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This paper brings new evidence for PROSODIC CORRESPONDENCE, where prosodic units (e.g. main-stressed nuclei and prominent syllables) of morphologically related forms are compared. Since prosodic correspondence was formalized in Crosswhite’s (1998) analysis of Chamorro, it has received almost no empirical discussion. I argue that Tgdaya Seediq (Austronesian, Atayalic) has vowel alternations that should be analyzed using prosodic correspondence. In Seediq, unsuffixed and suffixed forms tend to share the same stressed syllable nucleus. This VOWEL MATCHING pattern cannot be explained as surface harmony, but it can be explained as the result of a constraint enforcing vowel identity of main-stressed nuclei in morphologically related forms. Unlike the categorical alternations analyzed by Crosswhite (1998), Seediq vowel matching is gradient and only emerges on a statistical level. Nevertheless, prosodic correspondence appears to be active in the synchronic grammar of Seediq; in a production experiment, speakers applied vowel matching to novel forms and even over-generalized it to environments not predicted by lexical statistics. Vowel matching is modeled in Maximum Entropy Harmonic Grammar (Goldwater & Johnson 2003), a stochastic variant of OT. I use prosodic correspondence to enforce vowel matching, and Zuraw’s (2000, 2010) dual listing approach to capture the discrepancy between lexical and experimental results.

We introduce a novel 3D sensing method for recovering a consistent, dense 3D shape of a dynamic, non-rigid object in water. The method reconstructs a complete (or fuller) 3D surface of the target object in a canonical frame (e.g., rest shape) as it freely deforms and moves between frames by estimating underwater 3D scene flow and using it to integrate per-frame depth estimates recovered from two near-infrared observations. The reconstructed shape is refined in the course of this global non-rigid shape recovery by leveraging both geometric and radiometric constraints. We implement our method with a single camera and a light source without the orthographic assumption on either by deriving a practical calibration method that estimates the point source position with respect to the camera. Our reconstruction method also accounts for scattering by water. We prototype a video-rate imaging system and show 3D shape reconstruction results on a number of real-world static, deformable, and dynamic objects and creatures in real-world water. The results demonstrate the effectiveness of the method in recovering complete shapes of complex, non-rigid objects in water, which opens new avenues of application for underwater 3D sensing in the sub-meter range.

The K-means algorithm is the most commonly used clustering method for phonetic vowel description but has some properties that may be sub-optimal for representing phonetic data. This study compares K-means with an alternative algorithm, OPTICS, in two speech styles (lab vs. conversational) in English to test whether OPTICS is a viable alternative to K-means for characterizing vowel spaces. We find that with noisier data, OPTICS identifies clusters that more accurately represent the underlying data. Our results highlight the importance of choosing an algorithm whose assumptions are in line with the phonetic data being considered.

Background: Chyluria is a rare diagnosis classically associated with milky-appearing urine. It involves the leakage of chyle into the urinary tract. Although the most common cause of chyluria worldwide is infectious in nature, other noninfectious etiologies have been described. Classically chyluria resolves spontaneously or with conservative management. Surgical treatments have been described but are not often required. We present a case of iatrogenic pyelolymphatic fistula after robot-assisted laparoscopic dismembered pyeloplasty that was treated with endoscopic electrocautery of the fistulous tract. Case Presentation: A 50-year-old Caucasian man underwent a robot-assisted laparoscopic dismembered pyeloplasty with stent insertion for radiographically demonstrated left ureteropelvic junction obstruction. His postoperative course was uneventful until 4-week follow-up at which time he began to notice intermittent passage of milky-appearing urine. Urinalysis was notable for large protein and elevated urine triglycerides. He was initially managed conservatively dietary modifications without success. He then underwent endoscopic management with cystoscopy and ureteroscopy with fulguration of suspected pyelolymphatic fistula. He was maintained on a low-fat medium-chain triglyceride diet and octreotide injections while inpatient for 1 week postoperatively. His postoperative course was unremarkable and no return of chyluria was observed. His chyluria remained resolved at 9 months postoperatively. Conclusion: Pyelolymphatic fistula after robot-assisted laparoscopic pyeloplasty is a theoretical complication of perirenal dissection and has not been previously described in the literature. It should be considered as a rare iatrogenic cause of chyluria. Endoscopic management with fulguration is technically feasible and may obviate the need for more invasive surgical management.

Background: Ureteral stricture disease is a troubling urologic issue that can be managed with surgical reconstruction or, more conservatively, with chronic nephrostomy tubes or ureteral stents. These indwelling tubes require exchanges and are prone to complications such as encrustation or stent failure. Metallic ureteral stents are designed to be more resistant to extrinsic compression and allow for exchanges at longer intervals. However, encrustation or tissue ingrowth can occur with these stents as well. The removal of encrusted or embedded metallic ureteral stents poses a difficult clinical scenario. We present a case of an encrusted metallic stent embedded in a proximal ureteral stricture requiring percutaneous endoscopic removal with a novel looped-wire technique. Case Presentation: A 50-year-old Caucasian man with bilateral ureteral stricture disease, managed with chronic indwelling metallic stents, failed retrograde removal on the right during routine exchange. Staged procedures with percutaneous nephrostomy, followed by combined percutaneous antegrade and retrograde endoscopy were required to observe and access the embedded stent. The exposed metallic surface was unable to be grasped by available instruments through flexible endoscopy. Under endoscopic control with fluoroscopic guidance, a polytetrafluoroethylene (PTFE)-coated guidewire was looped around the metallic stent. With gentle traction on the wire loop, the embedded stent curl was delivered out of the stricture and into the renal pelvis from where it was extracted carefully with graspers inserted through a rigid nephroscope. Follow-up antegrade fluoroscopic studies with contrast showed no extravasation. Conclusion: Percutaneous removal of metallic stents retained within the ureter has unique challenges. We present a novel method of extraction of a retained metallic stent with a looped PTFE-coated guidewire, which may safely and effectively be used in complex situations.

This study aims to (i) identify patterns of sociophonetic variation in Taiwan Mandarin, and (ii) evaluate smartphone technologies as a tool for crowdsourcing sociophonetic data. Specifically, this study examines both phonological variables found in prior literature to be highly salient (deretroflexion, labiovelar glide deletion), and variables that are less likely to index social properties (merging of final /n, ŋ/, changes to Tones 2 and 3). Unlike past studies which have primarily relied on smaller sample sizes, I utilize a smartphone application to crowdsource audio recordings across Taiwan; subsequent Rbrul analysis of 292 recordings revealed robust patterns of sociolinguistic variation. Deretroflexion correlates strongly with gender and age, while glide deletion correlates with gender. Nasal final merging and tonal change exhibit less socio-indexical variation, but provide evidence of potential change in progress. These findings suggest that smartphone-based crowdsourcing can complement traditional sociolinguistic fieldwork, and reveal new knowledge about large-scale variation.

Mam (Guatemala: Mayan) is described as having a vowel length contrast, as well as a laryngeal contrast between glottalized and modal vowels [England 32–36 (1983)]. Glottalized vowels are described as having a falling pitch contour and being longer relative to their modal counterparts ( ibid.). However, there are no phonetic studies explicitly confirming this. In particular, the Todos Santos dialect has received almost no phonetic investigation, and the presence and realization of the length and laryngeal contrasts is not well-established. This study is one of the first phonetic studies of vowel length and glottalization in Todos Santos Mam. The authors collected data of one native speaker reading a list of words varying in vowel quality. We find evidence for both a length contrast and laryngeal contrast. For the length contrast, short vowels are significantly shorter in duration and lowered relative to long vowels. For the laryngeal contrast, glottalized vowels are found to have a falling pitch contour, while modal vowels have level/rising pitch. In addition, a lengthening effect was found such that short glottalized vowels are longer than their modal counterparts, but it is unclear whether the same effect is present for long glottalized vowels.

Objectives: To compare direct ureteral length measurements with predictive formulas used for the preoperative assessment of ureteral length, and to evaluate patient factors that impact the accuracy...

INTRODUCTION AND OBJECTIVE:Pyelolymphatic fistula is a rare cause of chyluria, the leakage of lymph and chylomicrons derived from fatty acids absorbed in the small intestine. It is classically asso...

The incidental detection of small renal masses (SRMs) is on the rise. However, not all require aggressive treatments as up to 20% are identified as benign, and the majority of malignant tumors harbor indolent features. Improved preoperative diagnostics are needed to differentiate tumors requiring aggressive treatment from those more suitable for surveillance. This chapter introduces the novel concept of confocal laser endomicroscopy (CLE) as a real-time, diagnostic optical biopsy tool for SRMs. Pertinent CLE studies in urology as well as other medical specialties are discussed, including a detailed review of a recent study specifically addressing CLE in ex vivo human SRMs. Future directions in CLE applications and research are explored for a comprehensive look at one of the leading optical imaging technologies currently under development.

In this paper, we introduce a novel method for reconstructing surface normals and depth of dynamic objects in water. Past shape recovery methods have leveraged various visual cues for estimating shape (e.g., depth) or surface normals. Methods that estimate both compute one from the other. We show that these two geometric surface properties can be simultaneously recovered for each pixel when the object is observed underwater. Our key idea is to leverage multi-wavelength near-infrared light absorption along different underwater light paths in conjunction with surface shading. Our method can handle both Lambertian and non-Lambertian surfaces. We derive a principled theory for this surface normals and shape from water method and a practical calibration method for determining its imaging parameters values. By construction, the method can be implemented as a one-shot imaging system. We prototype both an off-line and a video-rate imaging system and demonstrate the effectiveness of the method on a number of real-world static and dynamic objects. The results show that the method can recover intricate surface features that are otherwise inaccessible.

This paper introduces single-image geometric and appearance reconstruction from water reflection photography, i.e., images capturing direct and water-reflected real-world scenes. Water reflection offers an additional viewpoint to the direct sight, collectively forming a stereo pair. The water-reflected scene, however, includes internally scattered and reflected environmental illumination in addition to the scene radiance, which precludes direct stereo matching. We derive a principled iterative method that disentangles this scene radiometry and geometry for reconstructing 3D scene structure as well as its high-dynamic range appearance. In the presence of waves, we simultaneously recover the wave geometry as surface normal perturbations of the water surface. Most important, we show that the water reflection enables calibration of the camera. In other words, for the first time, we show that capturing a direct and water-reflected scene in a single exposure forms a self-calibrating HDR catadioptric stereo camera. We demonstrate our method on a number of images taken in the wild. The results demonstrate a new means for leveraging this accidental catadioptric camera., WACV 2020

Screening for vertebral fractures (VF) in primary hyperparathyroidism (PHPT) is recommended, but there are limited data regarding which patients are at greatest risk for VF. We evaluated risk factors for VF in PHPT.This is a retrospective cross-sectional analysis of 117 participants with PHPT. We assessed Grades 2 and 3 VF by vertebral fracture assessment (VFA) and the association of VF with the trabecular bone score (TBS), other skeletal parameters and clinical risk factors. VFA was performed only in those who met National Osteoporosis Foundation criteria for VFA screening.T-scores were in the osteopenic range and TBS was degraded. Overall VF rate based on VFA or other imaging was 12.8%. Serum PTH, calcium and TBS were not associated with VF. Those with VF were older (p = 0.04), had worse renal function (p = 0.04), were more likely to have received osteoporosis treatment (p = 0.03), and tended to have had a prior fracture (p = 0.06). T-scores did not differ by fracture status at any skeletal site. Those with VF had nine times the odds of osteoporosis at the hip (95% CI 2.4-34.5), but this risk factor had low sensitivity (46.7%) for VF. Hip T-score -2.6, Age 78.6 years, and GFR 58.8 ml/min/1.73 mIn PHPT, VF risk factors included older age, prior fracture, worse renal function and osteoporosis at the hip, but not osteoporosis at other sites, TBS or biochemical indices of PHPT. Since identified risk factors had low sensitivity and were generally inaccurate for categorizing those with VF, the data do not support limiting screening to PHPT patients with these specific VF risk factors.

The incidental detection of small renal masses is increasing. However, not all require aggressive treatments as up to 20% are benign and the majority of malignant tumors harbor indolent features. Improved preoperative diagnostics are needed to differentiate tumors requiring aggressive treatment from those more suitable for surveillance. We evaluated and compared confocal laser endomicroscopy with standard histopathology in ex vivo human kidney tumors as proof of principle towards diagnostic optical biopsy.Patients with a solitary small renal mass scheduled for partial or radical nephrectomy were enrolled in study. Two kidneys were infused with fluorescein via intraoperative intravenous injection and 18 tumors were bathed ex vivo in dilute fluorescein prior to confocal imaging. A 2.6 mm confocal laser endomicroscopy probe was used to image tumors and surrounding parenchyma from external and en face surfaces after specimen bisection. Confocal laser endomicroscopy images were compared to standard hematoxylin and eosin analysis of corresponding areas.Ex vivo confocal laser endomicroscopy imaging revealed normal renal structures that correlated well with histology findings. Tumor tissue was readily distinguishable from normal parenchyma, demonstrating features unique to benign and malignant tumor subtypes. Topical fluorescein administration provided more consistent confocal laser endomicroscopy imaging than the intravenous route. Additionally, en face tumor imaging was superior to external imaging.We report what is to our knowledge the first feasibility study using confocal laser endomicroscopy to evaluate small renal masses ex vivo and provide a preliminary atlas of images from various renal neoplasms with corresponding histology. These findings serve as an initial and promising step toward real-time diagnostic optical biopsy of small renal masses.

Despite guidelines, routine 24-hour urine testing is completed in10% of high-risk, recurrent stone formers. Using surrogates for metabolic testing, such as key patient characteristics, could obviate the cost and burden of this test while providing information needed for proper stone prevention counseling.We performed a retrospective study of 392 consecutive patients from 2007 to 2014 with ≥2 lifetime stone episodes,70% calcium oxalate by mineral analysis, and ≥1 24-hour urine collection. We compared mean 24-hour urine values by age in decades. We used logistic regression and receiver operating characteristic (ROC) curve analysis to assess the predictive ability of age, gender, body mass index (BMI), and comorbidities to detect abnormal 24-hour urine parameters.The mean age of the cohort was 51 ± 16 years. Older age was associated with greater urinary oxalate (p-trend0.001), lower urinary uric acid (UA) (p-trend = 0.007), and lower urinary pH (p-trend0.001). A nonlinear association was noted between age and urinary calcium or citrate (calcium peaked at 40-49 years, p = 0.03; citrate nadired at 18-29 years, p = 0.001). ROC analysis of age, gender, and BMI to predict 24-hour urine abnormalities performed the best for hyperuricosuria (area under the curve [AUC] 0.816), hyperoxaluria (AUC 0.737), and hypocitraturia (AUC 0.740). Including diabetes mellitus or hypertension did not improve AUC significantly.In our recurrent calcium oxalate cohort, age significantly impacted urinary calcium, oxalate, citrate, and pH. Along with gender and BMI, age can be used to predict key 24-hour urine stone risk results. These data lay the foundation for a risk prediction tool, which could be a surrogate for 24-hour urine results in recurrent stone formers, who are unwilling or unable to complete metabolic testing. Further validation of these findings is needed in other stone populations.

OBJECTIVE Individuals with type 1 diabetes who restrict insulin to control weight are at high risk for diabetes-related complications and premature death. However, little is known about this behavior or how to effectively intervene. The aim of the current study was to identify predictors of insulin restriction in the natural environment that might inform new treatment directions. RESEARCH DESIGN AND METHODS Eighty-three adults with type 1 diabetes and a range of eating disorder symptomatology completed 3 days of ecological momentary assessment. Participants reported emotions, eating, and insulin dosing throughout the day using their cellular telephone. Linear mixed models were used to estimate the effects of heightened negative affect (e.g., anxiety) before eating and characteristics of the eating episode (e.g., eating a large amount of food) on the risk of insulin restriction. RESULTS Individuals who reported greater-than-average negative affect (general negative affect and negative affect specifically about diabetes) during the study period were more likely to restrict insulin. Momentary increases in anxiety/nervousness and guilt/disgust with self before eating (relative to an individual’s typical level) further increased the odds of restricting insulin at the upcoming meal. Insulin restriction was more likely when individuals reported that they broke a dietary rule (e.g., “no desserts”). CONCLUSIONS Results suggest that insulin restriction might be decreased by helping patients with type 1 diabetes respond effectively to heightened negative affect (e.g., anxiety, guilt) and encouraging patients to take a less rigid, punitive approach to diabetes management.

Purkinje cells rapidly degenerate in pcd mice due to loss of function of tubulin deglutamylase cytosolic carboxypeptidase 1 (CCP1), which promotes mitochondrial fusion in a Drosophila model, CCP1 null cells, and pcd neurons. The CCP1-mediated increase in mitochondrial motility accounts for CCP1-dependent mitochondrial fusion, underscoring the linkage between regulation of mitochondria dynamics, mitochondria motility, and Purkinje neuron survival., A perplexing question in neurodegeneration is why different neurons degenerate. The Purkinje cell degeneration (pcd) mouse displays a dramatic phenotype of degeneration of cerebellar Purkinje cells. Loss of CCP1/Nna1 deglutamylation of tubulin accounts for pcd neurodegeneration, but the mechanism is unknown. In this study, we modulated the dosage of fission and fusion genes in a Drosophila melanogaster loss-of-function model and found that mitochondrial fragmentation and disease phenotypes were rescued by reduced Drp1. We observed mitochondrial fragmentation in CCP1 null cells and in neurons from pcd mice, and we documented reduced mitochondrial fusion in cells lacking CCP1. We examined the effect of tubulin hyperglutamylation on microtubule-mediated mitochondrial motility in pcd neurons and noted markedly reduced retrograde axonal transport. Mitochondrial stress promoted Parkin-dependent turnover of CCP1, and CCP1 and Parkin physically interacted. Our results indicate that CCP1 regulates mitochondrial motility through deglutamylation of tubulin and that loss of CCP1-mediated mitochondrial fusion accounts for the exquisite vulnerability of Purkinje neurons in pcd mice.

Since its initial description in 2000, robot-assisted laparoscopic radical prostatectomy (RALP) has rapidly grown in popularity with the majority of men with prostate cancer seeking this approach over other surgical techniques. As compared to conventional laparoscopic radical prostatectomy, RALP has experienced more rapid adoption by a broader range of urologists including those with limited laparoscopic training and in a brief few years has virtually supplanted the laparoscopic approach in the United States. While debate still remains as to its relative superiority over open surgery, its minimally invasive approach, superior optics, three-dimensional visualization and intuitive ergonomic movements of the wristed robotic instrumentation have made RALP more attractive to patients and surgeons alike. The technique of RALP has undergone considerable modifications since its early description, which was based upon the original standardized approach of laparoscopic radical prostatectomy. Herein, we describe the transperitoneal posterior approach to RALP.

Speakers of North American English are known to use a variety of tap/flap articulations depending on phonetic context (Derrick and Gick, 2011); it is also known that NAE taps/flaps are sometimes associated with a greatly lowered F4 frequency (Warner and Tucker, 2017). It has been less clear whether only certain articulatory variants show this acoustic effect. Since retroflex stops are also associated with lowered F4 (Blumstein and Stevens, 1975), we predict that flap retroflexion is associated with lowered F4. To test this prediction, synchronized ultrasound and audio recordings were made of words containing /t, d/ in a variety of contexts known to give rise to tap/flap variants. Based on visual inspection of ultrasound videos, these were coded as one of four articulatory variants (low tap, high tap, up flap, down flap: Derrick and Gick, 2011); formant frequencies were extracted from the audio at several timepoints relative to the tap/flap. Preliminary results from one speaker support the hypothesis: high taps and down flaps (variants with initial retroflexion) show an F4 drop into the consonant, while high taps and up flaps (variants with final retroflexion) show an F4 rise out of the consonant.

The purpose of this pilot study was to examine possible neurotoxic effects of prenatal methamphetamine (Meth) exposure on the developing brain and on cognition. Meth-exposed children (n=13) and unexposed control subjects (n=15) were evaluated with MRI. Global brain volumes and regional brain structures were quantified. Ten Meth-exposed and nine unexposed children also completed neurocognitive assessments. Meth-exposed children scored lower on measures of visual motor integration, attention, verbal memory and long-term spatial memory. There were no differences among the groups in motor skills, short delay spatial memory or measures of non-verbal intelligence. Despite comparable whole brain volumes in each group, the Meth-exposed children had smaller putamen bilaterally (-17.7%), smaller globus pallidus (left: -27%, right: 30%), smaller hippocampus volumes (left: -19%, right: -20%) and a trend for a smaller caudate bilaterally (-13%). The reduction in these brain structures correlated with poorer performance on sustained attention and delayed verbal memory. No group differences in volumes were noted in the thalamus, midbrain or the cerebellum. In summary, compared with the control group, children exposed to Meth prenatally exhibit smaller subcortical volumes and associated neurocognitive deficits. These preliminary findings suggest prenatal Meth exposure may be neurotoxic to the developing brain.

Myeloid cell leukemia-1 (MCL-1) is an anti-apoptotic BCL-2 protein that is highly expressed in myocardium, but little is known about its function in myocytes. Recently, we reported that MCL-1 is essential for myocardial homeostasis and autophagy. Cardiac-specific deletion of MCL-1 in mice led to rapid mitochondrial dysfunction, hypertrophy, and lethal cardiomyopathy. Despite extensive mitochondrial damage, MCL-1 deficient hearts failed to activate mitochondrial autophagy. Parkin, an E3 ubiquitin ligase, normally translocates to damaged mitochondria to promote mitochondrial autophagy, but loss of MCL-1 resulted in cytosolic accumulation of Parkin. However, we found no evidence that MCL-1 functions as a mitochondrial Parkin receptor or substrate. Instead, loss of MCL-1 reduced mitochondrial accumulation of PINK1, which is involved in Parkin recruitment. Additionally, we identified mitochondrial outer membrane (OM) and matrix isoforms of MCL-1 in mouse hearts and found that the two forms respond differently to ischemic injury. Four hours after myocardial infarction, MCL-1 OM levels were reduced by 40% in border zone tissue. After 24 hours, MCL-1 OM levels returned to baseline. Meanwhile, MCL-1 Matrix levels were preserved at four hours, and increased significantly compared to control 24 hours after infarction. These changes correlated with increased expression of HSP70, a chaperone protein that stabilizes MCL-1 and participates in import of mitochondrial proteins. Overexpression of MCL-1 Matrix promoted mitochondrial fusion in fibroblasts under baseline conditions and protected cells against FCCP-mediated mitochondrial fission. While 94.1% (1269 of 1349) of control cells exhibited fragmented mitochondria after two hours of FCCP treatment, mitochondria were only fragmented in 41.3% (391 of 947) of cells overexpressing MCL-1 Matrix . These data suggest MCL-1 isoforms play different roles in the cellular stress response. MCL-1 OM protects against apoptosis, whereas MCL-1 Matrix protects mitochondria by promoting fusion. In addition, upregulation of HSP70 may preserve mitochondrial function and cell viability in damaged cardiac myocytes by increasing the stability and mitochondrial import of MCL-1.

Food-borne Salmonella spp., are a major cause of hospitalization and death. Adenosine, an important immune regulator of inflammation, limits tissue damage during infection. CD39 (nucleoside triphosphate dephosphorylase) combined with ecto-5'-nucleotidase (CD73) metabolizes ATP to adenosine. We studied the expressions of CD39 and CD73 in tissues, and T helper cells in mice after Salmonella infection and evaluated the role of CD73 in regulating immune responses and bacterial clearance in wild-type and CD73-deficient (CD73(-/-)) mice. Both CD39 and CD73 transcript levels declined in the infected wild-type mice. Compared to wild-type mice, tissues from infected CD73(-/-) mice had significantly higher expression of pro-inflammatory cytokines and reduced anti-inflammatory responses. CD73(-/-) mice were more resistant to infection and had a greater inflammatory responses and a significantly lower bacterial load in the liver compared to wild-type mice. Thus, CD73 expression attenuates inflammation during murine Salmonellosis and impairs immunity, leading to increased bacterial colonization and prolonged infection.

BACKGROUND: Hair tourniquet syndrome involves fibers of hair or thread wrapped around an appendage producing tissue necrosis. Appendages commonly involved include the toe, finger, and penis. We report a hair tourniquet resulting in amputation of the clitoris. CASE: An adolescent presented with a 4-year history of intermittent genital pain that increased in severity over the preceding 5 days. Physical examination revealed a necrotic clitoris surrounded by a black hair. During the examination, the tissue fell off resulting in immediate improvement in the patient’s pain. CONCLUSION: We report a case of a clitoral hair tourniquet syndrome leading to autoamputation of the clitoris. A high index of suspicion for this condition is important because of the potential consequences of delayed treatment.

Inhibition of mitotic kinesins represents a novel approach for the discovery of a new generation of anti-mitotic cancer chemotherapeutics. We report here the discovery of the first potent and selective inhibitor of centromere-associated protein E (CENP-E) 3-chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide (GSK923295; 1), starting from a high-throughput screening hit, 3-chloro-4-isopropoxybenzoic acid 2. Compound 1 has demonstrated broad antitumor activity in vivo and is currently in human clinical trials.

Purpose To investigate the imaging capabilities of anterior segment optical coherence tomography (AS OCT) in microbial keratitis and to assess whether measurements of the quantitative parameters, infiltrate thickness and corneal thickness, were possible. Design Prospective, noncomparative, observational case series. Methods The study was conducted at a university hospital clinical setting. Seven patients (eyes) with suspected microbial keratitis underwent standard clinical examination and treatment based on slit-lamp clinical findings. AS OCT scanning was performed on presentation and at two follow-up appointments. All scans were carried out with the scanning beam passing through the center of the infiltration and at a specific meridian. Examination was carried out by the same operator. Results Corneal infiltration was imaged as a hyperreflective area in the corneal stroma on high-resolution AS OCT scans. Retrocorneal pathologic features and anterior chamber inflammatory cells could be imaged. Corneal and infiltrate thickness could be measured with calipers in six cases. In one case, corneal and infiltrate thickness could not be measured because of a thick inflammatory plaque attached to the endothelium. In this case, the width of the plaque was measured on serial scans. Conclusions AS OCT imaging provides a range of parameters that can be used to assess microbial keratitis and the treatment response objectively.

We previously reported that Sp1-dependent Cdc2 gene expression is inhibited by tetra- O -methyl nordihydroguaiaretic acid (M 4 N) and that M 4 N is likely responsible for causing growth arrest in M 4 N-treated transformed C3 cells. Here, we show that after M 4 N treatment and cell-cycle arrest, expression of the Sp1-dependent survivin gene, a member of the inhibitor of apoptosis family, is also suppressed, and the mitochondrial apoptotic pathway is activated. To confirm that inhibition of Cdc2 and survivin gene expression is necessary for M 4 N-induced growth arrest and apoptosis, we tested the effect of adding Cdc2 and survivin back to M 4 N-treated cells. Cell division was transiently restored in the presence of M 4 N after transfection of an exogenous Cdc2 gene copy under the control of the Sp1-independent cytomegalovirus promoter. Caspase-3 activation was also reduced by 50% and 75% in transiently and stably survivin-transfected C3 cells, respectively. The results suggest that M 4 N induces growth arrest and apoptosis by suppressing Cdc2 and survivin expression, which constitutes the cellular basis of its antitumoric action.

To determine fetal growth and the incidence of withdrawal symptoms in term infants exposed to methamphetamine in utero, we retrospectively identified neonates whose mothers used methamphetamine during pregnancy and matched them to unexposed newborns. Exclusion criteria included multiple and preterm gestations. Although there were no differences in infant growth parameters between the methamphetamine-exposed and methamphetamine-unexposed neonates, methamphetamine exposure throughout gestation was associated with decreased growth relative to infants exposed only for the first two trimesters. In addition, there were significantly more small for gestational age infants in the methamphetamine group compared with the unexposed group. Methamphetamine-exposed infants whose mothers smoked had significantly decreased growth relative to infants exposed to methamphetamine alone. Withdrawal symptoms (as determined by a previously reported scoring system) requiring pharmacologic intervention were observed in 4% of methamphetamine-exposed infants. These preliminary findings indicate that methamphetamine use is associated with growth restriction in infants born at term.

Neuroimaging studies in children have yielded conflicting information regarding the effects of prenatal cocaine exposure on the developing central nervous system. Retrospective reports in children exposed to cocaine have suggested an increased incidence of periventricular hemorrhage1–3 and subependymal and periventricular cysts.4 However, prospective controlled trials have failed to find an association between in utero cocaine exposure and abnormalities on cranial ultra-sound.5,6 More recently, a study demonstrated a positive correlation between the dosage of cocaine exposure and the incidence of subependymal hemorrhage.7 In addition to the conflicting neurosono-graphic data regarding brain structural abnormalities with cocaine exposure, the requirement for an acoustic window such as a fontanelle precludes the use of neurosonography past infancy. Computed tomography and magnetic resonance imaging (MRI) reports have found occasional structural abnormalities including cortical infarction,8 pachygyria,9 and schizencephaly.10 To date, no neuroimaging study has addressed the potential microscopic/biochemical damage to the normal appearing central nervous system when the developing human brain is exposed to cocaine. Proton magnetic resonance spectroscopy (1H-MRS) is an magnetic resonance-based technique that offers the opportunity to evaluate several markers of neuronal and glial integrity in targeted brain regions. 1H-MRS is well-suited for studying children because it does not require ionizing radiation and has been used to study both normal brain development11,12 and a variety of brain injuries and diseases in children, including lead intoxication.13–16 To our knowledge, 1H-MRS has not been used to study children exposed to cocaine antenatally. 1H-MRS studies in adult cocaine users suggest that cocaine may result in metabolic abnormalities in the setting of relatively normal structural MRI. To determine whether neuronal loss, cell membrane injury, or ischemic changes are detectable in children exposed to cocaine prenatally, we evaluated a small group of children exposed to cocaine in utero and a control participant population using quantitative measures of MRI and in vivo 1H-MRS.

Foodborne Listeria monocytogenes (LM) causes serious illness & death every year in the US. Ingestion of LM can lead to septicemia, meningitis, & abortion. IL17 is secreted by T cells and regulates the production of CXC chemokines for monocyte and neutrophil recruitment to infected tissue. Foodborne LM infection occurs through the oral route, but mice are highly resistant to oral infection. Here, using a murinized LM strain, we explored the role of IL17RA signaling following oral LM infection. Mortality & body weight loss were compared after LM infection of C57BL/6 & IL17RA-KO mice. LM-specific proliferative responses of splenocytes isolated from infected mice were performed. Viable LM from liver & spleen tissue were enumerated. Neutrophil infiltration & inflammation were evaluated histologically. RT-PCR arrays were used to quantitate cytokine/chemokine mRNA expression in infected tissues. IL17RA-KO mice lost more body weight and died earlier following oral infection than infected WT mice. LM-Ag treated splenocytes from KO mice proliferated less vigorously than WT splenocytes. Tissues from infected IL17RA-KO mice had lower mRNA expression for IFN-γ, IL1-β & iNOS. Liver, spleen & gastric tissues from infected IL17RAKO mice showed increased necrotic tissue damage & increased LM burden. These results indicate that IL17RA signaling is important in host resistance to oral LM infection.

Salmonella spp. is responsible for the vast majority of foodborne illnesses in the US. Adenosine is an antiinflammatory mediator that limits tissue damage during inflammation. Surface enzymes CD39 & CD73 mediate the synthesis of extracellular adenosine & can regulate immune responses. We studied the expression of CD39 & CD73 in liver & spleen after infection of C57BL/6 mice with Salmonella enterica serotype Typhimurium (ST) & evaluated the role of CD73 after oral infection of wildtype & CD73-KO mice, in regulating immune responses & bacterial persistence. Liver & spleen cytokine mRNA expression was tested by RT-PCR. Cytokines were assayed by ELISA from cultured supernatant of activated splenocytes. Splenocyte-derived Th cells were tested for intracellular cytokines by FACS. Inflammatory responses in infected CD73-/- mouse livers were tested in H&E sections. Bacterial count was done from liver tissues. After ST infection of wildtype mice, both CD39 & CD73 transcript levels declined in spleen & liver. Splenocytes from ST-infected CD73-/- mice produced significantly more IFN-γ & IL17a. Infected CD73-/- mice had higher expressions of IFN-γ & TNF-α mRNA in liver. Histological examinations of liver sections showed significantly greater number of “inflammatory-foci”. Liver bacterial load was significantly lower in CD73-/-mice. CD73 expression contributes to adenosine accumulation that attenuates inflammation during Salmonellosis & may impair immunity to favor bacterial persistence.

Salmonella spp. is a leading cause of hospitalization & death in the US associated with foodborne illness. Salmonella causes acute gut inflammation. Adenosine is an antiinflammatory mediator that limits tissue damage during inflammation. Surface enzymes CD39 & CD73 mediate the synthesis of adenosine. We studied the expression of CD39 & CD73 in liver, spleen, & CD4+ Th cells after infection of C57BL/6 mice with Salmonella enterica serotype Typhimurium (ST) & evaluated the role of CD73 in regulating ST-induced inflammation. Proinflammatory cytokine mRNA expression was assayed by RT-PCR arrays & cytokine proteins were tested by FACS & ELISA after ST infection or ST antigen (Ag) treatment. Function of CD73 was tested by examining proinflammatory cytokine production with or without CD73-inhibitor treatment of activated splenocytes exposed to ST Ag. Inflammatory responses to ST infection in CD73-/- mice were evaluated in liver & spleen tissue in H&E sections & in activated CD4+ Th cells stained for intracellular IL17a & IFN-γ. ST Ag-treated & CD73-inhibited splenocytes produced more proinflammatory cytokines (IL17A). Splenocytes from ST-infected CD73-/- mice produced more IL17a cytokine & Th17 cells & infected CD73-/- mice also had greater infiltration of inflammatory cells in the liver. Extracellular adenosine synthesized by CD73 may regulate host inflammation during murine Salmonellosis.

Background Cardiovascular disease is the leading cause of death in women and men. Psyllium, a soluble fiber has been known to reduce serum lipids. In this pilot study, we evaluated whether menopausal status would affect the serum lipid responses to psyllium fiber in women. Methods Eleven post-menopausal and eight pre-menopausal women with serum total cholesterol >200 mg/dL were included in the study. Subjects consumed their habitual diet and 15 g psyllium/d for 6 weeks. Psyllium was incorporated into cookies. Each cookie contained ≈5 g of psyllium fiber. Subjects ate one cookie in each meal. Results With psyllium fiber, total cholesterol concentration was significantly lower (≈5.2%, P < 0.05) in post-menopausal women but not in pre-menopausal women (≈1.3%). Also, there was a significant decrease in HDL-cholesterol in post-menopausal women (≈10.2%, P < 0.05). There were no significant changes observed in concentrations of LDL-cholesterol, triglycerides, apolipoprotein A1, and apolipoprotein B in both pre- and post-menopausal women with psyllium. Conclusion In this pilot study, post- and pre-menopausal, hypercholesterolemic women responded differently to psyllium fiber supplementation. Post-menopausal women would benefit from addition of psyllium to their diets in reducing the risk for heart diseases. The results of this study should be used with caution because the study was based on a small sample size.