Extrahepatic arteries of the human liver – anatomical variants and surgical relevancies

The purpose of our study was to investigate the anatomical variations of the extrahepatic arterial structures of the liver with particular attention to rare variations and their potential impact on liver surgery. A total of 50 human abdominal organ complexes were used to prepare corrosion casts. A multicomponent resin mixture was injected into the abdominal aorta. The portal vein was injected with a different colored resin in 16 cases. Digestion of soft tissues was achieved using cc. KOH solution at 60–65 °C. Extrahepatic arterial variations were classified according to Michels. All specimens underwent 3D volumetric CT reconstruction. Normal anatomy was seen in 42% of cases, and variants were seen in the other 58%. No Michels type VI or X variations were present; however, in 18% of cases the extrahepatic arterial anatomy did not fit into Michels' classification. We report four new extrahepatic arterial variations. In contrast to the available data, normal anatomy was found much less frequently, whereas the prevalence of unclassified arterial variations was higher. We detected four previously unknown variations. Our data may contribute to the reduction of complications during surgical and radiological interventions in the upper abdomen.     

Development of Urea-Bond-Containing Michael Acceptors as Antitrypanosomal Agents Targeting Rhodesain

Human African Trypanosomiasis (HAT) is a neglected tropical disease widespread in sub-Saharan Africa. Rhodesain, a cysteine protease of Trypanosoma brucei rhodesiense, has been identified as a valid target for the development of anti-HAT agents. Herein, we report a series of urea-bond-containing Michael acceptors, which were demonstrated to be potent rhodesain inhibitors with K_i values ranging from 0.15 to 2.51 nM, and five of them showed comparable k_2nd values to that of K11777, a potent antitrypanosomal agent. Moreover, most of the urea derivatives exhibited single-digit micromolar activity against the protozoa, and the presence of substituents at the P3 position appears to be essential for the antitrypanosomal effect. Replacement of Phe with Leu at the P2 site kept unchanged the inhibitory properties. Compound 7 (SPR7) showed the best compromise in terms of rhodesain inhibition, selectivity, and antiparasitic activity, thus representing a new lead compound for future SAR studies.     

Two distinct evolutionary conserved neural degeneration pathways characterized in a colonial chordate

Colonial tunicates are marine organisms that possess multiple brains simultaneously during their colonial phase. While the cyclical processes of neurogenesis and neurodegeneration characterizing their life cycle have been documented previously, the cellular and molecular changes associated with such processes and their relationship with variation in brain morphology and individual (zooid) behavior throughout adult life remains unknown. Here, we introduce Botryllus schlosseri as an invertebrate model for neurogenesis, neural degeneration, and evolutionary neuroscience. Our analysis reveals that during the weekly colony budding (i.e., asexual reproduction), prior to programmed cell death and removal by phagocytes, decreases in the number of neurons in the adult brain are associated with reduced behavioral response and significant change in the expression of 73 mammalian homologous genes associated with neurodegenerative disease. Similarly, when comparing young colonies (1 to 2 y of age) to those reared in a laboratory for ∼20 y, we found that older colonies contained significantly fewer neurons and exhibited reduced behavioral response alongside changes in the expression of 148 such genes (35 of which were differentially expressed across both timescales). The existence of two distinct yet apparently related neurodegenerative pathways represents a novel platform to study the gene products governing the relationship between aging, neural regeneration and degeneration, and loss of nervous system function. Indeed, as a member of an evolutionary clade considered to be a sister group of vertebrates, this organism may be a fundamental resource in understanding how evolution has shaped these processes across phylogeny and obtaining mechanistic insight.

Botryllus schlosseri, a marine colonial chordate, has produced valuable insight in the study of tissue regeneration (1, 2), allorecognition (3–6), and stem cells (7, 8). B. schlosseri can be developed as a chordate following sexual reproduction, which gives rise to a tadpole that hatches and finds a subtidal surface to attach to, before metamorphosis into a sessile invertebrate. The metamorphosed individual develops 1 to 3 buds (covered by a common gelatinous tunic) that develop the invertebrate body plan, and several individuals anastomose extracorporeal blood vessels in the tunic to form a colony. Every week this colonial organism undergoes a de novo robust regeneration mediated by adult stem cells that participate in the formation of all body organs, including the central nervous system. The lifespan of B. schlosseri is plastic and amenable to change. Wild colonies are characterized by short lifespans ranging from several months to a few years (9–12) whereas colonies grown in the laboratory can reach 20 y of age (12–17). Systemic changes occur over time in older colonies, including a slower heartbeat, reduced zooid size, decreased regenerative capacity, a shift in cellular composition (e.g., higher level of engulfing phagocytic, cytotoxic, and pigment cells), and shifting patterns of cyclic gene expression associated with aging (17). Despite the key evolutionary position of B. schlosseri as a member of a clade considered to be the sister group of vertebrates (the body plan of the sexually reproduced larval tadpole is along the architecture of most chordate fetuses) (18), and previous literature describing its central nervous system (19–22), little is known about changes in brain morphology, colony behavior, and gene expression associated with the regular, cyclical processes of neural generation and degeneration and how they vary with colony age.Here we introduce B. schlosseri as a model for evolutionary neuroscience. The B. schlosseri genome has been sequenced (5) and an atlas of the molecular and morphological signatures of each developmental stage has been previously generated using microscopy and RNA sequencing (RNA-seq) (22). B. schlosseri can reproduce either sexually through embryogenesis or asexually through blastogenesis. The sexually produced larvae develop two brains (a functional larval brain and the rudiment of the adult brain), a sensory organ detecting light and gravity, a notochord, and a dorsal nerve cord. The larval brain (along with the notochord, segmented musculature, and tail) is absorbed during the settlement and metamorphosis which precedes colony formation. As a sedentary organism, B. schlosseri buds new individuals that together live as a colony composed of individual zooids. Each zooid reproduces asexually in weekly, stem cell-mediated budding cycles (7). Budding occurs during this cycle when, simultaneously throughout the colony, a new generation of buds begin to develop into adult individuals. During budding, all organs including the brain, are created anew without passing through a larval (embryonic and fetal) stage. The life of adult zooids lasts ∼1 wk after which their bodies undergo a synchronized wave of programmed cell death and phagocytic removal called takeover (i.e., TO) (16, 23) in which the nervous systems of old zooids degenerate in tangent to brain formation in the young buds.In this study, we describe 2 different pathways of neurodegeneration that occur during the life cycle of the colonial chordate B. schlosseri. The first occurs every week as a part of a regenerative developmental cycle that occurs independent of age; the second is associated with colony aging. We integrate neural imaging (transmission electron microscopy [TEM] and confocal), three-dimensional (3D) reconstructions, behavioral assay, and RNA-seq of enriched brains (Fig. 1) to study morphological and molecular changes in brains of adult B. schlosseri across developmental stages and ages as associated with changes in zooid behavior. In providing evidence of the cellular and molecular linkages between each neurodegenerative process, we document an unanticipated degree of similarity between the 2 that may be useful in identifying the evolutionary basis of the pathological mechanisms responsible for age-induced loss of neuron structure and function in other phylogeny. Indeed, we argue that given 1) a unique and assayable life cycle, 2) real-time monitoring enabled by transparent body and vasculature, 3) adult tissue specific stem cells that can be enriched and transplanted, 4) morphological differences associated with colony age, and 5) a previously sequenced genome; B. schlosseri provides a novel and valuable platform for the study of neurogenesis, neurodegeneration, and evolutionary neuroscience.Open in a separate windowFig. 1.Sampling and methods used to characterize weekly cycles of neurodegeneration in B. schlosseri colonies. Schematic depicting the various methods employed over the course of the investigation including neural complex dissection, confocal staining, histology, TEM, behavioral experiments and the intervals over which neural complex sampling was conducted (over the weekly cycle and with age in adult individuals). Genetically identical subclones prepared via incision and separation were used in diverse experimental groups.     

Safety and outcomes of outpatient pediatric otolaryngology procedures at an ambulatory surgery center

Objectives: To determine the safety and outcomes of outpatient pediatric otolaryngology procedures performed at an ambulatory surgery center (ASC). Methods: Retrospective review of all pediatric otolaryngology cases performed at a freestanding, outpatient ASC of a tertiary care, academic children's medical center from 2000 to 2007. Results: Of all cases, 4979 (55%) were otolaryngology procedures. Twelve surgeons and 10 pediatric anesthesiologists staffed the cases; no residents/fellows were involved. The case breakdown is as follows: 2045 (41.1%) myringotomy and tympanostomy tube; 1438 (28.9%) adenoidectomy (with tympanostomy tube placement and/or turbinectomy); 880 (17.7%) tonsillectomy (with or without adenoidectomy). According to American Society of Anesthesiologist (ASA) classification: 84.2% were ASA I, 15.1% ASA II, 0.7% ASA III. There were nine unanticipated outcomes: four postadenotonsillectomy and one postadenoidectomy bleeds (three requiring reoperation the same day), two patients with low psuedocholinesterase levels, one postadenotonsillectomy patient requiring overnight monitoring, and one patient with an incidental finding of a subglottic mass. Preoperative ASA status on these nine patients was 7 (78%) ASA I, 2 (22%) ASA II. Conclusions: Pediatric otolaryngology procedures constitute significant volume at our ASC. Surgery at our ASC is extremely safe with a rate of unanticipated outcomes of 0.2%—a comparison not available in the literature. Pediatric otolaryngology procedures performed with a highly skilled team at an outpatient ASC result in high quality and safe surgery.     

Exertional leg pain: Teasing out arterial entrapments

Vascular causes of exertional lower extremity pain are relatively rare, but may be the answer in athletes refractory to treatment for the more common overuse syndromes of the lower extremities. It is important to differentiate these vascular causes from chronic exertional compartment syndrome (CECS), medial tibial stress syndrome (MTSS), and stress fractures in order to develop appropriate treatment plans, avoid complications, and return athletes to play expeditiously. Important vascular etiologies to be considered are popliteal artery entrapment syndrome (PAES), endofibrotic disease, popliteal artery aneurysm, cystic adventitial disease, and peripheral arterial dissections. The diagnostic workup involves angiography or noninvasive vascular studies such as Doppler ultrasound or magnetic resonance angiography in both the neutral and provocative positions. Treatment of these vascular abnormalities typically involves surgical correction of the vascular anomaly.     

Global Urine Metabolomics in Patients Treated with First-Line Tuberculosis Drugs and Identification of a Novel Metabolite of Ethambutol

Population level variation of drug metabolism phenotype (DMP) has great implications in treatment outcome, drug-related side effects, and resistance development. In this study, we used a gas chromatography-time of flight-mass spectrometry (GC-TOF-MS)-based untargeted urine metabolomics approach to understand the DMP of a tuberculosis (TB) patient cohort (n = 20) from Tripura, a state in the northeastern part of India. Urine samples collected at different postdose time points (2 h, 6 h, 12 h, 24 h, 36 h, and 48 h) from these newly diagnosed TB patients receiving first-line anti-TB drugs were analyzed, and we have successfully detected three of the four first-line drugs, viz., isoniazid (INH), ethambutol (ETB), and pyrazinamide (PZA). The majority of their known metabolites, acetyl-isoniazid (AcINH), isonicotinic acid (INA), isonicotinuric acid (INTA), 2,2′-(ethylenediimino)-dibutyric acid (EDBA), 5-hydroxypyrazinamide (5OH-PZA), pyrazinoic acid (POA), and 5-hydroxypyrazinoic acid (5OH-POA), were also detected. Analyzing the variation in abundances of drugs and their known metabolites and calculating the metabolic ratios in these samples, we offer comprehensive DMP information on this small patient cohort that represents Tripura, India. The majority (75%) of these patients are found to be slow acetylators of INH. The average metabolic ratios of POA/PZA and 5OH-POA/POA are 3.16 ± 3.03 and 6.09 ± 6.15, respectively. Employing correlation analysis of the metabolomics metadata and a manual prediction of drug catabolism, we have proposed 2-aminobutyric acid (AABA) as a novel metabolite of ETB. These observations indicate the usefulness of GC-MS-based metabolomics to characterize the DMP at a population level and also to identify novel drug metabolites.