that markedly improves the stability of ether-based electrolytes at a Li metal anode but is generally regarded as incompatible with alkyl carbonates. Here we find that contrary to common wisdom, cyclic carbonate solvents such as ethylene carbonate can dissolve up to 0.7 M LiNO3 without any additives, largely improving the anode reversibility. We demonstrate the significance of our findings by upgrading various state-of-the-art carbonate electrolytes with LiNO3 , which provides large improvements in batteries composed of thin lithium (50 µm) anode and high voltage cathodes. Capacity retentions of 90.5 % after 600 cycles and 92.5 % after 200 cycles are reported for LiNi0.6 Mn0.2 Co0.2 O2 (2 mAh cm-2 , 0.5 C) and LiNi0.8 Mn0.1 Co0.1 O2 cathode (4 mAh cm-2 , 0.2 C), respectively. 1 Ah pouch cells (≈300 Wh kg-1 ) retain more than 87.9 % after 100 cycles at 0.5 C. This work illustrates that reforming traditional carbonate electrolytes provides a scalable, cost-effective approach towards practical LMBs.

Prognostic Impact of Metastatic Site and Pattern in Patients with Metastatic Head and Neck Cancer.

OBJECTIVES/HYPOTHESIS: Investigate the relationship between site and pattern of distant metastasis (DM) and overall survival (OS) in a multi-institutional cohort of patients with DM head and neck cancer (HNC). STUDY DESIGN: Retrospective review. METHODS: 283 patients treated at 4 academic centers in the Midwest HNC Consortium between 2000 and 2015 were retrospectively reviewed. Disease patterns were divided between solitary metastatic versus polymetastatic (≥2 sites) disease. Survival functions for clinically relevant variables were estimated using Kaplan-Meier and Cox proportional hazards models. RESULTS: Median OS for all patients was 9.0 months (95% confidence interval [CI]: 7.4-10.6). Lung (n = 220, 77.7%) was the most common site of DM, followed by bone (n = 90, 31.8%), mediastinal lymph nodes (n = 55, 19.4%), liver (n = 41, 14.5%), and brain (n = 17, 6.0%). Bone metastases were independently associated with the worst prognosis (hazard ratio [HR] = 1.6, 95% CI: 1.3-2.1). On univariate analysis, brain metastases were associated with improved prognosis (HR = 0.5, 95% CI: 0.3-0.9), although this was not statistically significant on the multivariate analysis. Polymetastatic disease was present in the majority of patients (n = 230, 81.3%) and was associated with a worse prognosis compared to solitary metastatic disease (HR = 1.4, 95% CI: 1.0-2.0). CONCLUSION: Our large, multi-institutional review indicates that both the metastatic pattern and site of DM impact OS. Polymetastatic disease and bone metastasis are associated with worse prognosis, independent of treatment received. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1838-E1846, 2021.

Electrodiagnostic testing in acute facial palsy: Outcomes and comparison of methods.

OBJECTIVE: To study the relationship between various electrodiagnostic modalities in acute facial palsy. SETTING: Academic tertiary care center. PATIENTS: One-hundred and six patients who presented with traumatic or non-traumatic acute facial paralysis (House-Brackmann, HB, grade 6/6) between 2008 and 2017 and underwent acute electrodiagnostic testing. INTERVENTION: Electroneurography (ENoG) using nasolabial fold (NLF) or nasalis muscle (NM) methods, and volitional electromyography (EMG) in all patients. MAIN OUTCOME MEASURES: Percent degeneration of ipsilateral facial nerve compound muscle action potentials (CMAP) on NLF- and NM-ENoG, presence or absence of muscle unit potentials (MUPs) on EMG. RESULTS: Extent of facial nerve degeneration measured by NLF- and NM-ENoG were highly correlated (r = 0.85, P < .01) on each test and on serial testing. NLF- and NM-ENoG concordantly diagnosed ≥90% degeneration in 44 patients (80%), of whom 32 patients were diagnosed to have 100% degeneration by both methodologies. Absence of MUPs on EMG was 63% sensitive and 92% specific for ≥90% degeneration on ENoG, with a positive predictive value of 90%. For patients with Bell's palsy, percent degeneration on ENoG was also correlated to HB score at 1 year. Surgical decompression resulted in mean HB scores of 2.2 and 3.0 for patients with Bell's palsy and trauma, respectively. CONCLUSIONS: NM-ENoG may be a valid and comparable method to NLF-ENoG for predicting the recovery of facial nerve function in acute paralysis. Absence of MUPs on EMG is a specific measure of severe degeneration and highly predictive of candidacy for surgical decompression. LEVEL OF EVIDENCE: Level 3.

Surgical Outcomes in Idiopathic Recurrent Facial Nerve Paralysis: A Rare Clinical Entity.

OBJECTIVE: To evaluate the postoperative facial nerve dysfunction, audiometric outcomes, and long-term quality-of-life outcomes of patients with idiopathic recurrent facial nerve paralysis (RFP) after middle cranial fossa (MCF) microsurgical decompression. METHODS: Retrospective chart analysis of 11 (mean age 37.0 years, range 5 to 67) patients at an academic tertiary referral center who underwent MCF facial nerve decompression. Data analysis included evaluation of pre- and postoperative House-Brackmann (HB) score, pre- and postoperative pure-tone average (PTA), pre-and postoperative word recognition scores (WRS), and postoperative Facial Clinimetric Evaluation survey. RESULTS: Mean number of preoperative facial paralysis episodes was 3.5 (range 2 to 6), and preoperative HB score was 4.5 (range 1 to 6). Postoperatively, 0 patients had further episodes of facial nerve paralysis at an average of 6.5 years (range 0.1 to 17.6) (P = 0.005), and the average postoperative HB score was 2.1 (range 1 to 3) (P = 0.011). Postoperative audiometry was stably maintained as assessed with PTA and WRS scores. CONCLUSION: Microsurgical facial nerve decompression for idiopathic RFP may be a reliable therapeutic modality to prophylactically decrease the number of facial nerve paralysis episodes and may also help to improve facial nerve functional status. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:200-205, 2020.

Long-term audiologic outcomes after cochlear implantation for single-sided deafness.

OBJECTIVES: To evaluate the long-term audiometric outcomes, sound localization abilities, binaural benefits, and tinnitus assessment of subjects with cochlear implant (CI) after a diagnosis of unilateral severe-to-profound hearing loss. METHOD: The study group consisted of 60 (mean age 52 years, range 19-84) subjects with profound hearing loss in one ear and normal to near-normal hearing in the other ear who underwent CI. Data analysis included pre- and postoperative Consonant-Nucleus-Consonant (CNC) Word scores, AzBio Sentence scores, pure tone thresholds, sound localization, and Iowa Tinnitus Handicap Questionnaire scores. RESULTS: Preoperative average duration of deafness was 3.69 years (standard deviation 4.31), with an average follow-up time of 37.9 months (range 1-87). CNC and AzBio scores significantly improved (both P < 0.001) postoperatively among the entire cohort, and there was much heterogeneity in outcomes with respect to deafness etiology subgroup analysis. Sound localization abilities tended to improve longitudinally in the entire cohort. Binaural benefits using an adaptive Hearing in Noise Test test showed a significant (P < 0.001) improvement with head shadow effect. Utilizing the Iowa Tinnitus Handicap Questionnaire, there was significant improvement in social, physical, and emotional well-being (P = 0.011), along with hearing abilities (P = 0.001). CONCLUSIONS: This case series is the largest cohort of CI SSD subjects to date and systematically analyzes their functional outcomes. Subjects have meaningful improvement in word understanding, and sound localization tends to gradually improve over time. Binaural benefit analysis showed significant improvement with head shadow effect, which likely provides ease of listening. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:1805-1811, 2020.

Upconversion luminescence nanoparticles-based immunochromatographic assay for quantitative detection of triamcinolone acetonide in cosmetics.

Triamcinolone acetonide (TCA) abuse in cosmetics is a common phenomenon. A rapid lateral flow immunochromatographic assay (ICA) was developed for the quantitative detection of TCA using a probe based on upconversion luminescence nanoparticles. Lanthanide-doped upconversion nanoparticles (UCNPs) were synthesized in a system comprising water and ethylene glycol, and a silicon dioxide layer was covered at the carboxyl site. A binding site protection strategy was used to decrease the background signal of UCNPs-ICA. Using dexamethasone derivative as a coating antigen, the optimal UCNPs-ICA exhibits good dynamic linear detection for TCA in the range 1.0-100 ng mL-1 with a median inhibitory concentration of 9.8 ng mL-1. The detection limits for TCA in a cosmetic sample are 20 µg kg-1. The pretreatment of samples only needs dilution with water, suggesting the assay can quantitate TCA on-site using a portable upconversion luminescence reader with a cumulative analysis time of only 10 min.

ZIP4 Promotes Muscle Wasting and Cachexia in Mice With Orthotopic Pancreatic Tumors by Stimulating RAB27B-Regulated Release of Extracellular Vesicles From Cancer Cells.

BACKGROUND & AIMS: Cachexia, which includes muscle wasting, is a frequent complication of pancreatic cancer. There are no therapies that reduce cachexia and increase patient survival, so it is important to learn more about its mechanisms. The zinc transporter ZIP4 promotes growth and metastasis of pancreatic tumors. We investigated its effects on muscle catabolism via extracellular vesicle (EV)-mediated stimulation of mitogen-activated protein kinase 14 (p38 MAPK). METHODS: We studied nude mice with orthotopic tumors grown from human pancreatic cancer cell lines (AsPC-1 and BxPC-3); tumors were removed 8 days after cell injection and analyzed by histology. Mouse survival was analyzed by Kaplan-Meier curves. ZIP4 was knocked down in AsPC-1 and BxPC-3 cells with small hairpin RNAs; cells with empty vectors were used as controls. Muscle tissues were collected from mice and analyzed by histology and immunohistochemistry. Conditioned media from cell lines and 3-dimensional spheroid/organoid cultures of cancer cells were applied to C2C12 myotubes. The myotubes and the media were analyzed by immunoblots, enzyme-linked immunosorbent assays, and immunofluorescence microscopy. EVs were isolated from conditioned media and analyzed by immunoblots. RESULTS: Mice with orthotopic tumors grown from pancreatic cancer cells with knockdown of ZIP4 survived longer and lost less body weight and muscle mass than mice with control tumors. Conditioned media from cancer cells activated p38 MAPK, induced expression of F-box protein 32 and UBR2 in C2C12 myotubes, and also led to loss of myofibrillar protein myosin heavy chain and myotube thinning. Knockdown of ZIP4 in cancer cells reduced these effects. ZIP4 knockdown also reduced pancreatic cancer cell release of heat shock protein (HSP) 70 and HSP90, which are associated with EVs, by decreasing CREB-regulated expression of RAB27B. CONCLUSIONS: ZIP4 promotes growth of orthotopic pancreatic tumors in mice and loss of muscle mass by activating CREB-regulated expression of RAB27B, required for release of EVs from pancreatic cancer cells. These EVs activate p38 MAPK and induce expression of F-box protein 32 and UBR2 in myotubes, leading to loss of myofibrillar myosin heavy chain and myotube thinning. Strategies to disrupt these pathways might be developed to reduce pancreatic cancer progression and accompanying cachexia.

Transcanal Endoscopic Ear Surgery for the Management of Congenital Ossicular Fixation.

OBJECTIVES: 1) To describe the technique for transcanal endoscopic management of congenital ossicular chain fixation. 2) To highlight the utility and outcomes of the endoscopic approach for management of congenital ossicular fixation. STUDY DESIGN: Retrospective patient series. SETTING: Academic tertiary pediatric hospital. PATIENTS: Pediatric patients (age 6-12) undergoing transcanal endoscopic management of congenital ossicular fixation from May 2014 to December 2014. INTERVENTIONS: A transcanal endoscopic approach was used in eight procedures. Ossicular chain pathology was managed with either mobilization, ossiculoplasty with a stapes prosthesis, or incus interposition. MAIN OUTCOME MEASURES: Pure-tone averages, speech reception thresholds, and speech discrimination scores were recorded pre- and postoperatively for each subject. Preoperative computed tomography evaluations were compared to intraoperative findings for each subject. RESULTS: An improvement in the pure-tone average, as well as air-bone gap, was noted after six of eight procedures. No patients experienced a complication or a reduction in their bone conduction hearing. The chorda tympani nerve was preserved in all eight patients. Conversion to open approach was not necessary for any of the eight procedures performed. CONCLUSION: The transcanal endoscopic approach was successful in improving hearing in pediatric patients with congenital ossicular fixation that involves any of the three ossicles. An endoscopic transcanal approach provides an alternative method to manage congenital ossicular pathology with the advantage of providing excellent visualization and the avoidance of a postauricular incision.

Oral oestrogen reverses ovariectomy-induced morning surge hypertension in growth-restricted mice.

Perinatal growth restriction (GR) is associated with heightened sympathetic tone and hypertension. We have previously shown that naturally occurring neonatal GR programmes hypertension in male but not female mice. We therefore hypothesized that intact ovarian function or post-ovariectomy (OVX) oestrogen administration protects GR female mice from hypertension. Utilizing a non-interventional model that categorizes mice with weanling weights below the tenth percentile as GR, control and GR adult mice were studied at three distinct time points: baseline, post-OVX and post-OVX with oral oestrogen replacement. OVX elicited hypertension in GR mice that was significantly exacerbated by psychomotor arousal (systolic blood pressure at light to dark transition: control 122 ± 2; GR 119 ± 2; control-OVX 116 ± 3; GR-OVX 126 ± 3 mmHg). Oestrogen partially normalized the rising blood pressure surge seen in GR-OVX mice (23 ± 7% reduction). GR mice had left ventricular hypertrophy, and GR-OVX mice in particular had exaggerated bradycardic responses to sympathetic blockade. For GR mice, a baseline increase in baroreceptor reflex sensitivity and high frequency spectral power support a vagal compensatory mechanism, and that compensation was lost following OVX. For GR mice, the OVX-induced parasympathetic withdrawal was partially restored by oestrogen (40 ± 25% increase in high frequency spectral power, P<0.05). In conclusion, GR alters cardiac morphology and cardiovascular regulation. The haemodynamic consequences of GR are attenuated in ovarian-sufficient or oestrogen-replete females. Further investigations are needed to define the role of hormone replacement therapy targeted towards young women with oestrogen deficiency and additional cardiovascular risk factors, including perinatal GR, cardiac hypertrophy and morning surge hypertension.

Transcanal Endoscopic Management of Cerebrospinal Fluid Otorrhea Secondary to Congenital Inner Ear Malformations.

OBJECTIVE: To describe the feasibility of using a transcanal endoscopic approach for management of cerebrospinal leaks secondary to congenital inner ear malformations. PATIENTS: Two pediatric patients with congenital inner ear malformations and concurrent cerebrospinal fluid leakage. INTERVENTION: A stapedectomy was performed and the inner ear was packed with temporalis muscle using a transcanal endoscopic approach. MAIN OUTCOME MEASURE: Cessation of cerebrospinal fluid leakage from the inner ear to the middle ear. RESULTS: An otic capsule malformation with a modiolar defect as well as a defect in the stapes footplate was noted in both patients. Successful repair of cerebrospinal fluid otorrhea was achieved in both patients using a minimally invasive transcanal endoscopic approach. One patient developed postoperative meningitis that was successfully managed with antibiotics. CONCLUSIONS: Cerebrospinal fluid otorrhea from an inner ear malformation often presents as persistent clear otorrhea after tympanostomy tube placement or recurrent meningitis as was the case in the two patients in this series. A minimally invasive transcanal endoscopic approach is a viable alternative to manage this unique entity.

Growth restriction, leptin, and the programming of adult behavior in mice.

Prematurity and neonatal growth restriction (GR) are risk factors for autism and attention deficit hyperactivity disorder (ADHD). Leptin production is suppressed during periods of undernutrition, and we have shown that isolated neonatal leptin deficiency leads to adult hyperactivity while neonatal leptin supplementation normalizes the brain morphology of GR mice. We hypothesized that neonatal leptin would prevent the development of GR-associated behavioral abnormalities. From postnatal day 4-14, C57BL/6 mice were randomized to daily injections of saline or leptin (80ng/g), and GR was identified by a weanling weight below the tenth percentile. The behavioral phenotypes of GR and control mice were assessed beginning at 4 months. Within the tripartite chamber, GR mice had significantly impaired social interaction. Baseline escape times from the Barnes maze were faster for GR mice (65+/-6s vs 87+/-7s for controls, p<0.05), but GR mice exhibited regression in their escape times on days 2 and 3 (56% regressed vs 22% of control saline mice, p<0.05). Compared to controls, GR mice entered the open arms of the elevated plus maze more often and stayed there longer (72+/-10s vs 36+/-5s, p<0.01). Neonatal leptin supplementation normalized the behavior of GR mice across all behavioral assays. In conclusion, GR alters the social interactions, learning and activity of mice, and supplementation with the neurotrophic hormone leptin mitigates these effects. We speculate neonatal leptin deficiency may contribute to the adverse neurodevelopmental outcomes associated with postnatal growth restriction, and postnatal leptin therapy may be protective.

Recurrent cholesteatoma with massive extension to temporoparietal scalp: case report and literature review.

BACKGROUND: Cholesteatomas are locally destructive collections of epithelial debris arising from temporal bone squamous epithelium. Recurrences may occur after removal and are typically located within the temporal bone. OBJECTIVE: This study aimed to report a case of a massive, recurrent cholesteatoma with extension to temporoparietal scalp in a 37-year-old woman. METHODS: Case report with literature review. RESULTS: The patient underwent complete excision of a well-circumscribed left temporal mass, intraoperatively identified to arise from the middle ear and to contain keratin debris. CONCLUSION: We report a case of recurrent cholesteatoma with massive extension to temporoparietal scalp. Clinical suspicion of recurrent cholesteatoma should remain in the differential diagnosis of temporal mass with prior history of cholesteatoma.

Genotype-specific alterations in vascular smooth muscle cell function in cystic fibrosis piglets.

BACKGROUND: The most common CF-causing mutations interfere with CFTR trafficking from the endoplasmic reticulum (CFTR-F508del) or prematurely terminate transcription (CFTR-null). We suspected that genotype-specific patterns of CFTR expression would have differential effects on smooth muscle cell calcium signaling and hence vascular tone. We hypothesized that compared to wild-type or CFTR-null aorta, aorta from CFTR-F508del (dF) piglets will have reduced endoplasmic reticulum calcium mobilization and decreased vasoconstriction. METHODS: Aortic reactivity was assessed by myography, and ratiometric calcium imaging was performed in isolated vascular smooth muscle cells. RESULTS: Aorta from dF piglets had reduced myogenic tone (P<0.001) and decreased constriction to KCl (P<0.05). Combined inhibition of ryanodine and IP3 receptors decreased wild-type and CFTR-null responses to levels seen in dF aorta. Compared to wild-type cells, dF-expressing smooth muscle cells had reduced calcium transients, while CFTR-null cells had decreased baseline intracellular calcium concentrations. CONCLUSIONS: Expression of CFTR-F508del interferes with smooth muscle cell calcium handling and decreases aortic responsiveness.

A novel epigenetic CREB-miR-373 axis mediates ZIP4-induced pancreatic cancer growth.

Changes in the intracellular levels of the essential micronutrient zinc have been implicated in multiple diseases including pancreatic cancer; however, the molecular mechanism is poorly understood. Here, we report a novel mechanism where increased zinc mediated by the zinc importer ZIP4 transcriptionally induces miR-373 in pancreatic cancer to promote tumour growth. Reporter, expression and chromatin immunoprecipitation assays demonstrate that ZIP4 activates the zinc-dependent transcription factor CREB and requires this transcription factor to increase miR-373 expression through the regulation of its promoter. miR-373 induction is necessary for efficient ZIP4-dependent enhancement of cell proliferation, invasion, and tumour growth. Further analysis of miR-373 in vivo oncogenic function reveals that it is mediated through its negative regulation of TP53INP1, LATS2 and CD44. These results define a novel ZIP4-CREB-miR-373 signalling axis promoting pancreatic cancer growth, providing mechanistic insights explaining in part how a zinc transporter functions in cancer cells and may have broader implications as inappropriate regulation of intracellular zinc levels plays an important role in many other diseases.