Surgical Treatment of Developmental Dysplastic Lumbosacral Spondylolisthesis: Additional Help from an Intervertebral Distraction, Correction, and Reduction Device.

BACKGROUND: In mid- to high-grade adult dysplastic spondylolisthesis, surgeons are faced with three underlying components: angular, translational, and collapse of the disk. In extremely narrow intervertebral spaces, it is difficult to distract and lift the vertebral bodies by the pedicle screw system alone. In this prospective case control study, we analyzed the efficacy of the latest prototypes (distraction, correction, and reduction [DCR] instrument) with intervertebral application in terms of distraction, correction of segmental kyphosis, and slip reduction. METHODS: Twelve adult patients (5 male and 7 female patients) were enrolled in this study. The average age was 42 years (range: 17-67 years) and in all cases the maneuver was documented during the surgery. The amount of slip reduction, the lumbosacral angle according to the Spinal Deformity Study Group dysplastic angle (dys-SDGG), and the disk height were measured preoperatively, intraoperatively, 3 months after surgery, and during the latest follow-up (range: 3-44 months). The relative height of the lumbosacral disk was determined in relation to the disk height in L3/L4. RESULTS: Slippage ranged from 17 to 67%. Overall, the average slippage was 45% preoperatively and 4.8% after the reduction maneuver. The average ratio of the disk height was 0.3 preoperatively, 1.0 intraoperatively, and 0.9 at the latest follow-up. Two patients showed significant kyphotic changes, and these patients had an 18- and 21-degree lordotic improvement. From those who had a lumbosacral kyphosis >20 degrees, only one patient did not show any lordotic improvement. All other patients had a significant lordotic improvement. In total, the lumbosacral angle changed from 15 to 23 degrees. CONCLUSION: The application of an intervertebral distractor with a mobile thigh has a good clinical and radiologic outcome for mid- to high-grade adult dysplastic spondylolisthesis in terms of distraction, kyphosis correction, and reduction of underlying slippage. The described hardware failures and the complications were not related to the DCR device.

[Attainment of the Lessinvasive Neurospinal Surgery: Full Endoscopic Spinal Surgery].

Full endoscopic spinal surgery(FESS)is the the least invasive surgery among the current spinal surgeries. FESS approach can be used to perform discectomy, decompression for stenosis, posterolateral fusion, etc. with little destruction of the spinal structure and posterior supporting elements, under local or general anesthesia. A major difference from conventional spinal surgeries is "underwater surgery," in which surgery is performed under continuous saline irrigation. In addition, for neurosurgeons, there is a steep learning curve to becoming proficient in using a small diameter endoscope for full-endoscopic surgery as well as performing treatment with the surgical field completely. We would like to explain the indication and surgical procedure of the transforaminal approach, then introduce decompression by FESS at the cervical spine level as well as full endoscopic lateral lumbar interbody fusion(ELIF).

Focal molography is a new method for the in situ analysis of molecular interactions in biological samples.

Focal molography is a next-generation biosensor that visualizes specific biomolecular interactions in real time. It transduces affinity modulation on the sensor surface into refractive index modulation caused by target molecules that are bound to a precisely assembled nanopattern of molecular recognition sites, termed the 'mologram'. The mologram is designed so that laser light is scattered at specifically bound molecules, generating a strong signal in the focus of the mologram via constructive interference, while scattering at nonspecifically bound molecules does not contribute to the effect. We present the realization of molograms on a chip by submicrometre near-field reactive immersion lithography on a light-sensitive monolithic graft copolymer layer. We demonstrate the selective and sensitive detection of biomolecules, which bind to the recognition sites of the mologram in various complex biological samples. This allows the label-free analysis of non-covalent interactions in complex biological samples, without a need for extensive sample preparation, and enables novel time- and cost-saving ways of performing and developing immunoassays for diagnostic tests.

Percutaneous endoscopic treatment of foraminal and extraforaminal disc herniation at the L5-S1 level.

BACKGROUND: Microsurgery of foraminal and extraforaminal disc herniation at the L5-S1 level remains a challenge because of the limited access by a high iliac crest, the sacral ala, large transverse processes of L5 and hidden disc fragments lateral to the zygapophyseal joint. Our aim was to present the outcome of percutaneous endoscopic lumbar discectomy (PELD) of these lateral and far lateral disc herniations at the L5-S1 level using the newly described foraminal retreat technique in a group of patients with similar preoperative diagnostic studies. METHODS: A total of 22 patients, 13 males and 9 females, with foraminal and extraforaminal lumbar disc herniation at the L5-S1 level were treated by applying the PELD between September 2004 and April 2010. The clinical findings and MRI were the main diagnostic methods. Preoperative evaluation was performed with clinical examinations, the Visual Analog Pain Scale (VAS) and Oswestry Low Back Disability Index (ODI). FINDINGS: According to the Macnab criteria, overall excellent or good outcomes were obtained in 18 patients (81.8 %), fair outcomes in 3 patients (13.6 %) and a poor outcome in 1 patient (4.5 %) at the last follow-up. The mean ODI was 67.3 ± 19.4 preoperatively and 26.7 ± 23.4 postoperatively. Preoperative VAS was 88.6 ± 7.6 and 28.6 ± 22.8 at 2 days, 40.5 ± 22.8 at 3 weeks, 34.3 ± 25.1 at 6-months and 32 at the last follow-up. At follow-up, two patients (9.1 %) had recurrent disc herniations that were corrected with open surgery. At the time of surgery, 16 patients held jobs. Fifteen (15) patients (93.8 %) returned to their original jobs postoperatively; one patient could not return to his original job postoperatively because of a comorbidity. CONCLUSIONS: Percutaneous endoscopic discectomy using the foraminal retreat technique is an effective treatment method for patients with foraminal and extraforaminal disc herniations at the L5-S1 level on appropriately selected patients.

Aminothiazoles as γ-secretase modulators.

We herein report the discovery of a new γ-secretase modulator class with an aminothiazole core starting from a HTS hit (3). Synthesis and SAR of this series are discussed. These novel compounds demonstrate moderate to good in vitro potency in inhibiting amyloid beta (Aß) peptide production. Overall γ-secretase is not inhibited but the formation of the aggregating, toxic Aß42 peptide is shifted to smaller non-aggregating Aß peptides. Compound 15 reduced brain Aß42 in vivo in APPSwe transgenic mice at 30mg/kg p.o.

Benzodioxoles: novel cannabinoid-1 receptor inverse agonists for the treatment of obesity.

The application of the evolutionary fragment-based de novo design tool TOPology Assigning System (TOPAS), starting from a known CB1R (CB-1 receptor) ligand, followed by further refinement principles, including pharmacophore compliance, chemical tractability, and drug likeness, allowed the identification of benzodioxoles as a novel CB1R inverse agonist series. Extensive multidimensional optimization was rewarded by the identification of promising lead compounds, showing in vivo activity. These compounds reversed the CP-55940-induced hypothermia in Naval Medical Research Institute (NMRI) mice and reduced body-weight gain, as well as fat mass, in diet-induced obese Sprague-Dawley rats. Herein, we disclose the tools and strategies that were employed for rapid hit identification, synthesis and generation of structure-activity relationships, ultimately leading to the identification of (+)-[( R)-2-(2,4-dichloride-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone ( R)-14g . Biochemical, pharmacokinetic, and pharmacodynamic characteristics of ( R)-14g are discussed.

Cyclic guanidines as dual 5-HT5A/5-HT7 receptor ligands: structure-activity relationship elucidation.

The optimisation of affinity and selectivity in a novel series of dual 5-HT5A/5-HT7 receptor ligands is described. Brain penetrant 2-aminodihydroquinazolines with low nanomolar affinities were identified.

Cyclic guanidines as dual 5-HT5A/5-HT7 receptor ligands: optimising brain penetration.

The optimisation of molecular properties within a series of 2-amino dihydroquinazoline 5-HT5A/5-HT7 receptor ligands resulted in a significantly improved brain-to-plasma ratio, enhancing the pharmacological utility of these compounds. By modulating the lipophilicity and pKa, a 20-fold increase in brain-to-plasma ratio could be achieved, leading to micromolar brain concentrations after oral administration. The enantiomers of one representative of this series of improved compounds were separated, and the configuration of the eutomer was determined by X-ray crystallography.

Design, synthesis, and structure-activity relationship studies of new phenolic DNA gyrase inhibitors.

Starting from a biased needle screening hit 3a, we report herein the design and synthesis of a series of novel 2,3-dihydroisoindol-1-ones structurally related to cyclothialidine 2 with DNA gyrase inhibitory activity. In this series, some compounds exhibited promising antibacterial activity against gram-positive bacterial strains.

1,3-disubstituted 4-aminopiperidines as useful tools in the optimization of the 2-aminobenzo[a]quinolizine dipeptidyl peptidase IV inhibitors.

In a search for novel DPP-IV inhibitors, 2-aminobenzo[a]quinolizines were identified as submicromolar HTS hits. Due to the difficult synthetic access to this compound class, 1,3-disubstituted 4-aminopiperidines were used as model compounds for optimization. The developed synthetic methodology and the SAR could be transferred to the 2-aminobenzo[a]quinolizine series, leading to highly active DPP-IV inhibitors.