Dielectric Properties of Nanoconfined Water: A Canonical Thermopotentiostat Approach.

We introduce a novel approach to sample the canonical ensemble at constant temperature and applied electric potential. Our approach can be straightforwardly implemented into any density-functional theory code. Using thermopotentiostat molecular dynamics simulations allows us to compute the dielectric constant of nanoconfined water without any assumptions for the dielectric volume. Compared to the commonly used approach of calculating dielectric properties from polarization fluctuations, our thermopotentiostat technique reduces the required computational time by 2 orders of magnitude.

Prominent Optic Disc Featured in Inherited Retinopathy.

Background We investigated the relationship between prominent optic disc (POD) and inherited retinal dystrophy (IRD). Patients and Methods A cross-sectional consecutive study was performed in 10 children and 11 adults of 7 non-related families. We performed clinical phenotyping, including a detailed examination, fundus autofluorescence, and colour fundus and OCT imaging. Genetic testing was subsequently performed for all family members presenting retinal pathology. Results In 4 members of a 3-generation family, hyperfluorescent deposits on the surface of POD were related to a p.(L224M) heterozygous mutation in BEST1. In the second family, one member presented deposits located on the surface on hyperaemic OD and a compound p.(R141H);(A195V) mutation in BEST1. In the third family, POD was observed in father and child with early onset cone-rod dystrophy and a novel autosomal recessive p.(W31*) homozygous mutation in ABCA4. In the fourth family, POD with "mulberry-like" deposits and attenuated vessels were observed in a 7-year old girl, with a mutation in USH1A, and with early onset rod-cone dystrophy, associated with hearing loss. In the fifth family, blurry OD with tortuous vessels was observed in 4 consanguineous female carriers and a hemizygous boy with a p.(R200H) mutation in the X-linked retinoschisis RS1. In the sixth family, a mother and her son were both affected with POD and attenuated peripapillary vessels, and presented with a p.(Y836C) heterozygous mutation in TOPORS, thus confirming autosomal dominant RP. In the seventh family, in 3 family members with POD, compound p.(L541P;A1038 V);(G1961E) mutations in ABCA4 confirmed the diagnosis of Stargardt disease. Conclusions A variety of OD findings are found in a genetically heterogeneous group of IRDs. In the presence of POD, an inherited progressive photoreceptor disease should be ruled out.

Efficacy of Vitrectomy Combined with Subretinal rtPA Injection with Gas or Air Tamponade.

Background Functional and anatomical outcome after vitrectomy with rtPA combined with gas or air tamponade. Patients and methods Retrospective analysis of pseudophakic patients treated with subretinal rtPA and gas or air tamponade. The primary endpoint was displacement of haemorrhage six months after surgery. The secondary endpoints were visual acuity (BCVA), haemorrhage diameter (MHD) and central macular thickness (CMT), as measured by SD-OCT. Results 53 of 85 eyes were pseudophakic. 27 of these eyes were treated with air tamponade and 26 with gas tamponade. For patients with air tamponade, the mean BCVA improved from 20/530 to 20/355 (p = 0.01). MHD and CMT decreased from 6386 ± 2281 µm to 3805 ± 2397 µm (p < 0.001) and 895 ± 592 µm to 532 ± 386 µm (p < 0.001), respectively. For patients with gas tamponade, the mean BCVA improved only slightly, from 20/471 to 20/394 (p = 0.17). MHD and CMT exhibited statistically significant decreases from 6759 ± 1773 µm to 3525 ± 1548 µm (p < 0.001) and 1089 ± 587 µm to 537 ± 251 µm (p < 0.001), respectively. Conclusions Vitrectomy with subretinal rtPA injection has strong functional and anatomical effects on submacular haemorrhages with both gas and air tamponade.

Improvement in Visual Function in Patients with Inherited Diseases of the Retina Following Acupuncture Treatment.

BACKGROUND: The aim of this pilot study was to examine the short-term effect on visual function of acupuncture treatment in a cohort of patients with inherited diseases of the retina. PATIENTS AND METHODS: A prospective pilot study was performed on 14 patients (10 ♀, 4 ♂; mean age: 43.43 y (± 19.72 y)), with the clinically and electrophysiologically confirmed diagnosis of inherited disease of the retina. Acupuncture treatment consisted of needle application to the body and ears and was performed following a standardized protocol. The treatment was scheduled for 10 half-hour sessions over five weeks. Visual function was measured before acupuncture, between acupuncture treatments and after the end of treatment. Objective measurements included best corrected visual acuity (ETDRS charts), contrast vision (CSV-1000, Vector Vision) and Goldmann perimetry (isopters 3IIIe; Haag-Streit). Subjective evaluation was based on evaluation questionnaires. To exclude the effect of variability on the psychophysical tests, a non-acupuncture control group (Nr: 8; 5 ♀, 3 ♂; mean age: 38.56 y (± 9.08 y)) was taken for comparison. RESULTS: All patients with inherited diseases of the retina showed general improvement in objective visual functions, with post-/pre- acupuncture improvement in: visual acuity (p = 0.031, left eyes), contrast vision (p = 0.015 and p = 0.041; both eyes) and widening of the temporal radius of the visual field (0.013; left eyes). Subjectively, all patients reported better daytime, color and contrast vision, better visual focus and less visual tiredness. In addition, some general symptoms, such as longer sleep-onset time, feeling cold, and migraine/headache attacks were significantly reduced. CONCLUSIONS: The acupuncture protocol improved visual function in our patients with inherited diseases of the retina and was well tolerated. Nevertheless, the long-term effect of this complementary therapy remains to be evaluated.

Increased Prevalence of Flammer Syndrome in Patients with Retinitis Pigmentosa.

BACKGROUND: "Retinitis pigmentosa" refers to a group of degenerative eye diseases with a genetic background. Flammer syndrome encompasses a set of symptoms and signs, mainly but not exclusively related to dysregulation of blood vessels. The purpose of the present study was to determine, with the help of a questionnaire, whether symptoms of Flammer syndrome occur more often in patients with retinitis pigmentosa than in controls. METHODS: 76 patients with retinitis pigmentosa (members of the Swiss patient organization for retinitis pigmentosa) and 274 control subjects answered a questionnaire (Flammer Syndrome Questionnaire) on 15 symptoms and signs of Flammer syndrome. RESULTS: Seven of 15 symptoms and signs of Flammer syndrome were significantly more often positive in retinitis pigmentosa patients than in controls. Six additional symptoms and signs occurred non-significantly more often and 2 non-significantly less often in patients with retinitis pigmentosa. CONCLUSION: Retinitis pigmentosa patients suffer significantly more often from symptoms and signs of the Flammer syndrome than control subjects. This includes low body mass index, low blood pressure, feeling cold, migraine, increased smell perception and perfectionism. The reason for this association between retinitis pigmentosa and Flammer syndrome and the potential implications need to be determined.

Unexpected Effect of Calcium Channel Blockers on the Optic Nerve Compartment Syndrome.

BACKGROUND: The optic nerve compartment syndrome is a pathological condition in which cerebrospinal fluid of the subarachnoid space surrounding the optic nerve is partly or totally segregated from the cerebrospinal fluid of the intracranial subarachnoid space, leading - inter alia - to an increase in the diameter of the optic nerve sheath. The pathogenesis of this condition remains unclear. We have observed clinically that optic nerve compartment syndrome often occurs in normal tension glaucoma patients with Flammer syndrome. To treat Flammer syndrome, some glaucoma patients received a low dose of a calcium channel blocker and we analysed whether this treatment also had an effect on the optic nerve compartment syndrome. PATIENTS AND METHODS: We retrospectively analysed the data of 10 eyes of seven patients suffering from a combination of primary open angle glaucoma, optic nerve compartment syndrome, and Flammer syndrome. We included subjects who had eye socket echography before and after a few months of therapy with a calcium channel blocker. THERAPY AND RESULTS: All patients received a low dose of a calcium channel blocker (nifedipine or amlodipine) to treat Flammer syndrome. As expected, the symptoms of Flammer syndrome were mitigated. To our surprise, the optic nerve compartment syndrome also improved in eight of the 10 eyes (80 %), but remained unchanged in the remainder. CONCLUSIONS: To some extent, the optic nerve compartment syndrome is related to the combination of primary open angle glaucoma and Flammer syndrome. On the basis of our results, we hypothesise that treatment of Flammer syndrome may also improve the optic nerve compartment syndrome.

Comparing Short-Duration Electro-Oculograms with and without Mydriasis in Healthy Subjects.

BACKGROUND: In order to obtain artifact-free electro-oculogram recordings the subject's cooperation is necessary. The aim of our study is to evaluate the recording characteristics of short-duration EOG and to compare the effect of mydriasis on electro-oculogram recordings in a cohort of controls. PATIENTS AND METHODS: Electro-oculogram recordings were performed on a light-emitting diode stimulus screen using a RETI-port gamma plus2 system (RETIscan™, Roland Consult). Fast oscillations were set at 1.5 sec (6 cycles; total duration 75 sec).The dark phase included: pre-adaptation (6 min), alternate fixation (4 min), fixation-rest (20 sec), 100 sweeps. The light phase included: light adaptation (4 min), alternate fixation (10 min), fixation-rest (20 sec), 250 sweeps. The amplifier band pass was filtered at 0.1÷50 Hz. The background illumination in mydriasis was 100 cd/m2 and in miosis--450 cd/m2. RESULTS: A total of 55 controls participated and were divided into three age groups [number; mean (years, y); ±SD]: group 1: 18-20 years (19; 19.49 years; ±0.89); group 2: 20-40 years (18; 27.91 years; ±5.39) and group 3: 40-60 years (18; 48.66 years; ±4.00). The Arden ratio, dark-trough and light-peak did not differ between recordings with or without mydriasis (p=0.914; p=0.880; p=0.680, linear mixed-effects model). The age did not influence the Arden ratio, dark-trough, light-peak (p=0.206; p=0.112; p=0.155). Arden ratio, dark-trough, light-peak were comparable between tested eyes (p=0.934; p=0.193; p=0.270). CONCLUSIONS: Short-duration electro-oculograms allow successful recording, furthermore, the application of mydriasis does not influence the quality of the recording.

Tendinous muscle insertions (scleromuscular junctions of the recti muscles) in patients with ocular alignment problems.

BACKGROUND: The purpose of this study was to prove the hypothesis whether the scleromuscular junction of extraocular recti muscle is tendinous. PATIENTS AND METHODS: Muscle samples of the 41 extraocular recti muscles of 33 patients and 4 muscle-/eye-matched samples from 2 postmortem eyes, were processed for light/electron microscopy and immunohistochemistry with antibodies against desmin, smooth-muscle actin and muscle regulating proteins like myf3 and myf4 (myogenin), tenascin C and for 8 samples against collagens I to IV. RESULTS: Histological examination of the muscle samples confirmed a thick collagen-structured tissue, specific for muscle tendon; without appearance of muscle tissue. This was confirmed by immunohistochemistry with antibodies against desmin, smooth-muscle actin, myf3 and myf4 (myogenin) and for eight samples with collagens I to IV. Anti-tenascin C marker was only strongly positive in the connective tissue of the blood vessel walls. Electron microscopy demonstrated collagen bundles composed of parallel oriented fibrils with a moderate amount of ground substance. CONCLUSIONS: The absence of contractile fibers at the sclerotendinous junction is an entirely normal finding in humans and cannot be related to ocular alignment pathogenesis.

Endothelin-1 Plasma Levels in Patients with both Retinitis Pigmentosa and Flammer Syndrome.

BACKGROUND: Endothelin-1 is a strong endogenous vasoconstrictor and is also an agent reducing the ocular blood flow. Patients with retinitis pigmentosa are known to have reduced ocular blood flow. This can be secondary to retinal atrophy, but may also partially result from an additional condition, such as a Flammer syndrome. The aim of the study was to investigate whether the endothelin-1 plasma levels in retinitis pigmentosa patients with and without Flammer syndrome are different. PATIENTS AND METHODS: In the study we included patients with clinical signs and symptoms of retinitis pigmentosa, confirmed by electrophysiological findings. Blood samples were obtained from 6 retinitis pigmentosa patients with and 4 without Flammer syndrome. The results were related to 30 age- and sex-matched control subjects. Endothelin-1 plasma levels were determined by specific radioimmunoassay. RESULTS: The endothelin-1 plasma levels in retinitis pigmentosa patients with Flammer syndrome were significantly higher than those without Flammer syndrome. The mean (±SD) endothelin-1 levels (pg/mL) in retinitis pigmentosa patients with Flammer syndrome were 4.95 (±1.74), range: (2.37-6.76), whereas in patients without Flammer syndrome they were 1.10 (±0.08), range: 1.00-1.20. Our own normal values are: 1.56 (±0.30), range: (0.90-2.13). All retinitis pigmentosa patients with increased endothelin-1 plasma levels had signs and symptoms related to a Flammer syndrome, such as cold extremities, low blood pressure, reduced feeling of thirst, increased sensitivity in general, e.g., increased sensitivity to certain drugs, increased pain sensitivity and increased sense of smell. CONCLUSION: Endothelin-1 plasma levels were increased in retinitis pigmentosa patients with but not in patients without Flammer syndrome. Many questions remain open: Why so many retinitis pigmentosa patients suffer from Flammer syndrome, why is the endothelin-1 level in such patients higher than in healthy subjects with Flammer syndrome, how much of the ocular blood flow reduction is due to retinal degeneration and how much to the Flammer syndrome? We hypothesise that Flammer syndrome leads to an additional increase of the endothelin-1 level and an additional decrease of ocular blood flow in retinitis pigmentosa patients. Further studies are needed to analyse the causal relationship between retinitis pigmentosa and Flammer syndrome and evaluate potential therapeutic implications.

[Molecular based targets and endometrial cancer].

In recent years, increasing attention has been paid to the rate of spread of endometrial carcinoma, especially in the postmenopausal period. Along with routine diagnostic methods, giving information on the location and progression of the disease, there are some morphological methods determining very accurately the correlations in the development of this type of cancer and his prognosis. Moreover--in recent years, the accumulated information about the molecular profile of this type of cancer made it possible to implement a number of new drugs against the so-called molecular therapy -'targets' in the neoplastic process. Significant proportion of cases show response rates, it is more hope in the development of more successful formulas and target -based therapy. In this review, we present and discuss the role of certain molecular markers as potential indicators of prognosis and development, as well as determining the target treatment of endometrial carcinoma.

Retinal vessel oxygen saturation in giant cell arteritis patients without ocular symptoms.

BACKGROUND: The aim of this study was to determine subclinical ocular ischemia related to giant cell arteritis (GCA) by means of retinal oximetry (RO) measurements. PATIENTS AND METHODS: Four test-retest RO images per eye were taken with the retinal vessel analyser (IMEDOS Systems UG, Jena). RO measurements in arterial (A-SO2) and venous (V-SO2) retinal vessels and their difference (A-V SO2) were calculated in GCA patients and compared to those of age-matched controls. RESULTS: GCA biopsy and duplex sonography positive patients (n=8, 13 eyes) from the Basler Riesenzellarteriitis Kohorte study (BARK) were recruited. In controls (n=6, 10 eyes), the mean (± SD) A-SO2 and V-SO2 were measured at 93.89% (± 3.0) and at 55.60% (± 3.4), respectively. In the GCAs, a reduction in the A-SO2 to 93.37% (± 3.3) and an increase in V-SO2 to 61.13% (± 3.6) were found. The A-V SO2 difference was reduced in the GCAs to 32.24% (± 3.8) whereas in the controls the difference was 38.31% (± 2.8). CONCLUSIONS: Oxygen metabolism is affected in cases with GCA. Thus, RO may provide additional data in the diagnosis of GCA, even when no ophthalmic symptoms have been reported.

Unstable oxygen supply and glaucoma.

The pathogenesis of the glaucomatous optic neuropathy (GON) is an ongoing bone of contention. While the role of intraocular pressure (IOP) is well known, it is also clear that a variety of other factors, particularly those of a vascular nature, are involved as well. In contrast to other eye diseases, it is an unstable oxygen supply, as opposed to chronic hypoxia, that contributes to GON. The major cause of fluctuations in the local oxygen tension is an unstable ocular blood flow (OBF). OBF, in turn, fluctuates if the IOP spikes, blood pressure drops, or OBF autoregulation is defective. The main reason for disturbed autoregulation is a primary vascular dysregulation (PVD), particularly in the context of the so-called Flammer syndrome. Unstable oxygen tension leads to local oxidative stress with many detrimental effects, such as the activation of glial cells, which alters their morphology and gene expression. As a consequence, the local concentrations of nitric oxide and the metalloproteinases increase. The metalloproteinases digest extracellular matrix and thereby contribute to tissue remodelling. The short-lived nitric oxide easily diffuses into the neighbouring neuronal axons, allowing a fusion with the superoxide anion and thereby generating the cell-damaging peroxynitrite. Both this tissue remodelling and damage of the axons contribute to the development and progression of GON.

Retinal vessel oxygen saturation in patients suffering from inherited diseases of the retina.

PURPOSE: The aim of this study was to evaluate the oxygen saturation in patients with inherited diseases of the retina. METHODS: Fundus oximetry images were taken using a retinal vessel analyser (IMEDOS Systems UG, Jena, Germany). Retinal vessel oximetry was performed in 53 eyes of 27 patients suffering from inherited retinal diseases and compared to 22 eyes of 11 healthy controls. The oxygen saturation in all four major retinal arterioles (A-SO2) and venules (V-SO2) were measured and their difference (A-V SO2) was calculated. The data were compared within groups and to controls. RESULTS: Based on V-SO2 values, the rod-cone dystrophy group (66.46%; SD, ± 5.09) could well be differentiated from controls 54.02% (SD, ± 3.04), from cone-rod dystrophies 57.56% (SD, ± 5.66), as well as from inherited maculopathies 58.42% (SD, ± 4.74). The mean A-SO2 in the rod-cone dystrophy group was increased to 98.96% (SD, ± 6.06, p<0.014), while in the cone-rod group and in the maculopathy group it was 92.75% (SD, ± 3.75), respectively 94.44% (SD ± 4.85), closer to the normal values (92.68%; SD, ± 3.53, p>0.05). The A-V SO2 difference, as an indirect indicator for retinal oxygen use, was reduced in the rod-cone patients, however only when the controls were taken into account (p=0.01). CONCLUSION: This is to our knowledge the first study which proposes the retinal vessel oximetry to be a sensitive measure for differentiating rod-cone dystrophy patients not only from controls, but also from patients with other inherited retinal dystrophies.

The 2-global flash mfERG in glaucoma: attempting to increase sensitivity by reducing the focal flash luminance and changing filter settings.

PURPOSE: To test a new 2-flash multifocal electroretinogram (mfERG) paradigm in glaucoma using a reduced light intensity of the m-frame flash as opposed to the global flash, as it has been suggested that this may increase the responses induced by the global flash, which has been the part of the mfERG response where most changes have been noted in glaucoma. METHODS: A mfERG was recorded from one eye of 22 primary open angle glaucoma (POAG) patients [16 normal tension glaucoma (NTG), 6 high tension glaucoma (HTG)] and 20 control subjects. A binary m-sequence (2^13-1, Lmax 100 cd/m2, Lmin<1 cd/m2), followed by two global flashes (Lmax 200 cd/m2) at an interval of 26 ms (VERIS 6.0™, FMSIII), was used. The stimulus array consisted of 103 hexagons. Retinal signals were amplified (gain=50 K) and bandpass filtered at 1-300 Hz. For each focal response, the root mean square was calculated. We analyzed 5 larger response averages (central 15° and 4 adjoining quadrants) as well as 8 smaller response averages (central 10° and 7 surrounding response averages of approximately 7° radius each). Three epochs were analyzed: the direct component at 15-45 ms (DC) and the following two components induced by the effects of the preceding focal flash on the response to the global flashes at 45-75 ms (IC-1) and at 75-105 ms (IC-2). Statistical analysis was performed using linear mixed effects models adjusted for age. RESULTS: Responses differed significantly between POAG patients and controls in all central response averages. This difference was larger for the central 10° than for the response average of the central 15°. While these observations held true for all response epochs analyzed, the DC differed least and the IC-1 most when POAG was compared to control. For POAG, the most sensitive differential measure was IC-1 of the central 10° with an area under the ROC curve of 0.78. With a cutoff value of 12.52 nV/deg2, 80% of the POAG patients (100% HTG, 69% NTG) were correctly classified as abnormal, while 77% of the control subjects were correctly classified as normal. When the results of the mfERG were compared to the visual fields, there was a tendency for the mfERG to decrease as the mean defect increased. However, this correlation was only significant in the superior nasal quadrant when the IC-1 of the mfERG was compared to the corresponding area of the visual field. CONCLUSION: When compared to findings from previous studies, reducing the luminance of the m-frame flash in the 2-global flash paradigm did not increase the sensitivity and specificity of the mfERG to detect glaucoma further.

[A study on early-onset group "B" streptococcal neonatal infection].

The results achieved with 80% reduction in the incidence of early-onset neonatal group B streptococcal (GBS) sepsis following the implementation of the preliminary (1996, 2002) and subsequently the revised (2010) guidelines for intrapartum antibiotic prophylaxis imposed the discussion on a large scale of the updated:--algorithms for GBS screening (35-37 weeks of gestation) with the recommended dosage of penicillin-G for intrapartum antibiotic prophylaxis for women having normal labor and delivery;--algorithms for GBS screening and intrapartum antibiotic prophylaxis for women with preterm labor (PPROM) or premature rupture of membranes (PROM);--intrapartum antibiotic prophylaxis regimens for women with penicillin allergy;--algorithm for management of newborns with respect to risk of early-onset GBS disease. The present study is aimed at studying the distribution of the early-onset GBS disease in our country based on the data of leading obstetrics & gynecology clinics and wards. The aim is to diferrentiate clinically the cases and investigate the influence of the known risk factors on the part of the mother. A special accent is put over the microbiological diagnostics of cases in view of CDC expanded recommendations on the laboratory methods for identification of GBS. As a final conclusion the necessity for introduction of an official registration of the early- and late-onset GBS disease in the country is emphasized.

Non-radiative deactivation of excited cytosine: probing of different DFT functionals and basis sets in solvents with different polarity.

The vertical excitation and emission energies of the cytosine oxo-amino form were calculated at the TD DFT level of theory with several functionals, basis sets, and solvents with different polarity (PCM). They were compared with the experimental UV absorption and fluorescence maxima, revealing that the minimal deviation of the vertical excitation energies from the of UV absorption maxima can be achieved when the hybrid functional B3LYP is applied within the calculations. Regular correlations like curves with saturation between the vertical excitation/emission energies and the dielectric constants were registered. The relaxation of the 1ππ* excited state through an ethylene-like conical intersection S0/S1 should occur through decrease of the decay rate (commented qualitatively here) with the rise of the solvent polarity.

Asynchronous release of GABA via tonic cannabinoid receptor activation at identified interneuron synapses in rat CA1.

The influence of local circuit interneurons is thought to play an important role in adjusting synaptic strength via endogenous cannabinoid type 1 (CB1) receptors. Using paired whole-cell recordings, combined with double immunofluorescence and biocytin labelling in acute slices of rat CA1 at postnatal day 18-23, we investigated the properties of Cholecystokinin (CCK)-positive stratum radiatum local circuit interneuron connections that utilised CB1 receptors. Three types of synaptic connections were studied, lacunosum-moleculare-radiatum perforant path-associated (LM-R PPA) to Shaffer collateral-associated (SCA) interneurons, SCA-SCA interneurons and SCA-pyramidal cells. These three synapses were differentially under tonic reduction of inhibition that was blocked by the CB1 receptor inverse agonist AM-251 (10 microM), which enhanced IPSPs. The strength of tonic reduction of inhibition was correlated with asynchronous release which was apparent at connections among interneurons. AM-251 increased the ratio of synchronous to asynchronous release (synchronicity ratio), while the CB receptor agonist anandamide (14 microM) decreased the synchronicity ratio. Fast and slow calcium chelators (BAPTA-AM and EGTA-AM) also increased the synchronicity ratio, accelerated inhibitory time courses and reduced IPSP amplitudes. These data suggest that CB1 receptors at connections among interneuron synapses play a role in tonic suppression of inhibition and govern the asynchronous release of GABA, modulating the time windows of inhibition. Effects of calcium chelators suggest that asynchronous release is a result of a long-lasting presynaptic calcium transients and/or a large distance between calcium source and sensor of exocytosis. These properties of specialised inhibitory neurons may have important modulatory roles in controlling spike timing among local circuit interneurons.