High-throughput organ-on-chip platform with integrated programmable fluid flow and real-time sensing for complex tissue models in drug development workflows.

Drug development suffers from a lack of predictive and human-relevant in vitro models. Organ-on-chip (OOC) technology provides advanced culture capabilities to generate physiologically appropriate, human-based tissue in vitro, therefore providing a route to a predictive in vitro model. However, OOC technologies are often created at the expense of throughput, industry-standard form factors, and compatibility with state-of-the-art data collection tools. Here we present an OOC platform with advanced culture capabilities supporting a variety of human tissue models including liver, vascular, gastrointestinal, and kidney. The platform has 96 devices per industry standard plate and compatibility with contemporary high-throughput data collection tools. Specifically, we demonstrate programmable flow control over two physiologically relevant flow regimes: perfusion flow that enhances hepatic tissue function and high-shear stress flow that aligns endothelial monolayers. In addition, we integrate electrical sensors, demonstrating quantification of barrier function of primary gut colon tissue in real-time. We utilize optical access to the tissues to directly quantify renal active transport and oxygen consumption via integrated oxygen sensors. Finally, we leverage the compatibility and throughput of the platform to screen all 96 devices using high content screening (HCS) and evaluate gene expression using RNA sequencing (RNA-seq). By combining these capabilities in one platform, physiologically-relevant tissues can be generated and measured, accelerating optimization of an in vitro model, and ultimately increasing predictive accuracy of in vitro drug screening.

[The clinical spectrum of urea cycle defects in adult patients]. / Das klinische Spektrum von Harnstoffzyklusdefekten im Erwachsenenalter.

Urea cycle defects belong to the most common metabolic disorders with a cumulative incidence of 1:8000. A common trait of urea cycle defects is a disturbed detoxification of ammonia leading to hyperammonemia in the event of a high nitrogen load. Most patients develop symptoms in the neonatal period or in infancy, e. g. vomiting, seizures and disturbed consciousness. Depending on the affected enzyme and its residual activity, patients differ in the age at first presentation, the character and severity of symptoms and in the susceptibility to metabolic derangement. The presence of hyperammonemia and an altered plasma amino acid profile give the essential diagnostic clues. Since modern therapeutic measures have prolonged the life expectancy of these patients and provided the possibility of a first presentation in adulthood, patients with urea cycle defects have become an increasing challenge in internal medicine. The reported case series illustrates the heterogeneous clinical course of these disorders from childhood to adulthood.

Evaluation of pre-hospital trauma triage criteria: a prospective study at a Danish level I trauma centre.

BACKGROUND: The aim of the present study was to evaluate the precision of our trauma triage protocol [based on the American College of Surgeons, Committee on Trauma (ACS COT)] in identifying severely injured defined as an injury severity score (ISS) > 15. Our hypothesis was that isolated mechanism-of-injury criteria were responsible for a significant over-triage leading to over-use of our trauma team. DESIGN: A prospective cohort study. SETTING: A level I trauma centre, Aarhus, Denmark. PATIENTS AND PARTICIPANTS: Among all injured patients admitted during a 6-month period in 2003 we identified severely injured. During the study period, trauma team activations were consecutively registered and triage criteria were prospectively collected. Sensitivity, specificity, positive predictive value, over-triage and under-triage were calculated. RESULTS: Out of 15,162 patients in the emergency department, 848 injured patients were included and 59 (7%) were severely injured. We had 242 trauma team activations with 54 (22%) severely injured. Sensitivity was 92%, specificity 76%, giving an over-triage of 24% and an under-triage of 8%. The positive predictive value was 22%. Among 60 patients with mechanism-of-injury as the only criterion, five were severely injured in contrast to 12 out of 20 patients with mechanism-of-injury combined with physiological and/or anatomical criteria. CONCLUSION: The positive predictive value of our triage protocol was low, only 22%. This was mainly as a result of a significant over-triage from isolated mechanism-of-injury criteria. We recommend revision of the triage protocol and reallocation of our trauma team resources.

17 Beta-estradiol regulates nNOS and eNOS activity in the hippocampus.

Estrogen treatment in symptomatic postmenopausal women appears to improve cognitive performance including memory, an effect which may involve enhanced nitric oxide formation in hippocampal neurons. To study whether 17beta-estradiol (E2) affects NO synthase activity in the hippocampus, we investigated the influence of E2 on hippocampal NO synthase expression and activity in female rats. Ovariectomy, which significantly decreased E2 serum levels, reduced neuronal (nNOS) and endothelial NO synthase (eNOS) expression and Ca(2+)-dependent NOS activity. E2 substitution reversed these effects. It is concluded that E2 increases nNOS and eNOS expression and activity in female hippocampus and thus improves hippocampal function.

Vascular anatomy for right colon lymphadenectomy.

Since the superior mesenteric artery (SMA) mostly originates on the left side of the superior mesenteric vein (SMV), the ileocolic artery (ICA) and the right colic artery (RCA) cross the SMV. Understanding the three-dimensional relation of these vessels is important for dissecting these arteries to their origin. Hence, we conducted a study of the vascular anatomy of the right colon in 27 cadavers. The RCA was separate from the SMA in eight cases (30%). The RCA passed the SMV either anteriorly (5 cases, 63%) or posteriorly (3 cases, 38%). In seven (88%) of these eight cases, the ICA was posterior to the SMV. The ICA was identified in all 27 cases, and passed the SMV anteriorly in nine cases (33%) and posteriorly in 18 cases (67%). Thus, the ICA and the RCA may pass on either side of the SMV. The surgeon must dissect the arteries with the SMV, being aware of both possibilities.

[Local and systemic symptoms after snake bite by a diamondback rattlesnake (Crotalus atrox)]. / Lokale und systemische Symptome nach einem Schlangenbiss durch eine Diamantklapperschlange (Crotalus atrox).

The incidence of snake bites grows more and more. The effects of the snake poison depend on the snake species. They can be cardio-, neuro-, myo-, tissue-, and/or cytotoxic, as well as hemorrhagically. In most cases a symptomatically therapy together with close controls of the labor parameters and a good monitoring is enough. Antivenom-therapy should be reserved for cases with strong indication.

The anconeus muscle flap: its anatomy and clinical application.

The arterial anatomy, coverage area, and potential donor site morbidity of the anconeus muscle flap are described. Using 17 cadaveric upper extremities, we investigated the muscle's arterial anatomy in 12 specimens and defined the coverage area of the anconeus flap in 5 specimens. We also reviewed the records of 9 patients who underwent a pedicle anconeus muscle flap for elbow coverage to assess clinical results of the procedure. The anconeus muscle is supplied from 3 arterial pedicles: the recurrent posterior interosseus artery, the medial collateral artery, and the posterior branch of the radial collateral artery. The recurrent posterior interosseus artery and the medial collateral artery were present in all dissected cadavers and consistently anastomosed with each other underneath the anconeus muscle. By harvesting the muscle on the medial collateral artery, the anconeus muscle flap can be expected to cover a 7.3 cm2 defect over the radiocapitellar joint, a 6.1 cm2 defect over the distal triceps tendon, and a 7.2 cm2 defect over the olecranon. In this series, none of the patients experienced loss of elbow motion, stability, or extension strength. The results of this study indicate that the anconeus can be harvested with minimal risk of morbidity and provides effective coverage for soft tissue defects of the elbow.

Gas Exchange and Carbon Partitioning in the Leaves of Celery (Apium graveolens L.) at Various Levels of Root Zone Salinity.

Both mannitol and sucrose (Suc) are primary photosynthetic products in celery (Apium graveolens L.). In other biological systems mannitol has been shown to serve as a compatible solute or osmoprotectant involved in stress tolerance. Although mannitol, like Suc, is translocated and serves as a reserve carbohydrate in celery, its role in stress tolerance has yet to be resolved. Mature celery plants exposed to low (25 mM NaCl), intermediate (100 mM NaCl), and high (300 mM NaCl) salinities displayed substantial salt tolerance. Shoot fresh weight was increased at low NaCl concentrations when compared with controls, and growth continued, although at slower rates, even after prolonged exposure to high salinities. Gas-exchange analyses showed that low NaCl levels had little or no effect on photosynthetic carbon assimilation (A), but at intermediate levels decreases in stomatal conductance limited A, and at the highest NaCl levels carboxylation capacity (as measured by analyses of the CO2 assimilation response to changing internal CO2 partial pressures) and electron transport (as indicated by fluorescence measurements) were the apparent prevailing limits to A. Increasing salinities up to 300 mM, however, increased mannitol accumulation and decreased Suc and starch pools in leaf tissues, e.g. the ratio of mannitol to Suc increased almost 10-fold. These changes were due in part to shifts in photosynthetic carbon partitioning (as measured by 14C labeling) from Suc into mannitol. Salt treatments increased the activity of mannose-6-phosphate reductase (M6PR), a key enzyme in mannitol biosynthesis, 6-fold in young leaves and 2-fold in fully expanded, mature leaves, but increases in M6PR protein were not apparent in the older leaves. Mannitol biosynthetic capacity (as measured by labeling rates) was maintained despite salt treatment, and relative partitioning into mannitol consequently increased despite decreased photosynthetic capacity. The results support a suggested role for mannitol accumulation in adaptation to and tolerance of salinity stress.

Arthroscopic repair of combined Bankart and superior labral detachment anterior and posterior lesions: technique and preliminary results.

Over a 3-year period nine of 585 patients undergoing shoulder surgery were found to have a superior labral detachment anterior and posterior (SLAP) lesion. Seven patients also had an associated Bankart lesion and underwent arthroscopic repair of the entire anterior-inferior-superior-posterior labral detachment using the Suretac (Acufex Microsurgical Inc., Mansfield, MA) fixation device. The technique used requires an accessory anterior-lateral portal to access the superior-posterior labral detachment and an accessory anterior-inferior portal to access the Bankart lesion. Three to four Suretacs were required for repair in these cases. At an average follow-up of 19 months (range 15-22), five of seven patients had no pain, full range of motion, and a full premorbid activity level. One patient redislocated at 4 months postoperatively and was successfully managed with an open repair, and one patient developed a stiff shoulder that was successfully managed with arthroscopic release and manipulation. We conclude that this arthroscopic technique is a useful method to manage extensive labral detachment in selected patients.

The "arthroscopic impingement test".

Arthroscopic acromioplasty is an effective technique to treat refractory impingement syndrome of the shoulder; however, it is a technically demanding procedure and failure due to inadequate acromial resection has been reported. The purpose of this study was to describe a more reliable technique of arthroscopic acromioplasty ("arthroscopic impingement test") that allows determination of subacromial space available (SSA) during shoulder flexion after acromioplasty. During a 2-year period, 70 consecutive patients (group I) underwent arthroscopic acromioplasty by a conventional technique and 50 consecutive patients (group II) underwent the modified technique. Both groups were comparable in terms of age, gender, chronicity of symptoms, incidence of workman's compensation cases, side of surgery, and operative findings. In group I, four patients (6%) failed due to inadequate acromioplasty and at time of revision were found to have 0 mm SSA at 120 degrees flexion (contact of cuff on acromion). After revision acromioplasty, SSA at 120 degrees flexion was measured as > 3 mm, and impingement symptoms resolved postoperatively. In group II, there were no failures and SSA after initial acromioplasty was found to average 13 mm at 0 degree 10 mm at 45 degrees, 8 mm at 90 degrees, and 6 mm at 120 degrees flexion. In four cases, the "arthroscopic impingement test" determined that there was inadequate SSA at 120 degrees (< 3 mm) after initial acromioplasty, and these were revised by further acromioplasty at time of surgery. It was concluded that the "arthroscopic impingement test" improves reliability of arthroscopic acromioplasty by verifying adequate acromial resection in a position of impingement.

Ankle arthrodesis with an anterior tension plate.

The incidence of complications associated with arthrodesis of the ankle has remained high, especially in wound complications and infections. A new method to achieve arthrodesis of the ankle that utilizes an anterior surgical approach and an anterior tension plate was assessed in 17 patients. This method transforms the potentially deforming force of the tendoachilles into a compressive and corrective force and facilitates realignment of the ankle in all planes. Also, dissection and subperiosteal elevation is minimized while soft tissue coverage of the hardware is maximized. Whereas the predominant preoperative diagnosis was posttraumatic degenerative joint disease, others included failed ankle arthroplasty, failed arthrodesis, and a fixed equinus deformity. A solid arthrodesis was achieved in 82% of the patients. Although complications occurred and two patients required reoperations, there were no problems with respect to wound healing or infection, which is a marked contrast to other series. This technique is recommended as a simple, safe, and effective method to achieve an arthrodesis of the ankle joint.

[Acoustic neurinoma presenting with repeated intratumoral hemorrhage. Case report].

A case of acoustic neurinoma with multiple intratumoral hemorrhages is reported. A 56-year-old male noted sudden hearing reduction in his left ear in October of 1985. The diagnosis of a local physician was sudden deafness. About 10 months later, he had two episodes of severe headache without nausea or vomiting. The patient was hospitalized in October of 1986. Neurological examination cerebellar ataxia. cerebellar ataxia. Plain and enhanced computed tomography revealed only an unremarkable low-density area at the left cerebellopontine angle. In contrast, magnetic resonance imaging (MRI) clearly demonstrated a large (3 x 4 x 5 cm), multicystic tumor in the site. On exposure of the tumor at surgery, most of the cysts were found to be filled with a dark red or xanthochromic fluid. The tumor was completely removed following numerous cyst punctures to decrease its volume. There was no evidence of subarachnoid hemorrhage. Histological examination showed a typical acoustic neurinoma. The cyst wall contained numerous telangiectasia-like lesions. The initial symptom of this patient was sudden hearing loss, which is an atypical manifestation of acoustic neurinoma. The massive intratumoral hemorrhage was thought to be caused by telangiectatic lesions in the cyst wall. MRI clearly demonstrated the hemorrhagic cysts within the tumor, especially in the posterior fossa.