Network coupling and surgical treatment response in temporal lobe epilepsy: A proof-of-concept study.

OBJECTIVE: This proof-of-concept study aimed to examine the overlap between structural and functional activity (coupling) related to surgical response. METHODS: We studied intracranial rest and ictal stereoelectroencephalography (sEEG) recordings from 77 seizures in thirteen participants with temporal lobe epilepsy (TLE) who subsequently underwent resective/laser ablation surgery. We used the stereotactic coordinates of electrodes to construct functional (sEEG electrodes) and structural connectomes (diffusion tensor imaging). A Jaccard index was used to assess the similarity (coupling) between structural and functional connectivity at rest and at various intraictal timepoints. RESULTS: We observed that patients who did not become seizure free after surgery had higher connectome coupling recruitment than responders at rest and during early and mid seizure (and visa versa). SIGNIFICANCE: Structural networks provide a backbone for functional activity in TLE. The association between lack of seizure control after surgery and the strength of synchrony between these networks suggests that surgical intervention aimed to disrupt these networks may be ineffective in those that display strong synchrony. Our results, combined with findings of other groups, suggest a potential mechanism that explains why certain patients benefit from epilepsy surgery and why others do not. This insight has the potential to guide surgical planning (e.g., removal of high coupling nodes) following future research.

Enzyme selection, optimization, and production toward biodegradation of post-consumer poly(ethylene terephthalate) at scale.

Poly(ethylene terephthalate) (PET) is one of the world's most widely used polyester plastics. Due to its chemical stability, PET is extremely difficult to hydrolyze in a natural environment. Recent discoveries in new polyester hydrolases and breakthroughs in enzyme engineering strategies have inspired enormous research on biorecycling of PET. This study summarizes our research efforts toward large-scale, efficient, and economical biodegradation of post-consumer waste PET, including PET hydrolase selection and optimization, high-yield enzyme production, and high-capacity enzymatic degradation of post-consumer waste PET. First, genes encoding PETase and MHETase from Ideonella sakaiensis and the ICCG variant of leaf-branch compost cutinase (LCCICCG ) were codon-optimized and expressed in Escherichia coli BL21(DE3) for high-yield production. To further lower the enzyme production cost, a pelB leader sequence was fused to LCCICCG so that the enzyme can be secreted into the medium to facilitate recovery. To help bind the enzyme on the hydrophobic surface of PET, a substrate-binding module in a polyhydroxyalkanoate depolymerase from Alcaligenes faecalis (PBM) was fused to the C-terminus of LCCICCG . The resulting four different LCCICCG variants (LCC, PelB-LCC, LCC-PBM, and PelB-LCC-PBM), together with PETase and MHETase, were compared for PET degradation efficiency. A fed-batch fermentation process was developed to produce the target enzymes up to 1.2 g L-1 . Finally, the best enzyme, PelB-LCC, was selected and used for the efficient degradation of 200 g L-1 recycled PET in a well-controlled, stirred-tank reactor. The results will help develop an economical and scalable biorecycling process toward a circular PET economy.

Anti-Diabetic Therapy and Heart Failure: Recent Advances in Clinical Evidence and Molecular Mechanism.

Diabetic patients have a two- to four-fold increase in the risk of heart failure (HF), and the co-existence of diabetes and HF is associated with poor prognosis. In randomized clinical trials (RCTs), compelling evidence has demonstrated the beneficial effects of sodium-glucose co-transporter-2 inhibitors on HF. The mechanism includes increased glucosuria, restored tubular glomerular feedback with attenuated renin-angiotensin II-aldosterone activation, improved energy utilization, decreased sympathetic tone, improved mitochondria calcium homeostasis, enhanced autophagy, and reduced cardiac inflammation, oxidative stress, and fibrosis. The RCTs demonstrated a neutral effect of the glucagon-like peptide receptor agonist on HF despite its weight-reducing effect, probably due to it possibly increasing the heart rate via increasing cyclic adenosine monophosphate (cAMP). Observational studies supported the markedly beneficial effects of bariatric and metabolic surgery on HF despite no current supporting evidence from RCTs. Bromocriptine can be used to treat peripartum cardiomyopathy by reducing the harmful cleaved prolactin fragments during late pregnancy. Preclinical studies suggest the possible beneficial effect of imeglimin on HF through improving mitochondrial function, but further clinical evidence is needed. Although abundant preclinical and observational studies support the beneficial effects of metformin on HF, there is limited evidence from RCTs. Thiazolidinediones increase the risk of hospitalized HF through increasing renal tubular sodium reabsorption mediated via both the genomic and non-genomic action of PPARγ. RCTs suggest that dipeptidyl peptidase-4 inhibitors, including saxagliptin and possibly alogliptin, may increase the risk of hospitalized HF, probably owing to increased circulating vasoactive peptides, which impair endothelial function, activate sympathetic tones, and cause cardiac remodeling. Observational studies and RCTs have demonstrated the neutral effects of insulin, sulfonylureas, an alpha-glucosidase inhibitor, and lifestyle interventions on HF in diabetic patients.

Emerging Therapy for Diabetic Cardiomyopathy: From Molecular Mechanism to Clinical Practice.

Diabetic cardiomyopathy is characterized by abnormal myocardial structure or performance in the absence of coronary artery disease or significant valvular heart disease in patients with diabetes mellitus. The spectrum of diabetic cardiomyopathy ranges from subtle myocardial changes to myocardial fibrosis and diastolic function and finally to symptomatic heart failure. Except for sodium-glucose transport protein 2 inhibitors and possibly bariatric and metabolic surgery, there is currently no specific treatment for this distinct disease entity in patients with diabetes. The molecular mechanism of diabetic cardiomyopathy includes impaired nutrient-sensing signaling, dysregulated autophagy, impaired mitochondrial energetics, altered fuel utilization, oxidative stress and lipid peroxidation, advanced glycation end-products, inflammation, impaired calcium homeostasis, abnormal endothelial function and nitric oxide production, aberrant epidermal growth factor receptor signaling, the activation of the renin-angiotensin-aldosterone system and sympathetic hyperactivity, and extracellular matrix accumulation and fibrosis. Here, we summarize several important emerging treatments for diabetic cardiomyopathy targeting specific molecular mechanisms, with evidence from preclinical studies and clinical trials.

Understanding Consequences and Tradeoffs of Melt Processing as a Pretreatment for Enzymatic Depolymerization of Poly(ethylene terephthalate).

Melt extrusion pretreatment of poly(ethylene terephthalate) (PET) prior to enzymatic depolymerization with an unpurified leaf branch compost cutinase enzyme cocktail is explored to ascertain the efficiency gained by different processing methods on the enzymatic depolymerization of PET. Specific surface area (SSA) is investigated as a key factor in reducing depolymerization time. Higher SSA substrates (>5.6 mm2  mg-1 ) show higher depolymerization rates (≈0.88 g L-1 terephthalic acid [TPA] per day) and no induction phase, while lower SSA substrates (≈4.3, 4.4, and 5.6 mm2  mg-1 ) show, after an initial induction phase, similar depolymerization rates (≈0.46, 0.45, and 0.44 g L-1 TPA per day) despite increases in SSA of up to 30%. The mechanism of enzymatic depolymerization manifests in the appearance of anisotropic pitting. Longer incubation time used to overcome the induction phase in low SSA substrates allows for nearly full recovery of monomeric products, but manual pregrinding of extruded PET sharply increases SSA, depolymerization rate, and substrate crystallinity which may decrease the maximum recycled yield of the product materials. An estimate of the energy cost of increasing SSA is made and its effects on material properties are discussed. This work highlights key material structure and pretreatment aspects influencing the enzymatic recycling of PET.

Twisted Teeth: Ovarian Torsion Secondary to Mature Teratoma.

Evaluation of undifferentiated pediatric abdominal pain presents a unique set of challenges, especially in the setting of inconclusive and limited diagnostic imaging. In this case report, a female child presented to the emergency department with persistent abdominal pain, normal lab studies, and unusual trans-abdominal pelvic ultrasound findings. Urgent exploratory laparoscopy was completed, demonstrating a torsed adnexa rotated around a very large, mature teratoma, with irregular masses consistent with fully developed teeth. Early recognition of atypical pediatric abdominal pain in the setting of equivocal diagnostic imaging findings and collaboration with surgical colleagues resulted in a positive outcome for this patient.

Respiratory substrates regulate S-nitrosylation of mitochondrial proteins through a thiol-dependent pathway.

S-Nitrosylation is a reversible post-translational modification on cysteinyl thiols that can modulate the function of redox-sensitive proteins. The S-nitrosylation of mitochondrial proteins has been shown to regulate various mitochondrial activities involved in energy-transducing systems and mitochondrion-driven apoptosis. In isolated rat brain mitochondria, we demonstrate that mitochondrial protein S-nitrosylation is regulated by respiratory substrates (glutamate/malate) through a thiol-dependent pathway. Mitochondrial proteins become susceptible to S-nitrosoglutathione (GSNO)-induced S-nitrosylation in mitochondria with an oxidized environment (low glutathione (GSH), NADH, and NADPH, and high GSSG, NAD(+), and NADP(+)) caused by isolation of mitochondria using a discontinuous Percoll gradient. Activation of mitochondrial respiration by respiratory substrates leads to increased NAD(P)H and GSH levels, which in turn reduces mitochondrial S-nitrosylated proteins. 1-Chloro-2,4-dinitrobenzene (CDNB), which depletes mitochondrial GSH and inhibits the thioredoxin-thioredoxin reductase system, prevented the denitrosylation of mitochondrial proteins caused by respiratory substrate treatment. Using biotin-switch coupled with LC-MS/MS, several mitochondrial proteins were identified as targets of S-nitrosylation including adenine nucleotide translocase (ANT) and voltage-dependent anion channel (VDAC), important components of the mitochondria permeability transition pore (MPTP), as well as ATP synthase. The S-nitrosylation of ATP synthase by GSNO was found to inhibit its activity. These findings emphasize the importance of respiratory substrates in regulating S-nitrosylation through a thiol-dependent (GSH and/or thioredoxin) pathway, with implications for mitochondrial bioenergetics and mitochondrion-driven apoptosis.

Extracting data from electronic medical records: validation of a natural language processing program to assess prostate biopsy results.

OBJECTIVE: The extraction of specific data from electronic medical records (EMR) remains tedious and is often performed manually. Natural language processing (NLP) programs have been developed to identify and extract information within clinical narrative text. We performed a study to assess the validity of an NLP program to accurately identify patients with prostate cancer and to retrieve pertinent pathologic information from their EMR. MATERIALS AND METHODS: A retrospective review was performed of a prospectively collected database including patients from the Southern California Kaiser Permanente Medical Region that underwent prostate biopsies during a 2-week period. A NLP program was used to identify patients with prostate biopsies that were positive for prostatic adenocarcinoma from all pathology reports within this period. The application then processed 100 consecutive patients with prostate adenocarcinoma to extract 10 variables from their pathology reports. The extraction and retrieval of information by NLP was then compared to a blinded manual review. RESULTS: A consecutive series of 18,453 pathology reports were evaluated. NLP correctly detected 117 out of 118 patients (99.1%) with prostatic adenocarcinoma after TRUS-guided prostate biopsy. NLP had a positive predictive value of 99.1% with a 99.1% sensitivity and a 99.9% specificity to correctly identify patients with prostatic adenocarcinoma after biopsy. The overall ability of the NLP application to accurately extract variables from the pathology reports was 97.6%. CONCLUSIONS: Natural language processing is a reliable and accurate method to identify select patients and to extract relevant data from an existing EMR in order to establish a prospective clinical database.

Achieving proficiency with robot-assisted radical prostatectomy: Laparoscopic-trained versus robotics-trained surgeons.

BACKGROUND: Initiating a robotics program is complex, in regards to achieving favourable outcomes, effectively utilizing an expensive surgical tool, and granting console privileges to surgeons. We report the implementation of a community-based robotics program among minimally-invasive surgery (MIS) urologists with and without formal robotics training. METHODS: From August 2008 to December 2010 at Kaiser Permanente Southern California, 2 groups of urologists performing robot-assisted radical prostatectomy (RARP) were followed since the time of robot acquisition at a single institution. The robotics group included 4 surgeons with formal robotics training and the laparoscopic group with another 4 surgeons who were robot-naïve, but skilled in laparoscopy. The laparoscopic group underwent an initial 7-day mentorship period. Surgical proficiency was measured by various operative and pathological outcome variables. Data were evaluated using comparative statistics and multivariate analysis. RESULTS: A total of 420 and 549 RARPs were performed by the robotics and laparoscopic groups, respectively. Operative times were longer in the laparoscopic group (p = 0.002), but estimated blood loss was similar. The robotics group had a significantly better overall positive surgical margin rate of 19.9% compared to the laparoscopic group (27.8%) (p = 0.005). Both groups showed improvements in operative and pathological parameters as they accrued experience, and achieved similar results towards the end of the study. CONCLUSIONS: Robot-naïve laparoscopic surgeons may achieve similar outcomes to robotic surgeons relatively early after a graduated mentorship period. This study may apply to a community-based practice in which multiple urologists with varied training backgrounds are granted robot privileges.

Polyglandular autoimmune syndrome disguised as mental illness.

Our case acts to highlight the numerous presentations of polyglandular autoimmune syndromes. A 62-year-old Taiwanese woman with a history of schizophrenia presented to our emergency department with a brain tumour causing her headaches. She was admitted due to severe anaemia, and after further investigation, the patient was discovered to have pernicious anaemia and autoimmune thyroiditis-consistent with the diagnosis of polyglandular autoimmune syndrome IIIb. Her underlying primary psychiatric diagnosis was then questioned. The diagnosis of her endocrinopathies were likely delayed for many years due to the psychiatric disorder which may have been due to her long-standing autoimmune hypothyroidism and/or vitamin B12 deficiency. Initial treatment brought about major behavioural improvement, and encourages physicians to investigate secondary causes of psychosis and other coexisting autoimmune diseases when a patient presents with one endocrinopathy.

Impact of trainee involvement with robotic-assisted radical prostatectomy.

Robotic-assisted surgery has been rapidly adopted within urology practice. As a result, academic centers are challenged with the burden of how to effectively train residents and fellows to perform robotic-assisted surgery without compromising outcomes. We evaluated the perioperative outcomes of trainee involvement with robotic-assisted radical prostatectomy (RARP) within our healthcare organization. We retrospectively reviewed RARP cases performed at our institution between September 2008 and December 2010 using a single da Vinci robotic platform. Trainees consisted of urology residents and fellows who operated with staff surgeons on select operating days, whereas two staff surgeon teams performed RARP on alternate days. We compared clinicopathologic variables including operating time, estimated blood loss, surgical margin rates, and complication rates between the trainee and staff-only surgeon groups. Overall, 1,019 RARP surgeries were performed within the study period and trainees participated in 162 cases (16 %). Clinical characteristics were similar between men undergoing surgery with a trainee and those without. Positive surgical margin rates were lower for patients with pT2 disease for cases with trainee involvement (11 vs. 19 %, p = 0.02), although overall margin rates and margin rates for patients with pT3 disease were similar between the groups (p = 0.34). Surgical cases involving trainees were longer (241 vs. 200 min, p < 0.001) and resulted in higher estimated blood loss (190 vs. 120 mL, p < 0.001) than the two staff surgeon cases. However, transfusion rates as well as intraoperative and postoperative complication rates did not differ significantly between groups. In conclusion, surgical margin rates were lower in teaching cases for patients with pT2 disease. Importantly, trainee involvement in RARP is safe, with similar perioperative outcomes to staff-only surgical cases. This information may be useful for training and surgical planning.

Impact of median lobe anatomy: does its presence affect surgical margin rates during robot-assisted laparoscopic prostatectomy?

PURPOSE: To measure and describe the impact of median lobe anatomy on surgical margin status after robot-assisted laparoscopic prostatectomy (RALP). PATIENTS AND METHODS: We prospectively collected median lobe status, surgical margin status, and other perioperative data on 791 patients who underwent RALP at our institution by 12 surgeons between August 2008 and December 2010. We performed univariable and multivariable analysis to measure the association between median lobe status and positive surgical margin rates, including site. RESULTS: Compared with patients without a median lobe (n=672), patients with a median lobe (n=119) were less likely to have a positive surgical margin (16% vs 24.4%). They had a higher prostate-specific antigen (PSA) level (6.1 ng/dL vs 5.4 ng/dL), lower Gleason scores (<7, 58.1% vs 42.1%), lower pathologic stages (T(2), 87.4% vs 75.4%), and larger prostates (64 g vs 48 g) (all P<0.05). In our multivariable model, the effect of median lobe anatomy on surgical margin status, after adjusting for these factors, was not statistically significant (relative risk 0.97, 95% confidence interval, 0.64-1.47, P=0.88). Lower PSA level, Gleason score, and pathologic stage and larger prostates, however, predicted decreased positive surgical margin rates (P<0.01). CONCLUSION: Although presence of median lobe anatomy is not an independent predictor of positive surgical margins in RALP, it is associated with favorable pathologic characteristics that are known to predict decreased positive surgical margins.

Iron regulatory protein 2 turnover through a nonproteasomal pathway.

Iron regulatory protein 2 (IRP2) controls the synthesis of many proteins involved in iron metabolism, and the level of IRP2 itself is regulated by varying the rate of its degradation. The proteasome is known to mediate degradation, with specificity conferred by an iron-sensing E3 ligase. Most studies on the degradation of IRP2 have employed cells overexpressing IRP2 and also rendered iron deficient to further increase IRP2 levels. We utilized a sensitive, quantitative assay for IRP2, which allowed study of endogenous IRP2 degradation in HEK293A cells under more physiologic conditions. We found that under these conditions, the proteasome plays only a minor role in the degradation of IRP2, with almost all the IRP2 being degraded by a nonproteasomal pathway. This new pathway is calcium-dependent but is not mediated by calpain. Elevating the cellular level of IRP2 by inducing iron deficiency or by transfection causes the proteasomal pathway to account for the major fraction of IRP2 degradation. We conclude that under physiological, iron-sufficient conditions, the steady-state level of IRP2 in HEK293A cells is regulated by the nonproteasomal pathway.

A Semantic Web management model for integrative biomedical informatics.

BACKGROUND: Data, data everywhere. The diversity and magnitude of the data generated in the Life Sciences defies automated articulation among complementary efforts. The additional need in this field for managing property and access permissions compounds the difficulty very significantly. This is particularly the case when the integration involves multiple domains and disciplines, even more so when it includes clinical and high throughput molecular data. METHODOLOGY/PRINCIPAL FINDINGS: The emergence of Semantic Web technologies brings the promise of meaningful interoperation between data and analysis resources. In this report we identify a core model for biomedical Knowledge Engineering applications and demonstrate how this new technology can be used to weave a management model where multiple intertwined data structures can be hosted and managed by multiple authorities in a distributed management infrastructure. Specifically, the demonstration is performed by linking data sources associated with the Lung Cancer SPORE awarded to The University of Texas MD Anderson Cancer Center at Houston and the Southwestern Medical Center at Dallas. A software prototype, available with open source at www.s3db.org, was developed and its proposed design has been made publicly available as an open source instrument for shared, distributed data management. CONCLUSIONS/SIGNIFICANCE: The Semantic Web technologies have the potential to addresses the need for distributed and evolvable representations that are critical for systems Biology and translational biomedical research. As this technology is incorporated into application development we can expect that both general purpose productivity software and domain specific software installed on our personal computers will become increasingly integrated with the relevant remote resources. In this scenario, the acquisition of a new dataset should automatically trigger the delegation of its analysis.

A prospective, randomized trial evaluating the use of hydrogel coated latex versus all silicone urethral catheters after urethral reconstructive surgery.

PURPOSE: The superiority of silicone over latex based catheters following urethral reconstructive surgery for stricture disease has been theorized, and yet data comparing their use in this group of patients are lacking. We present our findings from a prospective, randomized trial comparing silicone to hydrogel coated latex catheters in patients following urethral reconstructive surgery. MATERIALS AND METHODS: From February 2004 to August 2006 men undergoing urethral reconstructive surgeries were randomized to receive an all-silicone or a hydrogel coated latex urethral catheter for postoperative bladder drainage. Patient demographics and the various reconstructive procedures used were analyzed. Complications and stricture recurrence were evaluated in the 2 groups. RESULTS: A total of 85 men were randomized to receive a silicone (43) or a latex (42) catheter following reconstructive surgery. Median followup was 20 months (range 10 to 36). Mean patient age, urethral stricture length, complication rate and type of reconstructive procedure did not significantly differ between the 2 groups. Five patients (11%) per group required repeat instrumentation for stricture recurrence (p = 0.97). Median time to stricture recurrence was not statistically different between the 2 groups. CONCLUSIONS: The theoretical benefit of silicone catheters over hydrogel coated latex catheters does not appear to translate into a clinical advantage after urethral reconstructive surgery since we found no difference in the rate of recurrence or operative complications at intermediate term followup. It appears that the 2 types of catheter are appropriate for urethral stenting following urethral reconstructive surgery.