Uniportal robotic assisted surgery for anatomical lung resection-First German experience.

BACKGROUND: Uniportal robotic-assisted thoracic surgery (uRATS) has emerged as a promising technique with potential advantages over multiportal approaches. This study aims to evaluate our initial outcomes of uRATS. MATERIAL AND METHODS: Five patients underwent anatomic lung resections with systematic nodal dissection through a uniportal robotic approach by one surgeon. The results were compared to the results of the first five uniportal video-assisted thoracic surgery (uVATS) anatomical resections performed by the same surgeon. RESULTS: No adverse events occurred during the uRATS-procedures. Comparable surgical outcomes were observed between uRATS and uVATS, including hospital stays, complication rates, and blood loss. The average procedural time was slightly but non-significantly longer in the uRATS-group. Average pain-scores were lower in the uRATS group. One patient in each group experienced major postoperative complications, with one case of in-hospital mortality in the uRATS-group. CONCLUSION: The outcomes of uRATS/uVATS were comparable, highlighting the potential and the feasibility of this technique. Prospective studies comparing the learning curves, complication rate and hospital-stay are required in order to justify the superiority of robotics over uVATS.

Vitrectomy with or without encircling band for pseudophakic retinal detachment: a multi-centre, three-arm, randomised clinical trial. VIPER Study Report No. 1--design and enrolment.

PURPOSE: Scleral buckling is currently used in addition to vitrectomy for the treatment of pseudophakic retinal detachment (PRD) to better support the vitreous base and better visualisation of the periphery. AIMS: The aims of this study are to evaluate (1) whether the combination of 20 G vitrectomy and scleral buckling is superior to 20 G vitrectomy alone (control) (confirmatory), and (2) whether transconjunctival 23/25 G vitrectomy is non-inferior to 20 G vitrectomy (both without scleral buckling) regarding operation success (exploratory). METHODS: The VIPER (Vitrectomy Plus Encircling Band Vs. Vitrectomy Alone For The Treatment Of Pseudophakic Retinal Detachment) study is an unmasked, multi-centre, three-arm randomised trial. Patients with PRD were eligible, excluding complicated retinal detachment or otherwise severe ophthalmologic impairment. Patients were randomised to one of three interventions: 20 G vitrectomy alone (control C), combination of 20 G vitrectomy and circumferential scleral buckling (experimental treatment E1) or 23/25 G vitrectomy alone (experimental treatment E2). The primary endpoint is the absence of any indication for a retina re-attaching procedure during 6 months of follow-up. Secondary endpoints include best corrected visual acuity, retina re-attaching procedures, complications and adverse events. RESULTS: From June 2011 to August 2013, 257 patients were enrolled in the study. The internet randomisation service assigned 100 patients each to the treatment arms C and E1, and 57 patients to treatment E2. The imbalance is due to the fact that several retinal surgeons did not qualify for performing E2. The random assignment was stratified and balanced (ie, 1:1 or 1:1:1 ratio) by surgeon. CONCLUSIONS: The described study represents a methodologically rigorous protocol evaluating the benefits of three different vitrectomy approaches to PRD. The projected results will help to establish their overall efficacy and will permit conclusions regarding their relative value. TRIAL REGISTRATION NUMBER: DRKS00003158 (German Clinical Trials Register, DRKS).

The accuracy of 3D fluoroscopy-navigated screw insertion in the upper and subaxial cervical spine.

PURPOSE: Due to better primary stability and repositioning options, pedicle screws are increasingly used during posterior stabilization of the cervical spine. However, the serious risks generally associated with the insertion of screws in the cervical spine remain. The purpose of this study is to examine the accuracy of pedicle screw insertion with the use of 3D fluoroscopy navigation systems, also accounting for various spine levels. METHODS: Data of 64 patients were collected during and after screw implantation (axial and subaxial) in the cervical spine. 207 screws were implanted from C1 to C7 and analyzed for placement accuracy according to postoperative CT scans and following the modified Gertzbein and Robbins classification. RESULTS: The accuracy of most of the inserted screws was assessed as grade 2 according to the modified Gertzbein and Robbins classification. 93.9% of the screws implanted at C1 or C2, and 78.51% of the screws implanted at levels C3-C7 showed placement accuracy grade 2 or better, indicating pedicle wall perforation of <2 mm. Overall, seven complications were observed. In three cases, the vertebral artery was affected, leading to one fatality. Surgical revision was necessary once because of Magerl screw misplacement and three times due to impaired wound healing. No radicular symptoms resulted from screw malposition. CONCLUSION: Axial and subaxial screws can be inserted with a high grade of accuracy using 3D fluoroscopy-based navigation systems. Nevertheless, while this useful innovation helps to minimize the risks of misplacement, the surgery is still a challenge, as arising complications remain severe.

Vesicle solubilization by bile salts: comparison of macroscopic theory and simulation.

Lipid metabolism is accompanied by the solubilization of lipid bilayer membranes by bile salts. We use Brownian dynamics simulations to study the solubilization of model membranes and vesicles by sodium cholate. The solubilization pathways of small and large vesicles are found to be different. Both results for small and large vesicles can be compared with predictions of a macroscopic theoretical description. The line tension of bilayer edges is an important parameter in the solubilization process. We propose a simple method to determine the line tension by analyzing the shape fluctuations of planar membrane patches. Macroscopic mechanical models provide a reasonable explanation for processes observed when a spherical vesicle consisting of lipids and adsorbed bile salt molecules is transformed into mixed lipid-bile salt micelles.

Factors contributing to severe early childhood caries in south-west Germany.

OBJECTIVES: The purpose of this study is to investigate the contribution of selected variables to the occurrence of severe early childhood caries (S-ECC) in 3- to 5-year-old kindergarten children. METHODS: A cross-sectional study was conducted in 2010 in 30 randomly selected kindergartens in the German Rhein-Neckar district. After informed consent, parents were asked to complete a questionnaire. The oral examinations took place in the selected kindergartens and the WHO methods as well as the criteria proposed by the American Academy of Pediatric Dentistry were followed. Logistic regression was applied to explore the main factors contributing to S-ECC in a multivariate model. RESULTS: In all, 1,007 children aged 3 to 5 years with an average age of 4.1 (SD = 0.8) years were examined. Five variables were associated significantly with the occurrence of S-ECC: breastfeeding for more than 12 months (OR = 3.27), use of the nursing bottle in bed (OR = 3.08), start of tooth brushing after the first anniversary (OR = 2.42), regular visits at the dentists (OR = 0.14) and mother with immigration background (OR = 4.05). Prevalence rate of S-ECC was 9.5 %. The mean d(3+4)mft values were 5.69 (S-ECC group) and 0.23 (non-S-ECC group). CONCLUSION: These results show that occurrence of S-ECC is a complex interaction between socioeconomic, psychological and behavioural factors of parents. New and specific ways to provide preventive dental care for toddlers and infants of caries risk groups have to be developed. CLINICAL RELEVANCE: Parents of newborn children have to receive information about timely start of tooth brushing and adequate use of nursing bottles.

Antinociceptive effects of two deltorphins analogs in the tail-immersion test in rats.

The antinociceptive effects of analogs of deltorphins: cyclo(Nδ,Nδ-carbonyl-D-Orn2, Orn4)deltorphin (DEL-6) and deltorphin II N-(ureidoethyl)amide (DK-4) after intracerebroventricular (i.c.v.) administration were investigated in the tail-immersion test in rats. Morphine, the most commonly used µ-opioid receptors (MOR) agonist, was employed as a reference compound. The contribution of the MOR, δ-(DOR) and κ-opioid receptors (KOR) in antinociceptive effects of the deltorphins analogs was studies using selective antagonists of these receptors. The results indicated that DK-4 (5, 10 and 20 nmol) and DEL-6 (5, 10 and 20 nmol) were the most effective in alleviating thermal pain at the dose of 20 nmol. The antinociceptive potency of DEL-6 at the dose of 20 nmol was approximately equal but DK-4 at the dose of 20 nmol was less effective than morphine at the dose of 13 nmol. DOR antagonist - naltrindole (NTI, 5 nmol) very strongly and, to the lower extent MOR antagonist - ß-funaltrexamine (ß-FNA, 5 nmol), inhibited antinociceptive effect of DK-4 (20 nmol). In turn, ß-FNA was more potent than NTI in inhibition of the antinociceptive effects of DEL-6. Co-administration of DEL-6 and morphine at doses of 5 nmol, which do not produce measurable antinociception, generated additive antinociceptive effect. Chronic intraperitoneal (i.p.) injection of morphine (9 days) displayed a marked analgesic tolerance to the challenge dose of morphine and a slight cross-tolerance to challenge doses of DEL-6 and DK-4, given i.c.v. These findings indicate that the new deltorphin analogs recruit DOR and MOR to attenuate the nociceptive response to acute thermal stimuli.

Lattice energies for crystals of colloidal spheroids.

Attractive interactions between adjacent spheroids and excluded volume effects favor their parallel alignment. Parallel spheroids can be arranged into a variety of densely packed two-dimensional and three-dimensional lattice configurations. All of these configurations turn out to have the same lattice energy. A similar degeneracy is also found for several classes of lattices with lower volume density. We discuss implications of this degeneracy for the stability of colloidal crystals consisting of spheroids.

Treating menopausal symptoms with a complex remedy or placebo: a randomized controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of a complex remedy compared with placebo to treat menopausal symptoms. METHODS: A total of 102 peri- and postmenopausal women requiring treatment for menopausal symptoms were randomized to receive a complex anthroposophic remedy prepared in the homeopathic manner (Apis regina tota GL D4, Argentum metallicum D5, Ovaria bovis GL D4), 3 × 10 globuli daily (2 × 12 weeks) and placebo (12 weeks) in different orders of remedy (R) and placebo (P) (1: R/R/P, 2: P/R/R, 3: R/P/R). The primary endpoint was change in climacteric symptoms assessed by the Menopause Rating Scale II (MRS II) after 12 weeks. Secondary endpoints were changes of symptoms and safety throughout the study. RESULTS: Reduction of symptoms after 12 weeks did not differ between remedy and placebo (total score MRS II: -1.4, 95% confidence interval (CI) -2.8 to 0 vs. -2.3, 95% CI -4.4 to -0.3, p = 0.441) and had no clinical relevance (defined as reduction in MRS II ≥ -3.5). Comparison of secondary outcomes at 12 weeks between remedy and placebo or between groups after the 2nd or 3rd period compared to previous periods did not differ. Treatment with remedy for 24 consecutive weeks did not reach clinical relevance either. However, total reduction of symptoms after three periods in Group 1 (R/R/P) (-5.0, 95% CI -7.5 to -2.5) and Group 2 (P/R/R) (-5.9, 95% CI -8.7 to -3.1) reached clinical relevance whereas almost no decrease of symptoms after three periods was seen in Group 3 (R/P/R) (-0.5, 95% CI -2.9 to 1.9). CONCLUSIONS: Treatment with the complex remedy for 12 or 24 weeks did not result in clinically significant improvement of menopausal symptoms.

Interactions between spheroidal colloidal particles.

Using Derjaguin's approximation, we have evaluated the interaction energy associated with van der Waals, electrostatic, depletion, and capillary forces between colloidal spheroids. If the interaction range between spheroids is distinctly smaller than the lengths of their principal axes, then simple pair potentials that depend on particle distance and orientation can be derived. Attractive interactions between adjacent spheroids favor their parallel alignment. Parallel spheroids can be arranged into a variety of densely packed configurations. All of these configurations turn out to have the same lattice energy. We discuss the implications of this degeneracy with respect to the stability of photonic crystals consisting of spheroids.

Depletion force between anisometric colloidal particles.

A simple mathematical model for the depletion force between two arbitrarily shaped large convex colloidal particles immersed in a suspension of small spherical particles is proposed. Using differential geometry, the interaction potential is expressed in terms of the mean and Gaussian curvature of the particle surfaces. The accuracy of theoretical results is tested by Monte Carlo simulations for parallel and nonparallel circular cylinders. The agreement between theoretical results and simulated data is very good if the density of the depletion agent is not too high.

Monte Carlo study of the self-assembly of achiral bolaform amphiphiles into helical nanofibers.

It is shown by coarse-grained off-lattice Monte Carlo simulations that a geometrically induced frustration of the parallel arrangement of rigid achiral bolaform amphiphiles can cause chirality in self-assembled nanostructures. The amphiphilic molecules are represented as rigid linear chains of 8 equally sized hydrophobic spheres (tail) and a hydrophilic sphere (head) at each end. The hydrophilic and hydrophobic spheres differ in size. A very simple interaction scheme consisting of only hard-core repulsion between all spheres and square-well attraction between hydrophobic spheres is sufficient for self-assembly into helical fibers for molecules with head/tail diameter ratios ranging from 1.3 to 1.8.

Monte Carlo simulations of small vesicles under osmotic pressure.

A simple model for amphiphilic molecules is sufficient to predict self-assembly into spherical vesicles. The model is also useful to study the influence of osmotic pressure on the shape of vesicles, which serve as carriers in biological cells. The stability of small vesicles subjected to relatively high osmotic pressures is demonstrated. Fluctuations of small vesicles under osmotic stress are found to be in semiquantitative agreement with a macroscopic description. Small deviations between simulated results for vesicle fluctuations and macroscopic elasticity theory could result from the relative large membrane thickness in comparison to the vesicle radius. The simulations demonstrate that an osmotic pressure exerted by solute molecules outside a spherical vesicle can cause a shape transition, in agreement with results based on the elasticity theory of membranes.

Monte Carlo simulation of surfactant adsorption on hydrophilic surfaces.

Monte Carlo simulations have been carried out to study the adsorption behavior of small flexible amphiphilic molecules on solid surfaces from aqueous solutions. A simple coarse-grained solvent-free off-lattice model, with a square-well pair potential and hard core excluded volume effect, has been used. Adsorption isotherms for weakly and strongly hydrophilic homogeneous surfaces have been determined. The adsorbed layer displays a coexistence region with an upper critical point. Below the critical temperature a densely packed patch coexists with a two-dimensional gas-analogous phase. Above the critical temperature, a percolating network forms at higher surfactant concentrations. Depending on the ratio between the strength of the hydrophobic effect and the adsorption energy, a large variety of associates has been observed. Monolayers, bilayers, admicelles, small clusters, and percolating networks as typical associate structures have been found. In the four-region model, which is extended by the coexistence region, a characteristic adsorbed layer structure for each region can be detected. Intermediate structure types have been produced by variation of the adsorption energy.

Second malignancy risk associated with treatment of Hodgkin's lymphoma: meta-analysis of the randomised trials.

BACKGROUND: Despite several investigations, second malignancy risks (SMR) following radiotherapy alone (RT), chemotherapy alone (CT) and combined chemoradiotherapy (CRT) for Hodgkin's lymphoma (HL) remain controversial. PATIENTS AND METHODS: We sought individual patient data from randomised trials comparing RT versus CRT, CT versus CRT, RT versus CT or involved-field (IF) versus extended-field (EF) RT for untreated HL. Overall SMR (including effects of salvage treatment) were compared using Peto's method. RESULTS: Data for between 53% and 69% of patients were obtained for the four comparisons. (i) RT versus CRT (15 trials, 3343 patients): SMR were lower with CRT than with RT as initial treatment (odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.62-0.98 and P = 0.03). (ii) CT versus CRT (16 trials, 2861 patients): SMR were marginally higher with CRT than with CT as initial treatment (OR = 1.38, CI 1.00-1.89 and P = 0.05). (iii) IF-RT versus EF-RT (19 trials, 3221 patients): no significant difference in SMR (P = 0.28) although more breast cancers occurred with EF-RT (P = 0.04 and OR = 3.25). CONCLUSIONS: Administration of CT in addition to RT as initial therapy for HL decreases overall SMR by reducing relapse and need for salvage therapy. Administration of RT additional to CT marginally increases overall SMR in advanced stages. Breast cancer risk (but not SMR in general) was substantially higher after EF-RT. Caution is needed in applying these findings to current therapies.

Monte carlo simulations of self-assembled surfactant aggregates.

Monte Carlo simulations provide some insight into the self-assembly of amphiphiles in aqueous environment. A rather simple solvent-free model, with only two adjustable parameters in the effective pair potential, allows one to describe the formation of micelles, stable curved membranes, and metastable vesicles. Characteristic features of the self-assembled aggregates, such as the distribution of the micelle size and the value of the curvature elastic constant for membranes, can be obtained from simulated data. The capability of the simple approach was demonstrated for a surfactant model with three spherical segments. The extension of the simulation to molecules with more segments and branched amphiphiles is straightforward.

Synthesis and biological evaluation of constrained analogues of the opioid peptide H-Tyr-D-Ala-Phe-Gly-NH2 using the 4-amino-2-benzazepin-3-one scaffold.

The synthesis of conformationally restricted dipeptidic moieties 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba)-Gly ([(4S)-amino-3-oxo-1,2,4,5-tetrahydro-1H-2-benzazepin-2-yl]-acetic acid) and 8-hydroxy-4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Hba)-D-Ala ([(4S)-amino-8-hydroxy-3-oxo-1,2,4,5-tetrahydro-benzo[c]azepin-2-yl]-propionic acid) was based on a synthetic strategy that uses an oxazolidinone as an N-acyliminium precursor. Introducing these Aba scaffolds into the N-terminal tetrapeptide of dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2)-induced remarkable shifts in affinity and selectivity towards the opioid mu- and delta-receptors. This paper provides the synthesis and biological in vitro and in vivo evaluation of constricted analogues of the N-terminal tetrapeptide H-Tyr-D-Ala-Phe-Gly-NH2, which is the minimal subunit of dermorphin needed for dermorphin-like opiate activity.

Novel endomorphin-2 analogs with mu-opioid receptor antagonist activity.

A series of position 4-substituted endomorphin-2 (Tyr-Pro-Phe-Phe-NH2) analogs containing 3-(1-naphthyl)-alanine (1-Nal) or 3-(2-naphthyl)-alanine (2-Nal) in L- or D-configuration, was synthesized. The opioid activity profiles of these peptides were determined in the mu-opioid receptor representative binding assay and in the Guinea-Pig Ileum assay/Mouse Vas Deferens assay (GPI/MVD) bioassays in vitro, as well as in the mouse hot-plate test of analgesia in vivo. In the binding assay the affinity of all new analogs for the mu-opioid receptor was reduced compared with endomorphin-2. The two most potent analogs were [D-1-Nal(4)]- and [D-2-Nal4]endomorphin-2, with IC50 values 14 +/- 1.25 and 19 +/- 2.1 nM, respectively, compared with 1.9 +/- 0.21 nM for endomorphin-2. In the GPI assay these analogs were found to be weak antagonists and they were inactive in the MVD assay. The in vitro GPI assay results were in agreement with those obtained in the in vivo hot-plate test. Antinociception induced by endomorphin-2 was reversed by concomitant intracerebroventricula (i.c.v.) administration of [D-1-Nal4]- and [D-2-Nal4]-endomorphin-2, indicating that these analogs were mu-opioid antagonists. Their antagonist activity was compared with that of naloxone. At a dose 5 microg per animal naloxone almost completely inhibited antinociceptive action of endomorphin-2, while [D-1-Nal4]endomorphin-2 in about 46%.

Type and location of fluorescent probes incorporated into the potent mu-opioid peptide [Dmt]DALDA affect potency, receptor selectivity and intrinsic efficacy.

The dermorphin-derived tetrapeptide H-Dmt-d-Arg-Phe-Lys-NH(2) (Dmt = 2',6'-dimethyltyrosine) ([Dmt(1)]DALDA) is a highly potent and selective mu-opioid agonist capable of crossing the blood-brain barrier and producing a potent, centrally mediated analgesic effect when given systemically. For the purpose of biodistribution studies by fluorescence techniques, [Dmt(1)]DALDA analogues containing various fluorescent labels [dansyl, anthraniloyl (atn), fluorescein, or 6-dimethylamino-2'-naphthoyl] in several different locations of the peptide were synthesized and characterized in vitro in the guinea-pig ileum and mouse vas deferens assays, and in mu-, delta- and kappa-opioid receptor-binding assays. The analogues showed various degrees of mu receptor-binding selectivity, but all of them were less mu-selective than the [Dmt(1)]DALDA parent peptide. Most analogues retained potent, full mu-agonist activity, except for one with fluorescein attached at the C-terminus (3a) (partial mu-agonist) and one containing beta-(6'-dimethylamino-2'-naphthoyl)alanine (aladan) in place of Phe(3) (4) (mu- and kappa-antagonist). The obtained data indicate that the receptor-binding affinity, receptor selectivity and intrinsic efficacy of the prepared analogues vary very significantly, depending on the type of fluorescent label used and on its location in the peptide. The results suggest that the biological activity profile of fluorescence-labeled peptide analogues should always be carefully determined prior to their use in biodistribution studies or other studies. One of the analogues containing the atn group (2a) proved highly useful in a study of cellular uptake and intracellular distribution by confocal laser scanning microscopy.

Cyclic enkephalin analogs containing various para-substituted phenylalanine derivatives in place of Tyr1 are potent opioid agonists.

The cyclic enkephalin analog H-Tyr-c[D-Cys-Gly-Phe(pNO(2))-D-Cys]NH(2) is a highly potent opioid agonist with IC(50)s of 35 pm and 19 pm in the guinea-pig ileum (GPI) and mouse vas deferens (MVD) assays, respectively. The Phe(1)-analog of this peptide showed 370-fold and 6790-fold lower agonist potency in the GPI and MVD assays, respectively, indicating the importance of the Tyr(1) hydroxyl-group in the interaction with mu and delta opioid receptors. In the present study, the effect of various substituents (-NH(2), -NO(2), -CN, -CH(3), -COOH, -COCH(3), -CONH(2)) introduced in the para-position of the Phe(1)-residue of H-Phe-c[D-Cys-Gly-Phe(pNO(2))-D-Cys]NH(2) on the in vitro opioid activity profile was examined. Most analogs showed enhanced mu and delta agonist potencies in the two bioassays, except for the Phe(pCOOH)(1)-analog, which was weakly active, probably as a consequence of the negative charge. The most potent compounds were the Phe(pCOH(3))(1)- and the Phe(pCONH(2))(1)-analogs. The latter compound showed subnanomolar mu and delta agonist potencies and represents the most potent enkephalin analog lacking the Tyr(1) hydroxyl-group reported to date. Taken together, these results indicate that various substituents introduced in the para-position of Phe(1) enhance opioid activity via hydrogen bonding or hydrophobic interactions with the receptor. Comparison with existing structure-activity relationship on phenolic hydroxyl replacements in morphinans indicates that these nonpeptide opiates and some of the cyclic enkephalin analogs described here may have different modes of binding to the receptor.