[Nonlinear Microscopy in Ophthalmology: Principles and Pathbreaking Applications]. / Nichtlineare Lasermikroskopie in der Ophthalmologie: Physikalische Prinzipien und wegweisende Anwendungen.

Nonlinear microscopy is a non-invasive imaging technique which allows a visualization of biological tissue with high signal contrast due to spectral separation combined with high resolution. In addition to two-photon fluorescence and second harmonic signals also four-wave mixing signals can be used for imaging ocular structures. This review article presents the physical principles of different contrast mechanisms. Exemplary experimental results based on various nonlinear signals are shown, opportunities of this technology are discussed and the prospect of translating this imaging technique into a clinical application is addressed.

[Implant Design by Means of Multiphoton Polymerization]. / Implantatdesign mittels Multiphotonen-Polymerisation.

BACKGROUND: Additive manufacturing and 3D printing create new paths for the design and manufacturing of implants. Technologies with high resolution are required for the development of microstructured eye implants. In the present study, we demonstrate how these technologies can be used during the design development and manufacturing of a multifocal diffractive aspheric intraocular lens. MATERIAL AND METHODS: Multiphoton polymerisation (MPP) is used to manufacture a diffractive relief with resolution in the sub-micrometer range. The relief is applied to the moulded body of a refractive lens, forming a trifocal lens. Propagation of light behind the lens is visualised in water with fluorescein. RESULTS: Multifocal lenses were successfully manufactured with this approach. The optical design with three foci is confirmed by the light propagation images. The images even clearly demonstrate the impact of the refractive and diffractive elements and may provide information on artefacts and aberrations. CONCLUSIONS: Multiphoton polymerisation is an interesting tool for the flexible manufacturing of complex multifocal lenses. With future technological progress in 3D printing with MPP, this is a promising method for on-demand manufacturing of patient individual intraocular lenses.

[Optimisation of the visualisation technique for optical paths through intraocular lenses for characterisation of multifocal imaging properties of Fresnel-zone plates]. / Optimierung der Visualisierungstechnik für Strahlenverläufe durch Intraokularlinsen zur Charakterisierung multifokaler Abbildungseigenschaften von Fresnel-Zonenplatten.

The utilisation of the diffractive properties of Fresnel zone plates offers the possibility of intraocular lens designs with multiple foci. Such intraocular lenses can be manufactured by two-photon polymerisation (2PP). This paper explains the underlying concept and shows the principles for visualisation of the focus properties of such implants.

[Effect of pseudophacic mini-monovision as an option for independence of spectacles in everyday life]. / Der Effekt der pseudophaken Minimonovision als Option einer Brillenunabhängigkeit im Alltag.

BACKGROUND: Modern day patients who undergo bilateral cataract surgery expect to be spectacles-independent after surgery. The options that are available to attain this goal are pseudophakic monovision, implanting multifocal IOLs or alternatively accommodative IOLs. The aim of this study is to establish the suitability in daily life when attaining minor monovision, named hereafter mini-monovision. MATERIAL/METHODS: In this clinical retrospective study 30 patients were examined. These subjects where bilaterally pseudophake and received either AcrySof®-IOL or Acreos® Adapt-IOL with a slight anisometropia of between 0.5 and 1.75 D and with a maximal astigmatism up to 1.5 D. Visual acuity (VA) for distance (ETDRS), intermediate (Jaeger 80 cm) and near (Jaeger 40 cm) as well as defocus curves were assessed. Furthermore were examined: the reading speed using the font size of the Radner reading chart, anisoconia (FA Oculus according to Esser), stereopsis (Titmus), subjective patient satisfaction (adapted VF-14-questionnaire) and the subjective dependence on having to wear spectacles. RESULTS: The median anisometropia was at 0.75 D; the age was between 61 and 80 (median being at 73 years). 12 patients were male and 18 female. When examined with binocular vision 100 % could attain distance VA of at least decimal 1.0 (LogMAR 0) and an intermediate VA of at least decimal 0.8 (LogMAR 0.1), up to 86.57 % a near VA of at least Jaeger 5, (LogMAR 0.4); up to 63.33 % even managed at least Jaeger 3 (LogMAR 0.3). The median average reading speed for binocular uncorrected reading under photopic conditions was 145 words/minute and under mesopic conditions 117 words/minute. The critical font size was LogRAD 0.60 (Jaeger 5-6), the anisoconia at 2 % and stereopsis at 80 arc seconds. The general dependence on glasses was reduced from 100 % preoperatively to 13 %, postoperatively. Simultaneously a high patient satisfaction score of 93.18 in the VF-14 questionnaire was attained. The result is comparable to those quoted in the literature on full monovision and mulitifocal IOLs. CONCLUSION: To attain spectacles independency, pseudophake mini-monovision is a cost efficient alternative to multifocal lenses for well selected patients. A relative reduction in near VA must be taken into account. To establish the refractive target further examinations are required. Establishing the accurate depth of vision will be helpful in attaining this.

Glutathione S-transferase P1 Ile105Val polymorphism modulates allergen-induced airway inflammation in human atopic asthmatics in vivo.

BACKGROUND: Glutathione S-transferase P1 is a Phase II cytoprotective and detoxifying enzyme that is widely expressed in human airways. The glutathione S-transferase P1 Ile105Val polymorphism has been linked with atopic disorders and asthma. Yet, little remains known about the regulation of allergic inflammation by glutathione S-transferase P1 in human asthmatics. OBJECTIVE: To establish the effect of the glutathione S-transferase P1 Ile105Val polymorphism on allergen-induced airway inflammation and oxidant stress, and non-specific bronchial hyperresponsiveness to methacholine and reactivity to specific allergen in mild human atopic asthmatics in vivo. METHODS: Five Val(105)/Val(105) , twelve Val(105)/Ile(105) and twenty Ile(105)/Ile(105) mild atopic asthmatics underwent methacholine challenge, inhaled allergen challenge and endobronchial allergen provocation through a bronchoscope. A panel of inflammatory cytokines and chemokines, F2 -isoprostanes and isofuranes, markers of oxidative stress, thromboxane B2 and immunoglobulin E were measured in bronchoalveolar lavage fluid at baseline and 24 h after allergen instillation. RESULTS: Asthmatics with glutathione S-transferase P1 Val(105)/Val(105) compared with asthmatics with the glutathione S-transferase P1 Val(105)/Ile(105) and Ile(105)/Ile(105) had greater generation of acute phase cytokines (TNF-α, IL-6, CXCL8), IL-12, CCL11, thromboxane B2 and immunoglobulin E at 24 h after local allergen challenge. The GSTP1 genotype had no effect on airway hyperresponsiveness to methacholine and the reactivity to specific allergen. CONCLUSION: The glutathione S-transferase P1 Ile105Val polymorphism markedly modifies allergen-provoked airway inflammation in atopic asthmatics in vivo. Modulation of the biochemical milieu in response to allergen provides a mechanistic explanation for regulatory effects of glutathione S-transferase P1 polymorphism on airway pathophysiology, and may guide improvement of future therapeutic methods in human atopic asthmatics. These findings must me confirmed in a larger study population of asthmatics with various ethnicities.

[Non-invasive, spatially resolved determination of tissue properties of the crystalline lens with regard to rheology, refractive index, density and protein concentration by using Brillouin spectroscopy]. / Non-invasive, ortsaufgelöste Bestimmung von Gewebeeigenschaften der Augenlinse hinsichtlich Rheologie, Brechungsindex, Dichte und Proteinkonzentration unter Anwendung der Brillouin-Spektroskopie.

The confocal Brillouin spectroscopy is an innovative measurement method that allows the non-invasive determination of the rheological properties of materials. Its application in ophthalmology can offer the possibility to determine in-vivo the deformation properties of sections of transparent biological tissue such as the cornea or eye lens with spatial resolution. This seems to be a promising approach concerning current presbyopia research. Due to the spatially resolved detection of the viscoelastic lens properties, a better understanding of the natural aging process of the lens and the influences of different lens opacities on the stiffness is expected. From the obtained spectral data the relative protein levels, the relative refractive index profile and the relative density profile within the lens tissue can be derived in addition. A measurement set-up for confocal Brillouin microscopy based on spectral analysis of spontaneous Brillouin scattering signals by using a high-resolution dispersive device is presented. First in-vitro test results on animal and human lenses are presented and evaluated concerning their rheological significance. These data are compared with known research results.

The vibrant soundbridge for conductive and mixed hearing losses: European multicenter study results.

BACKGROUND/AIMS: The Vibrant Soundbridge (VSB) is an active middle ear implant, 'direct-drive' hearing system for the treatment of hearing loss. Recently, the VSB has been applied to conductive and mixed hearing losses. The aim of this study is to evaluate aided benefit, speech recognition in quiet and noise, subjective benefits, changes in residual hearing, and medical and surgical complications in adults with conductive or mixed hearing losses implanted with the VSB using Round Window (RW) Vibroplasty. METHODS: Twelve German-speaking adults participated in a single-subject, repeated measures study design comparing their performance using the VSB with their own unaided preoperative performance. Hearing performance and changes in residual hearing were assessed using routine audiometric measures, sound field thresholds, and word and sentence recognition in quiet and in noise. Subjective benefits, including subjective hearing performance, device satisfaction, and quality of life were evaluated using the Abbreviated Profile of Hearing Aid Benefit, the Hearing Device Satisfaction Scale, and the Glasgow Benefit Inventory, respectively. RESULTS: Aided hearing thresholds, word recognition at conversational levels, and sentence recognition in quiet and noise were significantly improved without significant changes in residual cochlear hearing and without major medical and surgical complications. One subject required repositioning surgery to improve transducer coupling with the RW membrane. Subjective benefit and device satisfaction were good, as were overall and general quality of life. CONCLUSION: The VSB, implanted using RW vibroplasty, is a safe and effective treatment for adults with conductive and mixed hearing losses who may have few, if any, other options.

[Differential diagnosis of anorexia nervosa and depression. A case report of Addison's disease in a female patient]. / Differenzialdiagnose der Anorexia nervosa und der Depression. Fallbeispiel einer Patientin mit Morbus Addison.

Similar symptoms make the differential diagnosis of anorexia nervosa and Addison's disease difficult at times: vomiting, weight loss, hypotension, depressed mood, reduced drive, and increased irritability can occur in both disorders. Psychological factors are then frequently presumed to be causative, so that the diagnosis of Addison's disease is made only years after the onset of the disease. Against this background, our case report presents important differential features, particularly with regard to consultative psychiatry.

Non-TBI stem cell transplantation protocol for Fanconi anaemia using HLA-compatible sibling and unrelated donors.

Allogeneic haemopoietic stem cell transplantation (SCT) is the only curative option for severe bone marrow (BM) failure in patients with Fanconi anaemia (FA). We have developed a non total body irradiation (TBI) conditioning protocol consisting of fludarabine (120-150 mg/m(2)), low dose of cyclophosphamide (40 mg/kg) and antilymphocyte globulin (45 mg/kg). Graft-versus-host disease (GVHD) prophylaxis was with cyclosporin alone for sibling allografts but also included Campath-1 H (days 1-5 post SCT) for the unrelated allografts. We have performed two sibling and two unrelated BM transplants with a follow-up of 11-51 months. All patients experienced minimal toxicity and were discharged from hospital 28-32 days post SCT. Neutrophil and platelet engraftment occurred from days 11 to 19 and 15 to 34, respectively. All patients achieved stable full donor haemopoiesis with normalisation of the peripheral blood count despite one of them having myelodysplasia (MDS) with 8% blasts prior to the SCT. The only site of acute GVHD was in the skin (grade I-II) and only one patient progressed to limited chronic GVHD. This protocol is associated with reduced toxicity and prompt engraftment in FA patients with AA and/or MDS undergoing SCT using sibling or unrelated donors.

Improvement in cognition associated with novel antipsychotic drugs: a direct drug effect or reduction of EPS?

BACKGROUND: Administration of novel, versus classic, antipsychotic agents to patients suffering from psychosis is associated both with moderately better scores on cognitive tests, and with fewer extrapyramidal symptoms (EPS). Because improved motor functioning may enable better performance on some components of cognitive test batteries, and because the advantages of the novel antipsychotics on cognitive performance are not very large, it is sometimes difficult to discern if improvement in a given cognitive task is due to a direct effect of the novel antipsychotic drug, or is secondary to the novel drug's decreased propensity to induce EPS. In an attempt to distinguish between these two possibilities, the present study examined the ability of patients suffering from schizophrenia receiving classic, versus novel antipsychotics, to perform a computerized visuo-motor test (VMT). VMT assesses planning capabilities, attention and executive functions known to be impaired in schizophrenia, which are suggested to be affected by novel antipsychotics. METHODS: Seventy-six patients suffering from schizophrenia or schizophreniform disorder, receiving haloperidol (23 patients, mean dose 10.01+/-6.1mg/day), olanzapine (26 patients, mean dose 10.56 +/- 4.9 mg/day) or risperidone (27 patients, mean dose 4.35 +/- 1.7 mg/day) were assessed for EPS using the parkinsonian subscale of the Extrapyramidal Symptom Rating Subscale (ESRS), and with the VMT. RESULTS: Cognitive functioning as measured by the VMT was better for patients receiving risperidone or olanzapine, compared with those receiving haloperidol (F=6.636, df=2,67, P=0. 002), while the patients receiving haloperidol or risperidone suffered from more severe EPS compared with the patients receiving olanzapine (F=3.996, df=2,71, P=0.023). DISCUSSION: Although the patients receiving risperidone suffered from EPS similar in severity to the EPS of the patients receiving haloperidol, their performance on a task involving visuo-motor and attentional skills was similar to that of the patients receiving olanzapine. This finding implies that there is a dissociation between the antipsychotic drug's ability to affect cognitive functioning, and EPS. This dissociation indirectly suggests that the advantages offered by novel antipsychotics on cognitive performance are a direct effect, rather than being entirely mediated by improved movement abilities.

[A structured course for primary care physicians on breaking bad news].

Physicians are frequently required to break bad news to their patients. Previous research has shown that inconvenience, incompetence, and difficulty in dealing with patients' feelings are the main complaints expressed by physicians after such an encounter. Current educational programs dealing with breaking bad news are usually short, given in lecture format, and are inadequate in addressing essential issues such as knowledge, personal beliefs and attitudes, and previous personal experiences of physicians in such situations. In the past 8 years our Dept. of Family Medicine has implemented a course in breaking bad news that addresses these issues. A senior family practitioner and a medical social worker conduct 14 sessions of discussions and role-playing for small groups of residents and primary care physicians. The program is based on: theory dealing with methods of managing stress and crisis intervention, clarifying personal attitudes, discussions of previous personal encounters of the participants, various modalities of communication, methods of addressing patients' feelings and emotions, and coping with the emotions of the one breaking the bad news. On a 1-5 Likert scale questionnaire the course received an overall score of 4.47 (SD 0.51). Participants noted that they gained relevant communication skills for future patient encounters. A reliable examination of practitioners' competence in breaking bad news is mandatory in order to assess the efficiency of such courses.

Preparation of surface modified protein nanoparticles by introduction of sulfhydryl groups.

The objective of the present study was to establish several methods for the introduction of thiol groups onto the surface of human serum albumin (HSA) nanoparticles. Besides the epsilon-amino groups of lysine, the carboxyl groups of asparaginic and glutaminic acid, and the carbonyl groups of the cross-linker glutaraldehyde, sulfhydryl groups are possible targets for the covalent linkage of drugs to particle surfaces. In principle, the thiol groups were introduced by the reaction with dithiotreitol (DDT) or 2-iminothiolane, by quenching reactive aldehyde residues with cystaminiumdichloride or by coupling L-cysteine and cystaminiumdichloride by the aqueous carbodiimide reaction. The resulting nanoparticulate systems were characterised concerning the number of available sulfhydryl groups, particle size and particle density. It was shown, that by variation of the reaction conditions, e.g., the concentration of the coupling reagent or the sulfhydryl containing component as well as the reaction time, the proposed methods enabled the preparation of HSA nanoparticles with a well defined surface characteristic. Stability studies showed that the introduced thiol groups were relatively stable and lost their reactivity with a half-life of 28.2 days independently of the method used for the sulfhydryl group introduction. Besides the quantification of free sulfhydryl groups the covalent attachment of cystaminiumdichloride by the carbodiimide reaction was used to calculate the amount of free carboxyl groups on the surface of the nanoparticles. The toxicity of the modified nanoparticles was evaluated in cell culture experiments.

Sensitivity, functional analysis, and behavior genetics: a response to Freeman et al.

Freeman et al. (1998) asserted that sensitivity theory is circular, unsupported by empirical evidence, and represents an "either/or" decision in regard to applied behavior analysis. We reply by showing that sensitivities are objectively measured and that our theory permits testable predictions. Further, we briefly summarize the results of recent studies that support our theory, including investigations that link sensitivities to genes and challenging behavior. Finally, we reject the idea that sensitivity theory and functional analysis represent an "either/or" viewpoint and call again for research to integrate these approaches.

Hormonal control of ventral diaphragm myogenesis during metamorphosis of the moth, Manduca sexta.

Both the proliferation and differentiation of ventral diaphragm myoblasts are controlled by ecdysteroid during metamorphosis of the moth, Manduca sexta, but the responses have different hormonal requirements. Tonic exposure to moderate levels of ecdysteroid are required to stimulate myoblast proliferation. This is due to the presence of an ecdysteroid-dependent control point in the G(2) phase of the cell cycle. As a result, proliferation can be repeatedly turned on or off simply by adjusting the concentration of ecdysteroid to be above or below a critical threshold concentration. In contrast, high levels of ecdysteroid trigger irreversible proliferative arrest and differentiation of myofibers. Myoblast proliferation and differentiation also differ in their response to the juvenile hormone mimic, methoprene. Ecdysteroid-dependent proliferative arrest and differentiation are blocked by coculture with methoprene but methoprene has no effect on ecdysteroid-dependent proliferation. In the animal, premature exposure to high levels of ecdysteroid in the absence of juvenile hormone triggers precocious differentiation of the myoblasts, resulting in the formation of several thin bands of muscle rather than a complete diaphragm. Thus, ecdysteroid and juvenile hormone collaborate to determine the size and shape of the adult musculature.

Inductively coupled surface acoustic wave device for sensor application.

We present a new type of surface acoustic wave device for sensor applications where the need for bonding wires is eliminated. Instead the device is coupled inductively to the RF circuitry. The impedance of such devices and the necessary matching have been investigated both theoretically and experimentally. The devices have repeatedly been operated at temperatures up to 400 degrees C and have shown a good temperature resistance. In order to test the suitability of the new concept for sensor applications, several devices with an operating frequency of 363 MHz were coated with copper phthalocyanine for the detection of NO(2). From these measurements we derive a detection limit of these devices below 1 ppb for NO(2).

The Reiss Screen for Maladaptive Behavior: confirmatory factor analysis.

We tested the factorial stability of the Reiss Screen for Maladaptive Behavior (Reiss, 1988a, The Reiss Screen for Maladaptive Behavior test manual). Reasonable fit was demonstrated in a geographically diverse sample of 448 individuals with mild, moderate, severe and profound mental retardation according to four measures of overall fit: RMSEA, ECVI, NNFI, and NFI. The results confirm Reiss' (1988a) factor solution of this widely used dual diagnosis (mental retardation and mental illness) screening instrument.

Comments on the Reiss screen for maladaptive behaviour and its factor structure.

Sturmey's factor analysis of the Reiss Screen for Maladaptive Behavior is based upon several significant errors, some of which are of general interest because misuse of factor analysis is common (Ford et al. 1986). In this commentary, the author discusses; the concept of factor robustness; appropriate samples for evaluating the factor structure of a dual diagnosis instrument, the differences between exploratory and confirmatory analyses; and how the Reiss Screen was intended to fulfill its purpose. In the Sturmey study, the Reiss Screen may have actually performed well under adverse conditions. The criteria for conducting valid factor analytic studies of dual diagnosis instruments are identified in order to encourage future research evaluating the Reiss Screen and other instruments.

Sensitivity theory and mental retardation: why functional analysis is not enough.

Sensitivity theory holds that aberrant behavior is a function of aberrant contingencies (direct reinforcement of maladaptive behavior), aberrant motivation (a desire for an excessive amount of reinforcement), and aberrant environments (situations in which most people cannot satiate their fundamental desires by behaving appropriately). Applied behavior analysts are almost exclusively concerned with aberrant contingencies and, to a lesser extent, aberrant environments. Because they do not treat people for aberrant motivation, behaviorists tend to treat the same people repeatedly. When a person craves an excessive amount of attention, this desire must be reduced for a durable and generalized treatment outcome, but behaviorists do not even try to do this. Implications for communication theory, assessment, and treatment strategies were discussed.